Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[CH2:26](O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[CH2:26]([O:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(OCc3ccccc3)ccc3c2OCC3=O)CC1
Temperature: 110 °C
Reaction time: 5 h
Yield: 39.4 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.522 g, 1.50 mmol), benzyl alcohol (0.186 mL, 1.80 mmol) and triphenylphosphine (0.590 g, 2.25 mmol) in toluene (6 mL) was added with a 40% solution of diethyl azodicarboxylate in toluene (0.980 g, 2.25 mmol), and the mixture was stirred at 110° C. for 5 hours in a sealed tube. The reaction mixture was concentrated, and the resulting residue was subjected to silica gel column chromatography (chloroform/ethyl acetate) to obtain tert-butyl 4-{[6-(benzyloxy)-3-oxo-2,3-dihydrobenzofuran-7-yl]methyl}piperazine-1-carboxylate (0.259 g, 39%).
Reaction SMILES: C[O:2][C:3]1[CH2:8][CH:7]=[C:6]([CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH2:5][CH:4]=1>S(=O)(=O)(O)O>[OH:13][CH2:12][CH2:11][CH2:10][CH2:9][C:6]1[CH2:7][CH2:8][C:3](=[O:2])[CH2:4][CH:5]=1
Reactant: COC1=CCC(CCCCO)=CC1
Agent: O=S(=O)(O)O
Product: O=C1CC=C(CCCCO)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 4.76 g of 1-methoxy-4-(4-hydroxybutyl)cyclohexa-1,4-diene in 75 mL 1N sulfuric acid is stirred at room temperature for 11/2 hours and extracted with methylene chloride (2×40 mL). The combined organic extracts are washed with saturated sodium bicarbonate, dried (MgSO4), filtered and subjected to evaporation to obtain 4-(4-hydroxybutyl)cyclohex-3-ene-1-one as an oil.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH2:15]([O:17][CH2:18][C:19]1[CH:20]=[N:21][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([C@H:31]3[CH2:33][C@H:32]3[CH2:34][CH2:35][OH:36])[CH2:27][CH2:26]2)=[N:23][CH:24]=1)[CH3:16].[F:37][C:38]1[CH:43]=[C:42](O)[CH:41]=[CH:40][C:39]=1[CH2:45][C:46]([O:48][CH3:49])=[O:47].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:15]([O:17][CH2:18][C:19]1[CH:20]=[N:21][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([C@H:31]3[CH2:33][C@H:32]3[CH2:34][CH2:35][O:36][C:42]3[CH:41]=[CH:40][C:39]([CH2:45][C:46]([O:48][CH3:49])=[O:47])=[C:38]([F:37])[CH:43]=3)[CH2:27][CH2:26]2)=[N:23][CH:24]=1)[CH3:16]
Reactant: COC(=O)Cc1ccc(O)cc1F
Reactant: CCOCc1cnc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)OC)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
DIAD (0.955 ml, 4.91 mmol) was added to a stirred mixture of 2-[(1S,2R)-2-{1-[5-(ethoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl]ethanol (1 g, 3.27 mmol), methyl (2-fluoro-4-hydroxyphenyl)acetate (0.724 g, 3.93 mmol) and triphenylphosphine (1.288 g, 4.91 mmol) in toluene (10 ml). The mixture was stirred at RT for 5 hrs. The mixture was diluted with ethyl acetate (20 mL), washed with brine, dried over MgSO4, filtered and the solvent evaporated in vacuo. The residue was purified by column chromatography on silica gel, Biotage 100M, using a gradient eluant of 0-100% EtOAc/hexanes to afford the title compound. LC/MS (m/z): 472 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[C:4]([OH:14])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.[H-].[Na+].F[C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1>CN(C=O)C>[CH3:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[C:4]([O:14][C:26]2[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: COc1ccc(-c2c(C)cc3cc(OC)ccc3c2O)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(C)cc3cc(OC)ccc3c2Oc2ccc(C=O)cc2)cc1
Yield: 81 %

