Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11](=[O:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O>C(Cl)Cl>[CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11](=[O:23])[C:10]=1[Br:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(NCc2ccccc2)ccn1Cc1cccc(F)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: O=c1c(Br)c(NCc2ccccc2)ccn1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(benzylamino)-1-(3-fluorobenzyl)pyridin-2(1H)-one (0.50 g, 1.62 mmol) in anhydrous CH2Cl2 (10 mL) was added N-bromosuccinimide (NBS, 0.30 g, 1.7 mmol). The reaction was stirred at room temperature under a nitrogen atmosphere for 3 hours. The reaction mixture was purified by flash chromatography (silica gel) using ethyl acetate in hexane (1:1 v/v). The appropriate fractions were combined and concentrated. 1H-NMR (CD3OD, 400 MHz) δ 7.41 (d, 1H, J=7.6 Hz), 7.31 (m, 6H), 7.04 (m, 3H), 5.99 (d, 1H, J=7.6 Hz), 5.08 (s, 2H), 4.53 (s, 2H); ES-HRMS m/z 387.0508 (M+H calculated for C19H17N2OBrF requires 387.0504).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[C:7]([CH3:13])[CH:8]=[CH:9][C:10]=2[CH3:12])[NH:5][C:4]=1[C:14]([O:16][CH3:17])=[O:15])=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[SH:25].O>C(OCC)(=O)C>[S:25]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:1]1[C:3]1[C:11]2[C:6](=[C:7]([CH3:13])[CH:8]=[CH:9][C:10]=2[CH3:12])[NH:5][C:4]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: Nc1ccccc1S
Reactant: COC(=O)c1[nH]c2c(C)ccc(C)c2c1C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1[nH]c2c(C)ccc(C)c2c1-c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.6 %

Procedure:
In 10 ml of ethyl acetate were dissolved 0.50 g (2.16 mmol) of methyl 3-formyl-4,7-dimethylindole-2-carboxylate and 0.27 g (2.16 mmol) of o-aminothiophenol. The reaction mixture was stirred at room temperature overnight. After addition of 0.30 g of o-aminothiophenol, the reaction mixture was stirred for 1 day and then poured into water. The reaction mixture was extracted with diethyl ether, washed with water and concentrated. The crude crystals were purified by silica gel column chromatography (toluene) and recrystallized from methanol-water to provide 0.15 g of beige powder. Yield: 20%
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[C:15]([CH:17]=[C:18]([O-])[CH3:19])#[N:16].[Na+].[NH2:22]/[C:23](/[CH3:31])=[CH:24]\[C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26].C(O)(=O)C>CC(O)C>[C:15]([C:17]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:24]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])=[C:23]([CH3:31])[NH:22][C:18]=1[CH3:19])#[N:16]
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Reactant: CC([O-])=CC#N
Reactant: C/C(N)=C/C(=O)OC(C)C
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC1=C(C#N)C(c2cccc3c(=O)cc(C)oc23)C(C(=O)OC(C)C)=C(C)N1

Procedure:
100 mg (0.53 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 55.8 mg (0.53 mmol) of sodium 1-cyanoprop-1-en-2-olate, 76 mg (0.53 mmol) of isopropyl 3-aminocrotonate and 30 μl (0.53 mmol) of acetic acid in 3 ml of 2-propanol and heated under reflux under argon for 4 h. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. 93 mg (46% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:4]([C:17]([OH:19])=O)[CH:3]=1.[C:20](N1C=CN=C1)([N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1)=O.N1C[CH2:36][O:35][CH2:34]C1.O>CN(C)C=O>[N:22]1([CH2:26][CH2:25][NH:24][C:17]([C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=[N:6][C:5]=2[NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[O:19])[CH2:23][CH2:36][O:35][CH2:34][CH2:20]1
Reactant: C1COCCN1
Reactant: O=C(O)c1cc(Cl)nnc1Nc1ccc(I)cc1F
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCCN1CCOCC1)c1cc(Cl)nnc1Nc1ccc(I)cc1F
Reaction time: 12 h

Procedure:
6-chloro-3-[(2-fluoro-4-iodophenyl)amino]pyridazine-4-carboxylic acid (32 mg, 0.08 mmol.) and 1,1′-carbonylbis(1H-imidazole) (15.4 mg, 0.09 mmol) were suspended in N,N-dimethylformamide (0.6 ml). The mixture was stirred over night (12 hr). Morpholine (21.2 mg, 0.16 mmol) was then added. The reaction was stirred for another 5 h. Water (0.5 mL) was then added into the mixture. The desired product was precipitated and was collected by vacuum filtration. LC/MS [4.69 min; 506 (M+1)].
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[OH2:26]>CN(C=O)C.Cl[Cu].Cl[Pd]Cl>[Br:19][C:16]1[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@:4]([CH2:1][C:2](=[O:26])[CH3:3])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:9][C:8]2=[O:10])[CH3:12])=[CH:18][CH:17]=1
Reactant: C=CC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Reactant: O
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Solvent: CN(C)C=O
Product: CC(=O)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Temperature: 25 °C
Yield: 58 %

