Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].Br[C:19]1[S:23][C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C>[CH3:17][C:3]1([C:1]#[C:2][C:19]2[S:23][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:21][CH:20]=2)[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1
Reactant: Brc1ccc(-c2ccccn2)s1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1ccc(-c3ccccn3)s1)O2
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.4 %

Procedure:
A mixture of 2.3 g of rac-3,4-dihydro-2-ethynyl2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol, 3.6 g (15 mmol) of 2-(5-bromo-2-thienyl)pyridine, 0.39 g of triphenylphosphine, 95 mg of cuprous iodide, 3 ml of triethylamine and 100 ml of acetnitrile was degassed with argon for 10 minutes. Palladium acetate, 110 mg, was then added and the mixture was stirred at room temperature for 18 hrs. After evaporation under reduced pressure, the residue was partitioned between methylene chloride and water. The organic layer was dried and evaporated and the residue was chromatographed over 140 g of silica gel using 5% of ethyl acetate in methylene chloride. The combined clean fractions were evaporated and the residue was crystallized from ether/hexane to yield 2 g of colorless crystals with m.p. 159°-162°. The analytical sample was recrystallized from ethanol and had m.p. 160°-162°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[C:14]([CH:15]=[CH2:16])=[C:13]([OH:17])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:18])[CH:11]=2)[CH:6]=1.C(S([C:25]1[CH:30]=[CH:29][C:28]([S:31]([CH2:34][CH3:35])(=[O:33])=[O:32])=[CH:27][N:26]=1)(=O)=O)C.[I-].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O.CN(C)C=O>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[C:14]([CH:15]=[CH2:16])=[C:13]([O:17][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH2:34][CH3:35])(=[O:32])=[O:33])=[CH:27][N:26]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:18])[CH:11]=2)[CH:6]=1
Reactant: CCS(=O)(=O)c1ccc(S(=O)(=O)CC)nc1
Reactant: C=Cc1c(CC(=O)OC)cc2ccc(F)cc2c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: C=Cc1c(CC(=O)OC)cc2ccc(F)cc2c1Oc1ccc(S(=O)(=O)CC)cn1
Temperature: 100 °C
Yield: 36 %

Procedure:
A mixture of (6-fluoro-4-hydroxy-3-vinyl-naphthalen-2-yl)-acetic acid methyl ester (22 mg, 0.084 mmol), 2,5-bis-ethanesulfonyl-pyridine (33 mg, 0.126 mmol), potassium iodide (5 mg), and cesium carbonate (68 mg, 0.21 mmol), N,N-dimethylformamide (0.5 mL) and acetone (1.5 mL) was heated at 100° C. for 30 minutes with microwave irradiation. The mixture was then concentrated in vacuo. The residue was purified by flash column (gradient elution with 0-50% ethyl acetate in petroleum ether) to afford [4-(5-ethanesulfonyl-pyridin-2-yloxy)-6-fluoro-3-vinyl-naphthalen-2-yl]-acetic acid methyl ester (13 mg, 36.1%) as a yellow solid.
Reaction SMILES: [C:1](O[K])(C)(C)C.[O:7]=[C:8]1[N:12]([C:13]2[CH:14]=[CH:15][C:16]3[O:21][CH2:20][C:19](=[O:22])[NH:18][C:17]=3[CH:23]=2)[CH2:11][C@H:10]([CH2:24][CH2:25][CH:26]=O)[O:9]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.O>[CH2:24]([CH:10]1[O:9][C:8](=[O:7])[N:12]([C:13]2[CH:14]=[CH:15][C:16]3[O:21][CH2:20][C:19](=[O:22])[NH:18][C:17]=3[CH:23]=2)[CH2:11]1)[CH2:25][CH:26]=[CH2:1]
Reactant: O=CCC[C@H]1CN(c2ccc3c(c2)NC(=O)CO3)C(=O)O1
Reactant: CC(C)(C)O[K]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCC1CN(c2ccc3c(c2)NC(=O)CO3)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
A suspension of methyltriphenylphosphonium bromide (2.03 g) in THF (6 ml) was treated with tBuOK (638 mg) and the reaction mixture was further stirred at rt for 1 h. The mixture was cooled to 0° C. and treated with a suspension of 3-[(S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-oxazolidin-5-yl]-propionaldehyde (1.50 g; prepared according to WO 2010/041194, example AV) in THF (11 ml). The reaction mixture was stirred at 0° C. for 30 min and allowed to reach rt. The reaction mixture was diluted with water and the org. layer was separated. The aq. layer was extracted with EA. The combined org. extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by CC (Hex/EA 4:1), affording a yellow solid (1.25 g; 84% yield).
Reaction SMILES: [Br-].[CH2:2]([NH:4][C:5](=[O:29])[CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:3].CC([O-])(C)C.[K+].[OH:36][C@@H:37]([CH2:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)/[CH:38]=[CH:39]/[C@@H:40]1[C@@H:47]2[C@@H:43]([O:44][CH:45](O)[CH2:46]2)[CH2:42][C@H:41]1[OH:49]>C1COCC1>[CH3:3][CH2:2][NH:4][C:5]([CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:45]\[CH2:46][C@@H:47]1[C@@H:40](/[CH:39]=[CH:38]/[C@@H:37]([OH:36])[CH2:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@H:41]([OH:49])[CH2:42][C@@H:43]1[OH:44])=[O:29]
Reactant: OC1C[C@@H]2[C@@H](/C=C/[C@@H](O)CCc3ccccc3)[C@H](O)C[C@@H]2O1
Reactant: CCNC(=O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCNC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 49.2 %

