Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[CH2:8][O:7][C:6]=2[CH:17]=1.[BH4-].[Na+].O>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]([OH:12])[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[CH2:8][O:7][C:6]=2[CH:17]=1
Reactant: O=C1c2ccccc2COc2cc(F)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC1c2ccccc2COc2cc(F)ccc21
Reaction time: 1 h
Yield: 94.2 %

Procedure:
To a solution of 2.0 g of 3-fluoro-6,11-dihydrodibenz[b,e]oxepin-11-one in 20 ml of methanol is added 0.5 g of sodium borohydride with ice-cooling and then the mixture is stirred at the same temperature for 1 hour. The reaction mixture is poured into water and the resultant is extracted with toluene. The extract is washed with water and then dried over magnesium sulfate. Toluene is distilled off to give 1.9 g of 3-fluoro-6,11-dihydrodibenz[b,e]oxepin-11-ol (crystals). Mass spectrum m/z: 230(M+).
Reaction SMILES: [CH:1](=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].O.C(OCC)(=O)C.[CH3:20][C:21]([CH3:23])=[O:22]>>[C:4]1([CH:3]=[CH:2][CH:1]=[CH:20][C:21](=[O:22])[CH3:23])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)=O
Reactant: O=CC=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)C=CC=Cc1ccccc1
Reaction time: 0.5 h
Yield: 91 %

Procedure:
In a 250 ml single neck flask was charged 13.2 g (100 mmoles,1.0 eq) of cinnamaldehyde dissolved in 30 ml of acetone. To this was added 5 g of 10% aqueous sodium hydroxide solution (12.5 mmoles, 0.125 eq), dropwise and during the course of addition, temperature was kept no higher than 25° C., while the mixture was agitated continuously for 30 minutes. To the mixture was added 50 ml of water, followed by 100 ml of ethyl acetate, the phases were separated and the organic phase was washed with water three times and then dried, and concentrated to obtain 15.7 g of 4-(2-phenylethenyl)-3-buten-2-one as a faintly yellow oil in 91% yield.
Reaction SMILES: CON(C)[C:4]([C@H:6]1[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][C@@:8]2([C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:26])[CH2:7]1)=[O:5].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([Mg]Br)=[CH:31][CH:30]=1>C1COCC1>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:4]([C@H:6]2[N:10]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH2:9][C@@:8]3([C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][C:18]3=[O:26])[CH2:7]2)=[O:5])=[CH:31][CH:30]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)[C@@H]1C[C@]2(CN1C(=O)OC(C)(C)C)C(=O)Nc1ccccc12
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@]2(C[C@H]1C(=O)c1ccc(Cl)cc1)C(=O)Nc1ccccc12
Reaction time: 8 h
Yield: 68.1 %