Procedure:
To a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (20 g, 50 mmol) and CuCl (12.4 g, 125 mmol) in dry DMF (50 mL) was added H2O (12 mL) and PdCl2 (2.66 g, 15 mmol) at 0˜−1-5° C. After addition, the mixture was allowed to warm to rt gradually for 48 h under O2. After TLC showing the stating material had disappeared, the solid was filtered off. Water (200 mL) and EtOAc (50 mL) were added. The layers were separated and the aqueous layer was extracted with EtOAc (3×40 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give a residue, which was purified by column chromatography to give (S)-3-((S)-1-(4-bromo-phenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-oxazinan-2-one (12 g, 58%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCOCC1.[NH2:16][CH2:17][CH2:18][O:19][C:20]1[C:30]2[CH2:29][CH2:28][N:27]([C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])[CH2:26][CH2:25][C:24]=2[CH:23]=[CH:22][C:21]=1[Cl:37]>C(Cl)Cl>[C:1]([NH:16][CH2:17][CH2:18][O:19][C:20]1[C:30]2[CH2:29][CH2:28][N:27]([C:31](=[O:36])[C:32]([F:33])([F:35])[F:34])[CH2:26][CH2:25][C:24]=2[CH:23]=[CH:22][C:21]=1[Cl:37])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCOc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: C1COCCN1
Product: O=C(NCCOc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)c1ccccc1

Procedure:
Combine benzoyl chloride (19.3 mg, 0.137 mmol), PS-morpholine (109 mg, 0.272 mmol), 6-(2-amino-ethoxy)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (46 mg, 0.137 mmol) in DCM (1.5 mL) and stir at ambient temperature for 16 h. Filter the resin, wash with DCM and concentrate in vacuo. Purify by reverse phase HPLC (10-95% of solvent B in 12.8 min, 25 mL/min; solvent A: water, 0.1% trifluoroacetic acid; solvent B: acetonitrile, 0.1% trifluoroacetic acid; column: YMC SH-341-5, S-5μm, 12 nm, 100×20 mm) to give 6-(2-benzoylamino-ethoxy)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.
Reaction SMILES: [CH2:1]([CH:3]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:4][O:5][C:6](=[O:27])/[C:7](/[CH2:12][CH2:13][C:14]([F:26])([F:25])[C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])=[CH:8]\[C:9]([O-:11])=[O:10])[CH3:2].[S:32]([O-:35])([OH:34])=[O:33].[Na+:36].O.C(O)C>C(OCC)(=O)C>[CH2:1]([CH:3]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:4][O:5][C:6](=[O:27])[C:7]([CH2:12][CH2:13][C:14]([F:25])([F:26])[C:15]([F:23])([F:24])[C:16]([F:21])([F:22])[C:17]([F:19])([F:20])[F:18])([S:32]([OH:35])(=[O:34])=[O:33])[CH2:8][C:9]([O-:11])=[O:10])[CH3:2].[Na+:36]
Reactant: CCCCC(CC)COC(=O)/C(=C\C(=O)[O-])CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCC(CC)COC(=O)C(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(CC(=O)[O-])S(=O)(=O)O
Yield: 83.5 %

Procedure:
Mono(2-ethylhexyl)mono(3,3,4,4,5,5,6,6,6-nonafluorohexyl)maleate (137.5 g, 0.29 mol), sodium hydrogensulfite (33.2 g, 0.32 mol) and water/ethanol (140 mL, 1/1 (v/v)) were mixed and refluxed for 2 hours with heating. Thereafter, the reaction mixture was added with ethyl acetate (1000 mL), and the organic phase was washed with a saturated sodium chloride aqueous solution. The organic layer was collected, and the organic solvent was evaporated under reduced pressure. The residue was subjected to recrystallization from toluene (800 mL). Upon cooling on an ice bath, crystals deposited. The crystals were finally separated by filtration to obtain the target compound (140 g, yield: 84%), which was colorless and transparent.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15]([CH3:43])=[C:16]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=4)[C:17]4[N:18]([N:20]=[C:21]([NH:23][C:24]([NH:26]C5CCNCC5)=[O:25])[N:22]=4)[CH:19]=3)=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].C=O.C(O[BH-](O[C:56](=O)[CH3:57])OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[CH3:13][N:9]1[CH2:57][CH2:56][CH:4]([N:23]([C:21]2[N:22]=[C:17]3[C:16]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:40])([F:41])[F:42])[CH:34]=4)=[C:15]([CH3:43])[C:14]([C:13]4[N:9]([C:6]5[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=5)[N:10]=[CH:11][CH:12]=4)=[CH:19][N:18]3[N:20]=2)[C:24]([NH2:26])=[O:25])[CH2:5][CH2:6]1
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)NC3CCNCC3)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(N(C(N)=O)C3CCN(C)CC3)nc2c1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.4 %

