Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH:22]([CH3:24])[CH3:23])=O)=[CH:6][C:3]=1[C:4]#[N:5].[NH2:26][C:27]([NH2:29])=[O:28].Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1.ClCCl>[F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH:22]([CH3:24])[CH3:23])[NH:29][C:27](=[O:28])[N:26]=2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC(C)COc1ccccc1C(=O)CC(=O)c1ccc(F)c(C#N)c1
Reactant: NC(N)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)COc1ccccc1-c1cc(-c2ccc(F)c(C#N)c2)nc(=O)[nH]1
Temperature: 115 °C
Yield: 17.4 %

Procedure:
To a sealed vessel were added 2-fluoro-5-(3-(2-isobutoxyphenyl)-3-oxopropanoyl)benzonitrile (5.9 g, 17.4 mmol), urea (10 g) and a solution of 4 N HCl in dioxane (80 mL). The reaction mixture was heated at 115° C. for 4 h then cooled. More urea (10 g) and 4 N HCl in dioxane (50 mL) were added to the vessel and the reaction was again heated to 115° C. for 4 h. Upon cooling, a precipitate formed and the reaction mixture was filtered in vacuo. The filtrate was determined by LC/MS to contain the desired product and was concentrated in vacuo. The concentrated reaction mixture was dissolved in dichloromethane (100 mL) and was neutralized with a solution of saturated sodium bicarbonate and was then partitioned between dichloromethane and water. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo yielding 1.1 g crude 2-fluoro-5-(6-(2-isobutoxyphenyl)-2-oxo-1,2-dihydropyrimidin-4-yl)benzonitrile and was submitted to the next step with no further purification.
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.[C:16](Cl)(=[O:19])[CH:17]=[CH2:18].O>C1(C)C=CC=CC=1>[C:16]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]3[CH:11]([C:12](=[O:15])[NH:13][N:14]=2)[CH2:10]3)=[CH:6][CH:7]=1)(=[O:19])[CH:17]=[CH2:18]
Reactant: Nc1ccc(C2=NNC(=O)C3CC23)cc1
Reactant: C=CC(=O)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: C=CC(=O)Nc1ccc(C2=NNC(=O)C3CC23)cc1
Yield: 45 %

Procedure:
Using a method similar to Example 11, 6.0 g (29.8 millimoles) of 2-(p-aminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one (see Example 8a) are reacted with 4.05 g (44.7 millimoles) of acryloyl chloride in toluene. The product is filtered off at 10° C., washed first with toluene and then with water, and recrystallized from a dimethylformamide/water mixture. 3.5 g (45% of theory) of 2-(p-acryloylaminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one, hydrated with one mole of water per four moles of compound, are isolated as almost colorless crystals of melting point 240°-241° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]3[CH2:20][CH2:21][CH2:22][O:23][C:12]=23)=[O:10])[CH2:3][CH2:2]1.I[CH2:25][CH3:26]>>[CH2:25]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]3[CH2:20][CH2:21][CH2:22][O:23][C:12]=23)=[O:10])[CH2:3][CH2:2]1)[CH3:26]
Reactant: O=C(NCC1CCNCC1)c1c2n(c3ccccc13)CCCO2
Reactant: CCI
Product: CCN1CCC(CNC(=O)c2c3n(c4ccccc24)CCCO3)CC1

