Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:9]=[C:10]1[NH:16][C:15]2[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:14]=2[NH:13][CH2:12][CH:11]1[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].O=C1NC2C=CC=CC=2NCC1NC(OC(C)(C)C)=O>>[O:9]=[C:10]1[NH:16][C:15]2[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:14]=2[N:13]([C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:7])[CH2:12][CH:11]1[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2
Reactant: O=C(Cl)C1CCCC1
Agent: CC(C)(C)OC(=O)NC1CNc2ccccc2NC1=O
Product: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)C1CCCC1

Procedure:
Step 1 of Example 1 was repeated except that cyclopentylcarbonyl chloride was used instead of pivaloyl chloride, and that 2-oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine obtained from Referential Example 4 was used instead of 2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine, to thereby obtain the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:49])[CH2:14][C@@:15]1([C:33]([NH:35][CH:36]2[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]2)=[O:34])[C@H:19]([CH3:20])[CH2:18][N:17]([CH2:21][C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:32])[CH2:16]1)(C)(C)C>ClCCl>[Cl:32][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([C:28]([F:29])([F:31])[F:30])[C:22]=1[CH2:21][N:17]1[CH2:18][C@@H:19]([CH3:20])[C@@:15]([CH2:14][C:13]([OH:49])=[O:12])([C:33](=[O:34])[NH:35][CH:36]2[CH2:37][CH2:38][NH:39][CH2:40][CH2:41]2)[CH2:16]1
Reactant: C[C@@H]1CN(Cc2c(Cl)cccc2C(F)(F)F)C[C@]1(CC(=O)OC(C)(C)C)C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2c(Cl)cccc2C(F)(F)F)C[C@]1(CC(=O)O)C(=O)NC1CCNCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 117.2 %

Procedure:
Trifluoroacetic acid (3 mL) was added to a solution of tert-butyl 4-[(3R*,4S*)-3-[2-(tert-butoxy)-2-oxoethyl]-1-{[2-chloro-6-(trifluoromethyl)phenyl]methyl}-4-methylpyrrolidin-3-amido]piperidine-1-carboxylate obtained in Example 5c (82 mg, 0.133 mmol) in dichloromethane (dehydrated) (3 mL) under ice-cooling, followed by stirring at room temperature for 2.5 hours. The reaction liquid was concentrated under reduced pressure, and the residue was purified by ODS column chromatography (elution solvent: water/methanol) to give the title compound (72 mg, yield: quant.).
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][C:13]([NH:15][C:16]([CH3:18])=[O:17])=[O:14].CC(C)=O>ClCCl>[NH2:9][C:10]([NH2:15])=[S:11].[CH3:12][C:13]([N:15]([C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:16]([CH3:18])=[O:17])=[O:14]
Reactant: CC(=O)NC(C)=O
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(=O)N(C(C)=O)C(=O)c1ccccc1
Product: NC(N)=S

Procedure:
To a 250 mL 3-neck RBF equipped with a condenser, magnetic stirrer, thermo-probe, nitrogen purge and pressure-equilibrated addition funnel was added benzoyl isothiocyanate (25.0 g, 0.150 mol) followed by dichloromethane (100 mL). The mixture was cooled in an ice-water bath at a temperature below 5° C., at which point diacetamide (15.3 g, 0.150 mol) and acetone as the solvent and dichloromethane (100 mL) were added slowly over a period of time of about 30 minutes. The ice-water bath was removed and the reaction mixture was stirred under a nitrogen purge overnight. The reaction mixture was then concentrated in vacuo at a temperature of 40° C. and then dried to constant weight in vacuo at a temperature of 50° C. and a pressure of <1 mTorr.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH2:15])([CH3:4])([CH3:3])[CH3:2].C([O:21][C:22](=O)[CH2:23][C:24](=[O:37])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH:26]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH:15][C:22](=[O:21])[CH2:23][C:24](=[O:37])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH:26]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1