Procedure:
To a solution of 1-[6-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-piperidin-4-yl-urea (Ex. 50, 53 mg, 0.09 mmol) in DCM (2 mL) was added 37% aqueous formaldehyde solution (75 μL.) and 2 drops of MeOH, followed by sodium triacetoxyborohydride (160 mg, 0.75 mmol), and the solution was stirred at RT for 18 hrs. The reaction mixture was partitioned between DCM (15 ml) and aqueous 2 M Na2CO3, and the organic extract was dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a white solid (19 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7](O)[CH:6]=[CH:5]2.[CH2:13](O)[CH3:14].[C:16](=[O:19])([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:9]1([C:10]2[CH:11]=[CH:14][C:13]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:16]=2[OH:19])[C:4]2[CH2:3][C:2]3[C:10](=[CH:11][CH:2]=[CH:3][CH:4]=3)[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: O
Product: Oc1c(-c2cccc3c2Cc2ccccc2-3)ccc2ccccc12
Yield: 82.5 %

Procedure:
In a reaction vessel, 3.17 g (14.2 mmol) of 6-bromo-2-naphthol, 5.00 g (15.6 mmol) of 2-(9,9-dimethyl-9H-fluoren-2-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborane, 96.0 ml of ethanol, 6.78 g (21.3 mmol) of sodium carbonate, 48.0 ml of water, and 30 mg (14.2×10−3 mmol) of Pd(PPh3)2Cl2 were charged. Then, the resultant mixture was stirred under reflux for 4 hours and cooled. Then, water was poured to the mixture, and the mixture was filtered to produce crude crystals. The resulting crude crystals were washed with water and heptane to produce 3.94 g of fluorenylnaphthol in a yield of 82.5%.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([C:16]3[C:17]4[CH:31]=[CH:30][NH:29][C:18]=4[N:19]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=4)N=3)[CH:15]=2)=[CH:6][CH:5]=1.[CH3:32]C1N=C(C2N=C(C3C=C(C4C=CC(C=O)=CC=4)C=NC=3)C3C=CNC=3N=2)C=CC=1.Cl.CN.[CH3:65][O:66][C:67](=[O:70])CN>>[CH3:65][O:66][C:67](=[O:70])[CH2:1][NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([C:16]3[CH:32]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=4)[N:19]=[C:18]4[NH:29][CH:30]=[CH:31][C:17]=34)[CH:15]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)CN
Reactant: Cc1cccc(-c2nc(-c3cncc(-c4ccc(C=O)cc4)c3)c3cc[nH]c3n2)n1
Reactant: CNCc1ccc(-c2cncc(-c3nc(-c4cccc(C)n4)nc4[nH]ccc34)c2)cc1
Agent: CN
Agent: Cl
Product: COC(=O)CNCc1ccc(-c2cncc(-c3cc(-c4cccc(C)n4)nc4[nH]ccc34)c2)cc1

Procedure:
(4-{5-[6-(6-Methyl-pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-pyridin-3-yl}-benzylamino)-acetic acid methyl ester is prepared by an analogous method to that for methyl-(4-{5-[2-(6-methyl-pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyridin-3-yl}-benzyl)-amine (Example 39) by replacing 4-{5-[2-(6-Methyl-pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyridin-3-yl}-benzaldehyde (Intermediate 58) with 4-{5-[6-(6-methyl-pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-3-yl}-benzaldehyde (Intermediate 185) and methylamine hydrochloride with amino-acetic acid methyl ester (Rare Chemicals GmbH, Kiel, Germany).
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2([NH:12]C(=O)OC)[CH2:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[C:3]([C:8]2([NH2:12])[CH2:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)NC1(c2ncccc2F)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC1(c2ncccc2F)CCC1
Temperature: 150 °C
Yield: 92.6 %

