Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=O)[CH:3]=1.[CH3:12][O:13][C:14]([C:16]1[N:20]([CH:21]2C3C(=CC=CC=3)C[CH2:23][C:22]2([CH3:32])[CH3:31])[CH:19]=[N:18][CH:17]=1)=[O:15].C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[CH3:12][O:13][C:14]([C:16]1[N:20]([CH:21]2[C:3]3[C:4](=[CH:5][CH:6]=[CH:7][CH:2]=3)[C:8](=[O:10])[CH2:23][C:22]2([CH3:32])[CH3:31])[CH:19]=[N:18][CH:17]=1)=[O:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1cncn1C1c2ccccc2CCC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cncn1C1c2ccccc2C(=O)CC1(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 4 %

Procedure:
10.6 g of 3-chloroperbenzoic acid are added to a solution, cooled to 0° C., of 7.1 g of 1-(2,2-dimethyltetralin-1-yl)-5-imidazolecarboxylic acid methyl ester in 200 ml of methylene chloride. The mixture is stirred at room temperature for a further 72 hours. A solution of 7.5 g of sodium hydrogen carbonate in 100 ml of water is then added. The organic phase is separated off, washed with water, dried and concentrated by evaporation. The residue is purified by column chromatography on silica gel using chloroform as eluant. The product-containing fraction is again chromatographed on silica gel using a chloroform/methanol mixture (99.5:0.5). 0.3 g of 1-(2,2-dimethyl-4-oxotetralin-1-yl)-5-imidazolecarboxylic acid methyl ester is obtained in the form of a solid.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N:18]1([C:23]2[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[NH:28][C:27]([C:26]3[CH:25]=[CH:24][C:23]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[CH:30][CH:29]=3)=[N:2][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:12][CH:13]=1
Reactant: NCc1ccc(N2CCCC2)cc1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(C)cc1
Product: CCOC(=O)c1nc(-c2ccc(N3CCCC3)cc2)[nH]c1-c1ccc(C)cc1

Procedure:
Ethyl 2-hydroxyimino-3-(4-methylphenyl)-3-oxopropionate and 4-(1-pyrrolidinyl)benzylamine are reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 5-(4-methylphenyl)-2-(4-(1-pyrrolidinyl)phenyl)imidazole-4-carboxylate. Ethyl 5-(4-methylphenyl)-2-(4-(1-pyrrolidinyl)-phenyl)imidazole-4-carboxylate is reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 5-(4-methylphenyl)-2-(4-(1-pyrrolidinyl)phenyl)imidazole-4-carboxylic acid. 5-(4-Methylphenyl)-2-(4-(1-pyrrolidinyl)phenyl)imidazole-4-carboxylic acid is reacted and treated in the same manner as in Example 1 to give 5-(4-methylphenyl)-2-(4-(1-pyrrolidinyl)phenyl)-N-(2-thiazolyl)imidazole-4-carboxamide.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]1[S:12][CH:13]=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:20]N1C(=O)CCC1=O>ClCCl.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+].[OH-].[Na+]>[CH2:1]([O:8][C:9](=[O:19])[NH:10][C:11]1[S:12][C:13]([I:20])=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: NC(=O)c1ccsc1NC(=O)OCc1ccccc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC(=O)c1cc(I)sc1NC(=O)OCc1ccccc1

Procedure:
To a solution of benzyl[3-(aminocarbonyl)-2-thienyl]carbamate (4.39 g, 15.88 mmol) in dichloromethane (440 mL) was added N-iodosuccinimide (3.57 g, 15.88 mmol). An additional amount of N-iodosuccinimide (1.07 g) was added in 3 portions over the next 60 min to drive the reaction to completion. The dark reaction mixture was diluted with ethyl acetate (700 mL), hexanes (100 mL), aqueous sodium thiosulfate (1 M, 150 mL), and aqueous sodium hydroxide (1 M, 300 mL). The layers were separated, and the organic layer was washed with saturated aqueous sodium bicarbonate (100 mL) and brine (150 mL), dried over sodium sulfate, filtered, and concentrated to afford the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)=[O:4].O1CCCC1.[Br:20]N1C(C)(C)C(=O)N(Br)C1=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([Br:20])=[CH:8]2)=[O:4]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: COC(=O)c1ccc2ncccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2ncc(Br)cc2c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 9.6 %

