Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][C:32]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:33]=1[C:34](Cl)=[O:35]>C(Cl)Cl>[CH:21]1[CH:20]=[CH:19][N:11]2[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]([C:6]([C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:34](=[O:35])[C:33]4[CH:37]=[C:38]([F:41])[CH:39]=[CH:40][C:32]=4[CH3:31])=[CH:3][CH:4]=3)=[O:7])[CH2:9][C:10]=12
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: Cc1ccc(F)cc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 40.7 %

Procedure:
To a stirred solution of 500 mg of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]-benzodiazepine in 3 ml of methylene chloride, cooled to 0° C., under argon, is added 346 μl of triethylamine followed by the addition of 340 mg of 2-methyl-5-fluorobenzoyl chloride in 2 ml of methylene chloride. The cooling bath is removed and stirring continued for 18 hours. After cooling to 0° C., an additional 342 mg of 2-methyl-5-fluorobenzoyl chloride in 2 ml of methylene chloride is added. The cooling bath is removed and stirring continued for 18 hours. The volatiles are removed in vacuo to a residue which is dissolved in 50 ml of methylene chloride and washed with 20 ml each of water, 2 N citric acid, 1 M sodium bicarbonate and brine. The organic layer is dried over Na2SO4 and passed through a pad of hydrous magnesium silicate. The filtrate is evaporated in vacuo to a residue which is crystallized from ethyl acetate-hexane to give 295 mg of the desired product as a white solid, m.p. 170-180° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[C:15]1(C)[CH:20]=CC(S(O)(=O)=O)=C[CH:16]=1>C(O)C=C>[OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH2:20][CH:15]=[CH2:16])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13]
Reactant: O=C(O)c1ccc(CO)c([N+](=O)[O-])c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C=CCO
Product: C=CCOC(=O)c1ccc(CO)c([N+](=O)[O-])c1

Procedure:
In a 100 mL round bottom flask was placed 4-hydroxymethyl-3-nitrobenzoic acid (1.97 g, 10 mmol). Allyl alcohol (20 mL) was added, followed by p-toluenesulfonic acid (0.190 g, l mmol). The mixture was heated to reflux for 24 hr., at which time all the volatiles were removed in vacuo. The residue was taken up in EtOAc and washed with sat'd KHCO3. The organic layer was dried over MgSO4 and concentrated to afford the title compound as a cream colored solid; 2.4 g (100%).
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:21][C@@:20]2([CH3:22])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[C@H:18]([NH:23][C:24]([O:26][CH2:27][C:28]([Cl:31])([Cl:30])[Cl:29])=[O:25])[CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:6][C@@H:5]1[OH:37])[CH3:2].[C:38](OC(=O)C)(=[O:40])[CH3:39]>N1C=CC=CC=1.C(O)C>[C:38]([O:37][C@@H:5]1[C@@H:4]([O:3][CH2:1][CH3:2])[CH2:21][C@@:20]2([CH3:22])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[C@H:18]([NH:23][C:24]([O:26][CH2:27][C:28]([Cl:29])([Cl:30])[Cl:31])=[O:25])[CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:6]1)(=[O:40])[CH3:39]
Reactant: CCOC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCC)C[C@]4(C)[C@H]3[C@H](NC(=O)OCC(Cl)(Cl)Cl)C[C@]12C
Reactant: CC(=O)OC(C)=O
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC(C)=O)[C@@H](OCC)C[C@]4(C)[C@H]3[C@H](NC(=O)OCC(Cl)(Cl)Cl)C[C@]12C

