Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:49])[CH2:7][CH2:6][C@H:5]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([S:16]([N:19](CC3C=CC(OC)=CC=3OC)[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:18])=[O:17])=[C:11]([F:37])[CH:10]=2)[C@@H:4]([C:38]2[N:42](COCCOC)[N:41]=[CH:40][CH:39]=2)[CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.Cl>CO.ClCCl>[F:49][C:2]1([F:1])[CH2:7][CH2:6][C@H:5]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([S:16]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:18])=[O:17])=[C:11]([F:37])[CH:10]=2)[C@@H:4]([C:38]2[NH:42][N:41]=[CH:40][CH:39]=2)[CH2:3]1
Reactant: COCCOCn1nccc1[C@H]1CC(F)(F)CC[C@@H]1Oc1cc(F)c(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ccncn2)cc1C
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(S(=O)(=O)Nc2ccncn2)c(F)cc1O[C@H]1CCC(F)(F)C[C@@H]1c1ccn[nH]1
Yield: 65.8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 155i by using the 4-{[(1S*,2R*)-4,4-difluoro-2-{1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl}cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide (356 mg, 0.504 mmol) prepared in Example 157d, triethylsilane (0.50 mL), trifluoroacetic acid (5.0 mL), dichloromethane (5.0 mL), 6 M hydrochloric acid (5.0 mL) and methanol (15 mL), to yield the title compound (155 mg, 66%) as a colorless solid.
Reaction SMILES: C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:19]12([OH:29])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2.[C:30](O)(=[O:34])[C:31]([CH3:33])=[CH2:32]>O>[C:30]([O:29][C:19]12[CH2:26][CH:25]3[CH2:24][CH:23]([CH2:22][CH:21]([CH2:27]3)[CH2:20]1)[CH2:28]2)(=[O:34])[C:31]([CH3:33])=[CH2:32]
Reactant: C=C(C)C(=O)O
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OC12CC3CC(CC(C3)C1)C2

Procedure:
200 ml of toluene and 1 g of p-toluenesulfonic acid were added to 70 g of 1-adamantanol and 50 g of methacrylic acid. They were subjected to a reaction with heating and stirring, while water was distilled off using a Dean-Stark trap. The resulting organic phase was washed with water, a 10 mass % aqueous sodium hydrogencarbonate solution and water in this order and distilled to obtain crude 1-adamantyl methacrylate (a crude product) having a purity of 91 mass %.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=3)[N:11]=[C:10]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH:9]=2)=[CH:4][CH:3]=1>O.C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=3)[N:11]=[C:10]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCN(CC)c1cc(-c2ccc(N)cc2)c2cc(Cl)ccc2n1
Solvent: O
Solvent: CCO
Product: CCN(CC)C1=Nc2ccc(Cl)cc2C(c2ccc(N)cc2)C1

Procedure:
5.49 g of sodium/mercury amalgam were added over the course of 5 hours to a solution of 250 mg of 4-(4-aminophenyl)-6-chloro-2-diethylaminoquinoline in 2.5 ml of water and 16 ml of ethanol while stirring. The mixture was stirred overnight and decanted to remove the Hg precipitate, and the solvent was distilled under reduced pressure. The residue was mixed with water and extracted with ethyl acetate. The solid product as pale residue was dissolved in a little ethyl acetate, acidified with ethereal HCl, stirred at room temperature and filtered with suction.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[CH2:21][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH3:36][S:37](Cl)(=[O:39])=[O:38].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:16][C:15]=2[CH2:21][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(N)cc2CN(CC)C(=O)OCc2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(NS(C)(=O)=O)cc2CN(CC)C(=O)OCc2ccccc2)c1