Procedure:
To a 20 mL microwave reaction vial was added methyl 1-(3-fluoropyridin-2-yl)cyclobutylcarbamate (1.47 g, 6.56 mmol), ethanol (12 mL) and 3N aqueous sodium hydroxide (7 mL). The reaction mixture was heated in the microwave reactor at 150° C. for 30 min. The ethanol was evaporated under reduced pressure and the mixture was extracted with ethyl acetate (30 mL). The aqueous layer was then extracted with ethyl acetate (2×30 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated to give 1-(3-fluoropyridin-2-yl)cyclobutanamine (1.01 g) as a crude yellow oil that was used in the next reaction step without further purification.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COc1ccc2ccccc2c1Br
Reactant: OB(O)c1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc2ccccc2c1-c1ccccc1F
Yield: 60 %

Procedure:
Into a 500 mL three-neck flask were placed 8.7 g (35 mmol) of 1-bromo-2-methoxynaphthalene, and 5.0 g (35 mmol) of 2-fluorophenylboronic acid. The air in the flask was replaced with nitrogen. To this mixture were added 120 mL of toluene, 60 mL of ethanol, and 40 mL of an aqueous solution of sodium carbonate (2.0 mol/L). While the pressure was reduced, this mixture was stirred to be degassed. To this mixture was added 2.0 g (1.7 mmol) of tetrakis(triphenylphosphine)palladium(0), and the mixture was stirred at 80° C. for 8 hours under a nitrogen stream. The aqueous layer of the obtained mixture was subjected to extraction with toluene, and the obtained solution of the extract and the organic layer were combined and washed with saturated brine. The organic layer was dried with magnesium sulfate, and this mixture was gravity-filtered. An oily substance obtained by concentration of the obtained filtrate was dissolved in about 30 mL of toluene. This solution was suction-filtered through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), alumina, and Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135). An oily substance obtained by concentration of the obtained filtrate was dried under reduced pressure, so that 5.3 g of a pale yellow oily substance of the object of the synthesis was obtained in 60% yield. The reaction scheme of Step 1 is illustrated in (E2-1).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5](=[O:7])[CH:6]=1.[N+:8]([C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([C:25](=O)[CH3:26])[C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[CH:14]=[CH:15][CH:16]=1)([O-:10])=[O:9]>CN(C)C=O.CCOCC>[CH3:26][C:25]1[NH:1][C:2]2[N:3]([NH:4][C:5](=[O:7])[CH:6]=2)[CH:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N+:8]([O-:10])=[O:9])[CH:12]=2)[C:18]=1[C:19]([O:21][CH:22]([CH3:23])[CH3:24])=[O:20]
Reactant: NC1=CC(=O)N=N1
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OC(C)C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC1=C(C(=O)OC(C)C)C(c2cccc([N+](=O)[O-])c2)n2[nH]c(=O)cc2N1
Temperature: 70 °C

Procedure:
A mixture of 3-amino-5-pyrazolone (3.57 g; 36.1 mmole) and 2-[(3-nitrophenyl)methylene]-3-oxobutanoic acid, 1-methylethyl ester (10.0 g; 36.1 mmole) in dry dimethylformamide (30 ml) was heated at 70° C. under argon for 24 hours. The reaction mixture was allowed to cool to room temperature and then diluted with ether. The resultant precipitate was filtered off and recrystallized from isopropanol to provide the title compound in crystalline form (4.23 g; melting point 254°-256° C.).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[SH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.O>C(Cl)Cl>[C:2](=[O:9])([S:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Sc1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Sc1ccccn1)c1ccncc1
Reaction time: 0.08 h
Yield: 77.9 %

