Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5](Cl)=[N:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1.[CH2:14]([OH:19])[C:15]([F:18])([F:17])[F:16]>>[Br:3][C:4]1[C:5]([O:19][CH2:14][C:15]([F:18])([F:17])[F:16])=[N:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])c1cnc(OCC(F)(F)F)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
Sodium hydride (3.2 g, 80.02 mmol) was added carefully in small portions to 2,2,2-trifluroethanol (CAS Registry No. 75-89-8) (60 ml) at 0° C. under nitrogen atmosphere and stirred at 25° C. for 30 minutes. Then 3-bromo-2-chloro-5-nitropyridine (CAS Registry No. 5470-17-7) (2 g, 8.42 mmol) in trifluoroethanol was added, and the reaction mixture was refluxed for 16h. The solvent was evaporated in vacuo, and the residue was taken up in water and extracted with ethyl acetate (3×120 ml). The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated to get the crude residue (3 g). The crude was purified by column chromatography (3% ethyl acetate/hexane) to give the desired product (2.4 g, 95%) as yellow liquid. MS (LC/MS): not responding, NMR is in agreement with the structure: 1H-NMR (400 MHz, CDCl3): δ 4.90 (m, 2H), 8.68 (d, 1H), 8.98 (d, 1H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=O)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OP([CH2:31][C:32]#[N:33])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].COC1C=C(C(C2C=CC=C(OC)C=2)=CC#N)C=C(OC)C=1>C1COCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:31][C:32]#[N:33])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1ccc(C(=O)c2ccccc2)cc1OC1CCCC1
Agent: COc1cccc(C(=CC#N)c2cc(OC)cc(OC)c2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=CC#N)c2ccccc2)cc1OC1CCCC1
Yield: 75.5 %

Procedure:
(3-Cyclopentyloxy-4-methoxy-phenyl)-phenyl-methanone (0.5 g, 1.7 mmol), cyanomethylphosphonic acid diethyl ester (0.3 ml, 1.9 mmol) in anhydrous THF (10 ml), and lithium bis(trimethylsilyl)amide (1.3 M solution in THF, 1.4 ml, 1.9 mmol) were treated in the same manner as described above for the synthesis of 3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The crude was purified by flash column chromatography to give 3-(3-cyclopentyloxy-4-methoxy-phenyl)-3-phenyl-acrylonitrile as a solid (0.41 g, 76%): mp, 90.6-93° C.; 1H NMR (CDCl3) δ 7.54-7.24 (m, 10H), 7.05-6.73 (m, 6H), 5.66 (s, 1H), 5.60 (s, 1H), 4.81-4.62 (m, 2H), 3.89 (s, 3H), 3.87 (s, 3H), 2.00-1.45 (m, 16H); 13C NMR (CDCl3) δ 162.8, 162.8, 152.2, 151.6, 147.4, 147.3, 139.5, 137.2, 130.2, 129.9, 129.6, 129.3, 128.7, 128.5, 128.4, 123.0, 121.8, 118.4, 118.3, 116.1, 114.8, 111.3, 93.2, 92.7, 80.6, 56.0, 32.8, 32.7, 24.1, 24.0; Anal. Calcd. For C21H21NO2: C, 78.97; H, 6.63; N, 4.39. Found: C, 78.85; H, 6.59; N, 4.31.
Reaction SMILES: C(OO)(=[O:3])C.[C:6]([O:9][C@@H:10]1[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:14]([O:20][C:21](=[O:23])[CH3:22])[C@@H:13]([S:24][CH3:25])[O:12][C@H:11]1[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH2:42][C:43]([O:45][CH3:46])=[O:44])=[CH:36][CH:35]=2)[CH:27]=1)(=[O:8])[CH3:7]>CC(O)=O.CC#N>[C:6]([O:9][C@@H:10]1[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:14]([O:20][C:21](=[O:23])[CH3:22])[C@@H:13]([S@:24]([CH3:25])=[O:3])[O:12][C@H:11]1[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([CH2:40][CH2:41][CH2:42][C:43]([O:45][CH3:46])=[O:44])=[CH:38][CH:39]=2)[CH:27]=1)(=[O:8])[CH3:7]
Reactant: COC(=O)CCCc1ccc(Cc2cc([C@@H]3O[C@H](SC)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2C)cc1
Reactant: CC(=O)OO
Solvent: CC#N
Solvent: CC(=O)O
Product: COC(=O)CCCc1ccc(Cc2cc([C@@H]3O[C@H]([S@](C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2C)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 58.6 %

