Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1([CH3:29])C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:25]([F:28])([F:27])[F:26])=[CH:24][C:19]=4[O:18][N:17]=3)=[CH:11][CH:10]=2)[O:3]1.I[C:31]1[C:39]2[C:34](=[N:35][CH:36]=[N:37][C:38]=2[NH2:40])[N:33]([C@H:41]2[CH2:46][CH2:45][C@H:44]([N:47]3[CH2:52][CH2:51][N:50]([CH3:53])[CH2:49][CH2:48]3)[CH2:43][CH2:42]2)[N:32]=1.C(=O)([O-])[O-:55].[Na+].[Na+]>COCCOC.O>[C:2]([OH:55])(=[O:3])[CH3:29].[NH2:40][C:38]1[N:37]=[CH:36][N:35]=[C:34]2[N:33]([C@H:41]3[CH2:46][CH2:45][C@H:44]([N:47]4[CH2:52][CH2:51][N:50]([CH3:53])[CH2:49][CH2:48]4)[CH2:43][CH2:42]3)[N:32]=[C:31]([C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16]4[C:20]5[CH:21]=[CH:22][C:23]([C:25]([F:27])([F:28])[F:26])=[CH:24][C:19]=5[O:18][N:17]=4)=[CH:13][CH:14]=3)[C:39]=12
Reactant: O=C([O-])[O-]
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: CC1(C)OB(c2ccc(Nc3noc4cc(C(F)(F)F)ccc34)cc2)OC1(C)C
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(=O)O
Product: CN1CCN([C@H]2CC[C@H](n3nc(-c4ccc(Nc5noc6cc(C(F)(F)F)ccc56)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C

Procedure:
A mixture of N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N-[6-(trifluoromethyl)benzo[d]isoxazol-3-yl]amine (0.062 g, 0.000153 mol), trans-3-iodo-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.065 g, 0.000146 mol), tetrakis-(triphenylphosphine)palladium (0.010 g, 0.0000087 mol) and sodium carbonate (0.039 g, 0.000365 mol) was heated in a mixture of ethylene glycol dimethyl ether (4 mL) and water (2 mL) at 80° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure. The residue was purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-70% acetonitrile-0.1M ammonium acetate over 30 min, 21 mL/min) to yield trans-N3-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-6-(trifluoromethyl)benzo[d]isoxazol-3-amine acetate (0.026 g, 0.0000398 mol) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 10.05 (s, 1H), 8.44 (d, 1H), 8.23 (s, 1H), 8.16 (s, 1H), 7.88 (d, 2H), 7.79 (d, 1H), 7.69 (d, 2H), 4.67 (m, 1H), 2.6-2.2 (br, 9H), 2.13 (s, 3H), 2.05 (m, 6H), 1.91 (s, 3H), 1.46 (m, 2H); RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 20 min, 1 mL/min) Rt 16.18 min. MS: MH+ 592.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[N:15]=[N:16][C:17]([CH:20]([NH:22][C:23]([C:25]3[CH:26]=[C:27]4[C:31](=[CH:32][CH:33]=3)[NH:30][CH:29]=[CH:28]4)=O)[CH3:21])=[CH:18][N:19]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[NH:30]1[C:31]2[C:27](=[CH:26][C:25]([C:23]3[N:16]4[C:17]([CH:18]=[N:19][C:14]([NH:13][C:5]5[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=5)=[N:15]4)=[C:20]([CH3:21])[N:22]=3)=[CH:33][CH:32]=2)[CH:28]=[CH:29]1
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccc4[nH]ccc4c3)nn2)cc(OC)c1OC
Agent: c1nc[nH]n1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(Nc2ncc3c(C)nc(-c4ccc5[nH]ccc5c4)n3n2)cc(OC)c1OC
Yield: 37.5 %

