Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:7]([CH3:26])=[C:6]2[CH2:27][C:28]([OH:30])=[O:29].[CH2:31](OC(=O)CC1C2C(=CC=C(OC)C=2)N(CCCCCCCCCCCCCC)C=1C)C.[OH-].[Na+].Cl>CO>[CH3:31][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:7]([CH3:26])=[C:6]2[CH2:27][C:28]([OH:30])=[O:29]
Reactant: CCCCCCCCCCCCCCn1c(C)c(CC(=O)O)c2cc(OC)ccc21
Reactant: CCCCCCCCCCCCCCn1c(C)c(CC(=O)OCC)c2cc(OC)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCn1c(C)c(CC(=O)O)c2cc(C)ccc21
Yield: 90 %

Procedure:
5-Methoxy-2-methyl-1-tetradecyl-1H-indole-3-acetic acid. A solution of 1.60 g (3.6 mmol) of 5-methoxy-2-methyl-1-tetradecyl-1H-indole-3-acetic acid ethyl ester and 10 mL of 1N NaOH in 25 mL of MeOH was stirred 16 hours, made acidic with 1N HCl, and the precipitate filtered valve 1.36 g (90% yield) of 5-methyl-2-methyl-1-tetradecyl-1H-indole-3-acetic acid, mp, 105-107° C.
Reaction SMILES: N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:25]I.[C:27]([O:31][C:32](=[O:42])[NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40]O)([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl>[C:27]([O:31][C:32](=[O:42])[NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][I:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1CO
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccccc1CI
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a solution of imidazole (404 mg, 5.94 mmol) and triphenylphosphine (1.56 g, 5.94 mmol) in methylene chloride (50 mL) is added iodine (1.51 g, 5.94 mmol) in portions. When the reaction is complete, a solution of (2-hydroxymethylphenyl)-carbamic acid tert-butyl ester (1.2 g, 5.4 mmol) in methylene chloride (20 mL) is added dropwise and the mixture is stirred at RT for 75 min. The mixture is concentrated and the insoluble material is filtered. The filtrate is evaporated and the residue is purified by column chromatography using a gradient of 25-50% MTBE/methylene chloride as eluent to give the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH3:18])[C:6]([O:16][CH3:17])=[C:7]([CH:9]([OH:15])[C:10](=[NH:14])[O:11]CC)[CH:8]=1.[C:19](Cl)(Cl)=[O:20].C(N(CC)CC)C>O1CCCC1>[Cl:2][C:3]1[CH:4]=[C:5]([CH3:18])[C:6]([O:16][CH3:17])=[C:7]([CH:9]2[O:15][C:19](=[O:20])[NH:11][C:10]2=[O:14])[CH:8]=1
Reactant: CCOC(=N)C(O)c1cc(Cl)cc(C)c1OC
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1c(C)cc(Cl)cc1C1OC(=O)NC1=O
Temperature: 0 °C

Procedure:
By the procedure of Example 9, except that methylene chloride was used in place of chloroform for product extraction following the quench, ethyl 1-(5-chloro-2-methoxy-3-methylphenyl)-1-hydroxymethanecarboximidate hydrochloride (2.5 g., 8.5 mmoles) in 250 ml. of tetrahydrofuran was reacted with phosgene in the presence of triethylamine (2.7 g., 27 mmoles). The product was isolated by pouring the reaction mixture slowly over 1 liter of crushed ice. The aqueous phase was separated and extracted with three portions of methylene chloride. The combined organic phase/extracts was evaporated to solids. The crude product was taken up in 1 N sodium hydroxide, extracted with ether, and acidifed with 3 N hydrochloric acid to precipitate the desired product (1.81 g., 83%, m.p. 184°-186° C.). Recrystallization from toluene gave purified 5-(5-chloro-2-methoxy-3-methylphenyl)oxazolidine-2,4-dione (1.57 g., 72% overall; m.p. 187°-189° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:20]1(O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Reactant: OC1CCCCC1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1cc(F)ccc1F)C1CCCCC1
Yield: 61.6 %