Procedure:
N-(4-Piperidylmethyl) 3,4-dihydro-2 H-[1,3]oxazino[3,2-a]indole- 10-carboxamide (E21) was alkylated with iodoethane using the method of Example 22. The title compound was obtained as a white solid (27%), which was converted to its hydrochloride salt and crystallised from acetone/ethanol/ether as a white solid mp 243°-245° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C@@H:10]2[O:17][C@@H:16]3[C@@H:12]([O:13][C:14]([CH3:19])([CH3:18])[O:15]3)[C@@H:11]2[OH:20])=[O:9])=[CH:4][C:3]=1[CH2:21][C:22]1[CH:31]=[CH:30][C:25]2[O:26][CH2:27][CH2:28][O:29][C:24]=2[CH:23]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([OH:9])[C@@H:10]2[O:17][C@@H:16]3[C@@H:12]([O:13][C:14]([CH3:18])([CH3:19])[O:15]3)[C@@H:11]2[OH:20])=[CH:4][C:3]=1[CH2:21][C:22]1[CH:31]=[CH:30][C:25]2[O:26][CH2:27][CH2:28][O:29][C:24]=2[CH:23]=1
Reactant: CC1(C)O[C@@H]2O[C@@H](C(=O)c3ccc(Cl)c(Cc4ccc5c(c4)OCCO5)c3)[C@@H](O)[C@@H]2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)O[C@@H]2O[C@@H]([C@@H](O)c3ccc(Cl)c(Cc4ccc5c(c4)OCCO5)c3)[C@@H](O)[C@@H]2O1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
To a solution of compound 135 (0.77 g, 1.7 mmol) in CH3OH was added CeCl3.7H2O and the mixture was stirred at room temperature until all solids were dissolved. The mixture was then cooled to −78° C. and NaBH4 was added in portions. The mixture was stirred for 1 h at −78° C., slowly warmed to 0° C. and quenched with saturated NH4Cl solution. The mixture was concentrated under reduced pressure to remove CH3OH and then extracted with EtOAc and washed with saturated NaCl solution. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to afford the desired alcohol (0.67 g, 87%) as a white solid. The obtained product was used for the next step without purification.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[N:17]3[CH:18]=[CH:19][C:20]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:21][C:16]3=[N:15][CH:14]=1)[CH:9]=[C:8]2[C:27]1[O:31][CH:30]=[N:29][CH:28]=1.C([S-])C.[Na+]>CN(C=O)C>[CH3:26][O:25][CH2:24][CH2:23][O:22][C:20]1[CH:19]=[CH:18][N:17]2[C:13]([C:10]3[CH:9]=[C:8]([C:27]4[O:31][CH:30]=[N:29][CH:28]=4)[C:7]4[C:12](=[C:3]([OH:2])[CH:4]=[CH:5][CH:6]=4)[N:11]=3)=[CH:14][N:15]=[C:16]2[CH:21]=1
Reactant: COCCOc1ccn2c(-c3cc(-c4cnco4)c4cccc(OC)c4n3)cnc2c1
Agent: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1ccn2c(-c3cc(-c4cnco4)c4cccc(O)c4n3)cnc2c1
Temperature: 150 °C
Yield: 39 %

Procedure:
To 5-(8-methoxy-2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-4-yl)oxazole (80 mg, 0.19 mmol) in DMF (3 mL) was added sodium ethanethiolate (162 mg, 1.9 mmol). The reaction vial was sealed and heated to 150° C. for 2 hours. The reaction was then cooled to ambient temperature and concentrated. The residue was purified by flash column chromatography (DCM/MeOH 10:1) providing the desired product (39%).
Reaction SMILES: [CH:1]([C:3]1[N:8]=[CH:7][CH:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:5](=[O:19])[CH:4]=1)=[O:2].[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1.C(Cl)Cl>[C:20]([O:19][C:5]1[CH:4]=[C:3]([CH:1]=[O:2])[N:8]=[CH:7][C:6]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(COC2C=NC(C=O)=CC2=O)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(COc2cnc(C=O)cc2OC(C)=O)cc1
Reaction time: 2 h
Yield: 547.3 %