Procedure:
3-Methyl-6-(methyloxy)-2-[4-(methyloxy)phenyl]-1-naphthalenol (45) (0.30 g, 1.00 mmol) was treated with NaH in DMF followed by addition of 4-fluorobenzaldehyde to give 0.32 g (81%) of the title compound (46) as a light yellow foam. 1H NMR (400 MHz, CDCl3): δ 2.26 (s, 3H), 3.76 (s, 3H), 3.93 (s, 3H), 6.71 (d, J=8.8 Hz, 2H), 6.79 (d, J=8.7 Hz, 2H), 7.02-7.07 (m, 3H), 7.14 (d, J=2.6 Hz, 1H), 7.58 (s, 1H), 7.63 (d, J=8.8 Hz, 2H), 7.66 (d, J=9.1 Hz, 1H), 9.80 (s, 1H). LCMS (APCI): m/z 399 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:14]([N:18]=[N+:19]=[N-:20])[CH2:15][CH2:16][CH3:17]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C:12](=[O:13])[N:18]([CH2:14][CH2:15][CH2:16][CH3:17])[N:19]=[N:20]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCCCN=[N+]=[N-]
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: CCCCn1nnn(S(=O)(=O)c2ccc(Cl)cc2)c1=O

Procedure:
Equimolar mixtures of (p-chlorophenyl)-sulphonyl isocyanate and n-butylazide were dissolved at room temperature in toluene with a molar concentration of 0.6. 1-(p-chlorophenylsulphonyl)-4-n-butyl-2-tetrazolin-5-one was obtained, which was a white powder or a clear crystalline precipitate, according to whether the precipitation occurred fast or slow. The product had a melting range of 76.5°-77.5° C. The following results were obtained by elementary analysis:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1F)[CH:13]=[O:14])[CH3:8]>CN(C=O)C>[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[N:5]1[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]1)[CH:13]=[O:14])[CH3:8]
Reactant: Cc1c[nH]cn1
Reactant: CCOc1cc(C=O)ccc1F
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)ccc1-n1cnc(C)c1
Temperature: 150 °C
Reaction time: 4 h
Yield: 17.5 %

Procedure:
4-methylimidazole (244 mg) was added to a DMF (3 mL) solution of 3-ethoxy-4-fluorobenzaldehyde (250 mg) obtained above, and the reaction solution was agitated at 150° C. for 4 hours. The reaction solution was concentrated as it was after the reaction ended, water and ethyl acetate were added to the obtained reaction residue, and the organic layer was separated. The obtained organic layer was washed with a saturated sodium chloride solution, and the solvent was evaporated under reduced pressure after dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate 1:4), and 60 mg (18%) of 3-ethoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde was obtained. The physical properties of the compound are as follows.
Reaction SMILES: F[C:2](F)(F)[C:3]([NH2:5])=[O:4].[NH:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)C(=O)C2)[CH2:10][CH2:9]1.[OH-].[K+]>CO.O>[O:4]=[C:3]1[CH2:2][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:8][CH2:9][CH2:10]2)[CH2:12][CH2:13][NH:5]1
Reactant: O=C1CC2(CCNCC2)c2ccccc21
Reactant: NC(=O)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1CC2(CCN1)CCNc1ccccc12
Yield: 91.1 %

