Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[C:16]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]5[N:25]([S:28]([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=6)(=[O:30])=[O:29])[CH:26]=[CH:27][C:20]=45)[CH:15]=[C:14]([NH2:37])[C:13]=3[CH:12]=[N:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[Cl:47][CH2:48][C:49]1[S:50][CH:51]=[C:52]([C:54](Cl)=[O:55])[N:53]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl>[Cl:47][CH2:48][C:49]1[S:50][CH:51]=[C:52]([C:54]([NH:37][C:14]2[CH:15]=[C:16]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]4[N:25]([S:28]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)(=[O:29])=[O:30])[CH:26]=[CH:27][C:20]=34)[CH:17]=[C:18]3[C:13]=2[CH:12]=[N:11][N:10]3[S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])=[O:55])[N:53]=1
Reactant: Nc1cc(-c2ccnc3c2ccn3S(=O)(=O)c2ccccc2)cc2c1cnn2S(=O)(=O)c1ccccc1
Reactant: O=C(Cl)c1csc(CCl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(-c2ccnc3c2ccn3S(=O)(=O)c2ccccc2)cc2c1cnn2S(=O)(=O)c1ccccc1)c1csc(CCl)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 12.9 %

Procedure:
1-(Phenylsulfonyl)-6-[1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-indazol-4-amine (663 mg, 1.252 mmol) in chloroform (10 mL) was stirred at 0° C. DIPEA (0.437 mL, 2.504 mmol) was added into the reaction mixture, then 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (300 mg, 1.530 mmol) in chloroform (10.00 mL) was added. The reaction mixture was stirred at 0° C. for 15 mins. A further portion of 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (400 mg, 1.252 mmol) was added to the reaction mixture and stirring was continued. When no further product formation was observed, further 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (1.6 g, 1.252 mmol) was added to the reaction mixture which was stirred under nitrogen for 18 h. The solution was treated with DCM (25 mL) and saturated aqueous sodium bicarbonate (25 mL), then stirred for 10 mins. The organic layer was separated, washed with diluted aqueous sodium chloride (25 mL) and then passed through a hydrophobic frit. A part of the solvent was removed then the solution was applied to a silica column (Flasmaster II, 100 g silica cartridge) and eluted with a gradient of 0-100% ethylacetate/cyclohexane over 60 min. Fractions containing desired product we combined and the solvent was removed to afford the title compound as a white solid (111 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][CH2:6][CH2:5]2.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[N:7]([S:22]([C:19]1[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:21][CH:20]=1)(=[O:24])=[O:23])[CH2:6][CH2:5]2
Reactant: O=[N+]([O-])c1cc(Br)cc2c1NCC2
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)N2CCc3cc(Br)cc([N+](=O)[O-])c32)cc1

Procedure:
The preparation involved a straightforward reaction sequence with high yields (overall 48-56% in three or four steps). The commercially available 5-bromo-7-nitroindoline (16) was reacted with the 4-methoxybenzenesulfonyl chloride in pyridine to afford the 5-bromo-1-(4-methoxybenzenesulfonyl)-7-nitroindoline (17).
Reaction SMILES: [S:1]1[C:5](B(O)O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[Br:13][C:14]1[CH:19]=[CH:18][C:17](I)=[C:16]([F:21])[CH:15]=1.C([O-])(O)=O.[Na+]>COCCOC.O.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>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:5]2[S:1][C:2]3[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=3[CH:4]=2)=[C:16]([F:21])[CH:15]=1
Reactant: OB(O)c1cc2ccccc2s1
Reactant: Fc1cc(Br)ccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Fc1cc(Br)ccc1-c1cc2ccccc2s1
Temperature: 80 °C
Yield: 12.8 %