Procedure:
(5-(Ethylamino)-5-oxopentyl)triphenylphosphonium bromide 96 (1.37 g, 2.91 mmol, 6 eq.) was added to a flame dried Schlenk flask, under N2, and anhydrous THF (10 ml) added. The resulting suspension was cooled to 0° C. KOt-Bu (653.0 mg, 5.82 mmol, 12 eq.) was added in one portion and the resulting orange mixture stirred at 0° C. for 40 min. A solution of crude triol 94 (0.485 mmol, 1 eq.) in anhydrous THF (2.5 ml) was added dropwise via syringe. After complete addition the mixture was stirred at r.t. for 1 h. The reaction was quenched with saturated aq. NH4Cl (10 ml) and extracted with EtOAc (5×10 ml). The combined organic phases were dried (MgSO4), filtered, and concentrated to give the crude material as solids. These were triturated with EtOAc (10 ml) and the solids filtered and washed with EtOAc (4×10 ml). The filtrate was concentrated under vacuum and purified by column chromatography on silica, eluting with EtOAc/MeOH (97.5:2.5 to 95:5) to give 97 (99.2 mg) as a yellowish oil which was further purified by preparative TLC (EtOAc/MeOH 5%) to give 97 (82.6 mg, 41% over 2 steps) as a clear, colourless oil. Analytical data consistent with the literature (Zanoni, G. et al., Tetrahedron 66, 7472-7478 (2010); Gutman, A. et al., US 20090163596 (2009)).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:21])[CH:16](OCC)O)=[CH:11][C:10]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24])C1C=CC=CC=1.Cl.[F:28][C:29]1[CH:41]=[CH:40][C:32]([CH2:33][C:34]2([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35]2)=[CH:31][CH:30]=1.Cl>>[F:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:33][C:34]2([NH:39][CH2:16][CH:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([NH:22][S:23]([CH3:26])(=[O:24])=[O:25])[CH:11]=3)[OH:21])[CH2:38][CH2:37][CH2:36][CH2:35]2)=[CH:40][CH:41]=1
Reactant: CCOC(O)C(=O)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Reactant: NC1(Cc2ccc(F)cc2)CCCC1
Agent: Cl
Product: CS(=O)(=O)Nc1cc(C(O)CNC2(Cc3ccc(F)cc3)CCCC2)ccc1O