Procedure:
A solution of 49 mg (0.157 mmol) of the high RF material from Step B in methanol/water 4:1 with excess potassium hydroxide was stirred over night. The solution was concentrated and water and ethyl acetate were added to the residue. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to give 31 mg (0.143 mmol) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1.[CH3:18][O:19][CH2:20][CH2:21]O.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOC(C)=O>[C:14]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:21][CH2:20][O:19][CH3:18])=[CH:9][CH:8]=2)[N:5]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(O)cc2)n1
Reactant: COCCO
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCOc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-(5-amino-3-tert-butyl-pyrazol-1-yl)phenol (500 mg, 2.16 mmol), 2-methoxyethanol (164.5 mg, 2.16 mmol), ADDP (818.2 mg, 3.24 mmol, 1.5 eq), and triphenylphosphine (850.5 mg, 3.24 mmol, 1.5 eq) in anhydrous THF was stirred at ambient temperature under nitrogen for 18 h. The reaction mixture was poured into EtOAc, and the organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated at reduced pressure. Purification by MPLC (eluting with 25% EtOAc/hexane) gave an oil which solidified upon standing, 507 mg (81%). 1H-NMR (DMSO-d6) δ 7.39 (dd, J=6.6, 2.4 Hz, 2H), 6.97 (dd, J=6.9, 2.7 Hz, 2H), 5.30 (s, 1H), 5.02 (broad s, 2H), 4.09 to 4.06 (m, 2H), 3.65 to 3.62 (m, 2H), 3.28 (s, 3H), 1.16 (s, 9H); MS LC-MS [M+H]+=290, RT=1.35 min.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.[F:13][C:14]([F:28])([F:27])[C:15]1[C:16]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:17][CH:18]=[CH:19][CH:20]=1>>[Cl:12][C:8]1[C:9]([CH3:11])=[CH:10][C:4]2[N:3]=[C:2]([N:24]3[CH2:25][CH2:26][N:21]([C:16]4[C:15]([C:14]([F:28])([F:13])[F:27])=[CH:20][CH:19]=[CH:18][N:17]=4)[CH2:22][CH2:23]3)[NH:6][C:5]=2[CH:7]=1
Reactant: Cc1cc2[nH]c(Cl)nc2cc1Cl
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Product: Cc1cc2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2cc1Cl

Procedure:
The benzoimidazole from step (b) above (201 mg, 1.0 mmol) reacted with 1-(3-trifluoromethylpyridin-2-yl)piperazine (231 mg, 1.0 mmol, Oakwood) under the conditions of Example 3c to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 396.1 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]3=[C:20]([C:31]([OH:33])=[O:32])[C:21]([C:28]([OH:30])=O)=[C:22]4[CH:23]=[CH:24][C:25]([CH2:26][OH:27])=[C:17]([N:18]34)[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>>[C:34]([O:27][CH2:26][C:25]1[CH:24]=[CH:23][C:22]2[N:18]3[C:19]([C:15]([C:12]4[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)=[CH:14][CH:13]=4)=[CH:16][C:17]=13)=[C:20]1[C:31](=[O:32])[O:33][C:28](=[O:30])[C:21]1=2)(=[O:36])[CH3:35]
Reactant: O=C(O)c1c(C(=O)O)c2c(-c3ccc(OCc4ccccc4)cc3)cc3c(CO)ccc1n32
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCc1ccc2c3c(c4c(-c5ccc(OCc6ccccc6)cc5)cc1n24)C(=O)OC3=O

Procedure:
The general synthetic pathway outlined in example 81, step 5, and example 83 have been applied to proper starting materials in the preparation of 3-(4-benzyloxyphenyl)-5-hydroxymethylpyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylic acid, which was reacted with acetic acid anhydride by the general synthetic principles outlined in example 23, step 8, to afford 5-acetoxymethyl-3-(4-benzyloxyphenyl)pyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylic acid anhydride as red crystals in 86%. 1H-NMR (DMSO-d6, 300 MHz) δ: 2.17 (s, 3H); 5.22 (s, 2H); 5.67 (s, 2H); 7.19 (d, 2H); 7.32-7.48 (m, 3H); 7.52 (d, 2H); 8.10-8.19 (m, 2H); 8.27 (d, 2H); 8.34 (d, 1H).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:7]([O:16][C:17]2[CH:28]=[CH:27][C:20]([O:21][CH:22]([CH3:26])[C:23](O)=[O:24])=[C:19]([F:29])[CH:18]=2)=[N:8][CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1.C1C=CC=CC=1>CN(C)C=O>[Cl:5][C:6]1[C:7]([O:16][C:17]2[CH:28]=[CH:27][C:20]([O:21][CH:22]([CH3:26])[C:23]([Cl:3])=[O:24])=[C:19]([F:29])[CH:18]=2)=[N:8][CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1
Reactant: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1F)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1F)C(=O)Cl
Reaction time: 3 h