Procedure:
The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (240 mg, 0.793 mmol) obtained in Referential Example 1 was dissolved in toluene (20 ml). After addition of cyclohexanol (0.11 ml, 1.0 mmol) and cyanomethylenetri-n-butylphosphorane (250 mg, 1.0 mmol), the resulting mixture was heated under reflux for 14 hours under an argon atmosphere. The reaction mixture was allowed to cool and then, cyclohexanol (0.22 ml, 2.1 mmol) and cyanomethylenetri-n-butylphosphorane (500 mg, 2.08 mmol) were added thereto. Under an argon atmosphere, the resulting mixture was heated under reflux for 14 hours. The reaction mixture was allowed to cool and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=30:1) to give a white solid. The white solid was washed with hexane to give the title compound (188 mg, 62%) as a white powder.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[NH2:18][CH:19]1[CH2:23][CH2:22][NH:21][CH2:20]1>>[NH2:18][CH:19]1[CH2:23][CH2:22][N:21]([C:2]2[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:20]1
Reactant: NC1CCNC1
Reactant: Clc1nccnc1OCCOc1ccccc1
Product: NC1CCN(c2nccnc2OCCOc2ccccc2)C1

Procedure:
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-(2-phenoxyethoxy)pyrazine (150 mg, 0.60 mmol; from Example 1, Step 1) and 3-aminopyrrolidine (270 mg, 3.13 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 121 mg (67%) of the title product. Anal. (C16H19N4O2) C, H; N: calcd, 18.65; found, 18.0.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH2:17](O)[CH3:18]>>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([O:6][CH2:17][CH3:18])=[O:5]
Reactant: CCO
Reactant: Nc1ccc(Br)cc1C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(Br)ccc1N

Procedure:
2-Amino-5-bromobenzoic acid (24.7 g, 11.4 mol) was dissolved in 350 mL of ethanol and 2, and 5 mL of concentrated H2SO4 was added. The mixture was refluxed under N2 for 12 h. The solvent was removed and the residue was added with EtOAc. The mixture was extracted with 1N NaOH. The organic solution was washed with brine, dried over MgSO4. It was concentrated and chromatographed with CH2Cl2 to give 3.19 g of 2-amino-5-bromobenzoic acid, ethyl ester. MS (AP+): 243.9, 246, M+H.
Reaction SMILES: [S:1]=[C:2]1[NH:7][C:6]2[NH:8][C:9](=[O:12])[CH2:10][CH2:11][C:5]=2[C:4](=[O:13])[N:3]1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:16][CH:15]=1.C(=O)([O-])O.[Na+].I[CH2:32][CH3:33]>C(#N)C>[CH2:32]([S:1][C:2]1[N:3]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]([F:24])([F:23])[F:25])=[CH:18][CH:19]=2)[C:4](=[O:13])[C:5]2[CH2:11][CH2:10][C:9](=[O:12])[NH:8][C:6]=2[N:7]=1)[CH3:33]
Reactant: O=C1CCc2c([nH]c(=S)n(-c3ccc(OCC(F)(F)F)cc3)c2=O)N1
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCSc1nc2c(c(=O)n1-c1ccc(OCC(F)(F)F)cc1)CCC(=O)N2
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 2-thioxo-3-[4-(2,2,2-trifluoroethoxy)phenyl]-2,3,5,6-tetrahydropyrido[2,3-d]pyrimidine-4,7(1H,8H)-dione (0.1 g) in acetonitrile (2 mL) were added 1M aqueous sodium hydrogen carbonate solution (0.269 mL) and iodoethane (0.109 mL), and the mixture was stirred at 70° C. for 2 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.08 g).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.C(O)(=O)C.[O-:16][C:17]#[N:18].[Na+]>O1CCCC1>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[C:17]([NH2:18])=[O:16]
Reactant: N#C[O-]
Reactant: CNc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN(C(N)=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 24 h
Yield: 25.4 %

Procedure:
A 250-mL round bottom flask was charged with N-methyl-4-nitroaniline (1.94 g, 12.7 mmol) in tetrahydrofuran (50 mL). To this stirred solution at rt was added acetic acid (14.6 mL, 255 mmol) and sodium cyanate (8.29 g, 127.5 mmol). After 24 h, the reaction mixture was concentrated under reduced pressure. The residue was suspended in water (100 mL) and the resultant solid was isolated by filtration, washing sequentially with dichloromethane and ethyl acetate to afford the title compound (0.63 g, 25%) as a yellow solid. MW=195.18. 1H NMR (DMSO-d6, 500 MHz) δ 8.19-8.14 (m, 2H), 7.58-7.54 (m, 2H), 6.54 (br s, 2H), 3.27 (s, 3H).
Reaction SMILES: [CH2:1]([O:4][CH2:5][C@H:6]([NH:13]C(=O)C(F)(F)F)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].CO>O>[CH2:1]([O:4][CH2:5][C@@H:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:13])[CH:2]=[CH2:3]
Reactant: C=CCOC[C@H](NC(=O)C(F)(F)F)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C=CCOC[C@H](N)c1ccccc1
Yield: 54.4 %