Procedure:
In a similar manner as described for Example 9, N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)-1H-indole-5-carboxamide (Intermediate 38) (176 mg, 0.39 mmol), and 1,2,4-triazole (161 mg, 2.34 mmol) in pyridine (4 mL) and phosphorous oxychloride (0.11 mL, 1.2 mmol) gave 7-(1H-indol-5-yl)-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (63 mg, 37%) as a yellow solid. 1H NMR (CDCl3): δ8.87 (s, 1H), 8.79 (s, 1H), 8.35 (s, 1H), 8.29 (dd, J=8.61 and 1.46 Hz, 1H), 7.47 (d, J=8.61 Hz, 1H), 6.95 (s, 2H), 6.84 (s, 1H), 6.62 (s, 1H), 3.87 (s, 3H), 3.77 (s, 6H), 2.64 (s, 3H). MS m/z 430 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].[CH:14]1[C:19](=[O:20])[C:18]([OH:21])=[CH:17][O:16][C:15]=1[CH2:22]Cl>>[OH:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:22][C:15]1[O:16][CH:17]=[C:18]([OH:21])[C:19](=[O:20])[CH:14]=1)=[O:5]
Reactant: O=C(O)c1cccc(O)c1O
Reactant: O=c1cc(CCl)occ1O
Agent: [Na+]
Agent: [OH-]
Product: O=C(OCc1cc(=O)c(O)co1)c1cccc(O)c1O
Yield: 44.2 %

Procedure:
By following the procedure of Example 1 by employing 1.0 g(6.5 mmole) of 2,3-dihydroxybenzoic acid, 0.26 g (8.5 mmole) of sodium hydroxide and 0.92 g(7.6 mmole) of chlorokojic acid, there was obtained 0.8 g(50.2%) of 2-(2,3-dihydroxybenzoyl)oxymethyl-5-hydroxy-4H-pyran-4-one as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11]2)=[N:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].I[CH3:19]>CN(C=O)C>[CH3:19][O:15][CH:12]1[CH2:13][CH2:14][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=2)[CH2:11]1
Reactant: O=[N+]([O-])c1ccc(N2CCC(O)C2)nc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1CCN(c2ccc([N+](=O)[O-])cn2)C1
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-(5-nitro-pyridin-2-yl)-pyrrolidin-3-ol (120 mg, 0.57 mmol) in 5 mL of DMF was added 10 equivalent of sodium hydride (228 mg, 5.7 mmol, 60% in mineral oil). The mixture was stirred at 23° C. for 15 min followed by the addition of 10 equivalent of iodomethane (355 uL, 5.7 mmol). The reaction was continually stirred for 2 h and then extracted with ethyl acetate and water. The organic phase was dried and solvent was evaporated. The residue was purified on a flash chromatography column with EtOAc/hexanes to afford 2-(3-methoxy-pyrrolidin-1-yl)-5-nitro-pyridine. LRMS calcd for C10H13N3O3 (m/e) 223, obsd 224 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[C:12](=[S:15])([O-:14])[CH3:13].[K+]>C(O)C>[C:12]([S:15][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])(=[O:14])[CH3:13]
Reactant: O=C(O)c1cccc(CBr)c1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CCO
Product: CC(=O)SCc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of 3-(bromomethyl)benzoic acid (7 g, 32.56 mmol, 1.00 equiv) in ethanol (80 mL), and potassium ethanethioate (9.65 g, 84.65 mmol, 2.60 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 80 mL of water and adjusted to pH 3-4 with 10% hydrochloric acid. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1×50 mL of brine. The mixture was dried over sodium sulfate and concentrated under vacuum. This resulted in 4.4 g (64%) of 3-(acetylthiomethyl)benzoic acid as a brown solid.
Reaction SMILES: [SH:1][CH:2]([CH3:6])[C:3]([OH:5])=[O:4].[CH2:7]([OH:10])[CH:8]=[CH2:9].[C:11]1(C)[CH:16]=CC(S(O)(=O)=O)=C[CH:12]=1>>[OH:10][CH2:7][CH2:8][CH2:9][S:1][CH:2]([CH3:6])[C:3]([O:5][CH2:16][CH:11]=[CH2:12])=[O:4]
Reactant: CC(S)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C=CCO
Product: C=CCOC(=O)C(C)SCCCO
Temperature: 25 °C

