Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:42]([CH3:43])=[CH:41][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]4[N:26]=[C:25]([CH3:27])[N:24]([C@H:28]5[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29]5)[C:23]=4[CH:40]=3)[S:18][C:14]=2[C:13]=1[C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]>Cl.CC(O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:42]([CH3:43])=[CH:41][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]4[N:26]=[C:25]([CH3:27])[N:24]([C@H:28]5[CH2:32][CH2:31][NH:30][CH2:29]5)[C:23]=4[CH:40]=3)[S:18][C:14]=2[C:13]=1[C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4nc(C)n([C@H]5CCN(C(=O)OC(C)(C)C)C5)c4c3)sc2c1-c1ccc(Cl)cc1
Agent: Cl
Solvent: CC(C)O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4nc(C)n([C@H]5CCNC5)c4c3)sc2c1-c1ccc(Cl)cc1

Procedure:
A solution of (S)-tert-butyl 3-(6-(6-((S)-1-tert-butoxy-2-ethoxy-2-oxoethyl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-2-yl)-2-methyl-1H-benzo[d]imidazol-1-yl)pyrrolidine-1-carboxylate (70 mg, 0.10 mmol) in 1.25 M HCl in i-PrOH (20 mL) was stirred at 35° C. for 4 hours. The solution was then concentrated in vacuo to provide the desired product. LCMS-ESI+: calc'd for C34H38ClN4O3S: 617.2 (M+H+); Found: 617.2 (M+H+).
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]([OH:11])=O)[N:5]=[N:4][N:3]=1.Cl.[CH3:13][O:14][NH2:15].C(N(CC)CC)C.Cl>CN(C)C=O>[CH3:13][O:14][NH:15][C:9](=[O:11])[CH2:8][CH2:7][N:6]1[C:2]([SH:1])=[N:3][N:4]=[N:5]1
Reactant: CON
Reactant: O=C(O)CCn1nnnc1S
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CONC(=O)CCn1nnnc1S
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98.9 %

Procedure:
To an ice cold and stirred solution of 5-mercapto-1H-tetrazole-1-propionic acid (1.04 g) in N,N-dimethylformamide (60 ml) is added N,N'-carbonyldiimidazole (1.16 g). After stirring for 15 minutes at 0° C., the mixture is mixed with a solution of methoxyamine hydrochloride (600 mg) and triethylamine (720 mg) in N,N-dimethylformamide (6 ml) and stirred for 1 hour at 0° C. The reaction mixture is poured into diluted hydrochloric acid and extracted with a mixture of ethyl acetate and methyl ethyl ketone (2:1). The solvent is evaporated from the extract to leave crystalline 5-mercapto-1H-tetrazole-1-propionohydroxamic acid methyl ester (1.2 g). mp. 170°-171° C. (decomp.).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[OH:14])([O-])=O.Cl[Sn]Cl>CCO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:6][C:5]=1[OH:14]
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)cc1O
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1ccc(C(F)(F)F)cc1O

Procedure:
2-Amino-5-trifluoromethylphenol was prepared by treating 2-nitro-5-trifluoromethylphenol (500 mg, 2.41 mmol) with a solution of SnCl2(3.5 g, mmol) in EtOH at 23° C. for 12 h. The mixture was concentrated to 50 mL and adjusted to pH 7 using saturated sodium bicarbonate. The reaction mixture was partitioned between H2O and EtOAc. The aqueous layer was separated and extracted with EtOAc. The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting colorless oil(370 mg, 87%) was used without further purification. 1H NMR (CDCl3): 7.6 (s, 1H), 7.39(d, 1H, J=8.5 Hz), 7.08(d, 1H, J=8.5 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:15][CH:16]=2)[N:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:10]=1[CH:29]=[O:30])=[O:8].[CH3:35][Mg+].[Br-]>COCCOC>[F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:15][CH:16]=2)[N:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:10]=1[CH:29]([OH:30])[CH3:35])=[O:8]