Procedure:
Step Q (3): (R)-N-(2-(Allyloxy)-1-phenylethyl)-2,2,2-trifluoroacetamide (3.0 g, 11.0 mmol) from step Q (2), potassium carbonate (7.59 g, 55 mmol), methanol (300 mL) and H2O (20 mL) were heated to reflux for 16 h. The mixture was concentrated in vacuo. Water was added, and the aqueous layer was repeatedly extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, and concentrated in vacuo to afford 1.06 g (54% yield) of (R)-2-(allyloxy)-1-phenylethanamine as a yellow oil. The crude mixture was used without further purification. LC-MS (M+H)+=178.18. 1H NMR (300 MHz, CDCl3) δ ppm 2.02 (s, 2H) 3.38 (t, J=9.15 Hz, 1H) 3.48-3.63 (m, 1H) 3.99 (d, J=5.49 Hz, 2H) 4.19 (dd, J=9.15, 3.66 Hz, 1H) 5.05-5.31 (m, 2H) 5.74-5.99 (m, 1H) 7.15-7.42 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:15])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[C:19](Cl)(=[O:21])[CH3:20]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:19](=[O:21])[CH3:20])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(Sc2ccccc2N)c([N+](=O)[O-])c1
Solvent: ClCCl
Product: CC(=O)Nc1ccccc1Sc1ccc(C)cc1[N+](=O)[O-]

Procedure:
The material from Example 185a (0.990 3.80 mmol) was dissolved in CH2Cl2 to which acetyl chloride (0.328 g, 4.183 mmol) was added. Reaction mixture stirred at room temperature for 1 hr at which time the title compound was collected by filtration (910 mg, 79%).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([OH:19])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:23]2)=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:38][C:39]([CH3:46])([CH2:43][CH:44]=[CH2:45])[C:40](O)=[O:41]>>[Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:40](=[O:41])[C:39]([CH3:46])([CH3:38])[CH2:43][CH:44]=[CH2:45])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:23]2)=[CH:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C=CCC(C)(C)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: C=CCC(C)(C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 19.4 %

Procedure:
A procedure similar to that described in Example 3, above, was followed, but using 1.0 g (1.8 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above] and mg (3.6 mmol) of 2,2-dimethyl-4-pentenoic acid, to provide 231 mg of the title compound.
Reaction SMILES: [Li]CCCC.[Br-].[CH:7]1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:11][CH2:10][CH2:9][CH2:8]1.[Br:31][C:32]1[CH:33]=[CH:34][C:35]([O:40][CH3:41])=[C:36]([CH:39]=1)[CH:37]=O>C1COCC1>[Br:31][C:32]1[CH:33]=[CH:34][C:35]([O:40][CH3:41])=[C:36]([CH:39]=1)[CH:37]=[C:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: COc1ccc(Br)cc1C=O
Reactant: c1ccc([P+](c2ccccc2)(c2ccccc2)C2CCCC2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(Br)cc1C=C1CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
n-BuLi (1.6M solution in hexane) (72.5 ml, 116 mmol) was added dropwise at 0° C. to a solution of cyclopentyltriphenylphosphonium bromide (45.8 g, 111 mmol) in THF (300 ml). The red solution was stirred at 0° C. for 0.5 h then treated with a solution of 5-bromo-2-methoxybenzaldehyde (23.5 g, 109 mmol) in THF (150 ml). The reaction mixture was stirred at RT overnight, concentrated in vacuo, then partitioned between CH2Cl2 (250 ml) and water (150 ml). The organic phase was separated and combined with further CH2Cl2 extracts (2×50 ml). The organic phase was washed (brine; 50 ml), dried (Na2SO4), and concentrated in vacuo. The residue was subjected to chromatography (SiO2; CH2Cl2) to afford the title compound (24.6 g), as a colourless oil δH (80 MHz; CDCl3) 1.6-1.9 (4H, br m, CH2(CH2)2), 2.3-2.6 (4H, br m, CH2(CH2)2CH2), 3.76 (3H, s, OMe), 6.4-6.5 (1H, br m, CH═C), 6.65 (1H, d, J 8.5 Hz, ArH ortho to OMe), 7.18 (1H, dd, J 8.5, 2.4 Hz, ArH para to olefin), and 7.39 (1H, d, J 2.4 Hz, ArH ortho to olefin).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[Br:11]Br>C(Cl)(Cl)Cl.C(OCC)C>[Br:11][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:10]
Reactant: BrBr
Reactant: CC(=O)c1ccc(F)cc1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: O=C(CBr)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107 %

