Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:31])[CH2:7][CH:6]2[CH:8]([CH3:30])[C:9]([S:14]([NH:17][C:18](=[NH:29])[NH:19][CH2:20][CH2:21][CH2:22][C@@H:23]([C:25]([O:27][CH3:28])=[O:26])[NH2:24])(=[O:16])=[O:15])=[C:10]([CH3:13])[C:11]([CH3:12])=[C:5]2[O:4]1.C(N(CC)CC)C.[F:39][C:40]1[CH:50]=[CH:49][CH:48]=[CH:47][C:41]=1[CH:42]=[CH:43][C:44](O)=[O:45].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:39][C:40]1[CH:50]=[CH:49][CH:48]=[CH:47][C:41]=1[CH:42]=[CH:43][C:44]([NH:24][C@H:23]([C:25]([O:27][CH3:28])=[O:26])[CH2:22][CH2:21][CH2:20][NH:19][C:18](=[NH:29])[NH:17][S:14]([C:9]1[CH:8]([CH3:30])[CH:6]2[CH2:7][C:3]([CH3:31])([CH3:2])[O:4][C:5]2=[C:11]([CH3:12])[C:10]=1[CH3:13])(=[O:15])=[O:16])=[O:45]
Reactant: O=C(O)C=Cc1ccccc1F
Reactant: COC(=O)[C@@H](N)CCCNC(=N)NS(=O)(=O)C1=C(C)C(C)=C2OC(C)(C)CC2C1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCCNC(=N)NS(=O)(=O)C1=C(C)C(C)=C2OC(C)(C)CC2C1C)NC(=O)C=Cc1ccccc1F
Yield: 98.9 %

Procedure:
The same procedures as in Example 2 were carried out from methyl Nω-(2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl)-L-argininate hydrochloride (5.0 g), triethylamine (1.8 mL), 2-fluorocinnamic acid (2.1 g), WSC.HCl (2.4 g), and methylene chloride (150 mL), to give the captioned compound (6.1 g, 99%) as an amorphous solid product.
Reaction SMILES: CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.B.C1COCC1.[N:28]([CH2:31][C:32]([C:34]1[CH:45]=[CH:44][C:37]2[O:38][C:39]([CH3:43])([CH3:42])[O:40][CH2:41][C:36]=2[CH:35]=1)=[O:33])=[N+:29]=[N-:30].Cl>C1(C)C=CC=CC=1.C1COCC1>[N:28]([CH2:31][C@@H:32]([C:34]1[CH:45]=[CH:44][C:37]2[O:38][C:39]([CH3:43])([CH3:42])[O:40][CH2:41][C:36]=2[CH:35]=1)[OH:33])=[N+:29]=[N-:30]
Reactant: CC1(C)OCc2cc(C(=O)CN=[N+]=[N-])ccc2O1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1(C)OCc2cc([C@@H](O)CN=[N+]=[N-])ccc2O1
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
(R)-Tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole solution in toluene (1M, 7.5 ml) was added to THF (75 ml) and the solution was diluted to 0° C. Borane-THF complex (1M solution in THF, 125 ml) was added and the mixture was stirred under nitrogen for 15 min. A solution of 2-azido-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone (24.7 g) in THF (250 ml) was added dropwise over 1.5 h at 5° C. The mixture was stirred for a further 1 h and then cautiously treated with 2M HCl (100 ml). The reaction mixture was extracted with ether and the organic layer was washed with 2M HCl, NaHCO3, brine, dried (MgSO4). The solvent was removed by evaporation and the residue was chromatographed on a Biotage column eluting with ether-petroleum ether(40–60° C.) (1:9; 1:1) to give the title compound (16.99 g). ES+ve 250 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.O[CH2:12][C:13]1[O:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:12]([C:4]1[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])[NH:6][CH:5]=1)[C:13]1[O:19][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=1)=[CH:5][NH:6]2
Reactant: O=Cc1ccc(CO)o1
Reactant: Clc1cccc2[nH]ccc12
Product: OCc1ccc(C(c2c[nH]c3cccc(Cl)c23)c2c[nH]c3cccc(Cl)c23)o1

