Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1N1CCN2C3CCCCC=3C=C2C1=O)(=[O:3])[CH3:2].Br[C:42]1[CH:43]=[C:44]([NH:50][C:51]2[CH:55]=[C:54]([CH2:56][O:57][CH3:58])[N:53]([CH3:59])[N:52]=2)[C:45](=[O:49])[N:46]([CH3:48])[CH:47]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:20]4[CH2:19][CH2:18][CH2:17][CH2:16][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:42]1[CH:43]=[C:44]([NH:50][C:51]2[CH:55]=[C:54]([CH2:56][O:57][CH3:58])[N:53]([CH3:59])[N:52]=2)[C:45](=[O:49])[N:46]([CH3:48])[CH:47]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(N2CCn3c(cc4c3CCCC4)C2=O)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: COCc1cc(Nc2cc(Br)cn(C)c2=O)nn1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COCc1cc(Nc2cc(-c3cc(F)cc(N4CCn5c(cc6c5CCCC6)C4=O)c3COC(C)=O)cn(C)c2=O)nn1C
Temperature: 110 °C
Yield: 55.3 %

Procedure:
A sealed tube was charged with the mixture of 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 210d (230 mg, 0.48 mmol), 5-bromo-3-(5-(methoxymethyl)-1-methyl-1H-pyrazol-3-ylamino)-1-methylpyridin-2(1H)-one 176c (156 mg, 0.48 mmol), Pd(dppf)Cl2 (39 mg, 0.048 mmol), Na2CO3 (101 mg, 0.96 mmol) in DMF (18 mL). The system was evacuated and then refilled with N2. And the reaction mixture was heated at 110° C. for 2 h. Then, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography eluting with 15:1 methylene chloride/methanol to give 178a as a brown solid (160 mg, 53%). MS: [M+H]+ 603.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[F:16])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:24])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:24][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([S:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:7])=[O:8])=[C:10]([F:16])[CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)NC(C)(C)C)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)NS(=O)(=O)c1ccc(CBr)cc1F
Yield: 79.5 %

Procedure:
A mixture of N-tert-butyl-2-fluoro-4-methylbenzenesulfonamide (2 g), NBS (1.16 g) and AIBN (40 mg) in CCl4 (25 ml) was refluxed for 3 hours. The reaction mixture was cooled, filtered and concentrated to give a viscous syrup, which was purified by silica gel column chromatography to give 1.68 g 4-(bromomethyl)-N-tert-butyl-2-fluorobenzenesulfonamide as a colorless crystal solid.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)[N:12]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:24][CH:23]=3)[N:10]=1)[CH2:2]2.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39].[BH4-].[Na+]>CO.O1CCCC1>[OH:21][CH:18]1[CH2:17][CH2:16][N:15]([C:13]2[N:14]=[C:9]([N:3]3[CH2:4][CH:5]4[O:8][CH:1]([CH2:7][CH2:6]4)[CH2:2]3)[N:10]=[C:11]([C:22]3[CH:23]=[CH:24][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=4)=[O:30])=[CH:26][CH:27]=3)[N:12]=2)[CH2:20][CH2:19]1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]
Reactant: O=C1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(Nc1ccncc1)Nc1ccc(-c2nc(N3CCC(O)CC3)nc(N3CC4CCC(C3)O4)n2)cc1
Temperature: 25 °C

