Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]4[N:22]=[CH:21][C:20]([CH:23]5[CH2:25][CH2:24]5)=[CH:19][N:18]=4)[CH2:13][CH2:12]3)([CH3:10])[CH2:7][C:6]=2[CH:26]=1.CC1(C)C(C)(C)OB([C:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:36]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[CH:23]1([C:20]2[CH:19]=[N:18][C:17]([N:14]3[CH2:15][CH2:16][CH:11]([C:8]4([CH3:10])[CH2:7][C:6]5[CH:26]=[C:2]([C:35]6[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:36]=6)[CH:3]=[CH:4][C:5]=5[O:9]4)[CH2:12][CH2:13]3)=[N:22][CH:21]=2)[CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC1(C2CCN(c3ncc(C4CC4)cn3)CC2)Cc2cc(Br)ccc2O1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)CC(C)(C2CCN(c4ncc(C5CC5)cn4)CC2)O3)CC1
Temperature: 100 °C
Yield: 68.3 %

Procedure:
To a degassed solution of 2-(4-(5-bromo-2-methyl-2,3-dihydrobenzofuran-2-yl)piperidin-1-yl)-5-cyclopropylpyrimidine (424 mg, 1.02 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (380 mg, 1.23 mmol), and K2CO3 (424 mg, 3.07 mmol) in dioxane (6 mL) and water (2 mL) was added Pd(Ph3P)4 (59.1 mg, 0.051 mmol). Upon completion of addition, the reaction mixture was heated in 100° C. oil bath for 3 hours. After this time, the reaction mixture was cooled to room temperature, diluted with water, and extracted with CH2Cl2 (3×5 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated to yield a residue. The residue was purified by column chromatography (silica gel, hexanes/EtOAc gradient 0 to 50% EtOAc) to afford Compound 11F as a white solid (360 mg, 0.697 mmol, 68% yield). 1H NMR (500 MHz, CDCl3) δ ppm 8.11 (s, 2 H), 7.15 (s, 1 H), 7.13 (d, J=8.5 Hz, 1 H), 6.65-6.71 (m, 1 H), 5.88 (br. s., 1 H), 4.75-4.87 (m, 2 H), 4.05 (br. s., 2 H), 3.73 (t, J=6.2 Hz, 1 H), 3.62 (t, J=5.5 Hz, 2 H), 3.16 (d, J=15.7 Hz, 1 H), 2.74-2.87 (m, 2 H), 2.39-2.54 (m, 2 H), 1.86-1.96 (m, 2 H), 1.76-1.84 (m, 1 H), 1.67-1.74 (m, 1 H), 1.61 (m, 1 H), 1.49 (s, 9 H), 1.37-1.41 (m, 3 H), 1.23-1.36 (m, 1 H), 0.84-0.92 (m, 2 H), 0.54-0.60 (m, 2 H). LC/MS (m/z)=517 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:19][N:6]2[CH2:7][CH2:8][N:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][N:12]=3)[CH2:10][C@@H:5]2[CH2:4]1.[C:20]([C:22]1[CH:23]=[C:24](O)[CH:25]=[CH:26][CH:27]=1)#[N:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:20]([C:22]1[CH:27]=[C:26]([CH:25]=[CH:24][CH:23]=1)[O:1][CH2:2][C@@H:3]1[CH2:19][N:6]2[CH2:7][CH2:8][N:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][N:12]=3)[CH2:10][C@@H:5]2[CH2:4]1)#[N:21]
Reactant: N#Cc1cccc(O)c1
Reactant: N#Cc1ccc(N2CCN3C[C@@H](CO)C[C@H]3C2)nc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(N2CCN3C[C@@H](COc4cccc(C#N)c4)C[C@H]3C2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
The (7S,8aS)-7-hydroxymethyl-2-(5-cyanopyridin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine, 1.6 g (13.4 mmol) of 3-cyanophenol, and 2.8 g (11 mmol) of triphenylphosphine were dissolved in 20 mL of dry THF, the solution was treated with 1.7 mL (11 mmol) of diethyl azodicarboxylate (DEAD), and the reaction stirred at ambient temperature for 16 hours. The solvent was evaporated, the residue taken up in ethyl acetate, and washed with 1M NaOH (sodium hydroxide). The organic phase was extracted with 1M HCl (3×), and the aqueous acid was washed with ethyl acetate (1×). The aqueous phase was made basic with 1M NaOH, extracted with ethyl acetate (3×), and the combined organic phase dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 75:25 ethyl acetate:hexane gave 0.603 g (19%) of the title compound. Mp (.HCl) 197-200° C. HRMS calc'd for C21H22N5O (MH+): 360.1824, found: 360.1802.