Procedure:
To a mixture of quinoline-6-carboxylic acid methyl ester (0.50 g, 2.7 mmol) and tetrahydrofuran (10 mL) was added 1,3-dibromo-5,5-dimethyl hydantoin (0.76 g, 2.7 mmol) on an ice bath, and the solution was stirred at 50° C. for 4 hours. Water, an aqueous solution of saturated sodium bicarbonate and ethyl acetate were added to the reaction solution, which was then partitioned, the organic layer was washed with brine, the solvent was then evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1), and the title compound (69 mg, 0.26 mmol, 10%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[N:9]/[S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[C:4]([F:16])[CH:3]=1.[CH2:17]([Mg]Br)[CH3:18].CCOCC.[Cl-].[NH4+]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:9][S@@:10]([C:12]([CH3:13])([CH3:15])[CH3:14])=[O:11])[CH2:17][CH3:18])=[C:4]([F:16])[CH:3]=1
Reactant: CC(C)(C)[S@@](=O)/N=C/c1ccc(Cl)cc1F
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC[C@@H](N[S@](=O)C(C)(C)C)c1ccc(Cl)cc1F
Yield: 34 %

Procedure:
Step 1 To a solution of (R)-(+)-2-methyl-propane-2-sulfinic acid 1-(4-chloro-2-fluoro-phenyl)-meth-(E)-ylideneamide (50 g, 0.191 mol, 1.0 eq) in THF (1 L) at −75° C. was added 3M ethylmagnesium bromide in Et2O (127.4 ml, 0.382 mol, 2.0 eq) slowly at <−65° C. over 30 min. The reaction was stirred for 2.5 h at <−65° C. before addition of sat. ammonium chloride solution (500 ml). The solution was diluted with water (250 ml) and the organic layer separated. The aqueous layer was extracted with EtOAc (2×500 ml) and the combined organic layers were washed with brine (500 ml), dried over MgSO4, filtered and concentrated in vacuo to afford 59 g of crude material (3:1 mixture of diastereomers by 1H NMR). The crude material was purified by chromatography (silica, 1 Kg) eluting with 20% EtOAc/heptanes up to 30% EtOAc to give (R)-(+)-2-methyl-propane-2-sulfinic acid [(R)-1-(4-chloro-2-fluoro-phenyl)-propyl]-amide (19.9 g, 1H NMR>95%, 0.0682 mol, 34% yield). 1H NMR (270 MHz, CDCl3): 7.27-7.21 (1H, m), 7.13-7.04 (2H, m), 4.43 (1H, q), 3.50 (1H, d), 2.02-1.72 (2H, m), 1.21 (9H, s), 0.89 (3H, t).
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([F:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.Cl[C:34]([C@@H:36]([O:38]C(=O)C)[CH3:37])=[O:35]>>[OH:38][C@@H:36]([CH3:37])[C:34]([N:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([F:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)=[O:35]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)[C@H](C)O)C4)c[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide hydrochloride (example A165) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1OC(C)(C)C(C)(C)O1.BrC1[CH:28]=[CH:27][C:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:28]=[CH:27][C:19]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[CH:18][CH:17]=1
Reactant: CC1(C)OC(c2ccco2)OC1(C)C
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1ccc(-c2ccco2)cc1
Temperature: 90 °C
Reaction time: 15 h
Yield: 81.9 %