Procedure:
A mixture of Benzo[b]thiophene-2-boronic acid (0.71 g, 4 mmol), 1-bromo-3-fluoro-4-iodobenzene (1 g, 3.3 mmol), bis(triphenylphospine)palladium(II) chloride (46 mg, 2 mol %), NaHCO3 (0.83 g, 9.9 mmol) in DME (4 mL) and H2O (4 mL) was heated to 80° C. under N2 for 72 h. The reaction mixture was partitioned between 1N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (hexanes) to give the title compound as a white solid (0.13 g, 13%). 1H NMR (CDCl3): δ 7.33-7.41 (m, 4H), 7.57 (m, 1H), 7.72 (s, 1H), 1.80-7.86 (m, 2H).
Reaction SMILES: B(F)(F)F.CCOCC.[OH:10][C:11]1[C:20]([CH3:21])=[C:19]2[C:14]([CH:15]=[C:16]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:17](=[O:22])[O:18]2)=[C:13]([O:34][CH3:35])[CH:12]=1.ClC(Cl)(Cl)C(=N)O[C@H:40]1[C@@H:45]2[O:46][C:47](=[O:49])[O:48][C@@H:44]2[C@@H:43]([O:50][CH3:51])[C:42]([CH3:53])([CH3:52])[O:41]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:35][O:34][C:13]1[CH:12]=[C:11]([O:10][C@H:40]2[C@@H:45]3[O:46][C:47](=[O:49])[O:48][C@@H:44]3[C@@H:43]([O:50][CH3:51])[C:42]([CH3:53])([CH3:52])[O:41]2)[C:20]([CH3:21])=[C:19]2[C:14]=1[CH:15]=[C:16]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:17](=[O:22])[O:18]2
Reactant: COc1cc(O)c(C)c2oc(=O)c(NC(=O)OCc3ccccc3)cc12
Reactant: CO[C@@H]1[C@H]2OC(=O)O[C@H]2[C@H](OC(=N)C(Cl)(Cl)Cl)OC1(C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(O[C@@H]2OC(C)(C)[C@H](OC)[C@H]3OC(=O)O[C@@H]23)c(C)c2oc(=O)c(NC(=O)OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 73.5 %

Procedure:
Boron trifluoride etherate (18.5 μL, 0.15 mmol) was added to 23d (174 mg, 0.49 mmol) and (3aR,4S,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-3aH-[1.3]dioxolo[4,5-c]pyran-4-yl 2,2,2-trichloroacetimidate (621 mg, 1.71 mmol) in anhydrous CH2Cl2 (11.0 mL). After stirring at room temperature for 14 hours, triethylamine (150 μL) was added and the solvent was concentrated. The residue was purified via column chromatography (SiO2, 40:1 CH2Cl2:Acetone) to give 25d as a colorless foam (200 mg, 74%): 1H NMR (CDCl3, 500 MHz) 8.49 (s, 1H), 7.34-7.27 (m, 5H), 6.67 (s, 1H), 6.60 (s, 1H), 5.69 (s, 2H), 5.16 (d, J=5.3 Hz, 1H), 4.89 (t, J=7.8 Hz, 1H), 4.63 (dd, J=7.9, 2.4 Hz, 1H), 3.83 (s, 3H), 3.37 (s, 3H), 3.15 (d, J=8.0 Hz, 1H), 2.16 (s, 3H), 2.16 (s, 3H), 2.12 (s, 3H); 13C NMR (CDCl3, 125 MHz) 158.9, 156.0, 155.2, 154.2, 153.1 (2C), 149.4, 135.7, 128.7 (2C), 128.5, 128.2 (2C), 120.8, 117.4, 106.6, 105.4, 94.6, 94.1, 82.9, 67.4, 60.6, 60.6, 56.1, 56.0, 22.2, 22.0, 7.9; IR (film) νmax 2955, 2924, 2853, 1817, 1713, 1526, 1209, 1105, 1072, 1034, 976, 808 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C28H29NO11, 556.1819. found, 556.1826.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[N:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16])=[O:11].C(Cl)CCl.[NH3:26]>CN(C1C=CN=CC=1)C.ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[N:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([NH2:26])=[O:16])=[O:11]
Reactant: N
Reactant: O=C(Nc1ncccc1C(=O)O)c1cc2ccccc2s1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: NC(=O)c1cccnc1NC(=O)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A mixture of 2-[(1-benzothien-2-ylcarbonyl)amino]nicotinic acid (112 g, 4.0 mmol), EDC (2.3 g, 12.0 mmol) and DMAP (1.46 g, 12.0 mmol) in anhyd dichloromethane (50 mL) was stirred at room temperature for 2 h. To this mixture was added 40% aqueous ammonia (4.0 mL), and the resulting solution stirred at room temperature overnight. The solvent was removed in vacuo and the resulting solid was washed with satd NH4Cl solution, NaHCO3 solution, and water. The solid was dried to give product as white powder (0.92 g, 77%). HPLC/MS: (M+H)+298.15 m/z Retention time (LC-MS)=2.44 min. 1H NMR (DMSO-D6): 12.25 (1H, s); 8.54(1H, m); 8.21(1H, s); 8.18(1H, d); 8.07(2H, m); 7.52(2H, m); 7.32(1H, m).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH3:15])[CH2:10][CH2:9]2)[N:5]=[CH:4][N:3]=1.[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][C:31]=2[OH:33])[CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]3[N:5]=[CH:4][N:3]=[C:2]([O:33][C:31]4[CH:30]=[CH:29][CH:28]=[C:27]5[C:32]=4[CH:23]=[N:24][CH:25]=[CH:26]5)[CH:7]=3)[CH2:9][CH2:10]2)[CH3:15])=[CH:17][CH:18]=1
Reactant: CC(c1ccc(F)cc1)N1CCN(c2cc(F)ncn2)CC1
Reactant: Oc1cccc2ccncc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CC(c1ccc(F)cc1)N1CCN(c2cc(Oc3cccc4ccncc34)ncn2)CC1
Temperature: 115 °C