Procedure:
Into a 250 cc reaction flask equipped with stirrer, thermometer, reflux condenser and heating mantle are placed 26.5 grams of 2-mercapto propionic acid (0.25 moles); 58 grams allyl alcohol (1.0 moles) and 0.2 grams of para-toluene sulfonic acid. With stirring, the reaction mass is heated to reflux and maintained at reflux for a period of 8 hours. At the end of the 8 hour period, the reaction mass is cooled to room temperature and transferred to a separatory funnel. The reaction mass is then extracted with two 250 ml portions of methylene dichloride. The methylene dichloride extracts are combined and washed with one 100 ml portion of saturated sodium carbonate solution followed by one 100 ml portion of saturated sodium chloride solution. The resulting organic material is dried over anhydrous sodium sulfate, filtered and distilled on a micro Vigreux column yielding the following fractions:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([CH:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)C(Cl)=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[CH2:40][NH2:41]>>[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[CH2:40][NH:41][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6](=[O:7])[CH:25]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:18]
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: COc1ccc(CN)cc1OC
Product: CON=C1C[C@@H](C(=O)NCc2ccc(OC)c(OC)c2)N(C(=O)C(c2ccccc2)c2ccccc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, diphenylacetyl chloride, and 3,4-dimethoxybenzylamine the title compound was obtained in 74% purity by LC/MS. MS(ESI+): m/z=502.6.
Reaction SMILES: C([N:3]([CH2:14][CH3:15])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[CH3:12])C.[OH:16][CH2:17][C@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23]CC#N>>[OH:16][CH2:17][C@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23][CH2:15][C:14]1[NH:3][C:4](=[O:13])[C:5]2[C:6]([CH:12]=1)=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=2
Reactant: N#CCCN1CCC[C@@H]1CO
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Product: Cc1cccc2c(=O)[nH]c(CCN3CCC[C@@H]3CO)cc12
Yield: 12.1 %

Procedure:
By the reaction in the same manner as in Example 1a, using N,N-diethyl-2,3-dimethylbenzamide (81.4 g) and (R)-3-(2-hydroxymethylpyrrolidin-1-yl)propionitrile (55.6 g), (R)-3-[2-(2-hydroxymethylpyrrolidin-1-yl)ethyl]-5-methyl-2H-isoquinolin-1-one (12.5 g) was obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][C:8]([O:10]C)=[O:9])=[CH:5][C:4]2[CH:12]([CH3:22])[CH2:13][C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[C:16](=[O:17])[C:3]1=2.[OH-].[Na+]>C(O)C.O>[CH3:1][N:2]1[C:6]([CH2:7][C:8]([OH:10])=[O:9])=[CH:5][C:4]2[CH:12]([CH3:22])[CH2:13][C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[C:16](=[O:17])[C:3]1=2
Reactant: COC(=O)Cc1cc2c(n1C)C(=O)c1ccccc1CC2C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1Cc2ccccc2C(=O)c2c1cc(CC(=O)O)n2C

Procedure:
To a suspension of methyl 5,10-dihydro-1,4-dimethyl-10-oxo-4H-benzo-[5,6]-cyclohepta[1,2-b]pyrrol-2-acetate (26 mg, 0.087 mmoles) in a mixture of 4 cc ethanol and 0.5 cc water, slight ice-bath cooling, is added 0.06 cc of 2.5 N sodium hydroxide solution. After stirring overnight (nitrogen atmosphere) at ambient temperatures, water (4 cc) is added, the ethanol removed in vacuo, the mixture filtered, and the filtrate acidified with 2 N hydrochloric acid. After aging, the supernatent aqueous solution is decanted from the yellow oil that forms, and the oil washed well with water. The oil is then dissolved in ether, the ether solution dried and concentrated to 20.3 mg (83%) of 5,10-dihydro-1,4-dimethyl-10-oxo-4H-benzo[5,6]cyclohepta[1,2-b]pyrrol-2-yl-acetic acid as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.[OH-].[Na+]>O.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: NCCCCCCCC(=O)O
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=C(O)CCCCCCCNS(=O)(=O)c1ccc(F)cc1
Reaction time: 3 h
Yield: 46.2 %