Procedure:
{4′-Amino-2′-[(benzyloxycarbonyl-ethyl-amino)-methyl]-6-methoxy-biphenyl-3-yl}-acetic acid ethyl ester (0.080 g, 0.2 mmol), methanesulfonyl chloride (0.04 mL, 0.3 mmol), and triethylamine were reacted in CH2Cl2 to give the title compound.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14](=[O:29])[CH2:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([F:28])([F:27])[F:26])[C:18]=3[N:17]=2)[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14](=[O:29])[CH2:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([F:26])([F:27])[F:28])[C:18]=3[N:17]=2)[CH2:9]1
Reactant: O=C(Cc1nc2c(C(F)(F)F)cccc2[nH]1)N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(Cc1nc2c(C(F)(F)F)cccc2[nH]1)N[C@@H]1CCNC1
Yield: 82.1 %

Procedure:
In a round-bottom flask, a slurry of N-[(3R)-1-benzylpyrrolidin-3-yl]-2-[4-(trifluoromethyl)-1H-benzimidazol-2-yl]acetamide (800 mg, 1.99 mmol) and Palladium (10%) on Carbon (10 mg) in MeOH was purged with hydrogen gas for 2 min.; the reaction was then subjected to 1 atm of hydrogen gas overnight. The flask was purged with argon, then the mixture was filtered, concentrated and subjected to flash chromatography (ethyl acetate) to afford N-[(3R)-pyrrolidin-3-yl]-2-[4-(trifluoromethyl)-1H-benzimidazol-2-yl]acetamide (510 mg, 83%), as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([OH:11])=[C:6]([Br:12])[CH:5]=1.[C:14](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH3:14])=[C:6]([Br:12])[CH:5]=1
Reactant: COC(=O)c1cc(F)c(O)c(Br)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1cc(F)c(OC)c(Br)c1
Reaction time: 96 h

Procedure:
6 g (24.09 mmol) of the product obtained in step 1 were dissolved in 60 ml of acetone, 10.13 g (2.270 mmol) of potassium carbonate and 6.84 g (48.18 mmol) of iodomethane were added, and the mixture was stirred for 4 days. Then is was filtered and evaporated. The resulting product (5.8 g) was used in the next step without further purification.
Reaction SMILES: [C:1]1([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>C(OC)(C)(C)C>[CH3:18][N:19]([CH3:21])[CH:20]=[C:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:8]
Reactant: COC(OC)N(C)C
Reactant: O=C(Cc1ccccc1)c1ccccc1
Solvent: COC(C)(C)C
Product: CN(C)C=C(C(=O)c1ccccc1)c1ccccc1
Yield: 91.7 %

Procedure:
When only the 4,5-diphenyl isomer is desired the following procedure is preferred. A mixture of 778 g (3.96 mol) deoxybenzoin, 580 mL (4.38 mol) of N,N-dimethylformamide dimethyl acetal, and 775 mL of methyl tert-butyl ether was refluxed for 3 hours. The reaction mixture was cooled on ice to 0°-5° C. The precipitated solid was collected by filtration, the filter cake washed with 250 mL of cold methyl tert-butyl ether twice and dried in vacuum chamber at 65° C. to afford 913 g (92%) of 3-(dimethylamino)-1,2-diphenyl-2-propen-1-one, mp 128°-133° C. A slurry of 913 g (3.64 mol) of 3-(dimethylamino)-1,2-diphenyl-2-propen-1-one in 3.4 L of absolute ethanol was treated with 618 g (4 mol) of ethyl hydrazinoacetate hydrochloride in one portion. The mixture was stirred at room temperature for 1 hour, filtered through diatomaceous earth, and the filtrate treated with 7 L of 50% aqueous ethanol with stirring. Cooling of the resultant solution to 0°-5° C. provided a white solid which was collected by filtration, washed with 250 mL of cold 50% ethanol twice and dried in vacuum at 40° C. to provide 970 g (87%) of ethyl 4,5-diphenyl-1H-pyrazole-1-acetate, mp 76°-80° C., containing none of the 3,4-diphenyl isomer detectable by GLC.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][Si](C(C)C)(C(C)C)C(C)C)[N:7]=1)=[O:5])[CH3:2].Cl[CH2:24][C:25](=[O:27])[CH3:26]>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][CH2:24][C:25](=[O:27])[CH3:26])[N:7]=1)=[O:5])[CH3:2]
Reactant: CC(=O)CCl
Reactant: CCOC(=O)c1cccc(S[Si](C(C)C)(C(C)C)C(C)C)n1
Product: CCOC(=O)c1cccc(SCC(C)=O)n1