Procedure:
A mixture of 4-fluoro-6-(4-(1-(4-fluorophenyl)ethyl)piperazin-1-yl)pyrimidine, Example 33(a), (0.05 g, 0.17 mmol), isoquinolin-8-ol (0.037 g, 0.25 mmol, Monomer Chem, Inc.) cesium carbonate (0.081 g, 0.25 mmol), and DMSO (1 mL) was heated in a microwave synthesizer at 115° C. for 0.5 h. The reaction mixture was allowed to cool to room temperature, diluted with H2O (30 mL) and extracted with DCM (2×50 mL). The combined organic extracts were washed with H2O (2×30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient: 0-8% MeOH/DCM) to give the title compound as a white solid. Mp: 114° C. MS (ESI, pos. ion) m/z: 430 (M+1).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:21][C@@H:22]([C:26]1[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1)[CH2:23][CH2:24][OH:25].C(N(CC)C(C)C)(C)C>C(#N)C>[OH:25][CH2:24][CH2:23][C@@H:22]([NH:21][C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1)[C:26]1[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1
Reactant: Cc1ccc([C@H](N)CCO)cn1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCc3ncnc(N[C@H](CCO)c4ccc(C)nc4)c3C2)c(C#N)c1
Yield: 33.3 %

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (60 mg, 0.21 mmol) and (R)-3-amino-3-(6-methylpyridin-3-yl)propan-1-ol (35 mg, 0.21 mmol) in acetonitrile (2 mL) and N,N-diisopropylethylamine (73 μL, 0.42 mmol) was subjected to microwave irradiation at 180° C. for 3 h. The reaction mixture was concentrated and the residue was purified by silica gel column (0-30% MeOH/CH2Cl2) followed by preparative HPLC (100×20.2 mm, C18 column; 20-50% CH3CN-water [10 mM Et2NH]) to yield an off-white solid (29 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][NH2:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl[S:14]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=1)(=[O:16])=[O:15].[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[CH2:11][N:12]([CH2:33][C:32]1[CH:35]=[CH:36][C:29]([O:28][CH3:27])=[CH:30][CH:31]=1)[S:14]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: COc1ccc(CBr)cc1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(CN)cc1OC
Product: COc1ccc(CN(Cc2ccc(OC)c(OC)c2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-10 from (3,4-dimethoxyphenyl)methanamine, methyl 4-(chlorosulfonyl)benzoate (Example 5-10c) and 4-methoxybenzylbromide. MS (M−H, 470.10); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.49 (s, 3H), 3.67 (s, 3H), 3.68 (s, 3H), 4.20 (s, 2H), 4.22 (s, 2H), 6.41 (d, 1H, J=1.4 Hz), 6.58 (dd, 1H, J1=8.2 Hz, J2=1.4 Hz), 6.78 (m, 3H), 7.02 (d, 2H, J=8.6 Hz), 7.94 (d, 2H, J=8.4 Hz), 8.09 (d, 2H, J=8.4 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].CO.[BH4-].[Na+].C(O)(=O)C>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17]
Reactant: O=C(c1ccccc1)c1ccc(F)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(C(O)c2ccccc2)ccc1F