Procedure:
The compound Bis(4-chloroindol-3-yl)-(5-hydroxymethylfuran-2-yl)methane was prepared following procedure A, starting from 4-chloro indole and 5-hydroxymethyl furfural. LC: Tr 2.84 min, MS: 411 (M+H)+
Reaction SMILES: [CH:1]1([N:7]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([NH:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:17])=[O:16])=[CH:13][N:14]=2)[CH2:6][CH2:5]CC[CH2:2]1.[CH:30]1([N:35](C2CCCC2)[C:36](NC2SC=CN=2)=[O:37])CCCC1.[CH2:49](OC(=O)CNS(C1SC(N)=NC=1)(=O)=O)C>>[C:36]([N:35]1[CH2:30][CH2:2][CH:1]([N:7]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([NH:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:16])=[O:17])=[CH:13][N:14]=2)[CH2:6][CH2:5]1)(=[O:37])[CH3:49]
Reactant: O=C(Nc1nccs1)N(C1CCCC1)C1CCCC1
Reactant: CCOC(=O)CNS(=O)(=O)c1cnc(N)s1
Reactant: O=C(O)CNS(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Product: CC(=O)N1CCC(N(C(=O)Nc2ncc(S(=O)(=O)NCC(=O)O)s2)C2CCCCC2)CC1

Procedure:
Prepared in a similar manner to [2-(3,3-dicyclohexyl-ureido)-thiazole-5-sulfonylamino]-acetic acid via 1-(4-cyclohexylamino-piperidin-1-yl)-ethanone (General procedure 1) and (2-amino-thiazole-5-sulfonylamino)-acetic acid ethyl ester to give the title compound.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][CH2:13][C@@H:14]1[C@H:19]([CH2:20][CH2:21][CH:22]([OH:35])[C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17][N:16]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:15]1.C(N(CC)CC)C>ClCCl>[O:35]=[C:22]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][CH:24]=1)[CH2:21][CH2:20][C@@H:19]1[CH2:18][CH2:17][N:16]([C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])[CH2:15][C@@H:14]1[CH2:13][CH:12]=[O:11]
Reactant: COc1ccc2nccc(C(O)CC[C@@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3CCO)c2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ccc2nccc(C(=O)CC[C@@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3CC=O)c2c1
Temperature: 0 °C
Yield: 100.4 %

Procedure:
A mixture of 13.7 g of dimethyl sulfoxide in 65 cm3 of dichloromethane was slowly added, with stirring and under an inert atmosphere, to a solution, cooled to a temperature in the region of −60° C., of 8.3 cm3 of oxalyl chloride in 65 cm3 of dichloromethane. After stirring the mixture for 15 minutes, 10 g of (3R,4R)-3-(2-hydroxyethyl)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine, dissolved in 65 cm3 of dichloromethane, were slowly added. After stirring the mixture for 30 minutes, 61.7 cm3 of triethylamine, dissolved in 65 cm3 of dichloromethane, were finally added dropwise. The mixture was stirred for a further 3 hours at approximately −60° C. and then poured onto 400 cm3 of ice-cold water. After separating the mixture by settling, the organic phase was washed with 400 cm3 of a 10% (by mass) aqueous citric acid solution and then dried over magnesium sulfate, filtered, and evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 9.95 g of (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine-3-acetaldehyde were obtained in the form of an. oil with a brown color.
Reaction SMILES: [CH2:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=2[F:15])=[C:5]([O:18][CH3:19])[CH:4]=1)[CH3:2].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1.[BH4-].[Na+]>CO>[CH2:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:14]=[CH:13][C:11]([NH:12][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:10][C:9]=2[F:15])=[C:5]([O:18][CH3:19])[CH:4]=1)[CH3:2]
Reactant: O=Cc1cccnc1
Reactant: CCc1ccc(Oc2ccc(N)cc2F)c(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCc1ccc(Oc2ccc(NCc3cccnc3)cc2F)c(OC)c1
Temperature: 30 °C
Reaction time: 17 h
Yield: 45.5 %

Procedure:
To 4-(4-ethyl-2-methoxyphenoxy)-3-fluoroaniline (261.2 mg, 1 mmol) were added methanol (4 mL) and nicotinaldehyde (120 μL, 1.2 mmol). The reaction was stirred at 30° C. for 17 h under argon. To the reaction mixture was added NaBH4 (38 mg, 1 mmol). The reaction was stirred at 30° C. for 4 h under argon. The resulting mixture was concentrated in vacuo, dissolved in dichloromethane, washed with a saturated solution of NH4Cl and extracted with dichloromethane. Combined organic phases were dried over Na2SO4, concentrated in vacuo, to give the title product as a yellow oil (160.5 mg; 46%), after purification by preparative TLC (cyclohexane/ethyl acetate: 7/3).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].S(=O)(=O)(O)[OH:13].OO>C(O)(=O)C>[C:6]12[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH:1][C:2](=[O:13])[O:3][C:4]2=[O:5]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: O=S(=O)(O)O
Agent: OO
Solvent: CC(=O)O
Product: O=c1[nH]c2ccccc2c(=O)o1
Temperature: 25 °C