Reactant: CC(C)Oc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C=O)n(Cc3ccccn3)c2c1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: COCCOC
Product: CC(C)Oc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)O)n(Cc3ccccn3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-(3,4-difluorobenzyl)-2-formyl-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 105, 102 mg, 0.23 mmol) in 1,2-dimethoxy-ethane (15 ml) was added MeMgBr (1.4 M in toluene-THF, 0.5 ml, 0.70 mmol) at 0° C. The reaction was stirred at room temperature for 2 h and more MeMgBr (1.0 ml, 1.4 mmol) was added. The reaction was stirred at room temperature for another 2 h and was quenched with ice, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: C(Cl)CCl.[CH3:5][NH:6][CH2:7][C:8]1[NH:9][C:10]2[C:15]([C:16]=1[CH3:17])=[CH:14][CH:13]=[CH:12][CH:11]=2.Cl.[O:19]=[C:20]1[CH2:25][O:24][C:23]2[CH:26]=[C:27](/[CH:30]=[CH:31]/[C:32](O)=[O:33])[CH:28]=[N:29][C:22]=2[NH:21]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:5][N:6]([CH2:7][C:8]1[NH:9][C:10]2[C:15]([C:16]=1[CH3:17])=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:32](=[O:33])/[CH:31]=[CH:30]/[C:27]1[CH:28]=[N:29][C:22]2[NH:21][C:20](=[O:19])[CH2:25][O:24][C:23]=2[CH:26]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)OCC(=O)N2
Reactant: CNCc1[nH]c2ccccc2c1C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)OCC(=O)N3)[nH]c2ccccc12
Reaction time: 8 h
Yield: 3.2 %

Procedure:
EDC (149 mg, 1.3 mmol) was added to a solution of N-methyl(3-methyl-1H-indol-2-yl)methanamine (110 mg, 1.0 mmol), (E)-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)acrylic acid hydrochloride (220 mg, 1.1 mmol), HOBT.H2O (81 mg, 1.0 mmol) and DIPEA (0.43 mL, 3.0 mmol) in dry DMF (5 mL). After stirring overnight, water was added. The precipitate that formed was washed with ethyl acetate and dried to afford the title compound (12 mg, 4%). 1H NMR (300 MHz, DMSO-d6) δ 8.25 (s, 1H), 7.97 (s, 1H), 7.77 (d, J=7.1 Hz, 1H), 7.60 (s, 1H), 7.45 (d, J=7.4 Hz, 1H), 7.34 (m, 2H), 7.18 (s, 1H), 7.11 (m, 1H), 4.90-4.79 (rotamers, s, 2H), 4.72 (s, 2H), 4.60 (s, 3H), 2.31 (s, 3H); MS (EST): m/e 377.2 (C21H20N4O3+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])[N:4]=1.CN1C=CN=C1.[F:27][CH:28]([F:33])[S:29](Cl)(=[O:31])=[O:30].O>ClCCl>[F:27][CH:28]([F:33])[S:29]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([C:5]2[N:4]=[C:3]([O:2][CH3:1])[N:8]=[C:7]([O:9][CH3:10])[N:6]=2)[C:12]1=[O:20])(=[O:31])=[O:30]
Reactant: COc1nc(OC)nc(C2C(=O)Nc3ccccc32)n1
Reactant: O=S(=O)(Cl)C(F)F
Agent: Cn1ccnc1
Solvent: O
Solvent: ClCCl
Product: COc1nc(OC)nc(C2C(=O)N(S(=O)(=O)C(F)F)c3ccccc32)n1
Temperature: -5 °C

Procedure:
3-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-1,3-dihydro-2H-indol-2-one (10 g) and 1-methyl-1H-imidazole (5.4 g) are introduced as initial charge in 100 ml of dichloromethane and cooled to −5° C. under nitrogen. With stirring, difluoromethanesulfonyl chloride (7.03 g) is added dropwise at −5° C. to 0° C. over the course of 20 minutes, and the mixture is after-stirred at this temperature for 2.5 hours. The reaction mixture is admixed with 50 ml of water and mixed thoroughly. The organic solvent is largely distilled off in vacuo and the residue is filtered. The solid product is washed with water and acetonitrile and dried in a vacuum drying cabinet. This gives the title compound as a solid in an HPLC purity of 93% (12.5 g, 92% of theory). The UV absorption (maximum at 360 nm) verifies the N-sulfonylation of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:19])=[C:7]([C:13]3[O:17][N:16]=[C:15]([CH3:18])[CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([N:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=1.[OH-].[OH:30][CH2:31][CH2:32][N+:33]([CH3:36])([CH3:35])[CH3:34].O>CO>[OH:30][CH2:31][CH2:32][N+:33]([CH3:36])([CH3:35])[CH3:34].[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O-:19])=[C:7]([C:13]3[O:17][N:16]=[C:15]([CH3:18])[CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([N:26]([CH3:27])[CH3:28])=[CH:22][CH:21]=1
Reactant: Cc1cc(-c2c(O)c3cc(-c4ccc(N(C)C)cc4)c(Cl)cc3[nH]c2=O)on1
Agent: C[N+](C)(C)CCO
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(-c2c([O-])c3cc(-c4ccc(N(C)C)cc4)c(Cl)cc3[nH]c2=O)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
To a suspension of 7-chloro-6-(4-(dimethylamino)phenyl)-4-hydroxy-3-(3-methylisoxazol-5-yl) quinolin-2(1H)-one (Example 42) (1.5 g, 3.79 mmol) in methanol (8 mL) was added choline hydroxide 46% wt in water (1.997 g, 7.58 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered, washed with methanol and dried. The resulting solid was recrystallized with acetonitrile to give the title compound 7-chloro-6-(4-(dimethylamino)phenyl)-3-(3-methylisoxazol-5-yl)-2-oxo-1,2-dihydroquinolin-4-olate, N-2-hydroxyethyl-N,N-dimethylmethanaminium salt (1.2 g, 2.40 mmol, 63.5% yield) as off-white solid. LCMS: (M+H)+=396; Rt=2.39 min. HRMS: calculated for C21H19ClN3O3 (M+H)+: 396.1115. found: 396.1092.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:21]=[N:22][CH:23]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:6]([C:8](N(OC)C)=[O:9])[CH:7]=1.Cl[Mg][CH2:26][CH3:27]>O1CCCC1>[Cl:1][C:2]1[C:3]2[N:4]([CH:21]=[N:22][CH:23]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[C:6]([C:8](=[O:9])[CH2:26][CH3:27])[CH:7]=1
Reactant: CC[Mg]Cl
Reactant: CON(C)C(=O)c1cc(Cl)c2cncn2c1-c1cccc(F)c1
Solvent: C1CCOC1
Product: CCC(=O)c1cc(Cl)c2cncn2c1-c1cccc(F)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
To a solution of 8-chloro-5-(3-fluorophenyl)-N-methoxy-N-methylimidazo[1,5-a]pyridine-6-carboxamide (300 mg, 0.91 mmol) in tetrahydrofuran (3.0 mL) cooled at 0° C., a 2 M solution of chloro(ethyl)magnesium in tetrahydrofuran (1.6 mL, 3.2 mmol) was added slowly and the mixture was stirred for 3 hours at 0° C. The reaction was quenched with acetic acid (0.5 mL), poured into saturated sodium bicarbonate (25 mL) and extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. Purification on silica gel using ethyl acetate in hexanes (0-60%) gave the desired compound (130 mg, 49%). LCMS calculated for C16H13ClFN2O (M+H)+: m/z=303.1. found: 302.9.