Procedure:
Ethyl 2β-ethoxy-3α-hydroxy-11α-(2,2,2-trichloroethoxy-carbonylamino)-5α-androstane-17β-carboxylate (1.83 g) in pyridine (6 ml) was treated with acetic anhydride. After b 18 h. the reaction mixture was diluted with ethanol and evaporated to give a foam (1.91 g). A portion was purified by preparative t.l.c. in ethyl acetate/Petrol (1:2) to give the title compound, [α]D +30.7°, νmax 1724 cm-1.
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][NH:3][CH2:2]1.[H-].[Na+].O.[CH3:23]N(C=O)C>>[CH2:18]([O:17][C:15]([C:5]1[C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[CH2:1][CH2:2][N:3]([CH3:23])[CH:4]=1)=[O:16])[CH3:19]
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1ccccc21
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C1=CN(C)CCc2c1[nH]c1ccccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate (0.15 g, 0.6 mmol) in DMF (2 mL) was added sodium hydride (60%, 28 mg, 0.7 mmol) at 0° C. and a solution of Mel (38 μL, 0.7 mmol). The mixture was stirred for 30 min at 0° C. Water was added to the reaction mixture, which was then extracted by DCM. The combined organic layer was washed with water and dried over magnesium sulfate. Evaporation of solvent gave a crude product, which was purified by column chromatography on silica gel eluting with MeOH-DCM (5:95) and then further purified by preparative HPLC to afford the title compound (86 mg); 1H-NMR (CDCl3): δ 10.50 (1H, s), 8.26 (1H, m), 7.77 (1H, s), 7.40 (1H, d), 7.31 (1H, d), 7.05 (2H, m), 5.35 (1H, s), 4.28 (2H, q), 3.54 (2H, t), 3.26 (3H, s), 3.14 (2H, m), 1.36 (3H, t). MS (ES): 271 (MH+).
Reaction SMILES: Cl.C(OCC)(=O)C.[CH2:8]([O:15][C@H:16]1[C@@H:21]([NH:22][C:23]([C:25]2[NH:26][CH:27]=[CH:28][N:29]=2)=[O:24])[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.Br[C:47]1[S:48][C:49]([C:52]([O:54][CH2:55][CH3:56])=[O:53])=[CH:50][N:51]=1.Cl>>[CH2:8]([O:15][C@H:16]1[C@@H:21]([NH:22][C:23]([C:25]2[NH:26][CH:27]=[CH:28][N:29]=2)=[O:24])[CH2:20][CH2:19][N:18]([C:47]2[S:48][C:49]([C:52]([O:54][CH2:55][CH3:56])=[O:53])=[CH:50][N:51]=2)[CH2:17]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1cnc(Br)s1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)c2ncc[nH]2)[C@H](OCc2ccccc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(N2CC[C@H](NC(=O)c3ncc[nH]3)[C@H](OCc3ccccc3)C2)s1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 76.1 %

Procedure:
A 4 N hydrochloric acid/ethyl acetate solution (10 mL, 40 mmol) was added to tert-butyl cis(±)-3-(benzyloxy)-4-[(1H-imidazol-2-ylcarbonyl)amino]piperidine-1-carboxylate obtained in Example (90e) (0.3 g, 0.75 mmol), and the mixture was stirred at room temperature for 20 minutes. Following concentration under reduced pressure, the residue was dissolved in DMF (8 mL). Diisopropylethylamine (0.45 g, 3.5 mmol) and ethyl 2-bromo-1,3-thiazole-5-carboxylate (0.21 g, 0.9 mmol) were added, and the mixture was stirred at 70° C. for 1.5 hours. Dilute hydrochloric acid was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate solution and brine, and dried over anhydrous sodium magnesium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=5/1, ethyl acetate) to obtain 0.26 g of the title compound as a light brown solid (76%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:17])[C:5]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:6]([CH3:8])[CH:7]=1.C([Li])(C)(C)C.CCCCC.[CH2:28]([N:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37](=[O:44])[C:36]1=[O:45])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>COCCOC>[CH2:28]([N:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]([C:2]2[CH:3]=[C:4]([CH3:17])[C:5]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:6]([CH3:8])[CH:7]=2)([OH:44])[C:36]1=[O:45])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1C(=O)N(Cc2ccccc2)c2ccccc21
Reactant: Cc1cc(Br)cc(C)c1OCc1ccccc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: COCCOC
Product: Cc1cc(C2(O)C(=O)N(Cc3ccccc3)c3ccccc32)cc(C)c1OCc1ccccc1
Temperature: -70 °C
Reaction time: 18 h
Yield: 95.1 %