Procedure:
A mixture of 2-(furan-2-yl)-4,4,5,5-tetramethyl-1,3-dioxolane (500 mg, 2.6 mmol), tert-butyl 4-bromobenzoate (512 mg, 2 mmol) and sodium carbonate (636 mg, 6 mmol), tetra(triphenylphosphine) palladium (115 mg, 0.1 mmol) in mixed solution of 1,4-dioxane (20 ml) and water (4 ml) was stirred for 15 hours at 90° C. under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10:1) to give tert-butyl 4-(furan-2-yl)benzoate (400 mg, 82%) as a yellow oil. LRMS (M+H+) m/z: calcd 244.11. found 244. 1H NMR (300 MHz, CD3OD): δ 7.99-7.96 (m, 2H), 7.78-7.75 (m, 2H), 7.63-7.62 (m, 1H), 6.94-6.93 (m, 1H), 6.57-6.56 (m, 1H), 1.61 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:15][CH2:16][CH2:17]Cl)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:15][CH2:16][CH2:17][N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: ClCCOC(c1ccccc1)c1ccc(Cl)cc1
Product: Clc1ccc(C(OCCN2CCNCC2)c2ccccc2)cc1
Yield: 73 %

Procedure:
Following a procedure similar to that described in Preparation 1, but using 2-[α-(4-chlorophenyl)benzyloxy]ethyl chloride and anhydrous piperazine, the title compound was obtained in a yield of 73%.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](N1C=CN=C1)=[O:11])[CH2:2]2.[F:17][C:18]1[CH:19]=[C:20]([CH:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[OH:26])[CH:21]=[CH:22][C:23]=1[F:24]>>[F:17][C:18]1[CH:19]=[C:20]([CH:25]([O:26][C:10](=[O:11])[O:9][C@@H:3]2[CH:4]3[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]3)[CH2:2]2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: O=C(O[C@H]1CN2CCC1CC2)n1ccnc1
Reactant: OC(c1ccccc1)c1ccc(F)c(F)c1
Product: O=C(OC(c1ccccc1)c1ccc(F)c(F)c1)O[C@H]1CN2CCC1CC2

Procedure:
The desired product was prepared by reacting imidazole-1-carboxylic acid (R)-1-aza-bicyclo[2.2.2]oct-3-yl ester with (3,4-difluoro-phenyl)-phenyl-methanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[CH3:16][NH:17][CH3:18]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:17]([CH3:18])[CH3:16])(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: CNC
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1C(F)(F)F
Product: CN(C)S(=O)(=O)c1ccc(Br)cc1C(F)(F)F
Yield: 80 %