Reaction SMILES: [C:1]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:2][CH2:3][C:4]1[CH:10]=[CH:9][C:7]([OH:8])=[CH:6][CH:5]=1.[CH2:15](Br)[CH:16]=[CH2:17].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O>[CH2:17]([O:8][C:7]1[CH:9]=[CH:10][C:4]([CH2:3][CH2:2][C:1]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:6]=1)[CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: CCOC(=O)CCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(CCC(=O)OCC)cc1

Procedure:
38.8 g (0.2 mol) of ethyl phloretate (prepared from commercial phloretic acid (e.g. Merck, D-64271 Darmstadt, DE) by esterification with ethanol) were dissolved in 20 ml of acetone, and 36.3 g (0.3 mol) of allyl bromide, 48.3 g (0.35 mol) of potassium carbonate and 0.05 g of sodium iodide were added. The mixture was heated at reflux for 7 h and cooled, and the excess of carbonate was filtered off. Concentration of the filtrate gave ethyl 3-(4-allyloxyphenyl)propionate, which was hydrolyzed in customary manner with methanolic potassium hydroxide to give the free acid. Customary reaction of the acid with thionyl chloride in toluene at 80° C. gave the 3-(4-allyloxyphenyl)propionyl chloride (b.p. 0.01 hPa: 106-108° C.) in 93% yield. 51.2 g (0.22 mol) of this acid chloride and 39.2 g (0.22 mol) of hydroquinone monomethacrylate were dissolved in 300 ml of toluene at 65° C. 24.0 g (0.24 mol) of triethylamine were added dropwise with stirring, and the mixture was subsequently stirred for 3 h. After cooling, the amine hydrochloride was filtered off and the filtrate was worked up in a customary manner. Concentration of the organic residue and recrystallization of the solid residue from toluene/benzine (b.p. 100-140) gave 4-methacryloyloxyphenyl) 3-(4-allyloxyphenyl)propionate in 80% yield. The ester melts at 67° C.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[N:14]1[CH:18]=[C:17]([CH3:19])[CH:16]=[N:15]1.[OH-].[Li+]>C1COCC1.O>[CH3:13][S:10]([C:8]1[CH:7]=[CH:6][C:5]([N:14]2[CH:18]=[C:17]([CH3:19])[CH:16]=[N:15]2)=[C:4]([CH:9]=1)[C:3]([OH:20])=[O:2])(=[O:11])=[O:12]
Reactant: COC(=O)c1cc(S(C)(=O)=O)ccc1-n1cc(C)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnn(-c2ccc(S(C)(=O)=O)cc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2.08 mmol 5-Methanesulfonyl-2-(4-methyl-pyrazol-1-yl)-benzoic acid methyl ester in 2.2 ml THF and 2.2 ml water was added 3.12 mmol lithium hydroxide and the reaction mixture was stirred at RT for 2 hours. After such time the solvent was removed in vacuo, the residue was taken in water and acidified by addition of 3N HCl to yield after filtration the title compound as a white solid (88%). MS (m/e): 279.1 ([M−H], 100%).