Procedure:
Dissolve 5-bromo-1,3-dimethyl-2-(phenylmethoxy)-benzene (2.56 g, 8.8 mmol) in ethylene glycol dimethyl ether (40 mL) under nitrogen. Cool to −70° C. with a dry ice/acetone bath and add slowly a 1.7M solution of t-butyllithium in pentane (10.4 mL, 17.6 mmol). After 15 min add 1-benzyl-1H-indole-2,3-dione (1.90 g, 8 mmol) in ethylene glycol dimethyl ether (32 mL). Remove the bath and allow to warm to room temperature with stirring for 18 h. Quench with saturated NH4Cl solution and extract with ethyl acetate (2×). Wash combined organics with brine and then dry (Na2SO4), filter and concentrate in vacuo to give 3.42 g of a dark purple oil. Purify initially by flash chromatography (25% EtOAC/hexanes) to give 1.20 g of material which by TLC is mostly starting material and product. Purify further by chromatography (step gradient of CH2Cl2, 5% acetonitrile/CH2Cl2, 10% acetonitrile/CH2Cl2) to give 803 mg (22%) of the title compound as a yellow foam. MS (ES): m/z=432 (M+1−H2O); 1H NMR(DMSO-d6); δ7.50-7.18 (m, 12H), 7.00 (m, 2H), 6.95 (s, 2H), 6.77 (s, 1H), 4.93 (q, J=2 Hz, J=18 Hz, 2H), 4.77 (s, 2H), 2.20 (s, 6H).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.[C:11]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:10])[CH3:1])[CH:4]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CN(C)c1cccc(N)c1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CN(C)c1cccc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1

Procedure:
prepared by reaction of N,N-dimethyl-benzene-1,3-diamine with 4-tert-butyl-benzenesulfonyl chloride
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: CCOCc1cnc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Reactant: COC(=O)Cc1ccc(O)cc1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
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: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([Cl:18])[N:3]=1.[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1.C(N(CCCC)CCCC)CCC>O1CCOCC1>[Cl:18][C:4]1[N:3]=[C:2]([C:20]2[NH:19][CH:23]=[CH:22][N:21]=2)[C:11]2[C:6]([C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: Clc1nc(Cl)c2ccccc2c1-c1ccccc1
Reactant: c1c[nH]cn1
Solvent: CCCCN(CCCC)CCCC
Solvent: C1COCCO1
Product: Clc1nc(-c2ncc[nH]2)c2ccccc2c1-c1ccccc1

Procedure:
2.74 g (10 moles) of 1,3-dichloro-4-phenylisoquinoline, 1.02 g (15 mmoles) of imidazole and 2.7 g (15 mmoles) of tri-n-butylamine were heated for 18 hours in 5 ml of dioxane under reflux. Working was carried out as described under 1c.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[C:18]=2[NH2:24])=[CH:2]1.[CH:25](O)=O>>[N:23]1[C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11][CH2:10][C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[C:18]=2[NH:24][CH:25]=1
Reactant: O=CO
Reactant: Nc1cccc(OCCNCCCc2c[nH]c3ccccc23)c1N
Product: c1cc(OCCNCCCc2c[nH]c3ccccc23)c2[nH]cnc2c1
Temperature: 104 °C
Reaction time: 8 h