Procedure:
The isatin derivative (70 g) obtained in the above item (i), 200 ml of acetic acid and 0.8 ml of concentrated sulfuric acid were charged in a 500 ml two-neck flask and the mixture was stirred at room temperature. Then, 50 ml of 30% hydrogen peroxide was added dropwise to the mixture. After the completion of dropping, the mixture was stirred at 60° to 65° C. for one hour and a half and then cooled. The deposit was filtered, washed with water and dried under vacuum to give 35 g of a derivative of isatoic acid anhydride represented by the following formula (20): ##STR24##
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:21]([O:25][C:26]([N:28]1[CH:33]2[CH2:34][CH2:35][CH:29]1[CH2:30][N:31]([C:36]1[CH:37]=[N:38][C:39]([NH2:42])=[CH:40][CH:41]=1)[CH2:32]2)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[CH:29]2[CH2:35][CH2:34][CH:33]1[CH2:32][N:31]([C:36]1[CH:37]=[N:38][C:39]([NH:42][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:20])[CH3:1])[N:14]([CH:15]5[CH2:19][CH2:18][CH2:17][CH2:16]5)[C:8]=4[N:9]=3)=[CH:40][CH:41]=1)[CH2:30]2)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(c1ccc(N)nc1)C2
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CC5CCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCC1
Yield: 53.6 %

Procedure:
Using General Buchwald method 1, 2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (139 mg, 0.476 mmol, 1.0 eq) was combined with 3-(6-Amino-pyridin-3-yl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (145 mg, 0.476 mmol, 1.0 eq) to give 3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (143 mg, 51% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42 (s, 9H) 1.57-1.70 (m, 2H) 1.74-1.92 (m, 4H) 1.98 (br. s., 4H) 2.36-2.48 (m, 2H) 2.78 (d, J=10.11 Hz, 2H) 3.05 (br. s., 6H) 3.48 (d, J=10.11 Hz, 2H) 4.24 (br. s., 2H) 4.73 (qd, J=8.76, 8.59 Hz, 1H) 6.59 (s, 1H) 7.37 (dd, J=9.09, 3.03 Hz, 1H) 7.94 (d, J=3.03 Hz, 1H) 8.13 (d, J=9.09 Hz, 1H) 8.75 (s, 1H) 9.24 (s, 1H); MS m/z 561.3 (M+H).
Reaction SMILES: [C:1]1([CH2:7][NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:27][C:28]1[C:29]([C:35]([NH:37][CH3:38])=[O:36])=[N:30][C:31](Br)=[CH:32][N:33]=1>>[NH2:27][C:28]1[C:29]([C:35]([NH:37][CH3:38])=[O:36])=[N:30][C:31]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([S:9]([NH:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:10])=[O:11])[CH:13]=2)=[CH:32][N:33]=1
Reactant: CNC(=O)c1nc(Br)cnc1N
Reactant: CC1(C)OB(c2cccc(S(=O)(=O)NCc3ccccc3)c2)OC1(C)C
Product: CNC(=O)c1nc(-c2cccc(S(=O)(=O)NCc3ccccc3)c2)cnc1N
Yield: 20 %