Procedure:
Prepared according to the procedure described in Example 6, Step 2, using the following starting materials: 6-triisopropylsilanylsulfanyl-pyridine-2-carboxylic acid ethyl ester and chloroacetone.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[S:4]([C:8]1[CH:16]=[CH:15][C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=1)([O-])(=[O:6])=[O:5].[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([Cl:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1)([O-:19])=[O:18].N1(C2C=CN=CC=2)CCCC1.[N-]=[N+]=[N-].[Na+]>C(Cl)(Cl)Cl.CN(C)C=O>[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([Cl:29])(=[O:27])=[O:28])=[CH:22][CH:21]=1)([O-:19])=[O:18].[S:4]([N:1]=[N+:2]=[N-:3])([C:8]1[CH:16]=[CH:15][C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=1)(=[O:5])=[O:6]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)[O-])cc1
Reactant: [N-]=[N+]=[N-]
Agent: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: [N-]=[N+]=NS(=O)(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
Secondary alcohol 7 was converted to azide 8 through the formation of a secondary nosylate using 4-nitrobenzenesulfonyl chloride and 4-pyrrolidinopyridine in chloroform followed by azide displacement with sodium azide in N,N-dimethylformamide at 50° C. The p-methoxy trityl protecting group was selectively removed using 1% p-toluenesulfonic acid in methylene chloride. Nosylation of the primary alcohol with 4-nitrobenzenesulfonyl chloride and pyridine in chloroform provided azido-nosylate 9.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[C:6]([OH:16])[CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=2)[NH:4][N:3]=1.[H-].[Na+].I[CH2:20]C>CN(C=O)C.CCOC(C)=O>[CH3:20][O:16][C:6]1[CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=[C:10]2[C:5]=1[NH:4][N:3]=[C:2]2[CH3:1]
Reactant: CCI
Reactant: CCOC(=O)c1cc(O)c2[nH]nc(C)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(OC)c2[nH]nc(C)c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a 0° C. solution of ethyl 3-methyl-7-hydroxy-1H-indazole-5-carboxylate (0.84 g, 3.8 mmol) in DMF (25 mL) was added 60% oil dispersion of NaH (152 mg, 3.81 mmol). After stirring for 1 hour at 0° C., a solution of iodoethane (595 mg, 0.31 mL, 3.81 mmol) in DMF (3 mL) was added. The mixture was kept at 0° C. for several hours before allowing the mixture to warm to room temperature while stirring overnight. Dilute with EtOAc, wash with saturated aqueous NaHCO3, water, saturated aqueous NaCl and the organic extract was dried over Na2SO4, filtered and concentrated. The crude material was purified by CombiFlash (80 g column, 0-30% EtOAc/hexanes gradient) to provide ethyl 7-methoxy-3-methyl-1H-indazole-5-carboxylate (516 mg, 55%).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([NH2:12])[C:6]=2[CH:5]=[C:4]([CH3:13])[N:3]=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]=[C:23]=[O:24])=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][NH:22][C:23]([NH:12][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:6]=2[CH:5]=[C:4]([CH3:13])[N:3]=[C:2]3[CH3:1])=[O:24])=[CH:19][CH:20]=1
Reactant: O=C=NCc1ccc(Br)cc1
Reactant: Cc1cc2c(N)cccc2c(C)n1
Solvent: Cc1ccccc1
Product: Cc1cc2c(NC(=O)NCc3ccc(Br)cc3)cccc2c(C)n1
Temperature: 87.5 °C
Reaction time: 3 h