Procedure:
Peracetic acid (32% in dilute HOAc, 0.12 mL, 0.512 mmol) was added to a solution of (2S,3S,4R,5S,6R)-2-(3-(4-(4-methoxy-4-oxobutyl)benzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (9, 100 mg, 0.170 mmol) in 1 mL of HOAc and 2 mL of CH3CN at 0° C. The reaction was stirred for 20 min at 0° C. The reaction was quenched with 1N aqueous NaOH, then extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and the solvents were removed in vacuo to provide a 2:1 diastereomeric mixture of sulfoxides 60 (60 mg, 58% yield) that was carried to the next step without further purification. 1H NMR (400 MHz, CHLOROFORM-d, 2:1 mixture of diastereomers at S, designated as major Ha and minor Hb) δ ppm 7.11-7.17 (m, 2 H), 7.05-7.09 (m, 2 H), 6.97-7.02 (m, 3 H), 5.59 (t, J=9.3 Hz, 1 Hb), 5.46 (t, J=9.3 Hz, 1 Hb), 5.41 (t, J=9.6 Hz, 1 Ha), 5.21 (t, J=9.9 Hz, 1 Ha), 5.17 (t, J=9.3 Hz, 1 Hb), 5.13 (t, J=9.9 Hz, 1 Ha), 4.50 (t, J=10.4 Hz, 1 Ha), 4.48 (d, J=9.9 Hz, 1 Ha), 4.46 (d, J=10.1 Hz, 1 Hb), 4.31 (d, J=10.1 Hz, 1 Hb), 3.93 (m, 2 Hb), 3.92 (m, 2 Ha), 3.66 (s, 3 H), 2.67 (s, 3 Ha), 2.64 (s, 3 Hb), 2.61 (t, J=7.8 Hz, 2 H), 2.33 (t, J=7.3 Hz, 2 H), 2.23 (s, 3 H), 2.09 (s, 3 Ha), 2.08 (s, 3 Hb), 2.02 (s, 3 Hb), 2.01 (s, 3 Ha), 1.93 (quin, J=7.3 Hz, 2 H), 1.75 (s, 3 Ha), 1.74 (s, 3 Hb). MS (ES+) [M+H]+=603.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][N:5]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([N:22]3[CH2:27][CH2:26][N:25]([CH2:28][C:29]4[CH:37]=[CH:36][C:35]5[O:34][CH2:33][O:32][C:31]=5[CH:30]=4)[CH2:24][CH2:23]3)=[O:21])=[CH:14][CH:13]=2)[CH:3]=1.C(O)C>[C].[Pd].O1CCOCC1>[NH2:8][C:7]1[C:2]([CH3:1])=[CH:3][C:4]([O:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][C:20]([N:22]3[CH2:23][CH2:24][N:25]([CH2:28][C:29]4[CH:37]=[CH:36][C:35]5[O:34][CH2:33][O:32][C:31]=5[CH:30]=4)[CH2:26][CH2:27]3)=[O:21])=[CH:16][CH:17]=2)=[N:5][CH:6]=1
Reactant: Cc1cc(Oc2ccc(CCC(=O)N3CCN(Cc4ccc5c(c4)OCO5)CC3)cc2)ncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1cc(Oc2ccc(CCC(=O)N3CCN(Cc4ccc5c(c4)OCO5)CC3)cc2)ncc1N
Reaction time: 8 h

Procedure:
3-(4-hydroxyphenyl)-1-(4-piperonylpiperazin-1-yl)propan-1-one (0.38 g, 1.0 mmol) was dissolved in DMF (6 mL). To the resulting solution was added 60% sodium hydride (0.05 g, 1.2 mmol) and 2-chloro-4-methyl-5-nitropyridine (0.196 g, 1.1 mmol), and the resulting reaction solution was stirred overnight at room temperature. To the reaction solution was added saturated aqueous ammonium chloride, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate), to thereby yield the intermediate product 3-(4-(4-methyl-5-nitropyridin-2-yloxy)phenyl)-1-(4-piperonylpiperazin-1-yl)propan-1-one. The 3-(4-(4-methyl-5-nitropyridin-2-yloxy)phenyl)-1-(4-piperonylpiperazin-1-yl)propan-1-one was dissolved in a mixed solvent consisting of ethanol (4 mL) and dioxane (1 mL). To this solution was added 10% palladium-carbon (0.034 g), and the resulting solution was subjected to catalytic reduction for 8 hours at atmospheric pressure and room temperature. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (dichloromethane:methanol=20:1), to thereby yield 0.22 g of the title compound.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1.Cl[CH:23]1[C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[N:28]1[C:27]2[CH:23]([N:1]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=[C:2]3[NH:10][CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]3)[CH2:24][CH2:25][C:26]=2[CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Reactant: ClC1CCc2cccnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3n2C2CCc3cccnc32)CC1
Yield: 68.3 %