Procedure:
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-TFA (56 mg) was taken up in methanol/tetrahydrofuran (1:1, 6 mL), and the mixture at 0° C. was treated with sodium borohydride (10 mg). After warming to room temperature, the mixture was concentrated to a residue which then was purified by HPLC to give the title compound as its TFA salt.; MS (ES+) 503.0 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH2:11][CH2:12][C@H:13]([OH:23])[CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=[CH:9][CH:10]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH2:11][CH2:12][C@H:13]([O:23][S:32]([CH3:31])(=[O:34])=[O:33])[CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:18])=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(CC[C@H](O)CO[Si](C)(C)C(C)(C)C)s1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(CC[C@@H](CO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
To a stirred, ice-cold solution of 23.19 g (64.68 mmol) of the alcohol (16) and 13.5 ml (96.86 mmol) of triethylamine in 200 ml of CH2Cl2 was added 6.0 ml (77.52 mmol) of methanesulfonyl chloride. After 30 minutes at 0° C., the reaction mixture was warmed to room temperature. After another 30 minutes, the reaction mixture was diluted with CH2Cl2 and then washed sequentially with 0.5N HCl, saturated NaHCO3 and saturated NaCl. The organic layer was dried (MgSO4) and the solvent was removed under reduced pressure, yielding 26.61 g (94%) of the desired mesylate (17) as a colorless oil, which was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][B:12]1[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:1][CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:19])([CH3:20])[O:13]2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:24][CH:23]=1
Reactant: CCOC(=O)C(N)CCCCB1OC(C)(C)C(C)(C)O1
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCOC(=O)C(CCCCB1OC(C)(C)C(C)(C)O1)NCc1ccc(Cl)cc1
Reaction time: 0.17 h
Yield: 34.3 %

Procedure:
A solution of ethyl 2-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (119 mg, 0.42 mmol) in 1,2-dichloroethane (1 mL) was treated with 4-chlorobenzaldehyde (89 mg, 0.63 mmol). After stirring for 10 minutes, sodium triacetoxyborohydride (230 mg, 1.05 mmol) was added and stirring was continued for 18 hours. The reaction was diluted with ethyl acetate, washed with saturated aq sodium bicarbonate and sat'd aq sodium chloride, dried over MgSO4, and concentrated. Purification by column chromatography (4-32% ethyl acetate in heptane afford ethyl 2-(4-chlorobenzylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (59 mg, 34%). Rf 0.28 (20% ethyl acetate in heptane). 1H NMR (CDCl3, 300 MHz) δ 7.29-7.25 (m, 4H), 4.21 (q, J=7.7 Hz, 2H), 3.78, 3.58 (ABq, JAB=13.2 Hz, 2H), 3.20 (t, J=7.0 Hz, 1H), 1.80-1.57 (m, 2H), 1.42-1.34 (m, 4H), 1.30-1.21 (m, 15H), 0.77 (t, J=7.0 Hz, 2H). ESI MS found for C21H33B1Cl1N1O4 m/z [410.1 (M+1)].
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[CH2:9]([NH:16][C:17]1[N:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCOCC1>[CH2:9]([N:16]1[C:17]2[N:25]=[CH:24][CH:23]=[CH:22][C:18]=2[C:19](=[O:21])[O:20][C:2]1=[O:3])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: O=C(O)c1cccnc1NCc1ccccc1
Solvent: C1COCCO1
Product: O=c1oc(=O)n(Cc2ccccc2)c2ncccc12
Yield: 67.9 %