Procedure:
The product from Example 178A(375 mg, 2.2 mmol) in toluene (7 mL) was treated with 1-bromo-4-(isocyanatomethyl)benzene (0.31 mL, 2.2 mmol). After stirring at 85-90° C. for 3 hours, the mixture was cooled to room temperature and filtered. The filter cake was treated with methanolic HCl to provide the title compound as the hydrochloride salt. 1H NMR (300 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.17 (d, 1H, J=7.8 Hz), 7.80 (d, 1H, J=8.5 Hz), 7.45-7.60 (m, 4H), 7.32 (d, 2H, J=8.1 Hz), 7.06 (t, 1H, 5.7 Hz), 4.34 (d, 2H, 5.8 Hz), 2.84 (s, 3H), 2.75 (s, 3H); MS (ESI+) m/z 383/385 (M+H, 79Br/81Br).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[NH:51][C:52]2[CH:58]=[CH:57][CH:56]=[CH:55][C:53]=2[N:54]=1.N1C=CC=CC=1>C(Cl)Cl.O>[NH:51]1[C:52]2[CH:58]=[CH:57][CH:56]=[CH:55][C:53]=2[N:54]=[C:50]1[NH:49][C:40](=[O:42])[C@@H:39]([C:31]1[CH:32]=[CH:33][C:34]([S:35]([CH3:38])(=[O:36])=[O:37])=[C:29]([Cl:28])[CH:30]=1)[CH2:43][CH:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1
Reactant: Nc1nc2ccccc2[nH]1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2nc3ccccc3[nH]2)cc1Cl
Temperature: 0 °C
Yield: 55.1 %

Procedure:
A solution of triphenylphosphine (238 mg, 0.91 mmol) in methylene chloride (10 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (183 mg, 1.03 mmol). The reaction mixture was stirred at 0° C. until it became homogeneous. The resulting light purple reaction mixture was then treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 19, 200 mg, 0.61 mmol). The reaction mixture was stirred at 0° C. for 20 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminobenzimidazole (121 mg, 0.91 mmol) and pyridine (0.15 mL, 1.82 mmol), and the resulting reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was then diluted with water (15 mL) and extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 60/40 hexanes/ethyl acetate) afforded the N-(1H-benzoimidazol-2-yl)-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (150 mg, 56%) as a light brown solid: mp >215° C.; [α]23589=−21.9° (c=0.041, chloroform); EI-HRMS m/e calcd for C22H24ClN3O3S (M+) 445.1227, found 445.1235.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C(O)C.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1>C(N(CC)CC)C>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=2)=[CH:14][CH:15]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Nc1ccc(O)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Oc1ccc(Nc2cc(Cl)ncn2)cc1
Yield: 69.4 %