Procedure:
A mixture of ethyl 4-(1H-benzimidazol-2-ylamino)-1-piperidine-carboxylate (0.0289 mol), 7-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.0289 mol) and potassium carbonate (0.0867 mol) in acetonitrile (250 ml) was stirred and refluxed for 48 hours and then brought to room temperature. The reaction was carried out again using the same quantities. The mixtures were combined, poured out into H2O and extracted with EtOAc. The organic layer was separated, washed with H2O, dried (MgSO4), filtered and the solvent was evaporated. The residue (25 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH NH4OH 97/3/0.5; 20-45 μm). Two fractions were collected and their solvents were evaporated, yielding 8 g of ethyl 4-[[1-(6,7-dihydro-5H-1-pyrindin-7-yl) 1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate (interm. 22).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([O:25][CH3:26])=[O:24].O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN1CCC(NC(=O)OC(C)(C)C)CC1
Reaction time: 1 h

Procedure:
4-(tert-butoxycarbonylamino)piperidine (1.2 g) and potassium carbonate (1.2 g) were suspended in dimethylformamide (20 mL), and then methyl bromoacetate (0.62 mL) was added. The reaction solution was stirred for one hour and water was added, followed by extraction with ethyl acetate. The organic layer was washed in turn with water and saturated brine, and dried over anhydrous magnesium sulfate, and then the filtrate was concentrated. The residue was purified by silica gel chromatography (hexane:ethyl acetate=2:1→0:1) to obtain the title compound (1.36 g) having the following physical properties.
Reaction SMILES: [H-].[Na+].CS(C)=O.[Cl-].[C:8]([CH2:11][CH2:12][CH2:13][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:10])=[O:9].[CH3:33][O:34][C:35]1[CH:50]=[CH:49][C:38]([C:39]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)=O)=[CH:37][CH:36]=1>O1CCCC1>[CH3:33][O:34][C:35]1[CH:50]=[CH:49][C:38]([C:39]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)=[CH:13][CH2:12][CH2:11][C:8]([OH:10])=[O:9])=[CH:37][CH:36]=1
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Reactant: O=C(O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COc1ccc(C(=CCCC(=O)O)c2ccc(OC)cc2)cc1
Yield: 54.9 %

Procedure:
The reaction was performed as in Example 87 using sodium hydride (56% dispersion in oil; 9.5 g) dimethylsulfoxide (100 mL), (3-carboxypropyl)triphenylphosphonium chloride (35 g); 4,4'-dimethoxybenzophenone (26.4 g); and tetrahydrofuran (100 mL). After the usual work up, the crude acid was crystallized from dichloromethane-hexane to give 15.6 g of 5,5-bis(4-methoxyphenyl)-4-pentenoic acid, mp 113°-114° C. Anal. Calculated for C19H20O4 : C, 73.06; H, 6.45. Found: C, 73.00; H, 6.45.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][N:27]=[C:26](S(C)=O)[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38][NH2:39]>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:39][CH2:38][C:37]5[CH:40]=[CH:41][CH:42]=[C:35]([Cl:34])[CH:36]=5)[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1cccc(Cl)c1
Reactant: CS(=O)c1nccc(-c2cnc3c(NC4CCC(NC(=O)OC(C)(C)C)CC4)nccn23)n1
Product: CC(C)(C)OC(=O)NC1CCC(Nc2nccn3c(-c4ccnc(NCc5cccc(Cl)c5)n4)cnc23)CC1
Reaction time: 2 h