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a cooled (ice bath) solution of 24.5 parts of (4-fluoro-3-nitrophenyl) phenylmethanone in 120 parts of methanol were added portionwise 1.5 parts of sodium tetrahydroborate. Upon complete addition, stirring was continued for 15 minutes at 0° C. A solution of 3 parts of acetic acid in 25 parts of water was added dropwise to the mixture. Upon completion, the mixture was concentrated. Water was added to the residue and the product was extracted with dichloromethane. The extract was dried, filtered and concentrated, yielding 25.1 parts (100%) of 4-fluoro-3-nitro-α-phenylbenzenemethanol as an oily residue (int. 63).
Reaction SMILES: [SiH:1]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:2][CH3:3].[Cl:8][CH:9]([CH3:12])[CH:10]=[CH2:11]>>[Si:1]([Cl:8])([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:2][CH3:3].[Si:1]([CH2:11][CH2:10][CH:9]([Cl:8])[CH3:12])([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:2][CH3:3]
Reactant: C=CC(C)Cl
Reactant: CC[SiH](CC)CC
Product: CC[Si](CC)(CC)CCC(C)Cl
Product: CC[Si](Cl)(CC)CC
Temperature: 77 °C
Yield: 7.6 %
Yield: 58.9 %

Procedure:
In a 50 ml apparatus, there were combined 4.5 g (0.039 mol) of Et3SiH and 3.5 g (0.039 mol) of 3-chloro-1-butene. Pt catalyst solution (0.01 ml) was added at 22° C., followed by heating up to 77° C. over 70 min. Vacuum distillation yielded 3.46 g (58.9%) of Et3SiCl and 0.61 g (7.6%) of Et3SiCH2CH2CHMeCl. This example demonstrates the low yield of Et3SiCH2CH2CHMeCl from the unpromoted reaction of Et3SiH with 3-chloro-1-butene.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:15]2[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:14]=2[N:13]=[C:12]1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([NH2:30])[CH:23]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[S:42](Cl)(=[O:44])=[O:43]>O>[CH2:1]([O:8][C:9]([N:11]1[C:15]2[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:14]=2[N:13]=[C:12]1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([NH:30][S:42]([C:38]2[S:37][CH:41]=[CH:40][CH:39]=2)(=[O:44])=[O:43])[CH:23]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2nc3cc(Cl)c(Cl)cc3n2C(=O)OCc2ccccc2)cc1N
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(-c2nc3cc(Cl)c(Cl)cc3n2C(=O)OCc2ccccc2)cc1NS(=O)(=O)c1cccs1
Reaction time: 8 h

Procedure:
2-(3-Amino-4-methoxy-phenyl)-5,6-dichloro-benzoimidazole-1-carboxylic acid benzyl ester from Step C was mixed with pyridine (5 mL) and 2-thienylsulfonyl chloride (0.1283 g, 0.7 mmol) was added. The mixture was allowed to stand overnight. Water (100 mL) was added to the reaction mixture and the product crystallized within 5 hours. The solid was then collected by filtration and triturated with 1/1, hexanes/ethyl acetate (0.2 g), mp 195-198° C.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.Cl[CH2:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20]>C(O)(C)C>[F:12][C:11]([F:14])([F:13])[C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([S:1][CH2:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[NH2:20])=[N:3][C:4]=2[CH:10]=1
Reactant: Nc1ccccc1CCl
Reactant: FC(F)(F)c1ccc2nc(S)[nH]c2c1
Agent: Cl
Solvent: CC(C)O
Product: Nc1ccccc1CSc1nc2cc(C(F)(F)F)ccc2[nH]1
Yield: 37.1 %