Procedure:
To a solution of 4,6-dichloropyrimidine (24.8 g), ethanol (250 ml) and triethylamine (51 ml) was added 4-aminophenol (18.2 g) and the solution was heated at reflux for 6 hours. After cooling the precipitate was collected, washed with DCM (100 ml) and recrystallized in acetonitrile to give the title compound (25.6 g, 69%) as crystals. NMR: 6.59 (1H, s), 6.73 (2H, d), 7.28 (2H, d), 8.33 (1H, s), 9.28 (1H, s), 9.52 (1H, s); m/z 222 (NH+).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]3[N:10]=[C:11]([C@H:13]4[CH2:18][CH2:17][C@H:16]([O:19][CH2:20][CH:21]([OH:23])[CH3:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C1COCC1>[CH3:33][S:34]([O:23][CH:21]([CH3:22])[CH2:20][O:19][C@H:16]1[CH2:17][CH2:18][C@H:13]([C:11]2[O:12][C:8]3[CH:7]=[C:6]([O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[CH:25]=[CH:24][C:9]=3[N:10]=2)[CH2:14][CH2:15]1)(=[O:36])=[O:35]
Reactant: CC(O)CO[C@H]1CC[C@H](c2nc3ccc(OCC4CC4)cc3o2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(CO[C@H]1CC[C@H](c2nc3ccc(OCC4CC4)cc3o2)CC1)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-({trans-4-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]cyclohexyl}oxy)propan-2-ol (271 mg) and triethylamine (0.22 mL) in THF (5 mL) was added methanesulfonyl chloride (0.1 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 1 hr, and extracted with ethyl acetate and water. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (283 mg).
Reaction SMILES: C([NH:4][C:5]1[C:14]2[C:9](=[N:10][C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH:13]=2)[N:8]([CH3:30])[C:7](=[O:31])[C:6]=1[C:32]([O:34]C)=O)(=O)C.[NH3:36]>C1COCC1.CO>[NH2:4][C:5]1[C:14]2[C:9](=[N:10][C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])=[C:12]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)[CH:13]=2)[N:8]([CH3:30])[C:7](=[O:31])[C:6]=1[C:32]([NH2:36])=[O:34]
Reactant: N
Reactant: COC(=O)c1c(NC(C)=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(C)c1=O
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(=O)c(C(N)=O)c(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To the product of EXAMPLE 91 (30 mg) in THF (1 mL) was added 3 mL of NH3 in methanol (7 M). The reaction stirred for about 15 hours at room temperature before it was concentrated. The residue was dissolved in CH2Cl2 and washed with water. The solution was dried (Na2SO4) and concentrated. The concentrated residue was purified by preparative TLC on silica gel eluted with 100% EtOAc affording the title compound. HPLC/MS: 473.0 (M+1), 475.0 (M+3); Rt=4.19 min.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]=[C:11](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=CC=[CH:4][CH:3]=1.ClC(O[CH:26]([Cl:28])[CH3:27])=O.[Cl:29]CCl>>[Cl:29][C:4]1[CH:3]=[C:2]([CH:7]=[CH:27][C:26]=1[Cl:28])[CH2:1][N:8]1[CH2:13][CH:12]=[C:11](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1
Reactant: CC(Cl)OC(=O)Cl
Reactant: C1=C(/C=C/c2ccccc2)CCN(Cc2ccccc2)C1
Reactant: ClCCl
Product: Clc1ccc(CN2CC=C(/C=C/c3ccccc3)CC2)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a solution of (E)-1-benzyl-4-(2-phenylethenyl)-1,2,3,6-tetrahydropyridine (27 g, 100 mmol) in dichloromethane (400 ml) at 0° C. was added 1-chloroethyl chloroformate (13 ml, 120 mmol) via syringe, keeping the temperature below 5° C. The reaction was stirred at 0° C. for 1 hour and then warmed to room temperature over 2 hours. The solvent was evaporated, methanol (500 ml ) added to the residue, and the reaction refluxed for 90 minutes. The reaction was cooled to room temperature, the solvent evaporated to a slurry and ether (≈200 ml) added. The resultant solid was filtered and dried to give the title compound (17 g, 77%); δH (DMSO-d6) 2.55 (2H, br s, tetrahydropyridinyl CH2), 3.25 (2H, br s, tetrahydropyridinyl CH2), 3.71 (2H, br s, tetrahydropyridinyl CH2), 5.92 (1H, br s, tetrahydropyridinyl 5-CH), 6.62 (1H, d, J 16.3 Hz, ArCH=CHC), 6.97 (1H, d, J 16.3 Hz, ArCH=CHC), 7.25 (1H, d, J 7.3 Hz, 4-H), 7.35 (2H, t, J 7.3 Hz, 3-H, 5-H), 7.52 (2H, d, J 7.3 Hz, 2-H, 6-H), and 9.51 (1H, br s, NH); m/z (ES+) 306 (M+1)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][CH:15]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:16][C:17](O)=[O:18])(=[O:13])=[O:12].[NH2:26][CH:27]1[C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([C:36]#[N:37])[C:30]=2[CH2:29][CH2:28]1>>[C:36]([C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:30]=1[CH2:29][CH2:28][CH:27]2[NH:26][C:17](=[O:18])[CH2:16][CH:15]([NH:14][S:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:12])=[O:13])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)#[N:37]
Reactant: O=C(O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Reactant: N#Cc1cccc2c1CCC2N
Product: N#Cc1cccc2c1CCC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1