Procedure:
4′-Fluoroacetophenone (13.8 g) was dissolved in chloroform (60 mL) and diethyl ether (60 mL), and a solution of bromine (16.0 g) in chloroform (10 mL) was added dropwise while maintaining the reaction temperature at not higher than 25° C. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 30 min, and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give crude 2-bromo-1-(4-fluorophenyl)ethanone (23.2 g) as crystals. A solution (20 mL) of ethyl 3-oxobutanoate (11.7 g) in N,N-dimethylformamide was added dropwise to a suspension (50 mL) of sodium hydride (60% in oil, 4.00 g) in N,N-dimethylformamide with stirring under ice-cooling. After stirring at the same temperature for 15 min, a solution (10 mL) of crude 2-bromo-1-(4-fluorophenyl)ethanone (23.2 g) obtained above in N,N-dimethylformamide was added dropwise. The reaction mixture was stirred at room temperature for 2 hr, water was added, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude ethyl 2-acetyl-4-(4-fluorophenyl)-4-oxobutanoate as an oil (yield 23.20 g). Without further purification, the product was stirred with ammonium acetate (11.56 g, 0.15 mol) and acetic acid (100 mL) with heating at 80° C. for 20 hr. The reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:2). The residue was crystallized from hexane to give the title compound as crystals (yield 13.6 g, from ethyl 3-oxobutanoate, 61%).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:8]=1)(=O)[CH3:2].C(=O)([O-])[O-].[K+].[K+]>>[CH2:17]([O:16][C:14]([NH:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[C:1]([CH3:2])=[N:4][CH2:5][CH2:6]2)=[O:15])[CH3:18]
Reactant: CCOC(=O)Nc1cccc(CCNC(C)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)Nc1ccc2c(c1)CCN=C2C

Procedure:
Using 1.0 g of N-acetyl-N-(3-ethoxycarbonylaminophenethyl)amine (Preparation Example 30), cyclization reaction was conducted according to the procedure described in Heterocycles 31(2), 341 (1990). After the completion of the reaction, the reaction mixture was poured onto ice, the mixture was basified with potassium carbonate, and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give the title compound as brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](O)=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[CH3:34][O:35][CH2:36][CH:37]([NH2:39])[CH3:38].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](=[O:24])[NH:39][CH:37]([CH3:38])[CH2:36][O:35][CH3:34])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: COCC(C)N
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C(=O)NC(C)COC
Yield: 79.8 %

Procedure:
The same operation as in Example (247a) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl)-5-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid obtained in Example (50a) (250 mg, 0.50 mmol), 1-methoxy-2-propylamine (0.11 mL, 1.00 mmol), WSC hydrochloride (288 mg, 1.50 mmol) and 1-hydroxybenzotriazole (68 mg, 0.50 mmol), to obtain 228 mg of the title compound as a white solid (80%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.I[CH:14]([CH3:16])[CH3:15].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Oc1ccc2c(Cl)nccc2c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Oc1ccc2c(Cl)nccc2c1
Yield: 58.6 %