Procedure:
The title compound was prepared from (2-amino-4-chloro-phenyl)-carbamic acid tert-butyl ester (Example J4) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) according to the general procedure M. Obtained as a light brown solid (227 mg).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH:28]1([CH2:32][C:33](O)=[O:34])[CH2:31][CH2:30][CH2:29]1>>[CH:28]1([CH2:32][C:33]([NH:27][C@H:24]2[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]3[CH2:17][CH2:18][N:13]([C:9]4[N:10]=[CH:11][CH:12]=[C:7]5[CH2:6][CH2:5][O:4][C:8]=45)[CH2:14][CH2:15]3)[CH2:22][CH2:23]2)=[O:34])[CH2:31][CH2:30][CH2:29]1
Reactant: O=C(O)CC1CCC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(CC1CCC1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (50 mg, 73%), MS (ISP) m/z=427.3 [(M+H)+], mp 147.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (70.4 mg, 0.16 mmol) 2-cyclobutyl-acetic acid.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[C:8]([CH3:13])=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1.N1C2C(=CC=CC=2)C=C1.C(O)(C(F)(F)F)=O>CN1C(=O)CCC1.O>[F:29][C:19]([F:18])([F:28])[C:20]1[N:21]=[CH:22][C:23]([CH2:26][CH2:27][N:6]2[C:7]3[C:8]([CH3:13])=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)=[CH:24][CH:25]=1
Reactant: Cc1cccc2c3c([nH]c12)CCN(C)C3
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Agent: [K+]
Agent: [OH-]
Agent: c1ccc2[nH]ccc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cccc2c3c(n(CCc4ccc(C(F)(F)F)nc4)c12)CCN(C)C3
Reaction time: 0.17 h

Procedure:
To a solution of 2,3,4,5-tetrahydro-2,6-dimethyl-1H-pyrido[4,3-b]indole (200 mg, 1.0 mmol) in NMP (2.5 ml), powdered KOH (561 mg, 10 mmol) was added and stirred for 10 min at 25 deg C. After which 2-(trifluoromethyl)-5-vinylpyridine (346 mg, 2.0 mmol) was added slowly to the above solution and stirred for 16 h at 25 deg C. After completion of the reaction (monitored by LCMS), water (5 mL) was added to the crude, and extracted with the ethyl acetate. The organic layer was dried and concentrated. The resulting crude was purified by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL) to obtain 40 mg (8.2%) of 5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2,6-dimethyl-1H-pyrido[4; 3-b]indole as TFA salt.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]([S:14]([N:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.Cl[C:21]1[CH:30]=[N:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH3:18][N:17]([CH3:19])[S:14]([N:4]1[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=[C:3]1[CH2:2][NH:1][C:21]1[CH:30]=[N:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1)(=[O:15])=[O:16]
Reactant: Clc1cnc2ccccc2n1
Reactant: CN(C)S(=O)(=O)n1cc(-c2ccccc2)nc1CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cc(-c2ccccc2)nc1CNc1cnc2ccccc2n1
Temperature: 180 °C