Procedure:
To a solution of 0.05 g of 6-formyl-3-(p-methoxybenzyl)oxy-4-pyridone in 5 ml of pyridine is added 0.133 g of acetic anhydride, and the mixture is stirred for 2 hours. The reaction mixture is condensed under reduced pressure, and the residue is dissolved in 20 ml of methylene chloride, washed with water, 5% aqueous potassium hydrogen sulfatge solution and 7% aqueous sodium hydrogen carbonatge solution in this sequence, dried over magnesium sulfate, and condensed to dryness under reduced pressure to give 0.318 g of the title compound as colorless crystal.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.O1CCCC1.[OH-].[Na+].Cl[CH2:29][C:30]1[S:31][CH:32]=[CH:33][N:34]=1>CN(C)C=O>[S:31]1[CH:32]=[CH:33][N:34]=[C:30]1[CH2:29][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:10]2[CH:9]=[C:8]([C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=3)[O:12][N:11]=2)=[CH:15][CH:16]=1
Reactant: ClCc1nccs1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3nccs3)cc2)no1
Temperature: 60 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To 4-(5-(2-amino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (50.0 mg, 0.19 mmol) described in Manufacturing Example 5-1-1 were added tetrahydrofuran (3 mL) and a 5N aqueous sodium hydroxide solution (37.3 μL, 0.19 mmol), which was dissolved by irraidiating ultrasonic wave for 1 minute. The reaction mixture was then concentrated under a reduced pressure to obtain a white solid. An N,N-dimethylformamide (1 mL) solution of 2-chloromethyl-thiazole (29.8 mg, 0.22 mmol) described in Manufacturing Example 88-1-2 was added to a suspension of this solid and N,N-dimethylformamide (2 mL), which was stirred for 1 hour at 60° C. This mixture was cooled to room temperature, and partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (53.0 mg, 78%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]3[CH:31]=[CH:30][CH:29]=[CH:28][C:13]3=[C:14]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([CH:26]=[O:27])=[N:24][CH:25]=3)[CH:15]=2)[N:10]=[CH:9]1.[BH4-].[Na+].[Cl-].[NH4+]>CO>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]3[CH:31]=[CH:30][CH:29]=[CH:28][C:13]3=[C:14]([CH2:19][C:20]3[CH:25]=[N:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=3)[CH:15]=2)[N:10]=[CH:9]1
Reactant: O=Cc1ccc(Cc2cc3c(=O)n([C@@H]4CCCC[C@H]4O)cnc3c3ccccc23)cn1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: O=c1c2cc(Cc3ccc(CO)nc3)c3ccccc3c2ncn1[C@@H]1CCCC[C@H]1O
Reaction time: 1 h

Procedure:
To a solution of rac-5-({3-[trans-2-hydroxycyclohexyl]-4-oxo-3,4-dihydrobenzo[h]quinazolin-6-yl}methyl)pyridine-2-carbaldehyde (0.070 g, 0.17 mmol) in 3 mL of MeOH was added sodium borohydride (0.0096 g, 0.25 mmol). After 1 h, the mixture was treated with saturated aqueous ammonium chloride, concentrated in vacuo, and diluted with ethyl acetate. The organic solution was washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 416.0 for [M+H]+: 1H NMR (400 MHz, CD3OD) δ 9.06-9.04 (m, 1H), 8.53 (s, 1H), 8.31 (s, 1H), 8.07 (s, 1H), 8.02-7.95 (m, 1H), 7.70-7.67 (m, 1H), 7.46-7.43 (m, 1H), 7.12-7.10 (m, 1H), 4.71 (s, 2H), 4.69-4.61 (m, 1H), 4.49 (s, 2H), 4.04-4.00 (m, 1H), 2.28-2.18 (m, 1H), 1.94-1.88 (m, 1H), 1.72-1.40 (m, 6H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[N:7][CH:8]=1.OS(O)(=O)=O.[CH3:18]O>>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH3:18])=[O:11])=[N:7][CH:8]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(Br)cn1
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(Br)cn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
2-(5-Bromopyridin-2-yl)acetic acid hydrochloride (example 42e) (2.34 g, 9.3 mmol) was dissolved in MeOH (18 mL) and conc. H2SO4 (1.5 mL). The mixture was stirred at 80° C. overnight. The solvent was removed under reduced pressure and the mixture was treated with sat. NaHCO3 then extracted with EtOAc, washed with brine, dried over MgSO4, filtered and evaporated to give methyl 2-(5-bromopyridin-2-yl)acetate as a yellow oil (1.97 g, 92%). 1H NMR (400 MHz, dMSO): δ 3.60 (s, 3H), 3.83 (s, 2H), 7.34-36 (d, 1H), 7.99-8.02 (dd, 1H), 8.60-8.61 (d, 1H); MS+H (230, 231).
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:17])[N:5]([CH3:16])[C:6](=[O:15])[N:7]([CH3:14])[C:8]=1[CH:9]=[CH:10][N:11](C)C)#[N:2].[NH4+].[OH-]>CN(C=O)C>[NH2:2][C:1]1[C:3]2[C:4](=[O:17])[N:5]([CH3:16])[C:6](=[O:15])[N:7]([CH3:14])[C:8]=2[CH:9]=[CH:10][N:11]=1
Reactant: CN(C)C=Cc1c(C#N)c(=O)n(C)c(=O)n1C
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(N)nccc2n(C)c1=O
Temperature: 100 °C
Yield: 69.3 %