Procedure:
The title compound was prepared by the method of Example 1 using 4.36 g of 2-mercapto-5-(trifluoromethyl)benzimidazole instead of 2-mercaptobenzimidazole and 3.56 g of 2-(chloromethyl)aniline hydrochloride instead of 2-(chloromethyl)-N,N-dimethylaniline in isopropyl alcohol. The basic extraction used 5% sodium hydroxide instead of sodium carbonate. Washing the solid residue from the dichloromethane extract with additional dichloromethane gave 2.40 g of the title compound: m.p. ca. 155° C. Analysis. Calc'd. for C15H12N3F3S: C, 55.72; H, 3.74; N, 13.00; S, 9.92; F, 17.63. Found: C, 55.55; H, 3.68; N, 13.10; S, 10.12; F, 17.38.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:2]2.C(N(CC)CC)C.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1.O>C(Cl)(Cl)Cl>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:2]2[CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:4]3[CH2:7][CH:1]2[CH2:6][CH2:5]3)=[CH:24][CH:23]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)C1NC2CCC1C2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C1C2CCC(C2)N1Cc1ccc(OC)cc1
Yield: 85.8 %

Procedure:
To a solution of ethyl 2-azabicyclo[2.2.1]heptane-3-carboxylate (231 mg, 1.37 mmol) in chloroform (5 ml) were added triethylamine (0.20 ml, 1.43 mmol) and 4-methoxybenzyl chloride (0.19 ml, 1.43 mmol) while being cooled with ice. After a reaction at 60° C. for 20 hours, the reaction mixture, with water added thereto, was extracted with chloroform. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (1% methanol/chloroform), to give ethyl 2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3-carboxylate (340 mg, 86%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:18]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].C[O:33]B(OC)OC.OO>O1CCCC1.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:18]3[CH:19]=[CH:20][C:21]([F:23])=[C:22]([OH:33])[C:17]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COB(OC)OC
Reactant: CC(C)(C)OC(=O)N1CCC(c2noc3cc(F)ccc23)CC1
Agent: CC(C)[N-]C(C)C
Agent: OO
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2noc3c(O)c(F)ccc23)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
To a stirred solution of 4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.00 g, 3.13 mmol) in dry tetrahydrofuran (31.3 mL) cooled to −78° C. was added lithium diisopropylamide (1.72 mL, 3.35 mmoles). The resulting solution was stirred at −78° C. for 2 hours when trimethylborate (0.44 mL, 3.84 mmoles) was added. The resulting solution was stirred at −78° C. for 1 hour then was allowed to warm to room temperature over 3 hours when hydrogen peroxide (2.00 mL) and acetic acid (1.00 mL) were added. The resulting mixture was stirred at room temperature overnight when the mixture was quenched with saturated NH4Claq (20 mL) and 10% HClaq (20 mL). The resulting mixture was extracted with CH2Cl2 (4×50 mL). The combined extracts were washed with brine (50 mL), dried (MgSO4), filtered and evaporated. The residue was separated via column chromatography (1:1; Et2O/Pet. ether) yielding 0.619 g (59%) of the phenol as a white, crystalline solid, mp 169-170° C. Analysis calculated for C−17H21N2FO4; 60.70% C, 6.29% H, 8.33% N. Found: 60.72% C, 6.15% H, 8.22% N.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]([F:26])([F:25])[CH:15]1[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17][CH2:16]1.CI>O1CCCC1>[CH3:1][C:18]1([C:21]([O:23][CH3:24])=[O:22])[CH2:17][CH2:16][CH:15]([C:14]([F:25])([F:26])[F:13])[CH2:20][CH2:19]1
Reactant: COC(=O)C1CCC(C(F)(F)F)CC1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCC(C(F)(F)F)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 104.1 %