Procedure:
Thionyl chloride (7.24 g, 0.0608 mole) was added to a stirred solution of 2-(4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)-2-fluorophenoxy)propanoic acid (21.0 g, 0.0553 mole), benzene (150 ml), and dimethyl formamide (0.3 g). Refluxing was effected for three hours. The benzene and residual thionyl chloride were removed by distillation under vacuum. The resulting amber colored oil (21 g) was shown to be the desired acid chloride by NMR and IR spectroscopy. This material was used directly in subsequent reactions.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:15]([C:16](O)=[O:17])=[C:14]([Cl:19])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]>CN(C)C=O.C1(C)C=CC=CC=1>[Cl:3][C:16]([C:15]1[C:6]([Cl:5])=[C:7]([CH:12]=[CH:13][C:14]=1[Cl:19])[C:8]([O:10][CH3:11])=[O:9])=[O:17]
Reactant: COC(=O)c1ccc(Cl)c(C(=O)O)c1Cl
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cl)c(C(=O)Cl)c1Cl
Yield: 100 %

Procedure:
2 drops of dimethylformamide and 11.90 g (0.1 mol) of thionyl chloride were added to a solution of 5.00 g (0.02 mol) of methyl 2,4-dichloro-3-hydroxycarbonylbenzoate and 50 ml of dry toluene. The solution was heated under reflux for 4 hours. Removal of the solvent by distillation gave 5.35 g of methyl 3-chlorocarbonyl-2,4-dichlorobenzoate.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH:20]1([CH2:25][NH:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]2)[CH2:24][CH2:23][CH2:22][CH2:21]1>C(#N)C>[CH:20]1([CH2:25][NH:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][N:31]([C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[NH:8][C:7](=[O:15])[C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:30]2)[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: C1CCC(CNCCC2CCCNC2)C1
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ncccc21
Solvent: CC#N
Product: O=C1Nc2ccccc2N(C(=O)N2CCCC(CCNCC3CCCC3)C2)c2ncccc21
Yield: 61 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one and 3-[2-[(cyclopentyl)methylamino]ethyl]piperidine in a yield of 61% of theory. Colourless crystals, m.p. 148°-150° C. (acetonitrile).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:7]=3[C:6]=2[C:5]([Cl:17])=[CH:4][CH:3]=1.[H-].[Na+].CC1C=CC(S(O[CH2:31][CH2:32][C:33]2[CH:34]=[N:35][C:36]([CH3:39])=[CH:37][CH:38]=2)(=O)=O)=CC=1>CN(C=O)C>[Cl:1][C:2]1[C:10]2[N:9]([CH2:31][CH2:32][C:33]3[CH:34]=[N:35][C:36]([CH3:39])=[CH:37][CH:38]=3)[C:8]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:7]=3[C:6]=2[C:5]([Cl:17])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C)nc2)cc1
Reactant: CN1CCc2[nH]c3c(Cl)ccc(Cl)c3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(CCn2c3c(c4c(Cl)ccc(Cl)c42)CCN(C)CC3)cn1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7,10-dichloro-1,2,3,4,5,6-hexahydro-3-methylazepino[4,5-b]indole (200 mg, 0.746 mmol) in DMF (2 mL), sodium hydride (90 mg, 2.25 mmol) was added. After stirring at 60° C. for 30 min., 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (543 mg, 1.86 mmol) was added to the reaction mixture and the reaction mixture was stirred at the same temperature for 40 min. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to obtain the residue that was purified by reverse phase HPLC to obtain 7,10-dichloro-1,2,3,4,5,6-hexahydro-3-methyl-6-(2-(6-methylpyridin-3-yl)ethyl)azepino[4,5-b]indole. 1H NMR TFA: —CD3OD: 8.4 (s, 1H), 8.1 (d, 1H), 7.75 (d, 1H), 7.0 (q, 2H), 4.8 (m, 1H), 4.0 (m, 1H), 3.8 (m, 2H), 3.4 (m, 3H), 3.3 (m, 2H), 3.2 (t, 3H), 3.0 (s, 3H), 2.7 (s, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[C:9]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:10]=1)=[O:4].C1COCC1.O.[OH-].[Li+].Cl>O>[CH:11]1([C:9]2[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[N:7][C:8]=2[O:17][CH2:18][C:19]([F:21])([F:22])[F:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: COC(=O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.5 %