Procedure:
3-Amino-N-methyl-6-(3-{[(phenylmethyl)amino]sulfonyl}phenyl)pyrazine-2-carboxamide was synthesized from N-(phenylmethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide and 3-amino-6-bromo-N-methyl-2-pyrazincarboxamide as yellow solid. Yield 20%. 1H NMR (400 MHz, d6-DMSO): 8.84 (s, 1H), 8.80 (m, 1H), 8.46 (d, 1H), 8.38 (br s, 1H), 8.20 (t, 1H), 7.78 (d, 1H), 7.66 (t, 1H), 7.26 (m, 4H), 7.18 (m, 1H), 4.02 (d, 2H), 2.82 (d, 3H); MS (EI) for C19H19N5O3S: 398 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]2[CH2:18][C:19]([F:22])([F:21])[CH2:20][C:15]2=[N:14]1.C(O)(=[O:25])C>[O-2].[Cr+6].[O-2].[O-2]>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]2[C:18](=[O:25])[C:19]([F:21])([F:22])[CH2:20][C:15]2=[N:14]1
Reactant: CC(=O)O
Reactant: FC1(F)Cc2cn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)nc2C1
Agent: [Cr+6]
Agent: [O-2]
Product: O=C1c2cn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)nc2CC1(F)F
Temperature: 50 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
To a solution of (90) (36.7 mg, 103 mmol) in 1 mL acetic acid was added chromium(VI) oxide (31 mg, 308 mmol). The mixture was stirred at 50° C. for 12 h. The mixture was then chromatographed on a silica gel TLC plate using hexane/ethyl acetate (9:1) to give (91): yield 50%: 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.80 (s, 2H), 3.63 (t, 2H, J=11.77 Hz).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][C:16]#[N:17])[CH2:11][CH2:10]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][C:16]#[N:17])[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CC#N)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC[C@H]1CC[C@H](CN)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl(trans-4-(cyanomethyl)cyclohexyl)methylcarbamate (500 mg) in dichloromethane (5 mL) was slowly added trifluoroacetic acid (3 mL) at 0° C. The mixture was warmed to room temperature, stirred for 1 hour and concentrated. The residue was dried under vacuum to provide the title compound.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[OH:24].C[O:26][C:27](=[O:37])[CH:28](Br)[CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:30]1([CH2:29][CH:28]([N:4]2[C:3](=[O:15])[CH:2]=[C:7]([O:24][C:18]3[C:17]([F:16])=[CH:22][CH:21]=[CH:20][C:19]=3[F:23])[CH:6]=[N:5]2)[C:27]([OH:26])=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: Oc1c(F)cccc1F
Reactant: COC(=O)C(Br)CC1CCCCC1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Product: O=C(O)C(CC1CCCCC1)n1ncc(Oc2c(F)cccc2F)cc1=O

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 2,6-difluoro-phenol and alkylating with 2-bromo-3-cyclohexyl-propionic acid methyl ester (Intermediate 12) afforded 3-cyclohexyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid as a white solid (1.3 g, 99% for the final step); ES+-HRMS m/e calcd for C19H20N2O4F2 [M+H+] 379.1464, found 379.1463. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.63-1.31 (m, 6H) 1.33-2.19 (m, 7H) 5.38 (dd, J=10.9, 3.9 Hz, 1H) 6.08 (br s, 1H) 7.24-7.56 (m, 3H) 8.26 (d, J=2.7 Hz, 1H) 13.11 (br s, 1H).
Reaction SMILES: [BrH:1].O[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1>>[ClH:12].[Br:1][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1
Reactant: Br
Reactant: OCCNc1cccc(Cl)c1
Product: Cl
Product: Clc1cccc(NCCBr)c1
Temperature: 124 °C
Yield: 146.7 %

Procedure:
50 gm of 50% hydrobromic acid were slowly added dropwise to 19 gm of the product obtained in step (a), while stirring. The vessel containing the resulting mixture was then connected to a Vigreux-column, and the mixture was heated until a temperature of about 124° C. was reached. After three hours of heating at that temperature, about 35 ml of liquid were distilled off. The residue solidified upon cooling and was purified by washing with acetone, yielding 22 gm of the desired product which had a melting point of 148° C.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][C@@H:21]3[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]3)[CH2:16][CH2:15]2)=[O:13])[CH:7]=[CH:8][C:9]=1[Cl:10].C(N(CC)C(C)C)(C)C.[CH:36](=O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:36]([N:23]1[CH2:24][CH2:25][CH2:26][C@@H:21]([CH2:20][N:17]2[CH2:18][CH2:19][N:14]([C:12]([NH:11][C:6]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=3)=[O:13])[CH2:15][CH2:16]2)[CH2:22]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@@H]2CCCNC2)CC1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@@H]2CCCN(Cc3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
To a mixture of N-(3,4-dichlorophenyl)-1-[(3R)-piperidin-3-ylmethyl]piperazine-4-carboxamide dihydrochloride (800 mg) in dichloromethane (25 mL) was added N,N-di-iso-propylethylamine (0.94 mL) under argon. The mixture was stirred at room temperature for 5 minutes before benzaldehyde (0.22 mL) and sodium triacetoxyborohydride (573 mg) were added. The reaction mixture was stirred at room temperature under argon for 4 hours. The reaction was quenched with water and then partitioned between dichloromethane and water. The organic extract was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by silica column chromatography, eluting with a gradient of 0 to 10% MeOH in dichloromethane to give the title compound as a white solid (550 mg, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:24])[NH:10][CH2:11][CH:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([O:15]CC)=[O:14])=[CH:4][CH:3]=1.[OH-].[Na+].C1COCC1>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[NH:10][CH2:11][CH:12]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:13]([OH:15])=[O:14])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(CNC(=O)Nc1ccc(Cl)cc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(NCC(C(=O)O)c1ccccc1)Nc1ccc(Cl)cc1
Yield: 101.5 %