Procedure:
To a stirred solution of (3S,5′S)-tert-butyl 5′-(methoxy(methyl)carbamoyl)-2-oxospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate (310 mg, 0.826 mmol) in THF (4 mL) was added 4-chloro phenylmagnesium bromide (1.0 N in THF, 2.89 mL, 2.89 mmol) at about 0° C. The reaction mixture was warmed to about room temperature and stirred overnight. The reaction was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The crude product was purified by column chromatography (hexanes:EtOAc, 1:1) to give (3S,5′S)-tert-butyl 5′-(4-chlorobenzoyl)-2-oxospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate (0.240 g, 68%). LCMS (APCI+) m/z 427, 429 [M+H]+; Rt=3.94 min.
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11]CCCCCCCCC)=[N+:2]=[N-:3].[N:22](CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7]([C:8]1[NH:22][CH:11]=[CH:10][CH:9]=1)=[O:21])=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Reactant: [N-]=[N+]=NCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NCCNC(=O)c1ccc[nH]1
Yield: 65.4 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, (0.249 g, 1.17 mmol) was reacted with 2-azidoethanamine (0.101 g, 1.17 mmol) and triethylamine (0.237 g, 2.34 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-1H-pyrrole-2-carboxamide (0.137 g, 66%). 1H NMR (300 MHz, CD3OD) δ 6.88 (d, 1H), δ 6.77 (d, 1H), δ 6.14 (t, 1H), δ 3.46 (t, 2H), δ 3.37 (q, 2H) ppm; 13C NMR (75 MHz, CD3OD) δ 162.9, 125.6, 122.2, 121.9, 110.9, 109.2, 50.6, 38.9 ppm; HRMS (ESI) calcd for C7H9N5O (M+) 179.0807. found 179.0803.
Reaction SMILES: [CH:1]([NH:3][C@H:4]([C:9]([OH:11])=O)[CH2:5][CH2:6][S:7][CH3:8])=[O:2].ON1C2C=CC=CC=2N=N1.[F:22][C@:23]12[C@@H:43]([OH:44])[CH2:42][C@@:41]3([CH3:45])[C@@H:33]([CH2:34][C@H:35]([CH3:47])[C@:36]3([OH:46])[C:37](=[O:40])[CH2:38][SH:39])[C@@H:32]1[CH2:31][CH2:30][C:29]1[C@:24]2([CH3:49])[CH:25]=[CH:26][C:27](=[O:48])[CH:28]=1.C(N(CC)CC)C>C(OCC)(=O)C>[F:22][C@:23]12[C@@H:43]([OH:44])[CH2:42][C@@:41]3([CH3:45])[C@@H:33]([CH2:34][C@H:35]([CH3:47])[C@:36]3([OH:46])[C:37](=[O:40])[CH2:38][S:39][C:9](=[O:11])[CH:4]([NH:3][CH:1]=[O:2])[CH2:5][CH2:6][S:7][CH3:8])[C@@H:32]1[CH2:31][CH2:30][C:29]1[C@:24]2([CH3:49])[CH:25]=[CH:26][C:27](=[O:48])[CH:28]=1
Reactant: CSCC[C@H](NC=O)C(=O)O
Reactant: C[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CS
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CSCCC(NC=O)C(=O)SCC(=O)[C@@]1(O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Reaction time: 1.5 h
Yield: 87.1 %

Procedure:
To a stirred solution of N-formyl-L-methionine (11.13 gm) in dry ethyl acetate (200 ml) were added 1-hydroxybenzotriazol (9.71 gm) in dry ethyl acetate (100 ml) and dicyclohexylcarbodiimido (16.43 gm) in dry ethyl acetate (100 ml) each at room temperature. The reaction mixture was stirred for 1.5 hours. To the stirred reaction mixture was added dropwise a solution of 9-fluoro-11β,17-dihydroxy-16β-methylpregna -1,4-diene-3,20-dione-21-thiol (12.95 gm) and triethylamine (35 ml) in dry ethyl acetate (600 ml) at 0° C. for 1 hour. The reaction mixture was stirred at room temperature for 4.5 hours. The title compound (15.68 gm) was prepared by purifying the resulting reaction mixture in the same manner as in Synthetic Example 1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].C(N1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23])(OCC)=O>C1C=CC=CC=1>[C:14]1(=[O:23])[N:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7])[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: NCCCCCO
Solvent: c1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCCCCO
Temperature: 25 °C
Reaction time: 5 h
Yield: 0.1 %