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[OH:15])=[O:7])=[C:4]([O:19][CH3:20])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].[Br-].[CH3:30][CH:31]1[O:35][C:34](=[N+:36]([CH3:38])[CH3:37])[C:33]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:32]1>O.CC(C)CC(=O)C>[NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][N:12]([CH:31]([CH3:30])[CH2:32][C:33]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:34]([N:36]([CH3:37])[CH3:38])=[O:35])[CH2:11][C@H:10]2[OH:15])=[O:7])=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@@H]1CCNC[C@H]1O
Reactant: CC1CC(c2ccccc2)(c2ccccc2)C(=[N+](C)C)O1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [I-]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@@H]1CCN(C(C)CC(C(=O)N(C)C)(c2ccccc2)c2ccccc2)C[C@H]1O
Reaction time: 1 h
Yield: 30.6 %

Procedure:
A mixture of 4.5 parts of trans-4-amino-5-chloro-N-(3-hydroxy-4-piperidinyl)-2-methoxybenzamide, 4 parts of sodium carbonate, 0.1 parts of potassium iodide and 120 parts of 4-methyl-2-pentanone was stirred for 1 hour at reflux using a water separator. 5.95 Parts of N-(dihydro-5-methyl-3,3-diphenyl-2(3H)-furanylidene)-N-methylmethanaminium bromide were added and stirring was continued for 1 hour at reflux. The organic layer was washed successively with water, a sodium carbonate solution in water and water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was dried in vacuo at 80° C., yielding 2.66 parts (30.6%) of trans-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-hydroxy-N,N,γ-trimethyl-α,α-diphenyl-1-piperidinebutanamide; mp. 131.9° C. (compound 50).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[ClH:21].[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(Sc2ccccc2Cl)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1ccccc1SC1CCNCC1
Yield: 232.7 %

Procedure:
To a stirred solution of 2-chlorobenzenethiol (2.5 g, 0.017 mole) in DMF (20 mL) was added cesium carbonate (6.77 g, 0.0208 mole), followed by 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (4.8 g, 0.0173 mole). The reaction mixture was heated at 80° C. overnight. The mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 4.64 g (82%) of 4-(2-chloro-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester. LCMS: 328.11 (M+1)+, 95.12%. A solution of 4-(2-chloro-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester (4 g, 0.0122 mole) in dioxane.HCl (7 mL) was stirred at ambient temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure and the resulting residue was washed with hexane twice to afford 3.75 g (99%) of 4-(2-chloro-phenylsulfanyl)-piperidine hydrochloride. LCMS: 228.05 (M+1)+, 92.02%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25](Cl)=[O:26])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].ClC1C=C([C@@H](CC2CCCC2)[C:49]([NH:51]C2C=CN(CC3C=C(C=CC=3)C(N)=O)N=2)=O)C=CC=1S(C)(=O)=O.CN.O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([NH:51][CH3:49])=[O:26])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3cccc(C(N)=O)c3)n2)cc1Cl
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3cccc(C(=O)Cl)c3)n2)cc1Cl
Agent: CN
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
To a 0.166 M solution of crude 3-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoyl chloride in methylene chloride (prepared in Example 63, 1.71 mL, 0.28 mmol) was added a 40% solution of methylamine in water (250 μL, 0.32 mmol) and the reaction stirred at 25° C. for 30 min. The solution was diluted with methylene chloride (40 mL), washed with water (2×20 mL), saturated aqueous brine solution (2×20 mL), dried over magnesium sulfate and concentrated in vacuo to an off white foam. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 0% ethyl acetate/methylene chloride to 100% ethyl acetate/methylene chloride) afforded 3-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-N-methyl-benzamide (61 mg, 39%) as a white powder: ESI-LRMS m/e calcd for C27H31ClN4O4S [M+] 542.18, found 543.16 [M+H+]; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04-1.15 (m, 2H, CH2), 1.34-1.79 (m, 8H, 4×CH2), 2.00-2.17 (m, 1H, CH), 2.75 (d, J, 4.5 Hz, 3H, NCH3), 3.32 (s, 3H, SO2CH3), 3.82-3.90 (m, 1H, CH), 5.21 (s, 2H, NCH2), 6.45 (d, J=2.3 Hz, 1H, Ar), 7.28-7.34 (m, 1H, Ar), 7.38 (t, J=7.8 Hz, 1H, Ar), 7.55 (dd, Jo=8.3, Jm=1.6 Hz, 1H, Ar), 7.65 (d, Jm=1.6 Hz, 1H, Ar), 7.67-7.71 (m, 2H, Ar), 7.72 (d, J=2.3 Hz, 1H, Ar), 7.97 (d, Jo=8.3 Hz, 1H, Ar), 8.33-8.45 (brm, 1H, NH), 10.76 (s, 1H, NH).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30]O>>[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:21])([CH3:22])[C:6]=2[CH:23]=1