Procedure:
A solution of ethyl 3-(N′-(4-chlorophenyl)ureido)-2-phenylpropanoate (1.5 g) obtained in Example 4a) and 1 N sodium hydroxide (10 ml) in ethanol (20 ml)-THF (20 ml) was mixed at room temperature for 15 hours, and then the reaction solution was concentrated under reduced pressure. The solution was acidified by adding 1 N hydrochloric acid to the concentrated solution, and then extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as colorless powder (1.4 g, quantitative).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][C@H:5]([CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[N:6]([C:13](=[O:23])[CH2:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22])[C@H:7]2[CH3:12].[CH2:33](OB(C=C)OCCCC)[CH2:34]CC.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Si:26]([O:25][CH2:24][C@H:5]1[CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[CH:33]=[CH2:34])[C@H:7]([CH3:12])[N:6]1[C:13](=[O:23])[CH2:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22])([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: C[C@H]1c2cccc(Br)c2C[C@H](CO[Si](C)(C)C(C)(C)C)N1C(=O)Cc1c(Cl)cccc1Cl
Reactant: C=CB(OCCCC)OCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=Cc1cccc2c1C[C@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)Cc1c(Cl)cccc1Cl)[C@H]2C
Temperature: 80 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
Dissolve 1-[(1S,3R)-5-bromo-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-(2,6-dichlorophenyl)ethanone (300 mg, 0.54 mmol) and vinylboronic acid dibutyl ester (0.24 mL, 1.08 mmol) in 1,4-dioxane (5.4 mL). Add aqueous Na2CO3 solution (2.7 mL, 2M in water). Degas with nitrogen 10 min Add bis(triphenylphosphine)palladium(II) chloride (76 mg, 0.11 mmol). Heat to 80° C. Stir 2 hours. Add water and extract with ethyl acetate three times. Combine the ethyl acetate extracts, dry over sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue by silica gel chromatography, eluting with ethyl acetate:hexanes (gradient, 5-80%) to give the title compound as a white foam (220 mg, 0.44 mmol). MS (m/z): 504 (M+1).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[O:12]1[CH2:17]COC[CH2:13]1.O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl>[CH3:13][O:12][CH2:17][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1
Reactant: C1COCCO1
Reactant: COC(=O)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Product: COCc1ccc(C(=O)OC)cc1
Temperature: 100 °C
Reaction time: 4.5 h
Yield: 33 %

Procedure:
To a mixture of methyl 4-bromobenzoate (50 mg, 0.233 mmol) and 1,4-dioxane (1 ml) were added water (0.1 ml), cesium carbonate (228 mg, 0.7 mmol), potassium methoxymethyl trifluoroborate (71 mg, 0.467 mmol) and 1′,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) (17 mg, 0.023 mmol). Then, the reaction mixture was stirred at 100° C. (external temperature) for 4.5 hours. After the reaction mixture was cooled at room temperature, water and methylene chloride were added to the mixture, followed by filtration using celite. The separated organic layer was washed with an aqueous saturated sodium chloride solution. The organic layer was separated, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethylacetate=10:1) to obtain the title compound (13.9 mg, 33%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([OH:26])=O)=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[CH3:31][C:32]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:33]=1[NH2:34].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:22])([CH3:23])[O:21][C:17]=3[C:16]([C:24]([NH:34][C:33]3[CH:35]=[CH:36][C:37]([C:39]([F:40])([F:41])[F:42])=[CH:38][C:32]=3[CH3:31])=[O:26])=[CH:15][C:13]=2[N:14]=1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Reactant: Cc1cc(C(F)(F)F)ccc1N
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(F)(F)F)ccc1NC(=O)c1cc2nc(Nc3c(F)cccc3Cl)[nH]c2c2c1OC(C)(C)C2
Yield: 10.6 %

Procedure:
The title compound was prepared by following the procedure described for Example-108 using 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-15, 0.100 g, 0.266 mmol), thionyl chloride (2.0 mL), 2-methyl-4-(trifluoromethyl)aniline (0.070 g, 0.400 mmol), THF (10.0 mL) and DIPEA (2 mL). The obtained crude product was purified by column chromatography on neutral alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.015 g of the desired product. 1HNMR (DMSO-d6): δ 1.56 (s, 6H), 2.41 (s, 3H), 3.12 (s, 2H), 7.32-7.39 (m, 3H), 7.57 (d, J=7.2 Hz, 1H), 7.63 (s, 1H), 8.63 (d, J=8.4 Hz, 2H), 9.31 (s, 1H), 9.84 (s, 1H), 11.18 (s, 1H); MS [M−H]−: 531.41.