Procedure:
2-(Aminomethyl)-N,N-dimethyl-4-phenyl-1H-imidazole-1-sulfonamide (0.56 mmol), 2-chloroquinoxaline (138 mg, 0.84 mmol), and Hunig's base (195 μL, 1.12 mmol) were dissolved in anhydrous THF (4.5 mL) in a microwave vial. The vial was heated in the microwave (180° C., 40 min), then poured into saturated aqueous K2CO3 solution (50 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3×30 mL). The combined organic phases were washed with saturated aqueous NaCl (1×50 mL), dried (Na2SO4), filtered and concentrated to give N,N-dimethyl-4-phenyl-2-((quinoxalin-2-ylamino)methyl)-1H-imidazole-1-sulfonamide.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:21][C:22](=[O:52])[N:23]([CH2:36][C:37]2[CH:51]=[CH:50][C:40]([C:41]([NH:43][CH2:44][C@@H:45]([OH:49])[C:46]([OH:48])=[O:47])=[O:42])=[CH:39][CH:38]=2)C2C=CC(C3CCCCC3)=CC=2)[CH:13]=[CH:14][C:15]=1[O:16][C:17]([F:20])([F:19])[F:18])(C(C)(C)C)(C)C.[F-].[Cs+].[C:55](#N)[CH3:56].O>>[CH:10]1([C:56]2[CH:55]=[CH:39][C:38]([CH:36]([NH:23][C:22]([NH:21][C:12]3[CH:13]=[CH:14][C:15]([O:16][C:17]([F:20])([F:19])[F:18])=[C:10]([CH2:9][OH:8])[CH:11]=3)=[O:52])[C:37]3[CH:51]=[CH:50][C:40]([C:41]([NH:43][CH2:44][C@@H:45]([OH:49])[C:46]([OH:48])=[O:47])=[O:42])=[CH:39][CH:38]=3)=[CH:37][CH:36]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(NC(=O)N(Cc2ccc(C(=O)NC[C@@H](O)C(=O)O)cc2)c2ccc(C3CCCCC3)cc2)ccc1OC(F)(F)F
Reactant: CC#N
Agent: [Cs+]
Agent: [F-]
Solvent: O
Product: O=C(Nc1ccc(OC(F)(F)F)c(CO)c1)NC(c1ccc(C(=O)NC[C@@H](O)C(=O)O)cc1)c1ccc(C2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
(R)-3-{4-[3-[3-(tert-Butyldimethylsilanyloxymethyl)-4-trifluoromethoxyphenyl]-1-(4-cyclohexyl-phenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid (17 mg, 0.023 mmol) was dissolved in acetonitrile:water (9:1) (2 mL) and caesium fluoride (35 mg, 0.35 mmol) added. The reaction mixture was stirred at 80° C. for 6 hours and additional amounts of caesium fluoride (35 mg) added. The mixture was stirred at 60° C. overnight, concentrated in vacuo and diluted with ethyl acetate (10 mL) and water (5 mL). The organic phase was washed with water (3×5 mL) and dried with magnesium sulphate and concentrated in vacua. The residue was purified by preparative HPLC affording the title compound.
Reaction SMILES: [F:1][C:2]1[C:15]([F:16])=[C:14](F)[C:13]([F:18])=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH3:19][N:20]([CH2:22][CH:23]1[O:28][CH2:27][CH2:26][NH:25][CH2:24]1)[CH3:21].C(=O)([O-])O.[Na+]>C(#N)C>[CH3:19][N:20]([CH2:22][CH:23]1[CH2:24][N:25]([C:14]2[C:13]([F:18])=[CH:12][C:3]([C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])=[C:2]([F:1])[C:15]=2[F:16])[CH2:26][CH2:27][O:28]1)[CH3:21]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(F)c1F
Reactant: CN(C)CC1CNCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)CC(=O)c1cc(F)c(N2CCOC(CN(C)C)C2)c(F)c1F
Yield: 77 %

Procedure:
A suspension of 26.4 g of ethyl 2,3,4,5-tetrafluorobenzoylacetate, 18.7 g of 2-(dimethylaminomethyl)morpholine and 8.4 g sodium hydrogencarbonate in 130 ml of acetonitrile is refluxed for 7 hours. The reaction mixture is concentrated under reduced pressure, to the obtained residue is added 100 ml of chloroform and the solution is washed with water. After drying over anhydrous magnesium sulfate, the chloroform is distilled off under reduced pressure and the residue is purified by chromatography on silica gel to give 29.9 g of ethyl 4-[2-(dimethylaminomethyl)morpholino]-2,3,5-trifluorobenzoylacetate in 77% yield as an oily substance.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:34][C:35](Br)(Br)[F:36].C([Zn]CC)C>C1COCC1>[Br:34][C:35]([F:36])=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: FC(Br)(Br)Br
Agent: CC[Zn]CC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=C(F)Br)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 44 %

Procedure:
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (500 mg, 2.52 mmol), triphenylphosphine (808 mg, 3.02 mmol) and tribromofluoromethane (818 mg, 3.02 mmol) in 50 mL of anhydrous THF was added dropwise a solution of diethylzinc (1 M in hexane, 3.02 mL, 3.02 mmol) stirring at r.t. After 2.5 h, the reaction mixture was quenched with MeOH (10 mL), stirred for 30 min., evaporated to dryness in vacuo. Purification was carried out by automated flash liquid chromatography (Horizon™-Biotage) eluting with Petroleum Ether-EtOAc gradient from 95:5:0 to 90:10 to afford the title compound (326 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[CH:3]=1.C([Li])CCC.[CH3:16][N:17]([CH:19]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=1)[CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C:21]1=[O:26])[CH3:18].[Cl-:35].[NH4+]>O1CCCC1>[ClH:35].[O:8]1[C:5]2[CH:6]=[CH:7][C:2]([C:21]3([OH:26])[CH2:22][CH2:23][CH2:24][CH2:25][CH:20]3[CH:19]([N:17]([CH3:18])[CH3:16])[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=3)=[CH:3][C:4]=2[O:10][CH2:9]1
Reactant: COc1cccc(C(C2CCCCC2=O)N(C)C)c1
Reactant: Brc1ccc2c(c1)OCO2
Reactant: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cccc(C(C2CCCCC2(O)c2ccc3c(c2)OCO3)N(C)C)c1
Product: Cl
Temperature: -70 °C
Yield: 43.2 %