Procedure:
The mixture of {4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 48 supra) (100 mg, 0.212 mmol) and (3-chlorobenzylamine (120.3 mg, 0.849 mmol) was heated at 140° C. with stirring for 2 hours. The oil was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 30:1) to afford crude (4-{3-[2-(3-chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester. (Yield 80 mg). LC-MS: [M+H]+ 549.
Reaction SMILES: [CH2:1]([PH:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].C([Mg]Br)CCC.C(OP([O-])OCC)C.[CH3:25][Si:26](Cl)([CH3:28])[CH3:27]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH2:1]([P:5]([CH2:6][CH2:7][CH2:8][CH3:9])[O:10][Si:26]([CH3:28])([CH3:27])[CH3:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[PH](=O)CCCC
Reactant: C[Si](C)(C)Cl
Agent: CCCC[Mg]Br
Agent: CCOP([O-])OCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCP(CCCC)O[Si](C)(C)C
Temperature: 80 °C
Yield: 86 %

Procedure:
The procedure described in Tetrahedron, 1967, 23, 1065 (M. Grayson et al.) was followed. Dibutylphosphine oxide, prepared from butyl magnesium bromide and diethylphosphite, (3.3 g, 20 mmol) and triethylamine (2.02 g, 20 mml) were dissolved in toluene (20 mL) and treated with a solution of trimethylsilyl chloride (2.17 g, 20 mmol) in toluene (5 mL) at room temperature. The solution got very warm and a precipitate formed immediately. The mixture was heated at 80° C. for two hours, then filtered, washed with toluene, and concentrated. Kugelrohr distillation at 80° C. (1.5 mmHg) afforded 4.1 g (86%) of the desired product. 1H NMR (CDCl3) δ1.8-1.2 (m, 6 H), 1.1-0.7 (m, 3 H), 0.17 (s, 9 H).
Reaction SMILES: [Li].N.Cl.[NH:4]1[C:12]2[C:7](=[C:8]([C:13]3(O)[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.O1CCCC1>C(O)C>[NH:15]1[CH2:16][CH2:17][CH2:18][CH:13]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:7]=2[CH:6]=[CH:5][NH:4]3)[CH2:14]1
Reactant: OC1(c2cccc3[nH]ccc23)CCCNC1
Agent: Cl
Agent: N
Agent: [Li]
Solvent: CCO
Solvent: C1CCOC1
Product: c1cc(C2CCCNC2)c2cc[nH]c2c1
Yield: 69.9 %

Procedure:
700 mg of lithium were added in small fractions over one hour at -40° C. to a mixture of 100 ml of ammonia, 1.2 g of 3-(1H-indol-4-yl)-3-piperidinol hydrochloride, 20 ml of tetrahydrofuran and 10 ml of anhydrous ethanol and the ammonia was evaporated at room temperature. The residue was taken up in 100 ml of water and the aqueous phase was extracted with chloroform containing 10% methanol. The organic phase was washed with water, dried and filtered. The filtrate was evaporated to dryness and the 950 mg of residue was chromatographed over silica gel. Elution with a 7-2-1-chloroform-methanol-triethylamine mixture yielded 665 mg of 4-(piperidin-3-yl)-1H-indole.
Reaction SMILES: [Br:1]Br.[C:3]1([CH:10]=[CH:9][CH:8]=[C:6]([OH:7])[CH:5]=1)[OH:4]>ClCCl>[Br:1][C:5]1[C:6]([OH:7])=[CH:8][CH:9]=[CH:10][C:3]=1[OH:4]
Reactant: BrBr
Reactant: Oc1cccc(O)c1
Solvent: ClCCl
Product: Oc1cccc(O)c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromine (0.363 L) was added dropwise over 2 hours to a solution of resorcinol (250 g) in dichloromethane (3.5 L). The solution was stirred at room temperature for 18 hours at which time approximately 1 L of the dichloromethane was removed by distillation. MeOH was added and the distillation continued in this manner until all of the dichloromethane was removed and the solution contained approximately 1.5 L of MeOH. To this was added a solution of NaOH (181.5 g) and Na2SO3 (573 g) in H2O (7.5 L). The resulting mixture was stirred at ambient temperature for 1 hour. The solution was then acidified to pH=2 with concentrated HCl (75 mL) and extracted with tert-butyl methyl ether (TBME) (2×1 L). The combined organic layers were treated with activated charcoal (20 g) and filtered through Celite; the Celite was washed with an additional 500 mL of TBME. The solvent was then removed in vacuo. The resulting crude 2-bromoresorcinol was dissolved in a minimum amount of ethyl acetate and filtered through silica gel eluting with a gradient from 20% to 40% ethyl acetate in hexanes yielding 2-bromoresorcinol (122 g). m.p. 86-88°.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[CH:18]=2)[N:9]=1.[CH2:32]=O>CO.C(Cl)Cl>[CH3:32][N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@H:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH3:25])[CH:18]=2)[N:9]=1
Reactant: CC(Nc1cc(-c2cc3nccn3c(N3CC4CC3CN4)n2)ccn1)c1ccccc1
Reactant: C=O
Solvent: ClCCl
Solvent: CO
Product: C[C@H](Nc1cc(-c2cc3nccn3c(N3C[C@@H]4C[C@H]3CN4C)n2)ccn1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 96 mg (0.23 mmol) {4-[5-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-imidazo[1,2-c]pyrimidin-7-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine in 3 mL methanol was treated with 0.17 mL (2.3 mmol) formaldehyde (37% in water) and 150 mg (0.70 mmol) NaBH3(CN). The mixture was stirred at ambient temperature for 1 h when MS showed that all starting materials had converted to product. The reaction mixture was diluted with 50 mL DCM, washed with 50 mL satd. NaHCO3, and dried over anhydrous Na2SO4. After purification by HPLC, the title compound was obtained. MS (ES+): 426 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[CH:17]=[N:16][N:15]([CH3:18])[C:14]=3[C:19](O)=[O:20])=[O:11])[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1>>[CH3:18][N:15]1[C:14]([C:19](=[O:20])[NH:36][CH:33]2[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]2)=[C:13]([NH:12][C:10]([C:8]2[C:7]([NH:22][C:23]3[CH:28]=[N:27][CH:26]=[N:25][CH:24]=3)=[N:6][CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[N:9]=2)=[O:11])[CH:17]=[N:16]1
Reactant: CN1CCC(N)CC1
Reactant: Cn1ncc(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)c1C(=O)O
Product: CN1CCC(NC(=O)c2c(NC(=O)c3nc(C4CC4)cnc3Nc3cncnc3)cnn2C)CC1