Procedure:
Prepared from 645 mg (1.70 mmol) N-[2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-phenyl]-methanesulphonamide and 414 mg (1.70 mmol) 1-(4-fluoro-benzyl)-cyclopentylamine hydrochloride according to general method 6. Yield: 485 mg (62%, hydrochloride). Mass spectroscopy: [M+H]+=423.
Reaction SMILES: [C:1]1([C:11]2[N:12]=[C:13]([CH2:55][CH2:56][CH3:57])[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[N:35](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:34]=[N:33][N:32]=4)=[CH:21][CH:20]=3)[C:15]=2[CH:16]=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl>C1COCC1>[C:1]1([C:11]2[N:12]=[C:13]([CH2:55][CH2:56][CH3:57])[N:14]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[NH:35][N:34]=[N:33][N:32]=4)=[CH:23][CH:24]=3)[C:15]=2[CH:16]=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCCc1nc(-c2cccc3ccccc23)c(C=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1nc(-c2cccc3ccccc23)c(C=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
4-(Naphth-1-yl)-2-n-propyl-1-[(2'-(N-triphenylmethyl-(1H-tetrazol-5-yl))biphenyl-4-yl)methyl]imidazole-5-carboxaldehyde (1.50 g), THF (80 mL), and 10% HCl were stirred at room temperature. After 8 hr, the mixture was poured into ice/5% NaOH and the pH was adjusted to 10. The resultant solids were filtered and the pH of the filtrate was adjusted to 4-5 with 10% HCl. The turbide solution was extracted with 80/20 methylene chloride/i-propanol (3×100 mL), the organic phase was dried over sodium sulfate and evaporated under reduced pressure to yield 0.51 g of a white glass. NMR (CDCl3) δ 9.35 (s, 1H); 7.78 (m, 1H); 7.60-7.38 (m, 2H); 7.35-6.96 (m, 12H); 5.62 (s, 1H); 2.60 (m, 2H); 1.85 (m, 2H); 0.90 (t, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[CH2:7][C@@H:8]([C:10]([O-:12])=[O:11])[NH2:9])=[O:4].O[Li].O.C(O)(C(F)(F)F)=O.Cl>CC#N.O.C1COCC1>[C:3]([C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[CH2:7][C@@H:8]([C:10]([OH:12])=[O:11])[NH2:9])([OH:4])=[O:2]
Reactant: COC(=O)c1ccccc1C[C@H](N)C(=O)[O-]
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1ccccc1C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a 50 mL 3-necked flask equipped with a magnetic stirrer and a nitrogen inlet were added 0.12 g of methyl N-(4-(((2,4-diamino-6-pteridinyl)methyl)methylamino)benzoyl)-5-O-methyl-L-glutam-1-yl)-2-(methoxycarbonyl)-L-phenylalaninate and 10 mL of 1:1 H2O:THF. The mixture was treated with 29 mg of LiOH.H2O (J. T. Baker Chemical Co., Phillipsburg, N.J.) and stirred at RT under nitrogen. After 48 h, analysis by HPLC (C18, 75:25:0.1 H2O:MeCN:TFA) indicated a major new component at k'=1.70 (ca. 90%) and three minor components at K'=0.60, 1.03, and 2.58. The solution was neutralized by dropwise addition of 1 N aqueous HCl and concentrated in vacuo to dryness. The residue was dissolved in 10 mL of MeOH was removed by rotary evaporation and the remaining suspension was frozen and lyophilized to afford 65 mg (45%) of N-(4-(((2,4-diamino-6-pteridinyl)methyl)methylamino)benzoyl)-L-glutam-1-yl)-2-carboxy-L-phenylalanine as a yellow powder, m.p. 160° C. (dec).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:15]=[CH:14][C:13]=1[OH:22])([O-])=[O:2].[OH-].[Na+].C1C2C(=O)C3C(=CC=CC=3)C=2C=CC=1.N(C1C=CC=CC=1)=NC1C=CC=CC=1.S(=O)(=O)(O)O>O.C(O)(CC)C>[OH:22][C:13]1[CH:14]=[CH:15][C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:17][C:12]=1[N:11]1[N+:1]([O-:2])=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:10]1
Reactant: CC(C)(C)c1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Agent: O=C1c2ccccc2-c2ccccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCC(C)O
Solvent: O
Product: CC(C)(C)c1ccc(O)c(-n2nc3ccccc3[n+]2[O-])c1
Temperature: 65 °C
Reaction time: 5 h
Yield: 82.3 %

Procedure:
2-nitro-2'-hydroxy-5'-t-butylazobenzene 19.9 g was added to a mixture of secondary butanol 80 g, water 14 g and 97% sodium hydroxide 11.2 g, and the resultant mixture was stirred while raising temperature to 65° C. Thereafter, the mixture was cooled to 50° C., and 9-fluorenone 1.5 g was added to the mixture. The reaction mixture was then stirred at 90°~95° C. for five hours to effect reaction, thus almost all of the azobenzene having disappeared. Thereafter, water 50 ml was added to the reaction liquor, and the reaction liquor was neutralized to pH 8 with 62% sulfuric acid 15 g. The neutralized reaction liquor was then cooled to 20° C. or lower to precipitate a crystal. The crystal thus obtained was filtered to separate the crystal, and the separated crystal was then fully washed with water and further with a small amount of methanol. The washed crystal was then dried, thus producing 15.5 g of 2-(2-hydroxy-5-t-butylphenyl)benzotriazole-N-oxide having a melting point of 95° to 98° C. at the yield of 82.0%.
Reaction SMILES: [CH3:1][N:2](C(OCC1C=CC=CC=1)=O)[C:3]1([C:6]([O:8][CH3:9])=[O:7])[CH2:5][CH2:4]1>CO>[CH3:1][NH:2][C:3]1([C:6]([O:8][CH3:9])=[O:7])[CH2:5][CH2:4]1
Reactant: COC(=O)C1(N(C)C(=O)OCc2ccccc2)CC1
Solvent: CO
Product: CNC1(C(=O)OC)CC1
Yield: 45.7 %