Procedure:
2.61 g (13.0 mmole) of 4-bromo-1,2-methylenedioxybenzene were dissolved in 10 ml of tetrahydrofuran and cooled to −70° C. under nitrogen in a dry ice/isopropanol bath. 7.9 ml (13.0 mmole) of n-butyllithium (1.6 M in hexane) were added dropwise while stirring so that the temperature did not rise above −60° C. The reaction mixture was stirred for a further 30 minutes and then 3.0 g (10.8 mmole) of the 2-[dimethylamino-(3-methoxyphenyl)methyl]cyclohexanone prepared according to Example 9 and dissolved in 10 ml of tetrahydrofuran were added dropwise while cooling in an ice bath, and the whole was heated to RT within two hours. The reaction mixture was worked up by adding 20 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT, each time with 20 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 4.10 g of crude base (98.8% of theory) were obtained, from which 1.96 g of 1-benzo[1,3]dioxol-5-yl-2-[dimethylamino-(3-methoxyphenyl)methyl]cyclohexanol, hydrochloride (43.2% of theory) were obtained according to the procedure described in Example 1 (3rd stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 109° C.
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:9]([Cl:10])=[C:8]([Cl:11])[S:7][C:6]=1[CH2:12][C:13](O)=[O:14])(O)=[O:2].B.C1COCC1>C1COCC1>[Cl:10][C:9]1[C:5]([CH2:4][CH2:1][OH:2])=[C:6]([CH2:12][CH2:13][OH:14])[S:7][C:8]=1[Cl:11]
Reactant: O=C(O)Cc1sc(Cl)c(Cl)c1CC(=O)O
Agent: B
Solvent: C1CCOC1
Product: OCCc1sc(Cl)c(Cl)c1CCO
Temperature: 22 °C
Reaction time: 0.33 h
Yield: 88 %

Procedure:
A solution of the product from step d) (2.5 g, 9.33 mmol) in THF (85 ml) was cooled to 0° C. and a 1M solution of BH3-THF (46.6 ml, 46.6 mmol) was added dropwise over 10 minutes. and stirred for an additional 20 minutes after the addition was complete. The reaction was warmed to 22° C. and stirred for 2 hours. The reaction was poured into ice cold sat. NaHCO3 (150 ml) and extracted with EtOAc. The crude was passed through a plug of silica gel washing with EtOAc. Concentration of the eluent provided 1.99 g (88%) of the subtitle compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].[Li]N([Si](C)(C)C)[Si](C)(C)C.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]2[N:35]=[C:34]3[C:36]4[N:43]([CH3:44])[N:42]=[C:41]([C:45](OCC)=[O:46])[C:37]=4[CH2:38][CH2:39][CH2:40][C:33]3=[CH:32][N:31]=2)=[C:25]([O:50][CH3:51])[CH:24]=1>C1COCC1>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]2[N:35]=[C:34]3[C:36]4[N:43]([CH3:44])[N:42]=[C:41]([C:45]([NH:5][C:4]5[C:6]([CH2:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:3]=5[CH2:1][CH3:2])=[O:46])[C:37]=4[CH2:38][CH2:39][CH2:40][C:33]3=[CH:32][N:31]=2)=[C:25]([O:50][CH3:51])[CH:24]=1
Reactant: CCOC(=O)c1nn(C)c2c1CCCc1cnc(Nc3ccc(Br)cc3OC)nc1-2
Reactant: CCc1cccc(CC)c1N
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCCc1cnc(Nc3ccc(Br)cc3OC)nc1-2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 90.8 %