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: COCCOCCO
Product: COCCOCCOc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O

Procedure:
Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and 2-(2-methoxyethoxyl)ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][NH2:14])[CH2:8][CH2:7]1.[NH2:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](O)=[O:24]>>[NH2:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH:14][CH2:13][CH2:12][N:9]1[CH2:8][CH2:7][CH:6]([O:5][C:4]2[CH:15]=[CH:16][C:17]([Cl:18])=[C:2]([Cl:1])[CH:3]=2)[CH2:11][CH2:10]1)=[O:24]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: NCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Product: Nc1cccc(C(=O)NCCN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)c1

Procedure:
Prepared in a similar manner to the method of Example 14, Step b using the product from Example 3, Step b and 3-aminobenzoic acid to give the sub-title product (0.183 g).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[C:10]([NH2:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][N:6]=1.[F:18][CH:19]([F:36])[C:20]1[N:28]=[CH:27][C:26]([CH2:29][NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])=[CH:25][C:21]=1[C:22](O)=[O:23].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[F:36][CH:19]([F:18])[C:20]1[N:28]=[CH:27][C:26]([CH2:29][NH:30][C:31](=[O:35])[CH:32]([CH3:33])[CH3:34])=[CH:25][C:21]=1[C:22]([NH:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[CH:7][N:6]=[C:5]2[NH:4][CH2:3][C:2]([F:1])([F:16])[F:17])=[O:23]
Reactant: Nc1cccc2c(NCC(F)(F)F)ncnc12
Reactant: CC(C)C(=O)NCc1cnc(C(F)F)c(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C(=O)NCc1cnc(C(F)F)c(C(=O)Nc2cccc3c(NCC(F)(F)F)ncnc23)c1
Yield: 5 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(2,2,2-trifluoroethyl)quinazoline-4,8-diamine (Intermediate-65, 48 mg, 0.20 mmol), 2-(difluoromethyl)-5-(isobutyramidomethyl)nicotinic acid (Intermediate-66, 107 mg, 0.40 mmol), oxalyl chloride (50 mg, 0.40 mmol), DMF (1 drop) and DIPEA (127 mg, 0.99 mmol) in CH2Cl2 (2 mL) to afford 5 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.40 (s, 1H), 8.95 (t, 1H), 8.71 (d, 1H), 8.61 (s, 1H), 8.48 (t, 1H), 8.07 (m, 2H), 7.65 (t, 1H), 7.41-7.05 (t, J=54.0 Hz, 1H), 4.42 (m, 4H), 2.50 (m, 1H), 1.05 (d, J=7.2 Hz, 6H); MS [M+H]+: 497.52.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][CH:9]([C:25]1[N:26]=[CH:27][N:28]([C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29]=1[CH3:30])[CH:10]1[C:23](=[O:24])[N:14]2[C:15]3[C:20]([C:21]([CH3:22])=[C:13]2[CH2:12][CH2:11]1)=[CH:19][CH:18]=[CH:17][CH:16]=3>N1C=CC=CC=1>[C:1]([O:8][CH:9]([C:25]1[N:26]=[CH:27][N:28]([C:31]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:29]=1[CH3:30])[CH:10]1[C:23](=[O:24])[N:14]2[C:15]3[C:20]([C:21]([CH3:22])=[C:13]2[CH2:12][CH2:11]1)=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:3])[CH3:2]
Reactant: Cc1c2n(c3ccccc13)C(=O)C(C(O)c1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C)C1CCc2c(C)c3ccccc3n2C1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Acetic anhydride (5 ml) was added to a solution of 8,9-dihydro-7-[(hydroxy) (5-methyl-1-trityl-1H-imidazol-4-yl)methyl]-10-methylpyrido[1,2-a]indol-6(7H)-one (4 g, a mixture of the isomers A and B) in pyridine (50 ml). After being stirred at room temperature for 20 hours, the solution was evaporated in vacuo. Silica gel column chromatography (1% methanol-methylene chloride) of the oil obtained gave 7-[(acetoxy) (5-methyl-1-trityl-1H-imidazol-4-yl)methyl]-8,9-dihydro-10-methylpyrido[1,2-a]indol-6(7H)-one (4.30 g) as an amorphous powder.