Procedure:
Trichloromethyl chloroformate (2.5 mL, 21 mmol) was added slowly to a suspension of (1) (4 g, 17.5 mmol) in dioxane and refluxed for 8 h under nitrogen atmosphere. The solution was cooled and the solvent was removed under vacuum. The residue was dissolved in dichloromethane and washed by saturated NaHCO3 solution. The organic phase was dried over Na2SO4 and evaporated to yield a residue. The residue was recrystallized by ether to yields 3.02 g (68%) of 1-benzyl-1H-pyrido[2,3-d][1,3]oxazine-2,4-dione (2) as white solids. MP: 168° C.; 1H-NMR (DMSO-d6): δ 5.35 (s, 2H), 7.26 (m, 1H), 7.30 (m, 2H), 7.39 (m, 3H), 8.41 (dd, J=1.5, 7.5 Hz, 1H), 8.72 (dd, J=1.5, 7.5 Hz, 1H); EIMS: 277 (M+23).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:29](COCC[Si](C)(C)C)[C:28]([O:38][C@H:39]3[C@H:43]4[O:44][CH2:45][C@@H:46]([OH:47])[C@H:42]4[O:41][CH2:40]3)=[N:27][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:17][C:16]3([CH2:20][N:19]([C:21]4[N:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[CH2:18]3)[CH2:15]2)=[CH:10][CH:9]=1.[C:48]([OH:54])([C:50]([F:53])([F:52])[F:51])=[O:49]>C(Cl)Cl.CO>[F:51][C:50]([F:53])([F:52])[C:48]([OH:54])=[O:49].[Cl:1][C:2]1[CH:3]=[C:4]2[NH:29][C:28]([O:38][C@H:39]3[C@H:43]4[O:44][CH2:45][C@@H:46]([OH:47])[C@H:42]4[O:41][CH2:40]3)=[N:27][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:17][C:16]3([CH2:18][N:19]([C:21]4[N:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[CH2:20]3)[CH2:15]2)=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(N4CC5(C4)CN(c4ncccn4)C5)cc3)c(Cl)cc21
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(N4CC5(C4)CN(c4ncccn4)C5)cc3)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (3R,3aR,6R,6aR)-6-[6-chloro-5-[4-(6-pyrimidin-2-yl-2,6-diazaspiro[3,3]heptan-2-yl)phenyl]-1-(2-trimethylsilylethoxy-methyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (54.3 mg, 0.08 mmol) in TFA (0.5 mL) and DCM (0.5 mL) was stirred at room temperature. After 2 hours, the reaction mixture was evaporated to give an oil. The oil was dissolved in MeOH (1 mL) and purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-100% acetonitrile/water+0.05% TFA gradient followed by a 100% acetonitrile/water+0.05% TFA flush. The desired fractions were combined, evaporated under reduced pressure, and lyophilized from ethanol and benzene to give the title compound as a solid. LC-MS: calculated for C27H26ClN7O4 547.17 observed m/e: 548.35 (M+H)+ (Rt 0.70/2 min); 1H NMR δ (ppm) (CD3OD): 8.44 (d, 2H), 7.96 (s, 1H), 7.56 (d, 2H), 6.81 (m, 1H), 6.65 (d, 2H), 5.58 (qt, 1H), 4.96 (t, 1H), 4.48 (t, 1H), 4.43 (s, 4H), 4.26-4.31 (m, 1H), 4.18 (s, 4H), 4.16 (dd, 1H), 4.12 (dd, 1H), 3.90 (t, 1H), 3.60 (t, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:15]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(N(C(C)C)CC)(C)C>C(#N)C>[C:18]([O:17][C:15]([N:22]1[CH2:27][CH2:26][N:25]([C:5]2[N:4]=[N:3][C:2]([Cl:1])=[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=2)[CH2:24][CH2:23]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1cc(-c2ccccc2)c(Cl)nn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2cc(-c3ccccc3)c(Cl)nn2)CC1
Temperature: 180 °C
Reaction time: 0.67 h
Yield: 20.1 %

Procedure:
A mixture of 3,6-dichloro-4-phenyl-pyridazine (0.41 g, 1.82 mmol), prepared by following the procedure described in WO-2005/013907, N-Boc-piperazine (0.509 g, 2.73 mmol) and diisopropylethylamine (0.634 ml, 3.64 mmol) in acetonitrile (7.5 ml) was stirred at 180° C. for 40 min., under microwave irradiation, and then for a further 30 min. After this period, additional amounts of diisopropylethylamine (0.1 ml, 0.57 mmol) and N-Boc-piperazine (0.1 g, 0.54 mmol) were added and the resulting mixture was stirred at 180° C. for 40 min. The solvent was evaporated in vacuo and then, dichloromethane and a saturated solution of ammonium chloride were added. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The residue was then purified by column chromatography (silica gel; dichloromethane and heptane/ethyl acetate 8:2 to 7:3). The desired fractions were collected and evaporated in vacuo to yield D13 (0.137 g, 20%) as a white solid. C19H23ClN4O2 requires 374; Found 375 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[C:10]=1[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[O:31])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH3:33][O:32][C:30](=[O:31])[CH2:29][CH2:28][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:34]
Reactant: CCOC(=O)CCCOc1cccc(C#CCCCCOC2CCCCO2)c1C=CC(=O)OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOC2CCCCO2)c1CCC(=O)OC
Reaction time: 24 h