Procedure:
The product was obtained starting from 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-2-methyl-2H-pyrazole-3-carboxylic acid (25 mg, 66 μmol; example 236, step 3) and 1-methyl-piperidin-4-ylamine (10 mg, 85 pimp according to the method described in example 64, step 6 after purification by preparative HPLC using an acetonitrile/water gradient as yellow solid (17 mg, 50%).
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]3[CH2:12][NH:13][CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[O:16]=[C:9]1[N:10]2[CH2:15][CH2:14][N:13]([C:30]([NH:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:31])[CH2:12][CH:11]2[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[O:8]1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Reactant: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 60 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
To a solution of hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one (85 mg, 0.29 mmol) in toluene (3 mL) was added phenyl isocyanate (70 mg, 0.59 mmol), and the mixture was stirred at 60° C. for 4 hours. The reaction solution was concentrated. Then, the residue was purified with silica gel column chromatography (hexane:ethyl acetate=2:1) and crystallized from diisopropyl ether to obtain the title compound (0.12 g, yield 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.Cl[S:21]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([OH:29])=[O:28])(=[O:23])=[O:22]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:21]([C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27]([OH:29])=[O:28])(=[O:23])=[O:22])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Product: O=C(O)c1cccc(S(=O)(=O)Nc2cnc(Oc3cc4ccccc4cn3)c(Cl)c2)c1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 3-(chlorosulfonyl)benzoic acid.
Reaction SMILES: [OH-].[Na+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:10]1[C:16]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]1[CH2:12][N:13]([CH3:23])[CH2:14][CH2:15]2>C(O)CO>[OH:10][CH:11]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([S:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:15][CH2:14][N:13]([CH3:23])[CH2:12]1
Reactant: Sc1ccccc1
Reactant: CN1CCC2(c3ccccc3)OC2C1
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Product: CN1CCC(Sc2ccccc2)(c2ccccc2)C(O)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.8 %

Procedure:
9.6 Ml of 10% sodium hydroxide solution was added to a solution of 2.46 ml (0.024 mole) of thiophenol in 15 ml of ethylene glycol and the resulting solution stirred at room temperature for five minutes. 1.9 G (0.01 mole) of 3,4-epoxy-1-methyl-4-phenyl-piperidine was added with stirring to the above solution and the resulting solution stirred at room temperature for a further one hour. A solid began to separate after five minutes. The solid was filtered and suspended in acetone. Filtration of the solid gave 2.6 g of 3-hydroxy-1-methyl-4-phenyl-4-phenylthio-piperidine as a white solid having a melting point of 217°-9° C.