Procedure:
Methyl 1-(methyl{[(phenylmethyl)oxy]carbonyl}amino)cyclopropanecarboxylate (assumed 6.8 g, 25.91 mmol, 100% theoretical yield) was dissolved in 30 mL of MeOH, degassed and placed under argon. 10% Pd/C (2.04 g) was added, and the contents were thoroughly degassed and placed under a hydrogen balloon overnight. The contents were then degassed, and the Pd/C was removed by filtration through Celite, washing with MeOH. The filtrate was concentrated in vacuo to provide pure methyl 1-(methylamino)cyclopropanecarboxylate (1.53 g, 45% over two step). LCMS: (M+H)+: 130.1.
Reaction SMILES: [N:1]1([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)Cl>[C@H:3]12[O:24][C@H:4]1[CH2:5][N:1]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:2]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(OCc1ccccc1)N1CC=CC1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1C[C@@H]2O[C@@H]2C1
Temperature: 25 °C
Reaction time: 13 h
Yield: 81.5 %

Procedure:
To a solution of benzyl 2,5-dihydro-1H-pyrrole-1-carboxylate (2.00 g, 9.80 mmol) in CH2Cl2 (10 mL) was added slowly 3-chloroperbenzoic acid (3.00 g, 14.80 mmol) at 0° C. The reaction mixture was stirred for 13 h at room temperature, then quenched with saturated sodium thiosulfate aqueous solution and extracted with EtOAc. The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed with a silica gel column (eluting agent: 6:1 (v/v) PE/EtOAc) to give the title compound as colorless oil (1.75 g, 81.02%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([CH3:17])([CH3:16])[CH2:10][C:9]2=O)[CH2:2][CH2:3][CH3:4].[Cl-].[OH:20][NH3+:21].C([O-])(=O)C.[Na+]>C(O)C.O>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([CH3:17])([CH3:16])[CH2:10][C:9]2=[N:21][OH:20])[CH2:2][CH2:3][CH3:4]
Reactant: [NH3+]O
Reactant: CCCCOc1ccc2c(c1)C(=O)CC(C)(C)O2
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCOc1ccc2c(c1)C(=NO)CC(C)(C)O2
Reaction time: 3 h
Yield: 100.4 %

Procedure:
A solution of 52.0 g (0.21 mol) of 6-butoxy-2,2-dimethylchroman-4-one in 420 ml of ethanol were added dropwise in 30 min to a solution of 43.7 g (0.628 mol) of hydroxylammonium chloride and 51.5 g (0.628 mol) of sodium acetate in 420 ml of water and the mixture was kept at 60° C. for 3 h. The oily product phase was separated off and the aqueous phase was extracted with methylene chloride. After drying the organic phases over magnesium sulfate and concentrating in vacuo, 55.5 g of 6-butoxy-2,2-dimethylchroman-4-one oxime were obtained, which it was possible to crystallize by stirring with PE.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][S:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:28]#[C:29][C:30]4([CH3:34])[CH2:33][O:32][CH2:31]4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[CH3:35][C:36]1[N:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:34][C:30]1([C:29]#[C:28][C:12]2[CH:13]=[C:14]3[C@@:15]4([CH2:19][S:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[N:16]4)[C:4]4[C:5](=[N:6][CH:7]=[C:2]([C:39]5[CH:40]=[N:41][C:36]([CH3:35])=[CH:37][CH:38]=5)[CH:3]=4)[O:8][C:9]3=[CH:10][CH:11]=2)[CH2:31][O:32][CH2:33]1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: CC1(C#Cc2ccc3c(c2)[C@@]2(CSC(NC(=O)OC(C)(C)C)=N2)c2cc(Br)cnc2O3)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(-c2cnc3c(c2)[C@]2(CSC(NC(=O)OC(C)(C)C)=N2)c2cc(C#CC4(C)COC4)ccc2O3)cn1
Temperature: 80 °C
Yield: 49 %