Procedure:
1.0 g of 5-cyano-1,3-dimethyl-6-(2-dimethylaminovinyl)uracil and 5.0 ml of 30% ammonia aqueous solution were added to 22.5 ml of DMF. The solution was heated at 100° C. in a sealed tube for 24 hr. The precipitated crystals were separated by filtration, washed with ether and recrystallized from ethanol to give 0.61 g of 5-amino-1,3-dimethylpyrido[4,3-d]pyrimidine-2,4-dione (Compound 3).
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[N:8]=1)=O.[CH:27]1([NH:32]N)[CH2:31][CH2:30][CH2:29][CH2:28]1>CO>[CH:27]1([N:32]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:15]=[CH:16][C:17]([N:20]5[CH2:21][CH2:22][O:23][CH2:24][CH2:25]5)=[CH:18][CH:19]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CN(C)C=CC(=O)c1nn(-c2ccc(N3CCOCC3)cc2)ccc1=O
Reactant: NNC1CCCC1
Solvent: CO
Product: O=c1ccn(-c2ccc(N3CCOCC3)cc2)nc1-c1ccnn1C1CCCC1
Yield: 9 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-(4-morpholin-4-ylphenyl)pyridazin-4(1H)-one (300 mg, 0.85 mmol) in 20 mL of methanol, cyclopentylhydrazine (340 mg, 3.39 mmol) was added, the resulting mixture was refluxed for 4 hours, and then concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1 M acetic acid aqueous solution and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (30 mg, 9% yield) as a brown solid: 1H NMR (400 MHz, CDCl3): δ 1.46-1.69 (5H, m), 1.92-1.96 (1H, m), 2.04-2.09 (1H, m), 2.14-2.19 (1H, m), 3.22-3.25 (4H, m), 3.87-3.90 (4H, m), 5.10 (1H, quintet, J=3.6 Hz), 6.71 (1H, d, J=8.0 Hz), 6.98-7.01 (2H, m), 7.04 (1H, d, J=1.6 Hz), 7.44-7.47 (2H, m), 7.60 (1H, d, J=2.0 Hz), 8.16 (1H, d, J=7.6 Hz); LCMS (mobile phase: from 90% water and 10% CH3CN to 5% water and 95% CH3CN in 6 min, finally under these conditions for 0.5 min.) purity is >95%, Rt=3.196 min; MS Calcd.: 391, MS Found: 392 [M+H]+.
Reaction SMILES: Br/[C:2](/[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH3:18])[N:11]=1)=[CH:3]\[C@@H:4]1[NH:8][C:7](=[O:9])[CH2:6][CH2:5]1.[C:19]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O.O1CCOCC1>[C:19]([C:23]1[CH:28]=[CH:27][C:26](/[C:2](/[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH3:18])[N:11]=2)=[CH:3]\[C@@H:4]2[NH:8][C:7](=[O:9])[CH2:6][CH2:5]2)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1nc(/C(Br)=C/[C@H]2CCC(=O)N2)ccc1Cl
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)ccc1Cl
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
1,4-Dioxane (8 mL) and water (2 mL) were added to a mixture of (5R)-5-[(Z)-2-bromo-2-(5-chloro-6-methoxypyridin-2-yl)ethenyl]pyrrolidin-2-one obtained in Reference Example 4-18 (531 mg), 4-tert-butylphenylboronic acid (570 mg), tris(dibenzylideneacetone)dipalladium (147 mg), tri(2-furyl)phosphine (224 mg) and cesium carbonate (1.04 g), and the mixture was stirred at 90° C. for 2.5 hours. Water and ethyl acetate were added to the reaction solution and the insoluble matter was filtered off through celite, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10→60:40) to give (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(5-chloro-6-methoxypyridin-2-yl)ethenyl]pyrrolidin-2-one as a pale yellow amorphous (597 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][N:5]1[CH2:11][C:10]([CH2:12][N:13]=[N+]=[N-])=[CH:9][CH2:8][CH:7]([NH:16][C:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][N:20]=2)=[O:18])[C:6]1=[O:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[CH3:1][O:2][C:3](=[O:30])[CH2:4][N:5]1[CH2:11][C:10]([CH2:12][NH2:13])=[CH:9][CH2:8][CH:7]([NH:16][C:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][N:20]=2)=[O:18])[C:6]1=[O:29]
Reactant: COC(=O)CN1CC(CN=[N+]=[N-])=CCC(NC(=O)c2nccc3ccccc23)C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CN1CC(CN)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Reaction time: 18 h