Procedure:
5-Cyclohexyl-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid methyl ester (95 mg, 299 μmol) was combined with THF (4 mL) and water (2 mL) to give a light yellow solution. Lithium hydroxide hydrate (25.1 mg, 599 μmol) was added under argon. The reaction mixture stirred at ambient temperature overnight, subsequently poured into 6 mL 2 M HCl and extracted with isopropyl acetate (2×60 mL). The organic layers were combined, dried with Na2SO4 and concentrated in vacuo to give the title compound (92 mg, quant.) as white solid; MS (ESI) 302.0 (M−H)−.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:22])([F:21])[C:5]([C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][C@@H:15]2[CH3:20])=[N:12][CH:13]=1)([OH:7])[CH3:6].C(Cl)Cl.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[S:31](Cl)(=[O:33])=[O:32]>O>[F:22][C:4]([F:3])([F:21])[C:5]([C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([S:31]([C:27]3[S:26][CH:30]=[CH:29][CH:28]=3)(=[O:33])=[O:32])[CH2:16][C@@H:15]2[CH3:20])=[N:12][CH:13]=1)([OH:7])[CH3:6]
Reactant: C[C@H]1CNCCN1c1ncc(C(C)(O)C(F)(F)F)cn1
Reactant: O=S(=O)(Cl)c1cccs1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ncc(C(C)(O)C(F)(F)F)cn1
Reaction time: 0.25 h
Yield: 37.5 %

Procedure:
A 100 mL round-bottomed flask was charged with 1,1,1-trifluoro-2-(2-((2S)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-2-propanol dihydro chloride (0.250 g, 0.763 mmol) and 10 mL of CH2Cl2. To this was added 2-thiophenesulfonyl chloride (0.153 g, 0.839 mmol, Sigma-Aldrich, St. Louis, Mo.). After 15 min, the mixture was diluted with water (50 mL) and extracted with CH2Cl2 (2×50 mL). The combined extracts were dried (MgSO4), concentrated, and purified via column chromatography (40 g of silica, 0 to 50% EtOAc in hexanes) to give 1,1,1-trifluoro-2-(2-((2S)-2-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol (0.125 g) as mixture of two isomers.
Reaction SMILES: [Na].C([O:4][C:5](=[O:21])[CH2:6][S:7][C:8]1[N:13]=[C:12](Cl)[CH:11]=[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1)C.[CH3:22][OH:23]>>[CH3:22][O:23][C:12]1[CH:11]=[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=[C:8]([S:7][CH2:6][C:5]([OH:4])=[O:21])[N:13]=1
Reactant: CO
Reactant: CCOC(=O)CSc1nc(Cl)cc(-c2ccccc2)n1
Agent: [Na]
Product: COc1cc(-c2ccccc2)nc(SCC(=O)O)n1
Reaction time: 1.5 h