Procedure:
To a solution of 5-amino-1-pentanol (5.00 g, 48.5 mmol) in benzene (150 mL) was added N-carboethoxyphthalimide (11.0 g, 50.2 mmol) and the solution was stirred at room temperature for 5 h). The solvents were removed under reduced pressure to yield a yellow oil. Purification by flash column chromatography using 25% ethyl acetate in petroleum ether yielded the target compound as a clear colorless oil (9.6 mg, 84%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[S:26][C:25]([C:27]3([OH:32])[CH2:31][CH2:30][NH:29][CH2:28]3)=[N:24][CH:23]=2)=[CH:18][CH:17]=1)=[O:14].[C:33](O)(=O)C.C=O>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:11])[F:9])=[CH:4][C:3]=1[NH:12][C:13]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[S:26][C:25]([C:27]3([OH:32])[CH2:31][CH2:30][N:29]([CH3:33])[CH2:28]3)=[N:24][CH:23]=2)=[CH:20][CH:21]=1)=[O:14]
Reactant: CC(=O)O
Reactant: O=C(Nc1ccc(-c2cnc(C3(O)CCNC3)s2)cc1)Nc1cc(C(F)(F)F)ccc1F
Agent: C=O
Solvent: CO
Product: CN1CCC(O)(c2ncc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)s2)C1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To an ambient solution of Example 14 (0.050 g, 0.107 mmol) in methanol containing 1% v/v acetic acid 1 mL) was added formaldehyde (0.012 mL, 0.161 mmol, 37 wt % in H2O) and MP-CNBH3 (0.054 g, 0.161 mmol, 3.0 mmol/g). The reaction was heated to 50° C. and shaken for 16 h. The reaction was then filtered and concentrated under reduced pressure. The residue was purified by RP-HPLC (preparative reversed-phase high pressure liquid chromatography) using a Zorbax SB-C18 7M 21.2×250 mm column with UV detection analyzed at 220 and 254 nM (preparative method: water with 0.1% trifluoroacetic acid and CH3CN with 0.1% trifluoroacetic acid gradient 5-95% CH3CN over 30 minutes at 15 mL/min). The fractions containing the desired product were diluted with saturated aqueous NaHCO3 and extracted with ethyl acetate. The organic layer was dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 2.01-2.13 (m, 1H), 2.25-2.33 (m, 3H), 2.35-2.46 (m, 1H), 2.51-2.58 (m, 1H), 2.73-2.94 (m, 3H), 6.22-6.31 (m, 1H), 7.37-7.44 (m, 1H), 7.47-7.56 (m, 3H), 7.56-7.62 (m, 2H), 7.98 (s, 1H), 8.62 (m, 1H), 8.92 (m, 1H), 9.32 (s, 1H); MS (ESI) m/z 481 [M+H]+.
Reaction SMILES: C(OC([N:6]1[C:14]2[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C:9]=2[C:8]([NH:22][C:23]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][C:26]=2[N:31]2C(=O)C3C(=CC=CC=3)C2=O)=[O:24])=[N:7]1)=O)C.O.NN>CCO>[C:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][C:14]2[NH:6][N:7]=[C:8]([NH:22][C:23]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][C:26]=3[NH2:31])=[O:24])[C:9]=2[CH2:10]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)n1nc(NC(=O)c2ccncc2N2C(=O)c3ccccc3C2=O)c2c1CCN(C(=O)OC(C)(C)C)C2
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2[nH]nc(NC(=O)c3ccncc3N)c2C1
Yield: 74.4 %

Procedure:
To a mixture of 3-{[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-pyridine-4-carbonyl]-amino}-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-1,5-dicarboxylic acid 5-tert-butyl ester 1-ethyl ester (1.68 g, 3 mmol) in 35 mL of EtOH was added hydrazine hydrate (0.37 mL) and the solution was heated to reflux for 1 hour. After cooling, the precipitate was filtered off and the filtrate evaporated in vacuum. The product was chromatographed twice, using dichloromethane-MeOH 95:5 as eluant, to afford 3-[(3-amino-pyridine-4-carbonyl)-amino]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (0.8 g, 74% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:19][O:20][CH:21]1[CH2:24][NH:23][CH2:22]1>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:23]3[CH2:24][CH:21]([O:20][CH3:19])[CH2:22]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC1CNC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Agent: Cl
Product: COC1CN(c2ccc3c(c2)CN(C(=O)OC(C)(C)C)C3)C1

Procedure:
Prepared in analogy to Example A3(d) from 5-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and 3-methoxy-azetidine hydrochloride. Orange oil. MS (m/e): 305.4 ([M+H]+, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[N:8]([CH2:22][CH3:23])[C:9]2[C:14]([C:15]=1[N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[CH:13][CH:12]=[C:11]([CH3:21])[N:10]=2)=[O:5])[CH3:2].[NH:25]1CCNCC1>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[N:8]([CH2:22][CH3:23])[C:9]2[C:14]([C:15]=1[N:16]1[CH2:20][CH2:19][NH:25][CH2:18][CH2:17]1)=[CH:13][CH:12]=[C:11]([CH3:21])[N:10]=2)=[O:5])[CH3:2]
Reactant: C1CNCCN1
Reactant: CCOC(=O)c1c(N2CCCC2)c2ccc(C)nc2n(CC)c1=O
Solvent: CCO
Product: CCOC(=O)c1c(N2CCNCC2)c2ccc(C)nc2n(CC)c1=O