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:45])[C@@H:6]([OH:44])[C@@H:7]([NH:11][C:12]([C@@H:14]2[CH2:18][C@@H:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([N:32]4[CH:36]=[CH:35][CH:34]=[N:33]4)[CH:21]=3)[CH2:16][N:15]2C(OC(C)(C)C)=O)=[O:13])[CH2:8][CH2:9][CH3:10])[CH2:3][CH2:2]1.[ClH:46].COC(C)(C)C>CO>[Cl-:46].[CH:1]1([NH:4][C:5](=[O:45])[C@@H:6]([OH:44])[C@@H:7]([NH:11][C:12]([C@@H:14]2[CH2:18][C@@H:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([N:32]4[CH:36]=[CH:35][CH:34]=[N:33]4)[CH:21]=3)[CH2:16][NH2+:15]2)=[O:13])[CH2:8][CH2:9][CH3:10])[CH2:3][CH2:2]1
Reactant: CCC[C@H](NC(=O)[C@@H]1C[C@@H](Oc2cc(-n3cccn3)nc3cc(OC)ccc23)CN1C(=O)OC(C)(C)C)[C@H](O)C(=O)NC1CC1
Reactant: Cl
Solvent: COC(C)(C)C
Solvent: CO
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](Oc2cc(-n3cccn3)nc3cc(OC)ccc23)C[NH2+]1)[C@H](O)C(=O)NC1CC1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a cooled solution (0-5° C.) of (2S,4R)-tert-butyl 2-((2S,3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-ylcarbamoyl)-4-(7-methoxy-2-(1H-pyrazol-1-yl)quinolin-4-yloxy)pyrrolidine-1-carboxylate (3.0 g; 4.82 mmol) in methanol (10 mL) was added 17% methanolic hydrochloric acid (20 mL) dropwise. The reaction mixture was stirred at room temperature for 2 hours under nitrogen atmosphere. Completion of the reaction was monitored by TLC. Methyl t-butylether (50 mL) was added to the mixture and stirred for 10 minutes. The obtained solid was filtered and dried to yield 2.45 g (98%) of (2S,4R)-2-((2S,3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-ylcarbamoyl)-4-(7-methoxy-2-(1H-pyrazol-1-yl)quinolin-4-yloxy)pyrrolidinium chloride (HPLC purity: 97.74% by area; HPLC retention time: 13.30 minutes), which was used without further purification in the next step.
Reaction SMILES: Br[CH:2]1[CH2:8][CH2:7][O:6][C:5]2[CH:9]=[CH:10][C:11]([Br:13])=[CH:12][C:4]=2[C:3]1=O.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21]>>[Br:13][C:11]1[CH2:12][C:4]23[C:5](=[CH:9][CH:10]=1)[O:6][CH2:7][CH2:8][CH:2]=[C:3]2[N:21]=[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][N:15]13
Reactant: O=C1c2cc(Br)ccc2OCCC1Br
Reactant: Nc1ccccn1
Product: BrC1=CC=C2OCCC=C3N=C4C=CC=CN4C32C1
Temperature: 60 °C
Reaction time: 3 h
Yield: 12.2 %

Procedure:
A mixture of compound 4,7-dibromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one (330 mg, 1.031 mmol) and pyridin-2-amine (97 mg, 1.031 mmol) was stirred at 60° C. for 3 hours. The mixture was then purified using chromatography (petroleum ether:ethyl acetate=3:1) to provide 2-bromo-6,7-dihydrobenzo[2′,3′]oxepino[4′,3′:4,5]imidazo[1,2-a]pyridine (40 mg, yield: 12.3%). 1H-NMR (CDCl3, 400 MHz) δ 8.54 (d, J=2.8 Hz, 1H), 7.78 (d, J=6.8 Hz, 1H), 7.58 (d, J=9.2 Hz, 1H), 7.14˜7.24 (m, 2H), 6.78˜6.88 (m, 2H), 4.42 (d, J=5.2 Hz, 2H), 3.21 (d, J=5.2 Hz, 2H). MS (M+H)+: 315/317.