Procedure:
N-(4-Cyano-indan-1-yl)-3-(naphthalen-2-yl-sulfonylamino)-3-phenyl-propionamide was prepared from 3-(naphthalen-2-yl-sulfonylamino)-3-phenyl-propionic acid ( ) and 1-amino-indan-4-carbonitrile (Step E), using essentially the same procedure described in Example 1, Step F, yielding a white solid. MS (ESI) m/z 496 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([OH:14])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.Cl[CH2:17][C:18]([NH2:20])=[O:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:12]([O:14][CH2:17][C:18](=[O:19])[NH2:20])[CH:13]=[C:4]([C:3]([O:2][CH3:1])=[O:15])[CH:5]=1
Reactant: NC(=O)CCl
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OCC(N)=O)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 5-hydroxyisophthalic acid dimethyl ester (500 mg, 2.38 mmol) and chloroacetamide (245 mg, 2.62 mmol) in DMF (7 mL) is added potassium carbonate (986 mg, 7.14 mmol) and the mixture is stirred at room temperature for 2 days. Water is added to the mixture and then it is extracted with ethyl acetate. The organic phase is washed with water and brine and is dried over sodium sulfate. The organic solution is concentrated to one fourth volume to give a precipitate. The solid is filtered, washed with ethyl acetate and dried under reduced pressure to give 5-carbamoylmethoxyisophthalic acid dimethyl ester. MS 268.2 (M+1); 1H-NMR (400 MHz, CDCl3); δ ppm 3.96 (s, 6H), 4.59 (s, 2H), 5.87 (s, broad, 1H), 6.55 (s, broad, 1H), 7.79 (s, 2H), 8.37 (s, 1H).
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]([C:17]1[C:18]([I:44])=[C:19]([CH2:39][O:40]C(=O)C)[C:20]([I:38])=[C:21]([C:36]=1[I:37])[C:22]([NH:24][CH2:25][CH:26]([O:32]C(=O)C)[CH2:27][O:28]C(=O)C)=[O:23])[C:8]([CH:10]1[CH2:14][O:13]C(C)(C)[O:11]1)=[O:9])(=O)C.[OH-].[Na+].O>CO>[OH:4][CH2:5][CH2:6][N:7]([C:8](=[O:9])[CH:10]([OH:11])[CH2:14][OH:13])[C:17]1[C:18]([I:44])=[C:19]([CH2:39][OH:40])[C:20]([I:38])=[C:21]([C:36]=1[I:37])[C:22]([NH:24][CH2:25][CH:26]([OH:32])[CH2:27][OH:28])=[O:23]
Reactant: CC(=O)OCCN(C(=O)C1COC(C)(C)O1)c1c(I)c(COC(C)=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(NCC(O)CO)c1c(I)c(CO)c(I)c(N(CCO)C(=O)C(O)CO)c1I
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 76.2 %

Procedure:
5-[N′-(2-Acetoxyethyl)-2,2-dimethyl-1,3-dioxolane-4-carboxamido]-3-acetoxymethyl-N-(2,3-diacetoxypropyl)-2,4,6-triiodobenzamide (47 mg, 0.049 mmol) was dissolved in methanol (0.5 ml) and an aqueous solution of sodium hydroxide (2M, 0.25 ml) was added slowly followed by water (2 ml). After stirring at room temperature for 20 minutes, the reaction mixture was neutralized with a strongly acidic Son exchange resin. The resin was filtered off, and the filtrate acidified to pH=1 using hydrochloric acid (5M). After stirring at room temperature for 3.5 hours the reaction mixture was evaporated to dryness and the solid residue was purified by preparative HPLC giving 28 mg (76%) of product.