Procedure:
A 9.73 g (ca. 20 mmol) sample of crude rac-4-[2-(3-methoxy-3-oxo-1-propenyl)-3-[6-[(tetrahydro-2H-pyran-2-yl)oxy]-1-hexynyl]phenoxy]butanoic acid ethyl ester from the preceding example was hydrogenated in 275 mL of ethyl acetate, over 0.75 g of 10% palladium on carbon, at room temperature and 1 atmosphere, for 24 hr. rac-2-(4-Ethoxy-4-oxobutoxy)-6-[6-[(tetrahydro-2H-pyran-2-yl)oxy]hexyl]benzenepropanoic acid methyl ester, an oil, was isolated by filtration of the catalyst and concentration of the filtrate, in quantitative yield (9.74 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:9][C:10]2[CH:15]=[C:14]([C:16]([CH3:24])([CH3:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:13]=[C:12]([C:25]([CH3:33])([CH3:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:11]=2O)=[C:4]([N+:35]([O-])=O)[CH:3]=1.[N+](C1C=CC=CC=1N=NC1C=C(C(C)(C)C2C=CC=CC=2)C=C(C(C)(C)C2C=CC=CC=2)C=1O)([O-])=[O:39]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2=[N:8][N:9]([C:10]3[CH:11]=[C:12]([C:25]([CH3:33])([CH3:32])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=4[OH:39])[CH:13]=[C:14]([C:16]([CH3:23])([CH3:24])[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:35]=[C:4]2[CH:3]=1
Reactant: CC(C)(c1ccccc1)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)c2ccccc2)c1
Reactant: CC(C)(c1ccccc1)c1cc(N=Nc2ccc(Cl)cc2[N+](=O)[O-])c(O)c(C(C)(C)c2ccccc2)c1
Product: CC(C)(c1ccccc1)c1cc(-n2nc3ccc(Cl)cc3n2)cc(C(C)(C)c2ccccc2O)c1
Yield: 70 %

Procedure:
When, using the general procedure of example 3, the amount of 4-chloro-2-nitro-2'-hydroxy-3',5'-di-(α,α-dimethylbenzyl)azobenzene was substituted for 2-nitro-2'-hydroxy-3',5'-di-(α,α-dimethylbenzyl)azobenzene, the above-named compound was prepared in a yield of 70.0% as light tan crystalls melting at 160°-161° C.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][C:17]=3Br)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[I-].[C:34]1([Zn+])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[C:17]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:18][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:21]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(Br)c1
Reactant: [Zn+]c1ccccc1
Agent: [I-]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(-c2ccccc2)c1
Reaction time: 2 h
Yield: 63.4 %

Procedure:
Ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-bromophenyl)acetate (Example 46 step C; 24 mg, 0.046 mmol) was diluted with THF (1 mL) followed by the addition of bis(tri-1-butylphosphine)palladium (0) (2.4 mg, 0.0046 mmol) and phenylzinc iodide (0.23 ml, 0.12 mmol). After stirring for 2 hours, the reaction was loaded directly onto a silica gel column and eluted with hexanes:ethyl acetate (3:1) to yield Ethyl 2-(6-(4-(4-chlorophenethylcarbamoyl)phenoxy)biphenyl-3-yl)acetate (15 mg, 63% yield) as a clear oil.
Reaction SMILES: [C:1]([C:9]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:10]=1[NH:11][C:12](=[O:21])[C:13](=[N:19]O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl>[Zn].C(O)(=O)C>[Cl:26][C:24]1[CH:23]=[CH:22][C:10]2[NH:11][C:12](=[O:21])[CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:19]=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9]=2[CH:25]=1
Reactant: CCOC(=O)C(=NO)C(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)C1N=C(c2ccccc2)c2cc(Cl)ccc2NC1=O