Procedure:
8-Aminooctanoic acid (1.0 g, 0.006 mol) was treated with 4-fluorobenzenesulphonyl chloride (1.22 g, 0.006 mol) in the presence of sodium hydroxide (0.8 g, 0.019 mol) in 15 ml water, tetrabutylammonium hydroxide (4 drops, 40% solution) and dichloromethane and the resulting mixture was subjected to vigorous stirring for 3 hours. The organic layer was then separated and evaporated to dryness and the residue was recrystallised from 2-propanol-water to give the title compound (0.88 g, m.p. 97°-8° C.).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][N:11]=[C:10]3[NH:15][CH:16]=[CH:17][C:9]=23)[C:5]([C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=2)=[N:4]1)[CH3:2].[CH3:25][NH:26][CH3:27].[O:28]1[CH2:32]CCC1>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][N:11]=[C:10]3[NH:15][CH:16]=[CH:17][C:9]=23)[C:5]([C:18]2[CH:24]=[CH:23][C:21]([NH:22][C:32](=[O:28])[N:26]([CH3:27])[CH3:25])=[CH:20][CH:19]=2)=[N:4]1)[CH3:2]
Reactant: CNC
Reactant: C1CCOC1
Reactant: CCn1cc(-c2c(C)cnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Product: CCn1cc(-c2c(C)cnc3[nH]ccc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1

Procedure:
Following the procedure described in Example 5a with 4-[1-ethyl-4-(5-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline and 2M dimethylamine in tetrahydrofuran afforded the title compound. ESMS[M+H]+: 389.4
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[CH2:17]([N:24]=[C:25]=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:17]([NH:24][C:25]([NH:16][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([C:3]2[N:4]([CH3:7])[N:5]=[CH:6][C:2]=2[Br:1])[CH:9]=1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C=NCc1ccccc1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: COc1ccc(NC(=O)NCc2ccccc2)cc1-c1c(Br)cnn1C
Yield: 66.7 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.034 g, 0.12 mmol) was treated with benzyl isocyanate (0.017 g, 16.0 μL 0.13 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.10 to afford Compound 74 (0.031 g, 0.08 mmol, 62%) as a solid film. LCMS m/z (%)=415 (M+H79Br, 86), 417 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.05 (s, 1H), 7.64 (dd, J=2.7, 9.0 Hz, 1H), 7.47 (s, 1H), 7.40 (d, J=2.7 Hz, 1H), 7.27-7.37 (m, 4H), 7.22 (t, J=7.0 Hz, 1H), 7.07 (d, J=9.0 Hz, 1H), 6.21 (s, 1H), 4.41 (d, J=4.0 Hz, 2H), 3.79 (s, 3H), 3.66 (s, 3H).
Reaction SMILES: C(O[C:9]1[CH:27]=[CH:26][CH:25]=[CH:24][C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20](=[O:23])(=[O:22])[NH2:21])=[O:12])C1C=CC=CC=1.[F:28][C:29]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32].[C:39](=[O:42])([O-])[O-].[K+].[K+]>O.O1CCOCC1>[CH2:39]([O:42][C:25]1[CH:24]=[C:10]([CH:9]=[CH:27][CH:26]=1)[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([NH:21][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:29]=1[F:28])(=[O:22])=[O:23])=[O:12])[C:9]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:10]=1
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1ccccc1OCc1ccccc1
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1ccccc1S(=O)(=O)NC(=O)c1ccc(F)cc1F)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
A 300 mg (0.78 mmol) portion of benzyloxy-N-(2-sulfamoylphenyl)benzamide, 273 mg (1.55 mmol) of 2,4-difluorobenzoyl chloride and 374 mg (2.70 mmol) of potassium carbonate were dissolved in a mixed solvent (10 ml) of water and dioxane (1:1) and stirred at room temperature for 18 hours. After completion of the reaction, the solvent was evaporated under a reduced pressure. The resulting residue was extracted with ethyl acetate, washed with water and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 350 mg (yield: 86.0%) of the title compound.
Reaction SMILES: [C:1]12([NH2:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(CC)CC)C.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([CH:31]([CH3:34])[CH2:32]Br)[CH2:27][CH2:26]1.O>CN(C=O)C>[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:26][CH2:27][N:28]([CH:31]([CH3:34])[CH2:32][NH:11][C:1]23[CH2:8][CH:7]4[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]4)[CH2:2]2)[CH2:10]3)[CH2:29][CH2:30]1
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: CC(CBr)N1CCN(c2ccccn2)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(CNC12CC3CC(CC(C3)C1)C2)N1CCN(c2ccccn2)CC1
Temperature: 50 °C