Procedure:
To a solution of 2,6-diethylaniline (0.300 g, 2.01 mmol) in 10 mL of anhydrous THF under argon, 1M in THF solution of LiN(TMS)2 (4.02 mL, 4.02 mmol) at 0° C. were added dropwise. The mixture was stirred at 0° C. for 10 minutes then ethyl 9-[(4-bromo-2-methoxyphenyl)amino]-1-methyl-1,4,5,6-tetrahydropyrazolo[4′,3′:6,7]cyclohepta[1,2-d]pyrimidine-3-carboxylate (0.300 g, 0.67 mmol) in 10 mL of anhydrous THF at 0° C. were added dropwise. Ice bath was removed and the mixture was stirred at room temperature for 1 hour. Water (20 mL) was added and the mixture was extracted with AcOEt (2×30 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent evaporated to dryness. The crude solid was purified by flash chromatography on silica gel (eluant: AcOEt/cyclohexane 1/1) to afford 0.350 g (95% yield) of the title compound as a white solid.
Reaction SMILES: [C:1]1(=[O:12])[O:7][C:5](=O)[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)(=O)C>[C:14]1([N:13]2[C:5](=[O:7])[C:4]3=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]3[CH2:2][C:1]2=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1Cc2ccccc2C(=O)O1
Reactant: Nc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1Cc2ccccc2C(=O)N1c1ccccc1
Reaction time: 1 h
Yield: 68 %

Procedure:
0.871 g (5.37 mmol) of homophthalic anhydride and 0.4 g (4.30 mmol) of aniline were mixed, and melted at a temperature of 200° C. for 1 hour. The reactant was dissolved in ethyl acetate, washed with aqueous NaHCO3 solution, with water and then with saturated aqueous sodium chloride, dried over anhydrous MgSO4, and subjected to filtration with a folded filter paper. The filtrate was concentrated and evaporated to dryness. The residue was recrystallized by using a mixture of CH2Cl2 and hexane, to obtain 0.565 g (yield 68%) of the specified substance as light yellow granulated crystals.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[CH2:4][NH:5][CH3:6].C1C=CC=CC=1.[Cl:15][C:16]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:17]=1[O:18][CH:19]([C:21]1[S:25][C:24]([N:26]=[C:27]=[O:28])=[N:23][N:22]=1)[CH3:20]>CCCCCC.C(OCC)C>[Cl:15][C:16]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:17]=1[O:18][CH:19]([C:21]1[S:25][C:24]([NH:26][C:27](=[O:28])[N:5]([CH3:6])[CH2:4][CH:3]([O:7][CH3:8])[O:2][CH3:1])=[N:23][N:22]=1)[CH3:20]
Reactant: CC(Oc1ccc(Cl)cc1Cl)c1nnc(N=C=O)s1
Reactant: CNCC(OC)OC
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: CCCCCC
Product: COC(CN(C)C(=O)Nc1nnc(C(C)Oc2ccc(Cl)cc2Cl)s1)OC
Yield: 81.7 %

Procedure:
A 200 milliliter flask was charged with 2.1 grams (0.018 mole) of methylaminoacetaldehyde dimethylacetal, 50 milliliters of benzene and 5.8 grams (0.018 mole) of the 5-[1-(2,4-dichlorophenoxy)ethyl]-1,3,4-thiadiazol-2-yl isocyanate dimer (prepared above). The resulting slurry was refluxed for 15 minutes to form a yellow solution and cooled with formation of a few crystals. A minimum amount of hexane-diethylether was added, and crystallization occurred. The crystals were filtered off, and dried in a vacuum oven at 80°0 C. to give 6.4 grams of white crystals of 3-[5-[1-(2,4-dichlorophenoxy)-ethyl]-1,3,4-thiadiazol-2-yl]-1-methyl-1-(2,2-dimethoxyethyl)urea. (Melting point 125°-127° C.).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17]1[NH:18][CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]4[N:35]=[C:36]([C@@H:39]5[CH2:43][C:42]6([O:48][CH2:47][CH2:46][CH2:45][O:44]6)[CH2:41][N:40]5C(OCC5C=CC=CC=5)=O)[NH:37][CH:38]=4)=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)[N:21]=1)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4]>C(O)C.[Pd]>[CH2:41]1[C:42]2([O:48][CH2:47][CH2:46][CH2:45][O:44]2)[CH2:43][C@@H:39]([C:36]2[NH:37][CH:38]=[C:34]([C:31]3[CH:30]=[CH:29][C:28]([C:25]4[CH:26]=[CH:27][C:22]([C:20]5[N:21]=[C:17]([C@@H:13]6[CH2:14][CH2:15][CH2:16][N:12]6[C:10]([C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:7]([CH3:9])[CH3:8])=[O:11])[NH:18][CH:19]=5)=[CH:23][CH:24]=4)=[CH:33][CH:32]=3)[N:35]=2)[NH:40]1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CC6(CN5C(=O)OCc5ccccc5)OCCCO6)n4)cc3)cc2)c[nH]1)C(C)C
Agent: [Pd]
Solvent: CCO
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CC6(CN5)OCCCO6)n4)cc3)cc2)c[nH]1)C(C)C