Reaction SMILES: [CH3:1][C:2]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([CH3:18])[CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=[O:6].[C:19](O)(=O)CC(O)=O.C([O-])(=O)C.[Na+].C1(=O)OC(=O)C2=CC=CC=C12>C(O)(=O)C>[CH3:18][C:11]1[CH:10]=[C:4]2[C:3](=[C:2]([CH3:1])[C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8](=[O:9])[O:7][C:5]2([OH:6])[CH3:19]
Reactant: CCOC(=O)c1c(C)cc2c(c1C)C(=O)OC2=O
Reactant: O=C(O)CC(=O)O
Agent: CC(=O)[O-]
Agent: O=C1OC(=O)c2ccccc21
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)cc2c(c1C)C(=O)OC2(C)O
Yield: 77 %

Procedure:
A 500 ml. three-necked glass flask equipped with a reflux condenser, a thermometer and a stirrer was charged with a mixture consisting of 50 g of 3,5-dimethyl-4-ethoxycarbonyl-phthalic anhydride, 42 g of well-dried malonic acid, 30 g of sodium acetate and 200 g of acetic acid, and the flask was heated in an oil bath. The phthalic anhydride derivative was reacted with malonic acid at 90° to 95° C. for 15 hours with stirring. After the reaction, the reaction mixture was analyzed by high-speed liquid chromatography. It was found that the conversion was 90%, and the desired 5,7-dimethyl-6-ethoxycarbonyl-3-hydroxy-3-methylphthalide was obtained in a yield of 77%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[N:9]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6](=[O:16])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH2:13])=[N:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)Cn1ccc([N+](=O)[O-])n1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Cn1ccc(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
To a solution containing (3-nitro-pyrazol-1-yl)-acetic acid tert-butyl ester (104 mg, 0.46 mmol) in methanol (3 mL), palladium, 10 wt. % on activated carbon, wet (˜50 mg) was added to the solution. The vial was charged with hydrogen gas (via balloon) and the mixture was stirred for 16 h at 25° C. The mixture was passed through a plug of celite and concentrated in vacuo to give the desired (3-amino-pyrazol-1-yl)-acetic acid tert-butyl ester (80 mg, 89%) as a light blue oil: ESI-LRMS m/e calcd for C9H15N3O2 [M+] 197.1, found 395.2 [2M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[N:12]=[C:13]([C:15]([O:17]C)=[O:16])[CH:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[CH:25]=1.Cl>CC(C)=O>[OH2:16].[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[N:12]=[C:13]([C:15]([OH:17])=[O:16])[CH:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[CH:25]=1
Reactant: COC(=O)c1cc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Agent: Cl
Solvent: CC(C)=O
Product: O
Product: O=C(O)c1cc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Temperature: 25 °C

Procedure:
A mixture of 1.05 g. (3 mmol) of the end product of Example 9 in 3 ml. acetone and 30 ml. of 1 N HCl was heated to reflux for 2 hours. After cooling to room temperature, the mixture was concentrated in vacuo and the residue recrystallized twice from H2O/acetone/ether to give analytically pure end product as off-white prisms: mp 268°-269°.