Procedure:
A solution of 3-{2-[3-(1H-indol-3-yl)-propylamino]-ethoxy}-benzene-1,2-diamine (0.75 g, 2.3 mmol) dissolved in 15 ml formic acid (98%) was heated to 104° C. for 6 hours. Upon standing overnight at 25° C., the excess formic acid was removed by vacuum distillaton. Water (100 ml) and ethyl acetate (100 ml) was added thereto. The ethyl acetate layer was separated and washed once with water (50 ml), once with brine (75 ml) and dried over anhydrous magnesium sulfate. Concentration of the solvent gave 0.7 g of product as a brown solid. Purification by chromatography (2 N ammonia in methanol:methylene chloride=20:1.5) and crystallization from ethyl acetate-ethanol afforded 0.345 g (44.8%) of product as a white solid: mp 121-124° C. decomposed. The HCl salt was prepared in ethanol: mp 256-258° C. decomposed.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[Br:39]N1C(=O)CCC1=O>C(Cl)Cl>[Br:39][CH:13]1[C:14](=[O:17])[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12]1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCN(C(=O)OCc2ccccc2)CC1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a cooled (0° C.) solution of N-benzyloxycarbonyl-4-piperidone (501, 27.3 g 117 mmol) in DCM (3 ml/mmol) was added DIPEA (25.5 ml, 146.2 mmol, 1.25 eg) and trimethylsilyl trifluoromethane sulfonate (25.4 ml, 141 mmol, 1.2 eg). The mixture was stirred for 30 minutes at 0° C. Next, N-bromosuccinimide (21.2 g, 119.3 mml, 1.02 eg) was added and stirring was continued for 16 hrs at room temperature. The reaction mixture was washed with 5% NaHCO3 and the organic layer was dried (MgSO4) and subsequently concentrated under reduced pressure. The resulting oil was purified by silica gel chromatography (diethyl ether/petroleum ether, 1/1 to 1/0, v/v, Rf 0.1) giving 502 in a yield of 90% as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:13][C:14]1[N:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].CS(C)=O>CC(O)=O>[Cl:13][C:14]1[N:19]=[CH:18][C:17]([S:20]([NH:23][C:2]2[C:11]([Cl:12])=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)(=[O:21])=[O:22])=[CH:16][CH:15]=1
Reactant: NS(=O)(=O)c1ccc(Cl)nc1
Reactant: Clc1nc2ccccc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: O=S(=O)(Nc1nc2ccccc2nc1Cl)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 96.6 %

Procedure:
2,3-dichloroquinoxaline (1.09 g, 5.48 mmol), 6-chloropyridine-3-sulfonamide (1.05 g, 5.45 mmol), K2CO3 (753 mg, 5.45 mmol) and dry DMSO (30 mL) were combined and heated to 150 C with vigorous stirring for 3-4 hr. The reaction mixture was allowed to cool to room temperature, then poured into 1% AcOH in ice water (300 mL) with vigorous stirring. The resulting solids were filtered, washed with H2O and dried under high vacuum to give 6-chloro-N-(3-chloroquinoxalin-2-yl)pyridine-3-sulfonamide (1.87 g, 96%). MS (EI) for C13H8Cl2N4O2S: 354.99 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.Cl[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[O:41][CH3:42])[CH2:31][CH2:30]1>C(#N)C.O>[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:27][CH2:28][N:29]2[CH2:30][CH2:31][N:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])[CH2:33][CH2:34]2)[CH2:22][CH2:21]1
Reactant: Fc1ccc2[nH]cc(CC3CCNCC3)c2c1
Reactant: COc1ccccc1N1CCN(CCCl)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccccc1N1CCN(CCN2CCC(Cc3c[nH]c4ccc(F)cc34)CC2)CC1
Yield: 79.9 %