Procedure:
A stirred mixture of 1.47 g. (0.005 mole) of 1-ethyl-1,2-dihydro-4-chloro-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (Example 30) and 1.72 g. (0.02 mole) of piperazine in 20 ml. of ethanol was heated under reflux for 5 hours. The mixture was filtered and the filtrate was diluted with 100 ml. of water and was extracted with 50 ml. of diethyl ether. The ether layer was dried over magnesium sulfate, filtered and was evaporated in an evaporating dish at room temperature. The residue was recrystallized from heptane to give 0.3 g. of product, m.p. 137°-139° C.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Br[C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4ccc([N+](=O)[O-])cn4)cc3CC[C@@H]12
Yield: 72.7 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-bromo-5-nitropyridine (93 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 106 mg (73%) of the title compound as an amorphous foam. mp 188°-191°. FDMS: m/e=383. α[D]589 =+57.07 (c=0.68, chloroform).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:20][OH:21])[CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[N:13][CH:14]=1.Cl[C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[C:31]([CH3:35])([CH3:34])[CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:14]=[N:13][C:12]([C:15]([F:17])([F:18])[F:16])=[N:11][CH:10]=1)[CH2:20][O:21][C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[C:31]([CH3:35])([CH3:34])[CH2:30][N:26]2[C:27](=[O:29])[N:28]=1
Reactant: OCc1cc(F)c(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CN1c2cc(OCc3cc(F)c(Oc4cnc(C(F)(F)F)nc4)c(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenyl)methanol and 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one at −78° C. then rt.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([C:26]#[N:27])[C@H:12]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:11][NH:10][C@@H:9]2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=2[Cl:25])=[C:4]([F:28])[CH:3]=1.[CH3:29][O:30][C:31](=[O:41])[C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>C(Cl)Cl>[CH3:29][O:30][C:31](=[O:41])[C:32]1[CH:33]=[CH:34][C:35]([NH:38][C:39]([N:10]2[CH2:11][C@@H:12]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C@@:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[F:28])([C:26]#[N:27])[C@H:9]2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=2[Cl:25])=[O:40])=[CH:36][CH:37]=1
Reactant: COC(=O)c1ccc(N=C=O)cc1
Reactant: CC(C)(C)C[C@@H]1CN[C@H](c2cccc(Cl)c2Cl)[C@@]1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
A mixture of rac-4-{[(2S,3S,4S)-3-(4-chloro-2-fluoro-phenyl)-2-(2,3-dichloro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (88.0 mg, 0.20 mmol) and 4-isocyanato-benzoic acid methyl ester (Aldrich, 42.5 mg, 0.22 mmol) in CH2Cl2 (2 mL) was stirred at rt for 1 h. The reaction mixture was then concentrated and purified by flash column to give rac-4-{[(2S,3S,4S)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,3-dichloro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-benzoic acid methyl ester (98.6 mg, 79.9%) which was used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])[CH:15]=2)[CH:10]=1.C([BH3-])#N.[Na+].C(O)(=O)C.[CH3:38][N:39]1[CH:43]=[CH:42][N:41]=[C:40]1[CH:44]=O>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])[CH:15]=2)[CH:10]=1)[CH2:44][C:40]1[N:39]([CH3:38])[CH:43]=[CH:42][N:41]=1
Reactant: CCCN(CCC)CCCCc1ccc2cc(CNCc3ncc[nH]3)ccc2c1
Reactant: Cn1ccnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCc1ccc2cc(CN(Cc3ncc[nH]3)Cc3nccn3C)ccc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The compound (39.0 mg) obtained in Example 124-5 was dissolved in anhydrous methanol (1.0 ml) and then added with sodium cyanoborohydride (9.40 mg), acetic acid (1.00 ml), and 1-methyl-2-imidazole carboxaldehyde (12.0 mg), followed by stirring at room temperature for 2 days under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off and the residue was then dissolved in chloroform. The solution was added with a saturated aqueous sodium bicarbonate solution and stirred. The solution was subjected to extraction with chloroform and the extract was then washed with a saturated aqueous sodium bicarbonate solution and saturated saline solution. The organic layer was dried with anhydrous sodium sulfate and the solvent was then distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining hydrochloride (16.7 mg) of the subject compound as a white solid.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[C:12][Si](C)(C)C>O.CO>[C:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][CH3:3])#[CH:12]
Reactant: COc1ccccc1C#C[Si](C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C#Cc1ccccc1OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 123 %