Procedure:
A solution of 2 g. of ethyl 2'-benzoyl-4'-chloro-mesoxalanilate 2-oxime in 40 ml. of methylene chloride is treated with 2 g. of zinc dust. 4 ml. of glacial acetic acid are added dropwise within 5 minutes with stirring. After the addition, the mixture is stirred at room temperature for 1 hour. The reaction mixture is filtered and the filtrate evaporated. The residue is boiled under reflux for 2 hours in 20 ml. of benzene and 2 ml. of glacial acetic acid. The reaction mixture is washed out with 10% soda solution, dried over sodium sulphate and evaporated. Crystallization of the residue from alcohol yields ethyl 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one-3-carboxylate, m.p. 232°-234°. Further material crystallizes from the mother liquor.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]2[C:5]([CH:6]([NH:15][C:16]([NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[CH:21]=[N:22][NH:23]4)=[O:17])[CH2:7][C:8]3([O:12]2)[CH2:11][CH2:10][CH2:9]3)=[CH:4][CH:3]=1.[H-].[Na+].S(OC)(O[CH3:34])(=O)=O>CN(C)C=O>[F:1][C:2]1[CH:14]=[C:13]2[C:5]([CH:6]([NH:15][C:16]([NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[CH:21]=[N:22][N:23]4[CH3:34])=[O:17])[CH2:7][C:8]3([O:12]2)[CH2:11][CH2:10][CH2:9]3)=[CH:4][CH:3]=1
Reactant: O=C(Nc1cccc2[nH]ncc12)NC1CC2(CCC2)Oc2cc(F)ccc21
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncc2c(NC(=O)NC3CC4(CCC4)Oc4cc(F)ccc43)cccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of Example 3D (483 mg, 1.32 mmol) in N,N-dimethylformamide (5 mL) was treated with 60% NaH (65 mg, 1.63 mmol), and the mixture was stirred at room temperature for 45 min. Dimethyl sulfate (0.14 mL, 1.48 mmol) was then added, and the reaction was allowed to stir for 1 h. Concentration in vacuo, followed by silica gel:chromatography (98:2 CH2Cl2-methanol, eluent), afforded the title compound as an off-white solid, 121 mg (24%). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.74 (s, 1H), 8.03 (s, 1H), 7.72 (d, J=7.1 Hz, 1H), 7.29 (m, 2H), 7.16 (d, J=8.5 Hz, 1H), 6.77 (m, 2H), 6.66 (dd; J=10.5, 7.8 Hz; 1H), 4.97 (m, 1H), 4.01 (s, 3H), 2.40 (m, 1H), 2.12-2.30 (m, 4H), 1.65-1.99 (m, 3H). MS (ESI+) m/z 381 (M+H).
Reaction SMILES: [Si]([O:8][CH:9]([C:11]1[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][C:15]([C:23]([C:28]1[N:29]=[CH:30][NH:31][CH:32]=1)([OH:27])[CH:24]([CH3:26])[CH3:25])=[CH:16]2)[CH3:10])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][CH:9]([C:11]1[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][C:15]([C:23]([C:28]1[N:29]=[CH:30][NH:31][CH:32]=1)([OH:27])[CH:24]([CH3:26])[CH3:25])=[CH:16]2)[CH3:10]
Reactant: COc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1C(C)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1C(C)O
Temperature: 60 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
1-[5-[1-(tert-Butyldimethylsilyloxy)ethyl]-6-methoxynaphthalen-2-yl]-1-(1H-imidazol-4-yl)-2-methyl-1-propanol (0.499 g) was dissolved in THF (5 ml). To the solution was added tetrabutylammonium fluoride (1.0M in THF; 5 ml), and the mixture was stirred at 60° C. for 8 h. The reaction mixture was concentrated. The obtained residue was purified by silica gel column chromatography (eluent, ethyl acetate:methanol=1:0→10:1) and washed with hexane to give the titled compound (0.24 g) as an amorphous product.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.[OH-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[NH2:1][C:2]1[N:3]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1
Reactant: BrCc1ccccc1
Reactant: Nc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Nc1nc2cc(Cl)c(Cl)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
2-Amino-5,6-dichlorobenzimidazole (4) (1 g, 4.95 mmole) was dissolved in acetonitrile (200 ml) and NaOH (198 mg, 4.95 mmole) was added. After stirring for 1 hr at room temperature, benzyl bromide (0.589 ml, 4.95 mmole) was added and the mixture was allowed to stir overnight. The mixture was concentrated under reduced pressure and purified on a silica gel column (3.5×5 cm) using 5% MeOH/CHCl3 to give 1.23 g (85%) of 2-amino-1-benzyl-5,6-dichlorobenzimidazole (182). The compound was then recrystallized from EtOH/H2O to give a white powder. 1H NMR (DMSO-d6): d 5.28 ppm (s, 2H), 6.95 (s, 2H), 7.16 (d, 2H), 7.25 (d, 1H), 7.31 (m, 4H). 13C NMR (DMSO-d6): d 44.74 ppm, 109.15, 115.37, 119.62, 122.66, 126.82, 127.37, 128.55, 134.10, 136.46, 143.13, 156.91. MS (Electron Impact): m/e 291, 200, 158, 91, 65. MP: 245°-246° C. Elemental Analysis: (C14H11Cl2N3, ): Calculated: C, 57.55; H, 3.79; N, 14.38. Found: C, 57.66; H, 3.83; N, 13.98. UV Imax nm (e×104): (pH 7) 230 (0.761), 260 (0.324), 302 (0.452); (pH 1) 238 (0.306), 294 (0.383), 299 (0.359); (pH 11) 229 (0.869), 257 (0.316), 301 (0.443).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-].[Na+].[OH-].[Na+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: ClCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [I-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](OCc2ccccc2)C1
Temperature: 50 °C