Procedure:
In an analogous manner to General Procedure A, 4-Bromo-2-trifluoromethylbenzenesulfonyl chloride (0.50 g, 1.54 mmol) and dimethylamine (10 mL, 33% in ethanol) were stirred in sealed tube for 16 hours. 4-bromo-N,N-dimethyl-2-(trifluoromethyl)benzenesulfonamide (0.41 g, 80%) was provided after purification. MS (ESI) m/z 332. HPLC purity 100.0% at 210-370 nm, 9.3 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9]([S:10](Cl)(=[O:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=12.O1CCCC1.[NH3:19].[OH-].[NH4+]>O>[N:1]1[O:2][N:3]=[C:4]2[C:9]([S:10]([NH2:19])(=[O:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=S(=O)(Cl)c1cccc2nonc12
Reactant: N
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NS(=O)(=O)c1cccc2nonc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 3.0 g of 2,1,3-benzoxadiazole-4-sulfonyl chloride and 200 mL of tetrahydrofuran at -30° C. was added 10 mL of ammonia under an inert atmosphere. The resulting suspension was stirred at ambient temperature for 3 hours. Concentrated ammonium hydroxide (20 mL) and water (20 mL) were added. The reaction was extracted with ethyl acetate and the organic extracts were combined, dried over magnesium sulfate, filtered, and stripped to give a crude solid. Recrystallization from chlorobutaneethanol afforded 1.82 g of the title compound as an orange-tan solid, m.p. 157°-159° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH2:5][NH2:6].[CH:14]1[C:23]2[C:18](=[C:19]([CH:24]([CH3:28])[C:25](O)=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:11])([F:12])[F:13])[CH2:5][NH:6][C:25](=[O:26])[CH:24]([C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[CH:17]=[CH:16][N:15]=[CH:14]2)[CH3:28]
Reactant: NCc1ccc(C(F)(F)F)c(F)c1
Reactant: CC(C(=O)O)c1cccc2cnccc12
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C(=O)NCc1ccc(C(F)(F)F)c(F)c1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 3-fluoro-4-(trifluoromethyl)benzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 377 (M+H)+; MS (ESI−) m/z 375 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.53 (d, J 7.1, 3H), 4.35 (d, J 6.1, 2H), 4.47 (q, J 7.1, 1H), 7.18 (m, 2H), 7.70 (m, 3H), 8.05 (m, 2H), 8.53 (d, J 6.1, 1H), 8.68 (t, J 6.8, 1H), 9.32 (s, 1H); Anal. Calcd for C20H16F4N2O+1.25 HCl: C, 56.93; H, 4.12; N, 6.64. Found: C, 56.72; H, 4.45; N, 7.03.
Reaction SMILES: [OH:1][C@H:2]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[C@H:3]([NH:14][C:15](=[O:29])[C@@H:16]([NH:19][C:20](=[O:28])[CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH2:17][OH:18])[C:4]([O:6]CC1C=CC=CC=1)=[O:5]>C1COCC1.[Pd]>[OH:1][C@H:2]([C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)[C@H:3]([NH:14][C:15](=[O:29])[C@@H:16]([NH:19][C:20](=[O:28])[CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH2:17][OH:18])[C:4]([OH:6])=[O:5]
Reactant: COc1ccc([C@@H](O)[C@H](NC(=O)[C@H](CO)NC(=O)CN2CCOCC2)C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1ccc([C@@H](O)[C@H](NC(=O)[C@H](CO)NC(=O)CN2CCOCC2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
To a solution of (2S,3R)-benzyl 3-hydroxy-2-((S)-3-hydroxy-2-(2-morpholinoacetamido)propanamido)-3-(4-methoxyphenyl)propanoate (349 mg, 0.680 mmol) in THF (20 mL) was added Pd/C (100 mg, 10%). The mixture was stirred under a hydrogen atmosphere (1 atm) at ambient temperature overnight then filtered through a pad of celite. The filtrate was concentrated to afford (2S,3R)-3-hydroxy-2-((S)-3-hydroxy-2-(2-morpholinoacetamido)propanamido)-3-(4-methoxyphenyl)propanoic acid (121 mg, 42% yield) as a colorless solid.
Reaction SMILES: [CH:1]([C@H:14]1[CH2:20][C@H:19]2[C@H:17]([O:18]2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CO>C(O)C>[CH:1]([C@H:14]1[CH2:20][C@H:19]([OH:18])[C@@H:17]([NH:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccccc1
Reactant: c1ccc(C(c2ccccc2)[C@H]2C[C@@H]3O[C@@H]3CO2)cc1
Solvent: CCO
Solvent: CO
Product: O[C@H]1C[C@H](C(c2ccccc2)c2ccccc2)OC[C@@H]1NCc1ccccc1

Procedure:
(1R, 4R, 6S)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]-heptane 28c (0.022 g, 0.082 mmol) was reacted with benzylamine (0.18 g, 1.64 mmol) in ethanol (Procedure E) to yield (2R, 4S, 5S)-2-benzhydryl-5-benzylamino-tetrahydro-pyran-4-ol, (+)-29d 0.025 g (81%, [α]D=(+)53.7, c-=1, MeOH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[C:12]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:13]=1[C:14]#[N:15].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:12]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:13]=2[C:14]#[N:15])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cc([N+](=O)[O-])ccc1Sc1ccc(Cl)cc1
Temperature: 60 °C
Yield: 99.1 %

Procedure:
To a solution of 15.2 g (0.105 moles) of 4-chlorothiophenol dissolved in 150 ml of DMSO was added 4.2 g (0.105 moles) of NaOH. The mixture was heated to 60° C. and 18.3 g (0.100 moles) of 2-chloro-5-nitrobenzonitrile was added and the mixture heated at 60° C. for 21/2 hrs. The mixture was cooled and poured into a solution of 100 ml of 2 N aqueous NaOH and 600 ml of water. The product was collected by filtration, washed well with water and dried to obtain 28.8 g of product (99% yield). Recrystallization from ethanol afforded purified 2-((4-chlorophenyl)thio)-5-nitrobenzonitrile, mp 162°-164.5° C.
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].[Cl:5][C:6]1[CH:7]=[C:8]([CH2:13][C:14]#[N:15])[CH:9]=[C:10]([Cl:12])[CH:11]=1.C(OCC)(=O)C.C(O)(=O)C>C(O)C.C(COC)OC.CCCCCC.O>[Cl:5][C:6]1[CH:7]=[C:8]([CH:13]([C:2](=[O:3])[CH3:1])[C:14]#[N:15])[CH:9]=[C:10]([Cl:12])[CH:11]=1
Reactant: N#CCc1cc(Cl)cc(Cl)c1
Reactant: CC[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CC(=O)C(C#N)c1cc(Cl)cc(Cl)c1
Yield: 179.5 %