Procedure:
Add a solution of potassium hydroxide (3.66 g, 65.2 mmol) in water (30 mL) dropwise over 30 minutes to a stirred solution of (2-methoxy-phenylethynyl)-trimethylsilane (13.2 g, 64.6 mmol) in methanol (275 mL) and stir at room temperature for 1.5 hours. Concentrate, add brine to residue, and extract with EtOAc. Dry organic layer over MgSO4 and concentrate to get 10.5 grams of a black oil. Adsorb on SiO2 and purify the residue by flash chromatography on silica gel eluting with 0-5% EtOAc/hexanes to afford the title compound (7.6 g, 89%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][CH:5]=1.[N+:12]([O-])([OH:14])=[O:13].C(OCC)(=O)C>S(=O)(=O)(O)O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([I:10])=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(I)c([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 5 h
Yield: 33 %

Procedure:
A solution of 4-iodobenzoic acid methyl ester (5.24 g, 20.0 mmol) in sulfuric acid was treated with 1.43 mL of concentrated nitric acid in a dropwise fashion at 0° C. After 5 hours at room temperature, the reaction mixture was heated to 40° C. for 1 hour. The resulting orange solution was added to 100 g of ice, treated with 200 mL of ethyl acetate, shaken for 30 minutes, and filtered. The phases were separated and the aqueous layer was extracted with 200 mL of ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was passed through a column of silica gel (100% ethyl acetate) to give 2.0 g of 4-iodo-3-nitrobenzoic acid methyl ester as a yellow solid (33% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[NH:28]1[CH2:33][CH2:32][CH:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:30][CH2:29]1.CCN(C(C)C)C(C)C>C1COCC1>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([N:28]3[CH2:29][CH2:30][CH:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])[CH2:32][CH2:33]3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCC(NC(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
A mixture of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (0.992 g, 2.5 mmol), tert-butyl 4-piperidinylcarbamate (1.00 g, 5 mmol), and DIPEA (0.65 g, 5 mmol) in THF (100 mL) was stirred at room temperature for 30 min. The solution was then concentrated and diluted with water (100 mL) containing 1 mL of acetic acid. The resulting solid was collected, washed with water, and dried to give 1.38 g (98%) of tert-butyl 1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinylcarbamate: mp (MeOH) 208-209° C.; 1H NMR (CDCl3) δ 7.88 (d, J=8.1 Hz, 1H), 7.48 (t, JHF=53.6 Hz, 1H), 7.34 (t, J=8.2 Hz, 1H), 6.81 (d, J=7.9 Hz, 1H), 4.66 (br d, J=13.4 Hz, 2H), 4.46 (m, exchangeable with D2O, 1H), 4.04 (s, 3H), 3.87 (m, 4H), 3.78 (m, 5H), 3.12 (m, 2H), 2.07 (br d, J=14.0 Hz, 2H), 1.46 (s, 9H), 1.45-1.33 (m, 2H); Anal. Calcd. for C26H34F2N8O4: C, 55.7; H, 6.1; N, 20.0. Found: C, 55.85; H, 6.1; N, 20.1%.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=1[S:39](Cl)(=[O:41])=[O:40].[OH-].[Na+]>ClCCl.CN(C1C=CN=CC=1)C>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=1[S:39]([NH:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1)(=[O:41])=[O:40]
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(NS(=O)(=O)c2cc(Cl)ccc2Cl)cc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 177.6 %

Procedure:
A mixture of 0.10 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 0.050 g of triethylamine and 0.083 g of 2,5-dichlorobenzenesulfonyl chloride in 2 ml of dichloromethane is stirred at room temperature for 1 hour and then 4 mg of 4-(N,N-dimethylamino)pyridine is added. After another hour, 93 mg of 2,5-dichlorobenzenesulfonyl chloride is added along with 50 mg of triethylamine. The mixture is stirred at room temperature for 2 days and 1 N NaOH added. The mixture is extracted with ethyl acetate and the extract washed with 50% ammonium chloride solution, brine and dried (Na2SO4). The solvent is removed to give 0.30 g of solid. Trituration with ether-hexane gives 0.26 g of solid. This solid is dissolved in a mixture of 5 ml of tetrahydrofuran, 1 ml of methanol, 1 ml of 1 N NaOH and the mixture stirred for 18 hours at room temperature. The organic solvents are removed and the mixture extracted with ether acetate. The extract is washed with NaHCO3, brine and dried (Na2SO4). The solvent is removed and the residue (0.16 g) triturated with ether to give 0.14 g of yellow solid.