Procedure:
Following a general procedure (Rao et al., J. Org. Chem. 2000, 65: 1084), to a suspension of isonicotinoyl chloride hydrochloride (4.45 g, 25.0 mmol) in CH2Cl2 (50 mL) was added triethylamine (7 mL, 50 mmol). The mixture was stirred for 5 min under argon. To the resulting solution was added 2-mercaptopyridine (2.77 g, 25.0 mmol) in portions over 5 min with stirring. After 1 h, water was added and the layers were separated. The organic layer was washed (2 N NaOH, then water), dried (Na2SO4) and concentrated to dryness. The solid residue was recrystallized from ethyl acetate/hexanes to afford brown crystals (4.21 g, 77%): mp 115° C.; 1H NMR δ 7.34-7.38 (m, 1H), 7.69-7.38 (m, 4H), 8.69 (m, 1H), 8.83 (m, 2H); 13C NMR δ 120.5, 124.2, 130.8, 137.5, 142.8, 150.1, 150.8, 151.1; HRMS (FAB) obsd 217.0426, calcd 217.0436 (M++H, C11H9N2OS). Anal. Calcd for C11H8N2OS: C, 61.09; H, 3.73; N, 12.95. Found: C, 60.97; H, 3.72; N, 12.95.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH2:10][C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[O:12])[C:6](=[O:9])[C:7]=1[Br:8].[CH3:21][CH:22]1[CH:30]([OH:31])[CH2:29][CH:25]2[C:26]([CH3:28])([CH3:27])[CH:23]1[CH2:24]2.[H-].[Na+].O>O1CCOCC1>[Br:8][C:7]1[C:6](=[O:9])[N:5]([CH2:10][C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[O:12])[N:4]=[CH:3][C:2]=1[O:31][C@@H:30]1[CH2:29][C@@H:25]2[CH2:24][C@@H:23]([C:26]2([CH3:28])[CH3:27])[C@H:22]1[CH3:21]
Reactant: CC1C(O)CC2CC1C2(C)C
Reactant: O=C(Cn1ncc(Br)c(Br)c1=O)NCc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Oc1cnn(CC(=O)NCc3ccncc3)c(=O)c1Br)C2(C)C
Temperature: 100 °C
Reaction time: 120 h
Yield: 2.9 %

Procedure:
To 2-(4,5-dibromo-6-oxopyridazin-1(6H)-yl)-N-(pyridin-4-ylmethyl)acetamide (50 mg, 0.124 mmol) and (1R,2R,3R,5S)-(−)-isopinocampheol (50 mg, 0.324 mmol) in 1,4-dioxane (2 mL), sodium hydride (15 mg, 0.313 mmol) was added at 0° C., and stirred at 100° C. for 5 days. After completion of the reaction, the reaction mixture was mixed with water and extracted with chloroform and ethyl acetate. The combined organic layer was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate) to give the desired product (1.7 mg, 3% yield).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:25][C:26]1[C:30]([N:31]=[C:32]=[O:33])=[C:29]([CH3:34])[O:28][N:27]=1>O1CCCC1>[CH3:25][C:26]1[C:30]([NH:31][C:32]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:33])=[C:29]([CH3:34])[O:28][N:27]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: Cc1noc(C)c1N=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1noc(C)c1NC(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2.5 ml) was added 3,5-dimethylisoxazol-4-yl isocyanate (168 mg, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from a mixed solvent of hexane and ethyl acetate to give 214 mg (68.6%) of the desired product as a solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]([N+:11]#[C-:12])([CH3:10])([CH3:9])[CH3:8].[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1>Cl(O)(=O)(=O)=O>[C:7]([NH:11][C:12]1[N:6]2[C:2]([S:3][CH:4]=[CH:5]2)=[N:1][C:13]=1[C:14]1[CH:21]=[CH:20][C:17]([CH3:18])=[CH:16][CH:15]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: Nc1nccs1
Reactant: Cc1ccc(C=O)cc1
Reactant: [C-]#[N+]C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Product: Cc1ccc(-c2nc3sccn3c2NC(C)(C)C)cc1

Procedure:
Compound 38 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) 2-amino thiazole solution (0.1 M, MC), 0.575 ml (0.115 mmol) tert-butylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) 4-methylbenzaldehyde solution (0.3 M, MC) and 10 μl perchloric acid (w=20%) in a substance library.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21]([C:24]5[S:28][C:27]([C:29](Cl)=[O:30])=[CH:26][CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C[CH2:33][N:34](C(C)C)C(C)C.CN>C(Cl)Cl.C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21]([C:24]5[S:28][C:27]([C:29]([NH:34][CH3:33])=[O:30])=[CH:26][CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C(=O)Cl)s5)cn34)ccnc2c1
Agent: CN
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)c1ccc(-c2ccc3nnc(COc4ccnc5cc(OC)ccc45)n3c2)s1
Yield: 18.8 %

Procedure:
To a solution of 5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)thiophene-2-carbonyl chloride (0.150 g, 0.33 mmol) and Hunig's Base (0.17 ml, 1.00 mmol) in DCM (2.5 mL) was added methanamine (0.17 ml, 0.33 mmol) in THF dropwise. The solution was stirred at room temperature for 3 hours, at which point an additional 1.5 equivalents of amine were added. The solution was concentrated in vacuo and purified via flash chromatography eluting with 3-8% MeOH:NH4OH in DCM. There remained an impurity, so the product was triturated with MeCN, filtered and washed with DCM to yield 5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-N-methylthiophene-2-carboxamide (0.0276 g, 19% yield) as an amorphous tan solid.