Procedure:
A solution of {6-azidomethyl-3-[(isoquinoline-1-carbonyl)-amino]-2-oxo-2,3,4,7-tetrahydro-azepin-1-yl}-acetic methyl ester, 28, (0.46 g, 1.12 mmol) in THF (10 mL) and 5 drops of water is treated with triphenylphosphine (0.6 g, 2.25 mmol) at room temperature. The solution is stirred for 18 hours after which the solvent is solvent is removed in vacuo and the resulting residue is purified by HPLC to afford the desired product which is immediately used for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][CH3:18])[C:13](O)=[S:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=1.C(N(CC)CC)C.[I-].C[N+]1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][CH3:18])[C:13]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][CH:26]=2)=[S:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCCC(NS(=O)(=O)c1ccc(Cl)cc1)C(O)=S
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCC(NS(=O)(=O)c1ccc(Cl)cc1)C(=S)Nc1ccc(CC(=O)OCC)cc1
Yield: 23.5 %

Procedure:
The procedure described in Example 177 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-4-methylthiobutanoic acid (1 g) and ethyl 4-aminophenylacetate hydrochloride (599 mg) were condensed in chloroform (30 ml) in the presence of triethylamine (1.72 ml) and 1-methyl-2-chloropyridinium iodide (946.8 mg) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-methylthiobutanamide (306.3 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([OH:27])=[O:26].CCN(C(C)C)C(C)C>CC(O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=2[C:25]([OH:27])=[O:26])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Reactant: Nc1ccccc1C(=O)O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccccc4C(=O)O)nc(Cl)nc32)cc1
Temperature: 85 °C