Procedure:
To a stirred solution of NaOEt (from 0.69 g sodium), in ethanol (25 ml) at reflux, was added over 5 minutes a mixture of 3,5-dichlorophenylacetonitrile (9.3 g) and ethyl acetate (3.3 g) in dry dimethoxyethane (10 ml). After stirring at reflux for 4 hours, the mixture was cooled on ice, acidified with acetic acid, poured into cold water and extracted with dichlormethane. The combined extracts were washed with water and concentrated to give an oil. Trituration with hexane gave 2-(3,5-dichlorophenyl)-3-oxobutyronitrile as a colourless solid (4.15 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[N:7]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=2)[C:6]=1[C:25]1[CH:30]=[CH:29][C:28]([C:31]([O:33]C)=[O:32])=[CH:27][CH:26]=1)=[O:4].[Cl:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1>>[C:31]([C:28]1[CH:27]=[CH:26][C:25]([C:6]2[N:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:23])[CH3:24])=[CH:17][CH:16]=3)[C:8]3[C:13]([C:5]=2[C:3]([OH:2])=[O:4])=[CH:12][C:11]([O:14][C:40]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:35])[CH:41]=2)=[CH:10][CH:9]=3)=[CH:30][CH:29]=1)([OH:33])=[O:32]
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(-c2c(C(=O)OC)c3cc(O)ccc3n2-c2ccc(OC(C)C)cc2)cc1
Product: CC(C)Oc1ccc(-n2c(-c3ccc(C(=O)O)cc3)c(C(=O)O)c3cc(Oc4cccc(Cl)c4)ccc32)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 5-hydroxy-1-(4-isopropoxyphenyl)-2-(4-methoxycarbonylphenyl)indole-3-carboxylic acid methyl ester (150 mg, 0.32 mmol, see step (b) Example 43) and 3-chloro-phenylboronic acid (100 mg, 0.64 mmol. Yield 97 mg (54%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([C:14]([OH:16])=[O:15])[CH2:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:18]>C(Cl)Cl.CO>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([C:14]([O:16][CH3:18])=[O:15])[CH2:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(C(=O)O)c2ccc(F)cc2O1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1CC(C)(C)Oc2cc(F)ccc21
Yield: 75.5 %

Procedure:
To 7-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromene-4-carboxylic acid (0.280 g, 1.25 mmol) in CH2Cl2 (5 mL) and MeOH (1 mL) was added TMSCHN2 (0.937 mL, 1.87 mmol) dropwise. After the addition, the reaction was concentrated, loaded onto silica gel, and the product eluted using a gradient of 5% ethyl acetate/hexanes to 40% ethyl acetate/hexanes to provide the title compound (0.225 g, 75.6% yield).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([CH:8]([C:15](=O)[CH3:16])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=O)=[CH:4][CH:3]=1.[N:20]1([NH2:25])[CH:24]=[CH:23][CH:22]=[CH:21]1.C(OCC)(=O)C.O>C(O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][C:8]1[C:15]([CH3:16])=[N:25][N:20]2[CH:24]=[CH:23][CH:22]=[C:21]2[C:6]=1[C:5]1[CH:18]=[CH:19][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:14]
Reactant: Nn1cccc1
Reactant: CCOC(=O)CC(C(C)=O)C(=O)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)Cc1c(C)nn2cccc2c1-c1ccc(F)cc1
Yield: 116.2 %