Procedure:
To a solution of diisopropylamine (22.0 mL, 124.0 mmol) in tetrahydrofuran (60 mL) was added n-BuLi (2.0 M solution in hexane, 59.0 mL, 95.0 mmol) at 0° C. and the reaction mixture was allowed to stir at same temperature for 20 minutes before cooled to −78° C. Methyl 4-(trifluoromethyl)cyclohexanecarboxylate (10.0 g, 48.0 mmol) in tetrahydrofuran (60 mL) was added dropwise at −78° C. The reaction mixture was stirred at same temperature for 2 hours and then neat methyl iodide (4.5 mL, 72.0 mmol) was added dropwise. After stirring at −78° C. for 1 hour, the reaction mixture was warmed to ambient temperature and stirred for 16 hours, before quenched with 25% aqueous ammonium chloride solution (100 mL) at 0° C. and extracted with ethyl acetate. The organic layer was washed with brine; dried over anhydrous sodium sulfate and concentrated in vacuo to afford the title compound (11.2 g, 99%) as a brown colored oil: 1H NMR (300 MHz, CDCl3) δ 3.70 (s, 3H), 2.32-2.28 (m, 2H), 2.01-1.80 (m, 3H), 1.42-1.08 (m, 7H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10])[CH3:2].[CH2:12]=[O:13].CC([O-])(C)C.[K+]>CS(C)=O.C(O)(C)(C)C>[N+:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH:1]([CH3:2])[CH2:12][OH:13])([O-:11])=[O:10]
Reactant: C=O
Reactant: CCc1ccccc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CS(C)=O
Product: CC(CO)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
1-Ethyl-2-nitrobenzene (13.5 mL, 100 mmol) was dissolved in dimethylsulfoxide (100 mL). Paraformaldehyde (4.50 g, 150 mmol) and KOtBu (2.81 g, 25 mmol) in t-butyl alcohol (30 mL) were added and the mixture was stirred at room temperature for 3 h. The solution was washed with a molar solution of HCl (25 mL), followed by brine (3×100 mL). All the aqueous layers were combined and extracted with ethyl acetate(3×100 mL). The organic portion was dried (MgSO4), filtered and the solvent was removed in vacuo. The crude product was purified on a silica gel column. Elution of the column with 20-30% ethyl acetate in hexanes gave 16.12 g (89 mmol, 89% yield) of 2-(2-nitrophenyl)propanol. 1H-NMR (600 MHz, DMSO-d6): δ 7.75 (d, J=8.10 Hz, 1H, Ar—H), 7.63 (t, J=7.62 Hz, 1H, Ar—H), 7.58 (d, J =7.80 Hz, 1H, Ar—H), 7.42 (t, J=7.50, 1H, Ar—H), 4.73 (t, J=5.30 Hz, 1H, OH), 3.50 (m, 2H, CH 2), 3.19 (m, 1H, CH), 1.21 (d, J=6.90 Hz, 3H, CH3). TLC: 20% ethyl acetate in hexane, Rf=0.3.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:19]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[Sn].Cl>C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:19]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(NCCCOc1cccc(CN2CCCCC2)c1)Nc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [Sn]
Solvent: CCO
Product: Nc1cccc(NC(=O)NCCCOc2cccc(CN3CCCCC3)c2)c1
Yield: 42.2 %

Procedure:
To the mixture of N-(3-nitrophenyl)-N'-[3-(3-piperidinomethylphenoxy)propyl]urea (4.6 g) in ethanol (46 ml) was added tin (2.6 g). To the reaction mixture was added concentrated hydrochloric acid (1.9 ml) at room temperature under stirring, further added concentrated hydrochloric acid (18.2 ml) under heating on a water bath. The reaction mixture was refluxed for 6 hours, concentrated under reduced pressure, diluted with water (100 ml), alkalized with aqueous sodium hydroxide solution and extracted with dichloromethane (200 ml). The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude precipitate (3.8 g; yield 88.4 %). This precipitate was recrystallized two times from ethanol to give the title compound (1.8 g), mp 116°-118 ° C. Analysis (%) for C22H30N4O2, Calcd. (Found): C, 69.08 (68.91); H, 7.91 (7.90); N, 14.65 (14.54).