Procedure:
A mixture of 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (25 g, 73.1 mmol), 2-aminobenzoic acid (10.02 g, 73.1 mmol) and DIPEA (63.8 mL, 365 mmol) in iPrOH (300 mL) was heated at 85° C. bath for 17 h. The resulting mixture was allowed to cool to rt and was concentrated to about half volume. EtOAc (400 mL) was added, followed by a 1N aqueous HCl solution (400 mL). The resulting slurry was filtered, the solids were washed with EtOAc and triturated using Et2O to obtain 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzoic acid as a yellow solid (28.44 g 88%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.36 (s, 3H), 7.11-7.23 (m, 1H), 7.47 (d. J=8.61 Hz, 2H), 7.56-7.67 (m, 1H), 7.76 (d, J=3.85 Hz, 1H), 7.95 (dd, J=7.69 Hz, 1.46 Hz, 1H), 7.97-8.02 (m, 2H), 8.29-8.36 (m, 1H), 11.36 (s, 1H); ESIMS (M+H)+=443.06.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C1(OC2C=CC=CC=2)C=CC=CC=1.[O-]CC.[Na+].C([O:31][C:32](=O)[CH:33]=[C:34]([NH2:36])[CH3:35])C>C(O)C>[CH2:6]([O:5][C:3]([C:2]1[C:1](=[O:9])[NH:36][C:34]([CH3:35])=[CH:33][C:32]=1[OH:31])=[O:4])[CH3:7]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCOC(=O)C=C(C)N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c(O)cc(C)[nH]c1=O
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
In a 22 L vessel fitted with a mechanical stirrer and distillation head was charged 2.5 L (16.47 mol) diethyl malonate followed by 4.0 L diphenyl ether. Agitation was started and 1.12 Kg (16.47 mol, 1 eq) of sodium ethoxide was added via a powder funnel. The mixture was gradually, heated to 160° C. and the liberated ethanol was removed via distillation, approximately 950 mL. After 30 min, ethanol distillation ceased and 2.127 Kg (16.47 mol, 1 eq) of 3-amino-but-2-enoic acid ethyl ester was added, and the resulting ethanol formed removed via distillation. After 30 minutes the mechanical stirrer could no longer stir the foamy mass. At this point, external heating was ceased and the mixture allowed to cool to ambient temperature. To the mixture was charged 4 L of methyl-tert-butyl ether (MTBE) and the granular solid broken up with a spatula. The solid was filtered and washed with MTBE. To the solid was then added 100 mL of conc. HCl and 2 L of chloroform to solublize the mixture. The mixture was then taken up three times in 4 L chloroform, and decanted into a 20 L bucket. The combined organic phases were dried over sodium sulfate. The mixture was concentrated in vacuo to afford an orange gummy mass, which was triturated with MTBE and filtered, washing the filter cake with MTBE. The resulting solid was recrystallized from ethanol to afford the desired product as pinkish needles.
Reaction SMILES: C[Li].[CH3:3]COCC.CN(OC)[C:10]([C:12]1[CH:16]=[C:15]([S:17](=[O:20])(=[O:19])[NH2:18])[S:14][C:13]=1[Cl:21])=[O:11]>C1COCC1>[C:10]([C:12]1[CH:16]=[C:15]([S:17]([NH2:18])(=[O:20])=[O:19])[S:14][C:13]=1[Cl:21])(=[O:11])[CH3:3]
Reactant: CON(C)C(=O)c1cc(S(N)(=O)=O)sc1Cl
Reactant: CCOCC
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(=O)c1cc(S(N)(=O)=O)sc1Cl
Temperature: -78 °C
Reaction time: 2 h
Yield: 64.5 %

Procedure:
A solution of 1.5M methyllithium/ether (26 mL, 0.039 mol) was added dropwise to a solution of N-methyl-N-methoxy-2-chloro-5-sulfamoylthiophene-3-carboxamide (3.25 g, 0.011 mol) in dry THF (145 mL) under a nitrogen atmosphere, cooled to -78° C. After two hours, the reaction mixture was poured carefully into ice/dil. HCl and the product was extracted into ethyl acetate. This extract was washed with water and brine, dried (Na2SO4), filtered and evaporated to give 2.82 g of crude solid product. This material was chromatographed on silica gel and eluted with 40% ethyl acetate/hexane to give 1.7 g (74%) of product. Recrystallization from ethyl acetate/hexane gave 1.68 g of product, mp 128°-130° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(O)C.[Cl:26][C:27]1[CH:28]=[C:29]([C:33]([N:35]=[C:36]=[S:37])=[O:34])[CH:30]=[CH:31][CH:32]=1>C1(C)C=CC=CC=1>[Cl:26][C:27]1[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=1)[C:33]([NH:35][C:36]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][CH:18]=1)=[S:37])=[O:34]
Reactant: O=C(N=C=S)c1cccc(Cl)c1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(Cl)c4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 3-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (77 mg, yield 93%).