Procedure:
A suspension of 1-adamantylamine (12.0 grams; 0.079 moles) in 250 cc of DMF is prepared. Triethylamine (21.9 cc; 0.158 moles), is added and the mixture is warmed to about 50° C. To the warm solution, there is added over a period of 3 hours, 1-(2-pyridyl)-4-(2-bromo-1-methylethyl)piperazine (18.0 grams; 0.063 moles) keeping the temperature about the same. The reaction mixture is poured into 500 cc of water and then extracted with ether. The ethereal phase, washed with water, then washed to neutrality and allowed to evaporate, gives as a residue, a crude oily product, which is purified by column chromatography. (THF-diisopropyl ether-Et3N 50:40:10). Compound (26) is an oil, which solidifies after prolonged standing; m.p. 67°-68° C. from n-hexane); Rf=0.22 (from ethyl acetate Et3N 9:1); IR (nujol) νmax: 1590, 1480, 1430, 1310, 1240, 1160, 775 cm-1 ; νN-H: 3250 cm-1 ; 1H-NMR (CDCl3): 0.93 (d, J=5 Hz; 3H); 1.20-2.23 (m; 16H); 2.23-3.00 (m; 7H); 3.20-3.70 (m; 4H); 6.40-6.73 (m; 2H; 7.23-7.63 (m; 1H); 8.03-8.27 (m; 1H); tripicrate: m.p. 185° C. (from ethanol).
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH3:4][N:5]1[C:9]([CH3:10])=[C:8]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([N:24]4[CH2:29][CH2:28][CH:27]([CH2:30]OS(C5C=CC(C)=CC=5)(=O)=O)[CH2:26][CH2:25]4)=[N:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)[CH:7]=[N:6]1.[ClH:42]>CS(C)=O.C(#N)C>[ClH:42].[CH3:4][N:5]1[C:9]([CH3:10])=[C:8]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([N:24]4[CH2:25][CH2:26][CH:27]([CH2:30][C:1]#[N:2])[CH2:28][CH2:29]4)=[N:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)[CH:7]=[N:6]1
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(c3nccnc3N3CCN(Cc4cnn(C)c4C)CC3)CC2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC#N
Product: Cc1c(CN2CCN(c3nccnc3N3CCC(CC#N)CC3)CC2)cnn1C
Temperature: 50 °C
Reaction time: 5.75 h
Yield: 101.4 %