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]1[C:11]([CH3:12])=[C:10]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)(=[O:16])=[O:15])[O:9][N:8]=1.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[C:23]1([NH:29][C:30]([C:22]2[C:17]([S:14]([NH:13][C:10]3[O:9][N:8]=[C:7]([CH3:6])[C:11]=3[CH3:12])(=[O:15])=[O:16])=[N:18][CH:19]=[CH:20][CH:21]=2)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1noc(NS(=O)(=O)c2ccccn2)c1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2ncccc2C(=O)Nc2ccccc2)c1C
Temperature: -78 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
nBuLi (1.8 ml, 2.34M) was slowly added to a solution of N-(3,4-dimethyl-5-isoxazolyl)pyridine-2-sulfonamide (500 mg, 2.0 mmol) in THF (14 ml) at -78° C. The mixture was stirred at -78° C. for 1 hour. Phenylisocyanate (3.55 mg, 2.9 mmol) was then added slowly and the mixture was allowed to warm room temperature. The reaction was quenched with H2O and the volatiles were removed under reduced pressure. The aqueous residue was extracted with EtOAc (2×50 ml). The aqueous layer was acidified with concenrated HCl to pH 4(~50 ml) and extracted with EtOH (2×50 ml). The combined organic layer was dried (MgSO4), filtered and evaporated to give a yellow oil, which was purified by HPLC to give an 88% yield with a m.p. of 199°-200° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[Cl:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([C:15]2[CH:16]=[CH:17][C:12]([C:11]([F:22])([F:21])[F:10])=[CH:13][CH:14]=2)[N:3]=1
Reactant: Cc1cc(Cl)nc(Br)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
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: COCCOC
Solvent: O
Product: Cc1cc(Cl)nc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 55 °C
Yield: 67.4 %

Procedure:
To a degassed solution of 2-bromo-6-chloro-4-methyl-pyridine (900 mg, 4.37 mmol), 4-trifluoromethylbenzeneboronic acid (830 mg, 4.37 mmol), 2N Na2CO3 (4 mL) in DME (40 mL) was added tetrakis(triphenylphosphine)palladium (320 mg, 0.3 mmol) under argon. The mixture was heated to 55° C. for 5 h, cooled to room temperature, diluted with water, and extracted with methylene chloride (3×). The organic solution was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel (10-25% methylene chloride in heptane) to give the product as an off white solid (800 mg, 68%). 1H NMR (300 MHz, CDCl3) δ 8.09 (d, J=7.91 Hz, 2H), 7.71 (d, J=8.29 Hz, 2H), 7.49 (s, 1H), 7.16 (s, 1H), 2.43 (s, 3H). MS m/e 272.1 (M+H).
Reaction SMILES: [OH:1][CH:2]([CH:9]1[O:23][C:12]2=[C:13]3[C:18](=[C:19]([CH3:21])[CH:20]=[C:11]2[CH2:10]1)[NH:17][C:16](=[O:22])[CH:15]=[CH:14]3)[CH2:3]OS(C)(=O)=O.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C)C=O>[N:24]([CH2:3][CH:2]([CH:9]1[O:23][C:12]2=[C:13]3[C:18](=[C:19]([CH3:21])[CH:20]=[C:11]2[CH2:10]1)[NH:17][C:16](=[O:22])[CH:15]=[CH:14]3)[OH:1])=[N+:25]=[N-:26]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(C(O)COS(C)(=O)=O)C2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(C(O)CN=[N+]=[N-])C2
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 84.8 %

Procedure:
2-(1-Hydroxy-2-methanesulfonyloxyethyl)-5-methyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (1.66 g, 4.90 mmol) was dissolved in dimethylformamide (50 ml). Sodium azide (1.91 g, 29.4 mmol) was added to the mixture, and the mixture was stirred at 100° C. for 2.5 hours. The reaction mixture was condensed under reduced pressure, and the residue was extracted from chloroform-water. The organic phase was dried over sodium sulfate, and condensed under reduced pressure. The resultant residue was purified by silica gel column chromatography (eluent=chloroform: methanol=10:1) to obtain 1.19 g of the title compound as pale yellow powdery crystals (85.0%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH:6]([CH3:9])[CH2:7][NH2:8].[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25][CH2:26]OS(C1C=CC(C)=CC=1)(=O)=O.C(N(CC)CC)C.O>C(S(CC)=O)C>[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25][CH2:26][NH:8][CH2:7][CH:6]([O:5][C:4]1[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=1[O:2][CH3:1])[CH3:9]
Reactant: Cc1ccc(S(=O)(=O)OCCCc2c[nH]c3ccc(F)cc23)cc1
Reactant: COc1ccccc1OC(C)CN
Agent: CCS(=O)CC
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccccc1OC(C)CNCCCc1c[nH]c2ccc(F)cc12
Temperature: 90 °C
Reaction time: 8 h
Yield: 23.4 %

Procedure:
A solution of 2-(2-methoxy-phenoxy)propylamine (0.26 g, 1.2 mmol), 5-fluoro-3-(3-p-toluenesulfonyloxypropyl)indole (0.26 g, 0.81 mol) and triethylamine (0.13 g, 1.2 mmol) in anhydrous diethylsulfoxide (20 ml) was allowed to stir for 8 hours at 90° C. The mixture was poured into water (100 ml) and extracted with methylene chloride (3×100 ml). The organic layer was washed with water (3×100 ml), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. Chromatography (10% methanol-methylene chloride plus ammonium hydroxide) afforded 0.1 g (36%) of product of product as a yellow oil.