Procedure:
Phenylmethyl (3S)-3-(4-{4′-[2-((2S)-1-{N-[(methyloxy)carbonyl]-L-valyl}-2-pyrrolidinyl)-1H-imidazol-4-yl]-4-biphenylyl}-1H-imidazol-2-yl)-6,10-dioxa-2-azaspiro[4.5]decane-2-carboxylate (Intermediate 22) (1.44 g, 1.83 mmol) was hydrogenated in ethanol (100 mL) with balloon under the catalysis of Pd/C for 20 hrs to give methyl [(1S)-1-({(2S)-2-[4-(4′-{2-[(3S)-6,10-dioxa-2-azaspiro[4.5]dec-3-yl]-1H-imidazol-4-yl]-4-biphenylyl)-1H-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)-2-methylpropyl]carbamate (Intermediate 19). ES LC-MS m/z=654.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:35])=[C:5]([C:31]([O:33][CH3:34])=[O:32])[CH:6]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:7]=1[C:8]1[O:12][N:11]=[C:10]([CH2:13][S:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:9]=1.ClC1C=C(C=CC=1)C(OO)=[O:41].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[NH:3][C:4]([CH3:35])=[C:5]([C:31]([O:33][CH3:34])=[O:32])[CH:6]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:7]=1[C:8]1[O:12][N:11]=[C:10]([CH2:13][S:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:41])[N:9]=1
Reactant: COC(=O)C1=C(C)NC(C)=C(c2nc(CSCc3ccccc3)no2)C1c1cccc([N+](=O)[O-])c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)C1=C(C)NC(C)=C(c2nc(CS(=O)Cc3ccccc3)no2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
To a solution of 1.00 g of methyl 1,4-dihydro-2,6-dimethyl-3-(3-benzylthiomethyl-1,2,4-oxadiazol-5-yl)-4-(3-nitrophenyl)pyridine-5-carboxylate in 50 ml of chloroform was added 0.47 g of m-chloroperoxybenzoic acid. After the mixture was stirred at room temperature for 3 hours, the aqueous sodium bicarbonate was added and the stirring was continued for a while. The chloroform layer was separated, washed, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel using chloroform-methanol (30:1) as eluent to give 980 mg of methyl 1,4-dihydro-2,6-dimethyl-3-(3-benzylsulfinylmethyl-1,2,4-oxadiazol-5-yl)-4-(3-nitrophenyl)pyridine-5-carboxylate, IR νmaxneat cm-1 : 3290, 3210, 1680, 1645, 1520, 1490, 1230.
Reaction SMILES: [CH2:1]([S:8](C1(C2C3C(=NC=CC=3)NC=2)C2C(=CC=CC=2)C(Br)=CN1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][N:38]=2)[CH:33]=[CH:32]1.[Br:40][C:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[N:43][CH:42]=1>>[CH2:1]([S:8]([N:43]1[CH:42]=[C:41]([Br:40])[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]1[C:33]1[C:34]2[C:39](=[N:38][CH:37]=[CH:36][CH:35]=2)[NH:31][CH:32]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cc1ccccc1)C1(c2c[nH]c3ncccc23)NC=C(Br)c2ccccc21
Reactant: c1cnc2[nH]ccc2c1
Reactant: Brc1cncc2ccccc12
Product: O=S(=O)(Cc1ccccc1)N1C=C(Br)c2ccccc2C1c1c[nH]c2ncccc12
Yield: 61 %

Procedure:
2(benzylsulfonyl-1-(7-aza-1H-indol-3-yl)-4-bromo-1,2-dihydroisoquinoline: Following the procedure of Example 1, 29.54 mg (0.25 mmol) of 7-azaindole was treated with 104.03 mg (0.5 mmole) of 4-bromoisoquinoline and 47.67 mg (0.25 mmol) of α-phenylmethylsulphonyl chloride to yield 71.98 mg (61% Yield) of 2(benzylsulfonyl)-1-(7-aza-1H-indol-3-yl)-4-bromo-1,2-dihydroisoquinoline.