Procedure:
To a solution of 0.46 g of sodium metal in 50 ml. of absolute methanol was added 3.2 g of (4-chloro-6-phenyl-2-pyrimidinylthio)acetic acid ethyl ester as prepared in the preceding Example. The reaction mixture was heated under reflux for 3 hr. then filtered. The filtrate was taken to dryness in a rotary evaporator. The residue was dissolved in 30 ml. of 50% sodium hydroxide and the solution was diluted to 200 ml. The reaction mixture was allowed to stand at room temperature for 1.5 hr, cooled in ice and acidified with concentrated hydrochloric acid. The resulting precipitate was recrystallized from aqueous ethanol affording 1.4 g of product, mp. 157°-159°C.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][C:8]1C=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:9]=1C(O)=O>CN(C=O)C.C(Cl)Cl>[CH3:7][C:8]1[CH:9]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][C:1]=1[C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc([N+](=O)[O-])cc1C(=O)Cl
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Oxalyl chloride (0.31 g) was added dropwise to a stirred mixture of 2-methyl-5-nitrobenzoic acid (0.4 g), DMF (a few drops) and methylene chloride (25 ml) which had been cooled to 0° C. The mixture was allowed to warm to ambient temperature and was stirred for five hours. The mixture was evaporated to give 2-methyl-5-nitrobenzoyl chloride which was dissolved in methylene chloride (10 ml) and added dropwise to a stirred mixture of 3-(4-methylpiperazin-1-ylmethyl)aniline (0.44 g), triethylamine (0.49 g) and methylene chloride (10 ml). The mixture was stirred at ambient temperature for 16 hours. The mixture was washed with a saturated aqueous sodium bicarbonate solution. The organic phase was evaporated and the residue was purified by column chromatography on an isolute SCX ion exchange column using initially methanol and then a 99:1 mixture of methanol and a saturated aqueous ammonium hydroxide solution as eluent. There was thus obtained N-[3-(4-methylpiperazin-1-ylmethyl)phenyl]-2-methyl-5-nitrobenzamide(0.46 g); Mass Spectrum: M+H+ 369.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]=1[OH:16])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]=1[OH:16]
Reactant: O=[N+]([O-])c1cccc(-c2ccccc2)c1O
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(-c2ccccc2)c1O
Yield: 90 %

Procedure:
To a solution of 2-nitro-6-phenylphenol (900 mg, 4.2 mmol) in methanol (50 ml) was added 10% Pd/C (100 mg). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5%MeOH/CH2CH2) gave the desired product (700 mg, 90%). 1H NMR (CD3OD): d 7.55-7.27 (m, 5H), 6.77-6.61 (m, 3H)
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][O:13][CH2:14][CH2:15][CH2:16][NH2:17]>>[CH3:12][O:13][CH2:14][CH2:15][CH2:16][NH:17][C:2]1[N:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(Cl)nc1
Reactant: COCCCN
Product: COCCCNc1ccc(S(N)(=O)=O)cn1
Temperature: 100 °C
Reaction time: 12 h
Yield: 78 %

Procedure:
A mixture of 6-chloropyridine-3-sulfonamide (5 g, 0.025 mol) and 3-methoxy propylamine (50 ml) is stirred at 100° C. for 12 h. The mixture is cooled and excess reagent is removed by distillation. The residue is suspended in DCM (25 ml) and cooled. The precipitate is filtered, washed with cold ammonium hydroxide (2×50 ml) and dried under vacuum to afford 5 g (78%) of the titled compound as a white solid. mp: 129-132° C., LC/MS: (ES+) 246.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2O)=[N:13][C:14]=1[CH2:15][CH3:16].Br[C:31]1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2CC)=N[C:36]=1CC>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[CH2:31][CH3:36])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2CC)c(CC)nc1Br
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1CC

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting (+/−)-5-bromo-3,6-diethyl-N-[cis-2-ethyl-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine and making non-critical variations provided the title compound as a light yellow semi-solid. IR (liq.) 3452, 2965, 2934, 2874, 1589, 1566, 1551, 1495, 1470, 1392, 1377, 1203, 1175, 1101, 752 cm−1; OAMS supporting ions at: ESI+ 439.8; HRMS (FAB) calcd for C25H27CL2N3+H1 440.1660, found 440.1648. Anal. Calcd for C25H27Cl2N3: C, 68.18; H, 6.18; N. 9.54. Found: C, 68.33; H, 6.36; N, 9.30.