Reaction SMILES: Br.[NH2:2][C:3]1[C:8]([CH2:9][OH:10])=[CH:7][C:6]([Br:11])=[CH:5][N:4]=1.C(N(CC)CC)C.Cl[C:20](OC(Cl)(Cl)Cl)=[O:21]>ClCCl>[Br:11][C:6]1[CH:5]=[N:4][C:3]2[NH:2][C:20](=[O:21])[O:10][CH2:9][C:8]=2[CH:7]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ncc(Br)cc1CO
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1Nc2ncc(Br)cc2CO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 2-amino-5-bromo-3-hydroxymethylpyridine hydrobromide (Apollo, Cheshire, UK, 0.528 mmol) in dichloromethane (1.25 ml) and triethylamine (1.162 mmol) was cooled with an ice-bath. Was added to the RM trichloromethyl chloroformate (0.317 mmol) in dichloromethane and the RM was stirred for 30 min at 0° C. and 1 h at rt. The RM was diluted with dichloromethane, washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered and evaporated. The residue was absorbed on silica gel and separated by flash chromatography (heptane/EtOAc 0% to 80%). The fractions containing product were evaporated together to give the title compound as a yellow solid. (HPLC: tR 2.16 min (Method A); M+H=229, 231 MS-ES)
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].Br[CH2:7][CH2:8][CH2:9][CH:10](Br)[CH3:11].C([O-])([O-])=O.[Na+].[Na+]>CCO>[CH3:7][C@H:8]1[CH2:9][CH2:10][CH2:11][N:1]1[C@@H:2]([CH3:5])[CH2:3][OH:4]
Reactant: C[C@H](N)CO
Reactant: CC(Br)CCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C[C@@H](CO)N1CCC[C@@H]1C
Temperature: 100 °C
Yield: 8.8 %

Procedure:
A mixture of (S)-2-aminopropan-1-ol (12.5 g, 0.166 mol), 1,4-dibromopentane (42 g, 0.18 mol) and Na2CO3 (53 g, 0.51 mol) in EtOH (800 mL) was heated at 100° C. for 24 h. The mixture was filtered, and the filter cake was washed with EtOH (50 mL). The combined filtrate was concentrated under reduced pressure, and the crude product was purified on a silica gel column (NH4OH/MeOH/DCM=1/6/300) to give (S)-2-((S)-2-methylpyrrolidin-1-yl)propan-1-ol (2.1 g) as a colorless oil and a crude mixture containing (S)-2-(R)-2-methylpyrrolidin-1-yl)propan-1-ol. 1H NMR (DMSO-d6): δ 4.22 (br s, 1H), 3.36 (dd, 1H), 3.22 (dd, 1H), 2.82 (m, 1H), 2.65 (m, 2H), 2.42 (q, 1H), 1.78 (m, 1H), 1.60 (m, 2H), 1.25 (m, 1H), 0.95 (d, 3H), 0.84 (d, 3H); LCMS: 144 (M+H)+.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[C:19]1([SH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C[O-].[Na+].CO.Cl>O.CO>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([S:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:3][C:4]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:8][CH:9]=1
Reactant: O=C(O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: Sc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)CCc1oc(Sc2ccccc2)nc1-c1ccc(Cl)cc1
Yield: 89 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid (1.43 g), thiophenol (0.54 ml), sodium methoxide-methanol solution (28% 2.00 g) and methanol (15 ml) was stirred under reflux for 16 hours. Water was added to the reaction mixture, which was then acidified with 2 N hydrochloric acid. The crystals thus precipitated were collected by filtration to obtain 4-(4-chlorophenyl)-2-phenylthio-5-oxazolepropionic acid (1.60 g, 89%). This was recrystallized from methanol to give colorless needles. mp 156-157° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(OC(OCC)OCC)C.[N-:23]=[N+:24]=[N-:25].[Na+].[C:27](=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.O>[N:1]1([C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:27]=[N:25][N:24]=[N:23]1
Reactant: O=C([O-])[O-]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1cccc(N)c1
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: CCOC(=O)c1cccc(-n2cnnn2)c1
Reaction time: 5 h

Procedure:
The mixture of ethyl 3-aminobenzoate (3.0 g), tri(ethoxy)methane (3.0 ml) and sodium azide (1.2 g) in acetic acid (30 ml) was stirred for 5 hours at 60°-70° C. To the reaction mixture was added water and the mixture was adjusted to pH 8 with potassium carbonate. The isolated precipitate was collected by filtration and the precipitate was dissolved in a mixture of ethyl acetate and tetrahydrofuran. The mixture was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from a mixture of ethanol and diisopropyl ether to give ethyl 3-(1H-tetrazol-1-yl)benzoate (2.44 g).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:20](=[S:21])[N:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([C:30]([F:33])([F:32])[F:31])[CH:23]=3)[C:18](=[O:34])[C:14]32[CH2:17][CH2:16][CH2:15]3)=[CH:9][CH:8]=1.CCCCCC>ClCCl.[H-].C([Al+]CC(C)C)C(C)C>[O:34]=[C:18]1[C:14]2([CH2:17][CH2:16][CH2:15]2)[N:13]([C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][CH2:4][CH:3]=[O:2])=[CH:12][CH:11]=2)[C:20](=[S:21])[N:19]1[C:22]1[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([C:30]([F:33])([F:32])[F:31])[CH:23]=1
Reactant: COC(=O)CCCc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: ClCCl
Product: N#Cc1ccc(N2C(=O)C3(CCC3)N(c3ccc(CCCC=O)cc3)C2=S)cc1C(F)(F)F
Temperature: 21 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-{4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-phenyl}-butyric acid methyl ester (67) [ND-4] (61 mg, 0.12 mmol) in dichloromethane (5 mL), 1M diisobutylaluminum hydride (DIBAL) solution in hexane (0.16 mL, 0.16 mmol) was added at −78° C. After 30 min, the reaction mixture was quenched with saturated Rochelle's salt solution. The resulting mixture was stirred at 21° C. until both phases were clearly separated and the organic layer was clear. After extraction, the separated organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The crude mixture of (66) and (68) was purified by flash column chromatography (hexane:ethyl acetate,
Reaction SMILES: Cl.C(O[N:5]=[CH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:17]=[C:18]([NH:22][C:23]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[CH:19]=[CH:20][CH:21]=1)C.[NH2:31][NH:32][C:33](=O)[CH2:34][N:35]([CH3:37])[CH3:36].C[O-].[Na+]>CO>[CH3:36][N:35]([CH2:34][C:33]1[NH:32][N:31]=[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[C:10]3[C:16]2[CH:17]=[C:18]([NH:22][C:23]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[O:24])[CH:19]=[CH:20][CH:21]=2)[N:5]=1)[CH3:37]
Reactant: CCON=Cc1ccc2[nH]nc(-c3cccc(NC(=O)c4cccnc4)c3)c2c1
Reactant: CN(C)CC(=O)NN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN(C)Cc1nc(-c2ccc3[nH]nc(-c4cccc(NC(=O)c5cccnc5)c4)c3c2)n[nH]1

Procedure:
The title compound was prepared according to example Example 329 C using N-{3-[5-(ethoxyiminomethyl)(1H-indazol-3-yl)]phenyl}-3-pyridylcarboxamide hydrochloride (0.400 g, 0.873 mmol), N-amino-2-(dimethylamino)acetamide (0.306 g, 2.62 mmol) and sodium methoxide in methanol (0.609 mL, 4.37 M). The title compound was isolated after purification by preparative HPLC (0.037 g, 10% yield): 1H NMR (CD3OD) δ 9.16 (dd, 1H), 8.79 (d, 1H), 8.75 (dd, 1H), 8.43 (dt, 1H), 8.39 (s, 1H), 8.09 (dd, 1H), 7.89–7.83 (m, 2H), 7.72 (d, 1H), 7.65–7.56 (m, 2H), 4.06 (br s, 2H), 2.61 (br s, 6H); ES-MS (m/z) 439 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:3][CH2:2]1.[O:20]1[CH2:24][CH2:23][N:22]=[C:21]1[C:25]([NH2:28])([CH3:27])[CH3:26]>>[O:20]1[CH2:24][CH2:23][N:22]=[C:21]1[C:25]([NH:28][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([CH3:27])[CH3:26]
Reactant: CC(C)(N)C1=NCCO1
Reactant: O=C(O)c1ccc(N2CCCC2)c(OCC2CC2)n1
Product: CC(C)(NC(=O)c1ccc(N2CCCC2)c(OCC2CC2)n1)C1=NCCO1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid (Example 14 a) and 1-(4,5-dihydro-oxazol-2-yl)-1-methyl-ethylamine as starting materials, MS (EI): m/e=373.2 [M+H]+.