Procedure:
Add sodium cyanide (78.46 mg, 1.60 mmol, 2.4 eq) to a solution of toluene-4-sulfonic acid 1-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-piperidin-4-ylmethyl ester (0.36 g, 0.667 mmol, 1 eq) in dimethyl sulfoxide (5 mL). Heat the solution to 50° C. with stirring for 5.75 hr. and then cool to room temperature. Add water (20 mL) and extract the aqueous layer three times with DCM (20 mL). Combine the organic extracts, dry over magnesium sulphate, filter and concentrate. Purify by flash chromatography on a 40 g silica gel column, eluting with a gradient of 2-10% methanol in DCM. Further purify by high pH reverse phase HPLC (UV guided). Dissolve this material (148 mg, 0.38 mmol) in the minimum quantity of 50% aqueous acetonitrile. Add 2M aqueous hydrogen chloride (190 μL, 0.38 mmol) and lyophilize to give {1-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-piperidin-4-yl}-acetonitrile hydrochloride (166 mg, 58%). MS (m/z): 395.2 (M+1).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][CH:10]1[C:40]1[C:48]2[O:47][CH2:46][CH2:45][C:44]=2[C:43]([Cl:49])=[C:42]([CH2:50][O:51][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[O:11][CH:10]1[C:40]1[C:48]2[O:47][CH2:46][CH2:45][C:44]=2[C:43]([Cl:49])=[C:42]([CH2:50][OH:51])[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OCc1cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c2c(c1Cl)CCO2)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCc1cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c2c(c1Cl)CCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a solution of compound 47(827 mg, 0.87 mmol) in THF (4.0 mL) was added dropwise tetra-n-butylammonium fluoride (1.0M in THF, 2.17 mL, 2.17 mmol) at 0° C. After being stirred for 2 hours at room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the product 48 (578 mg, 93%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]3[N:12]=[C:13]([NH2:15])[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[N:18]([CH3:20])[CH3:19].Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>N1C=CC=CC=1.C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]3[N:12]=[C:13]([NH:15][C:22](=[O:23])[O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[N:18]([CH3:20])[CH3:19]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN(C)c1cc(-c2ccc3nc(N)sc3c2)cnc1Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)c1cc(-c2ccc3nc(NC(=O)Oc4ccccc4)sc3c2)cnc1Cl
Reaction time: 8 h

Procedure:
To a mixture of 6-(6-chloro-5-(dimethylamino)pyridin-3-yl)benzo[d]thiazol-2-amine (100 mg, 328 μmol) in pyridine (0.3 mL) and DCM (2 mL) was added phenyl chloroformate (200 μl, 1594 mmol). A clear solution formed. After overnight at rt, the slurry was diluted with EtOAc (10 mL) and filtered. The solid was washed with EtOAc, then H2O (2×3 mL). LCMS indicted that the organic liquid contains most of product and by-product. The small amount of solid remained on the filter was pure product (35 mg). MS (ESI, pos. ion) m/z: calc'd for C21H17ClN4O2S: 424.1. found: 425.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.85 (s, 6H) 7.33 (t, J=7.53 Hz, 3H) 7.48 (t, J=7.78 Hz, 2H) 7.76-7.88 (m, 3H) 8.35 (s, 1H) 8.43 (s, 1H) 12.73 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]([CH2:11]O)[CH3:10])[CH:3]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]([CH3:11])[CH3:10])[CH:3]=1
Reactant: CC(CO)c1cc(Cl)ccc1O
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)c1cc(Cl)ccc1O
Yield: 79.7 %

Procedure:
To a −10° C. solution of 4-chloro-2-(hydroxypropan-2-yl)phenol (6.00 g, 32.15 mmol) in 100 mL of methylene chloride add triethylsilane (31.0 mL, 194.08 mmol) and boron trifluoride diethyl etherate (66 mL, 520.82 mmol) dropwise over a period of 10 minutes. Keep the reaction mixture cold and stir for an additional hour before quenching with aqueous sodium bicarbonate. Separate the mixture, and extract the aqueous phase with methylene chloride. Wash combined organic phases with aqueous sodium bicarbonate and brine, dry over anhydrous magnesium sulfate, filter, and concentrate to give a purple oil. Purify by flash chromatography using 25% ethyl acetate in hexanes to give 4.37 g (80%) of pure 4-chloro-2-isopropylphenol as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.15 (d, J=2.6 Hz, 1H), 7.01 (dd, J=8.5, 2.6 Hz, 1H), 6.66 (d, J=8.5 Hz, 1H), 4.77 (s, 1H), 3.17 (sept, 1H), 1.24 (d, J=6.9 Hz, 6H). 3C NMR (101 MHz, CDCl3) δ 151.26, 136.37, 126.56, 126.36, 125.81, 116.46, 27.14, 22.33. MS: m/e 171.