Procedure:
A vial was charged with (S)-tert-butyl 3-bromo-7-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazole]-2′-ylcarbamate (0.054 g, 0.10 mmol), 6-methylpyridin-3-ylboronic acid (0.041 g, 0.30 mmol), potassium carbonate (0.069 g, 0.50 mmol), and Pd(AmPhos)2Cl2 (7.05 mg, 9.95 μmol). The vial was flushed with Ar (g), then dioxane (0.66 mL) and water (0.33 mL) were added in sequence. The vial was sealed and heated at 80° C. for 16 h. The reaction was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography on silica gel (0-75% EtOAc:Hex) to afford (S)-tert-butyl 7-((3-methyloxetan-3-yl)ethynyl)-3-(6-methylpyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazole]-2′-ylcarbamate (0.027 g, 0.049 mmol, 48.9% yield) as a white solid. MS m/z=555.3 [M+H]+. Calculated for C31H30N4O4S: 554.20.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]3[CH:11]([C:12](=[O:15])[NH:13][N:14]=2)[CH2:10]3)=[CH:4][CH:3]=1.[Cl:16][C:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1>O1CCCC1>[Cl:16][C:17]1([C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:9]4[CH:11]([C:12](=[O:15])[NH:13][N:14]=3)[CH2:10]4)=[CH:6][CH:7]=2)=[O:21])[CH2:19][CH2:18]1
Reactant: O=C(Cl)C1(Cl)CC1
Reactant: Nc1ccc(C2=NNC(=O)C3CC23)cc1
Solvent: C1CCOC1
Product: O=C1NN=C(c2ccc(NC(=O)C3(Cl)CC3)cc2)C2CC12
Yield: 62.4 %

Procedure:
5.0 g (24.8 millimoles) of 2-(p-aminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one, 4.5 g (32.4 millimoles) of 1-chlorocyclopropanecarboxylic acid chloride and 100 ml of absolute tetrahydrofuran are kept at room temperature for 6 hours. The product is filtered off at 10° C., washed first with tetrahydrofuran and then with water, and recrystallized from methanol. 4.7 g (62% of theory) of 2-[p-(1-chlorocyclopropylcarbonylamino)-phenyl]-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one are isolated as colorless crystals, of melting point 221°-222° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[C:18]([C:24]4[CH:25]=[CH:26][C:27]([O:34][CH3:35])=[C:28]([CH:33]=4)[C:29]([O:31]C)=[O:30])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.O.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[C:18]([C:24]4[CH:25]=[CH:26][C:27]([O:34][CH3:35])=[C:28]([CH:33]=4)[C:29]([OH:31])=[O:30])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(-c3ccc(OC)c(C(=O)OC)c3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(-c3ccc(OC)c(C(=O)O)c3)cc12
Temperature: 50 °C

Procedure:
To a solution of methyl 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-nitrobenzofuran-5-yl)-2-methoxybenzoate (200 mg, 0.418 mmol) in THF (12 mL)/water (4.0 mL) at room temperature was added sodium hydroxide (1.045 mL, 2.090 mmol). The reaction mixture was heated to 50° C. and maintained at the same temperature for overnight. The reaction mixture was concentrated under vacuum to remove the solvent. The residue was diluted with water, acidified with 1.5 N HCl. The solid obtained was filtered and dried under suction. Yield: 175 mg (86%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.81 (br. s, 1H). 8.58 (q, J=4.52 Hz, 1H), 8.49 (s, 1H), 8.08-8.02 (m, 2H), 7.70 (s, 1H), 7.66 (d, J=2.51 Hz, 1H), 7.53 (dd, J=8.66, 2.38 Hz, 1H), 7.49-7.42 (m, 2H), 7.25 (s, 1H), 3.89 (s, 3H), 2.85 (d, J=4.77 Hz, 3H).
Reaction SMILES: [C:1]([C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl:17][C:18]1[CH:19]=[C:20]([CH2:24][CH2:25][NH2:26])[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:19]=[C:20]([CH2:24][CH2:25][NH:26][CH2:13][C:12]2[CH:15]=[CH:16][C:9]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:10][CH:11]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: CCCCCCC#Cc1ccc(C=O)cc1
Reactant: NCCc1cccc(Cl)c1
Product: CCCCCCC#Cc1ccc(CNCCc2cccc(Cl)c2)cc1
Yield: 62 %