Procedure:
N-tert-butoxycarbonyl-(R)-3-hydroxypyrrolidine prepared separately was dissolved in 748 mg of toluene followed by adding 16 mg of tetra-n-butyl ammonium bromide and 9 mg of sodium iodide. Further, after 666 mg of 30% aqueous solution of sodium hydroxide was added and the mixture was heated to 50° C., 164 mg of benzyl chloride was dropped. A reaction temperature was cooled to 25° C. to stop the reaction at the stage where a remaining N-tert-butoxycarbonyl-(R)-3-hydroxypyrrolidine became 6.4 wt % with respect to
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[N:7]=1)=O.N>CO>[NH2:5][C:6]1[CH2:10][CH:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:8]([C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:28])[C:24]([F:25])([F:27])[F:26])=[CH:19][CH:18]=2)[N:7]=1
Reactant: O=C(NC1=NN(c2ccc(C(=O)C(F)(F)F)cc2)C(c2ccccc2)C1)C(F)(F)F
Agent: N
Solvent: CO
Product: NC1=NN(c2ccc(C(=O)C(F)(F)F)cc2)C(c2ccccc2)C1
Reaction time: 16 h

Procedure:
A solution of 1.0 g. of 2,2,2-trifluoro-N-[5-phenyl-1-(p-trifluoroacetylphenyl)-2-pyrazolin-3-yl]acetamide (prepared as described in Example 9) in 100 ml. of methanol is saturated with ammonia gas, then is stored in a refrigerator for 16 hours. The solution is evaporated to dryness in vacuo. The residue is chromatographed by preparative column chromatography using silica gel and eluting with acetone:hexane, 50:50, to collect the most polar product. The product is recrystallized from dichloromethanehexane to yield 0.25 g. of the product of the Example as yellow needles, m.p. 214°-216° C.