Procedure:
A mixture of ethyl 3-(4-fluorobenzoyl)-4-oxopentanoate (800 mg), 1H-pyrrol-1-amine (265 mg), and p-toluenesulfonic acid monohydrate (31 mg) in ethanol (5 ml) was refluxed for 5 hours. The mixture was partioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:4) to give ethyl[4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]acetate (1.09 g) as an oil.
Reaction SMILES: C([O:8][C:9](=[O:36])[CH2:10][C@@H:11]([C:24]1[CH:28]=[CH:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH:25]=1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])C1C=CC=CC=1.CC(OC)(C)C>CCO>[CH3:17][C:16]([CH3:19])([CH3:18])[C@H:15]([NH:14][C:12](=[O:13])[C@H:11]([C:24]1[CH:28]=[CH:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH:25]=1)[CH2:10][C:9]([OH:36])=[O:8])[C:20](=[O:23])[NH:21][CH3:22]
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)c1ccn(-c2ccc(F)cc2)c1)C(C)(C)C
Solvent: CCO
Solvent: COC(C)(C)C
Product: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)O)c1ccn(-c2ccc(F)cc2)c1)C(C)(C)C

Procedure:
As described in Example 1(a), N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]-3(S)-[1-(4-fluorophenyl)-1H-pyrrol-3-yl]succinamic acid benzyl ester was hydrogenolyzed in EtOH after 1.5 hours. Trituration with MTBE/hex gave in quantitative yield N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]-3(S)-[1-(4-fluorophenyl)-1H-pyrrol-3-yl]succinamic acid as a colorless amorphous solid. 1H NMR: δ 7.27-7.23 (m, 2H), 7.07 (t, 2H, J=8.6 Hz), 6.90-6.89 (m, 2H), 6.21 (t, 1H, J=2.2 Hz), 6.13-6.10 (m, 1H), 4.24 (d, 1H, J=9.6 Hz), 4.03 (dd, 1H, J=5.2, 8.5 Hz), 3.14 (dd, 1H, J=8.5, 16.6 Hz), 2.80 (dd, 1H, J=5.7, 16.7 Hz), 2.72 (d, 3H, J=4.8 Hz), 0.94 (s, 9H). Anal. Calculated for C21H26N3O4F: C, 63.17; H, 6.80; N, 10.09. Found: C, 62.89; H, 6.93; N, 9.81.
Reaction SMILES: [OH-].[Na+].[C:3]([NH:6][C:7]1[C:8](=[O:21])[O:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[NH2:20])[CH:12]=1)(=[O:5])[CH3:4].O1CCCC1.Cl>O>[C:3]([NH:6]/[C:7](=[CH:12]/[C:11]1[C:13]2[C:14](=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)[NH:20][CH:10]=1)/[C:8]([OH:9])=[O:21])(=[O:5])[CH3:4]
Reactant: CC(=O)Nc1cc(-c2ccc(C)cc2N)coc1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N/C(=C/c1c[nH]c2cc(C)ccc12)C(=O)O
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
110 ml. of 1 N sodium hydroxide were added dropwise over 30 minutes to a mixture of 26.95 g. (10.2 mmol) of crude 3-acetamido-5-(2-amino-4-methylphenyl)-2H-pyran-2-one in 200 ml. of tetrahydrofuran and 200 ml. of water under a nitrogen atmosphere. The resulting dark suspension was stirred for 30 minutes. 110 ml. of 1 N hydrochloric acid were added dropwise to the dark suspension. After removal of the tetrahydrofuran in vacuo and adjustment to pH 3, the dark suspension was cooled to 5° C., and filtered. The filter cake (21.1 g.) was dissolved in 1100 ml. of boiling methanol, treated with 2.0 g. of charcoal for 10 minutes and filtered through a bed of diatomaceous earth (which was washed with 200 ml. of hot methanol). The filtrate was concentrated to about 750 ml.; 150 ml. of water were added portionwise thereto; and the resulting solution was allowed to crystallize. A total of 16.1 g. (61%) of (E)-α-acetamido-6-methylindole-3-acrylic acid (mp 204.5-206° C.) was obtained in two crops.