Procedure:
A mixture of 1-chloroisoquinolin-6-ol (898 mg, 5 mmol), 2-iodopropane (1700 mg, 10.00 mmol), and K2CO3 (2073 mg, 15.00 mmol) in acetone (20 mL) was refluxed for 16 h. The reaction mixture was filtrated and washed with acetone. the filtrate was concentrated and purified by silica gel chromatography eluting with 10-20% ethyl acetate in hexane to give 650 mg of the product 1-chloro-6-isopropoxyisoquinoline as a solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.30-8.13 (m, 2H), 7.47 (d, J=5.3 Hz, 1H), 7.27 (d, J=2.5 Hz, 1H), 7.09 (d, J=2.5 Hz, 1H), 4.77 (dt, J=12.2, 6.1 Hz, 1H), 1.45 (d, J=6.0 Hz, 6H); MS: MS m/z 222.16 (M++1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)[CH:2]=1.[NH2:15][C:16]1[S:17][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:20]=1.C(O)(=O)C.[BH4-].[Na+]>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][NH:15][C:16]3[S:17][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:20]=3)=[CH:9][CH:8]=2)[CH:2]=1
Reactant: O=Cc1ccc(-c2cccnc2)cc1
Reactant: COC(=O)c1cnc(N)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)c1cnc(NCc2ccc(-c3cccnc3)cc2)s1
Temperature: 0 °C

Procedure:
In a 250 mL round-bottomed flask was added 4-(pyridin-3-yl)benzaldehyde (4 g, 21.83 mmol), methyl 2-aminothiazole-5-carboxylate (3.45 g, 21.83 mmol), and acetic acid (0.375 ml, 6.55 mmol) in toluene (109 ml). The mixture was heated at reflux under Dean-Stark conditions for 3 hours, cooled, concentrated and redissolved in methanol. The mixture was cooled to 0° C. and sodium borohydride (1.322 g, 34.9 mmol) was carefully added. The mixture was warmed to room temperature and the resulting suspension was filtered with water washes to provide the title compound after drying.
Reaction SMILES: C([O:3][C:4](=[O:44])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:17]=[C:16]([C:31]#[C:32][C:33]3[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=3)[CH:15]=2)=[CH:9][C:8]=1[CH3:43])C.[OH-].[Na+].Cl>C(O)C>[CH3:42][S:39]([C:36]1[CH:35]=[CH:34][C:33]([C:32]#[C:31][C:16]2[CH:15]=[C:14]([S:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:44])=[O:3])=[C:8]([CH3:43])[CH:9]=3)[CH:19]=[C:18]([O:20][C:21]3[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:17]=2)=[CH:38][CH:37]=1)(=[O:40])=[O:41]
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(S(C)(=O)=O)cc3)cc(Oc3ncccc3C(F)(F)F)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Sc2cc(C#Cc3ccc(S(C)(=O)=O)cc3)cc(Oc3ncccc3C(F)(F)F)c2)ccc1OCC(=O)O
Reaction time: 16 h

Procedure:
{4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (197 mg; 0.31 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate, dried and evaporated to dryness. The organic phase was purified by preparative HPLC (method B). Yield: 150 mg (80%). HPLC-MS: m/z: 614.4 (M+H)+; Rt: 2.42 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]=[CH:7]2.[C:13]1([C:19](B(O)O)=[CH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>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>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH2:20])[N:8]=[CH:7]2
Reactant: C=C(B(O)O)c1ccccc1
Reactant: Clc1ncc2cccc(Br)c2n1
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: Cc1ccccc1
Product: C=C(c1ccccc1)c1ncc2cccc(Br)c2n1
Temperature: 90 °C
Reaction time: 60 h
Yield: 14.9 %

Procedure:
A suspension of 8-bromo-2-chloroquinazoline (Ark Pharm, Inc., Libertyville, Ill.; 2.00 g, 8.21 mmol), (1-phenylvinyl)boronic acid (Aldrich; 1.215 g, 8.21 mmol), potassium carbonate (2.384 g, 17.25 mmol), and Pd(PPh3)4 (0.190 g, 0.164 mmol) in toluene (75 mL) was stirred under argon at 90° C. for 2.5 d. The reaction was cooled to 25° C. and partitioned between EtOAc (200 mL) and water (100 mL). The organic layer was separated, sequentially washed with water (2×80 mL) and brine (80 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-100% hexanes/DCM) furnished 8-bromo-2-(1-phenylvinyl)quinazoline (380 mg, 1.221 mmol, 15% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ ppm 9.36 (1H, s), 8.20 (1H, s), 7.88 (1H, d, J=8.0 Hz), 7.58-7.65 (2H, m), 7.44-7.51 (2H, m), 7.40-7.44 (2H, m), 6.84 (1H, s), 5.99 (1H, s). m/z (ESI, +ve) 311.0 (M+H)+.