Procedure:
The same procedure as employed in the preparation of Example 1 (step a) but using 4-oct-1-ynylbenzaldehyde and [2-(3-chlorophenyl)ethyl]amine gave the title compound as a colorless oil (62%). 1H NMR (CDCl3, 300 MHz) δ 7.26 (d, J=8.3 Hz, 2H), 7.19-7.08 (m, 5H), 7.03-6.96 (m, 1H), 3.71 (s, 2H), 2.83-2.67 (m, 2H), 2.32 (t, J=7.2 Hz, 2H), 1.63-1.44 to (m, 2H), 1.44-1.31 (m, 2H), 1.31-1.15 (m, 6H), 0.83 (t, J=8.3 Hz, 3H). M+(LC/MS(ESI)): 354.4. HPLC (Condition A), Rt: 4.31 min (HPLC purity: 97.5%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])[CH:3]=1.[C:13]([O:17][C:18](=[O:26])[NH:19][C:20]1[S:21][CH:22]=[C:23]([CH3:25])[N:24]=1)([CH3:16])([CH3:15])[CH3:14]>CCOC(C)=O>[C:13]([O:17][C:18](=[O:26])[NH:19][C:20]1[S:21][C:22]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]([C:9]#[N:10])([CH3:12])[CH3:11])[CH:3]=2)=[C:23]([CH3:25])[N:24]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C#N)c1cc(I)ccn1
Reactant: Cc1csc(NC(=O)OC(C)(C)C)n1
Solvent: CCOC(C)=O
Product: Cc1nc(NC(=O)OC(C)(C)C)sc1-c1ccnc(C(C)(C)C#N)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
The title compound is prepared in analogy to the procedure described in Step 1.3, but using 2-(4-iodo-pyridin-2-yl)-2-methyl-propionitrile (Step 21.5) and (4-methyl-thiazol-2-yl)-carbamic acid tert-butyl ester (Step 18.4). The reaction mixture is stirred for 3 h at 100° C. Title compound: ESI-MS: 359.1 [M+H]+; TLC: Rf=0.47 (Hex/EtOAc, 1:1).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:7][CH:8]=1.[NH2:20][C:21]1[C:25]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=2)=[CH:24][NH:23][N:22]=1>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:22]3[N:23]=[CH:24][C:25]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=4)=[C:21]3[N:20]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cc(-c2c[nH]nc2N)ccn1
Reactant: O=C(CC(=O)C(F)(F)F)c1cccc(C(F)(F)F)c1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)ccn1
Yield: 51.1 %

Procedure:
Reaction of 1-(3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (142 mg, 0.5 mmol), prepared from commercially available 3-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [see part synthesis of amino-pyrazole derivatives] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (108 mg, 51%). MS (ISP) 423.3 [(M+H)+]; mp 232° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][C@@H:17]3[CH2:21][CH2:20][CH2:19][N:18]3C(OC(C)(C)C)=O)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][C@@H:17]3[CH2:21][CH2:20][CH2:19][NH:18]3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ccnc(Nc2cccc(Cl)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1cccc(Nc2nccc(NC[C@@H]3CCCN3)n2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32 %

Procedure:
To a solution of tert-butyl (2S)-2-[({2-[(3-chlorophenyl)amino]-pyrimidin-4-yl}amino)methyl]pyrrolidine-1-carboxylate, 15, (150 mg, 0.37 mmol) in CH2Cl2 (5 mL) is added trifluoroacetic acid (3 mL). The reaction is stirred at room temperature for 24 hours then partitioned between EtOAc and sat. NaHCO3. The organic layer is dried (MgSO4), concentrated in vacuo, and purified over silica (MeOH/CH2Cl2) to afford 36 mg (32% yield) of the desired material: 1H NMR (CDCl3, 300 MHz) δ 1.43-1.56 (m, 1H), 1.70-1.91 (m, 2H), 1.93-2.06 (m, 1H), 2.97 (t, J=6.9 Hz, 2H), 3.16-3.29 (m, 1H), 3.41-3.52 (m, 1H), 3.54-3.66 (m, 1H), 5.71 (t, J=5.1 Hz, 1H), 5.91 (d, J=6.0 Hz, 1H), 6.96 (ddd, J=7.8, 5.7, 0.9 Hz, 1H), 7.20 (t, J=8.1 Hz, 1H), 7.26-7.32 (m, 1H), 7.57 (bs, 1H), 7.91 (d, J=5.7 Hz, 1H), 7.99 (s, 1H); HRMS calcd for C15H18ClN5, 304.1329 m/z (M+H)+; observed 304.1319 m/z.