Procedure:
Pulverized potassium carbonate (0.76 g, 5.5 mmole) and potassium iodide (0.97 g, 5.5 mmole) was added to a mixture of 4-(5-fluoro-1H-indol-3-ylmethyl)piperidine (1.16 g, 5.0 mmole) and 1-(2-chloroethyl)-4-(2-methoxyphenyl)piperazine (1.27 g, 5.0 mmole) in 25 ml of acetonitrile. The resulting mixture was heated to reflux under nitrogen for 5 hours. After cooling, it was diluted with water (150 ml) and the product extracted into ethyl acetate (50 ml). The organic layer was washed with water (50 ml), brine (50 ml), and after drying over sodium sulfate, filtration and concentration in vacuo afforded the required product as a white solid (1.8 g, 80%). Treatment with an excess of 1M etheral hydrochloric acid gave the acid addition salt, which was recrystallized from methanol.
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].[CH2:7]([NH2:10])[C:8]#[CH:9].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1C=CC=CC=1>[CH:11](=[N:10][CH2:7][C:8]#[CH:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: C#CCN
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: c1ccccc1
Product: C#CCN=Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
10 g of magnesium sulfate was added to a stirred solution of 13.8 g of propargylamine and 26.5 g of benzaldehyde in 75 ml of benzene and the resulting mixture was stirred at room temperature for 30 minutes. The mixture then was filtered and water was removed from the filtrate by azeotropic distillation. Then the remaining benzene was evaporated and the residue was distilled to give N-benzylidene-2-propyn-1-amine (1A) b.p.: 64°-66° C. (0.2 Torr.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:15]([F:23])[CH:14]=3)[N:11]=[C:10]([C:24]([F:27])([F:26])[F:25])[CH:9]=2)[CH:5]=[CH:4][C:3]=1[OH:28].[Cl-:29].O>C(Cl)Cl>[Cl:29][C:4]1[CH:5]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:15]([F:23])[CH:14]=3)[N:11]=[C:10]([C:24]([F:25])([F:26])[F:27])[CH:9]=2)[CH:7]=[C:2]([CH3:1])[C:3]=1[OH:28]
Reactant: Cc1cc(-c2cc(C(F)(F)F)nn2-c2ccc(S(C)(=O)=O)c(F)c2)ccc1O
Reactant: [Cl-]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(-c2cc(C(F)(F)F)nn2-c2ccc(S(C)(=O)=O)c(F)c2)cc(Cl)c1O
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
To a stirred solution of 2-methyl-4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenol (0.332 g, 0.8 mmol) in CH2Cl2 (10 ml) was added sulfryl chloride (0.113 g, 0.84 mmol) at room temperature, and the mixture was stirred for 30 minutes. The reaction mixture was poured into water, and the whole was extracted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was recystallized with CH2Cl2-hexane to give the subtitle compound (0.318 g, 88.6% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:10]([CH:11]=[O:12])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[C:20]([Mg]Br)#[CH:21]>>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:10]([CH:11]([OH:12])[C:20]#[CH:21])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Reactant: C#C[Mg]Br
Product: C#CC(O)c1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Yield: 88.1 %

Procedure:
In a similar manner as described in Example 34 from 7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine-3-carbaldehyde (5.49 g, 20.0 mmol) and ethynylmagnesium bromide (100 mL, 0.5 M in tetrahydrofuran, 50.0 mmol) at 0° C., recrystallized from dichloromethane, was obtained 1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-propyn-1-ol (5.3 g, 88%) as a pale yellow crystalline solid. 1H NMR (CDCl3): δ 8.04 (d, 1H), 7.79 (m, 2H), 7.20 (m, 3H), 7.01 (d, 1H), 5.77 (m, 1H), 2.69 (d, 1H), 2.32 (d, 1H); MS m/z 301 (M+1).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH3:27][S:28]([C:31]1[S:35][C:34]([C:36](O)=[O:37])=[CH:33][CH:32]=1)(=[O:30])=[O:29]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:36]([C:34]3[S:35][C:31]([S:28]([CH3:27])(=[O:30])=[O:29])=[CH:32][CH:33]=3)=[O:37])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)s1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: CS(=O)(=O)c1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCCCC3c3coc4cccc-4c3)CC2)s1

Procedure:
The title compound, yellow solid (101 mg, 78%), MS (ISP) m/z=515.3 [(M+H)+], mp 214° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 5-methanesulfonyl-thiophene-2-carboxylic acid.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[CH3:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:25])[CH:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH2:13][S:14]2)=[CH:9][CH:8]=1.CC(C)([O-])C.[K+].O>CS(C)=O>[CH3:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:25])[C:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)([CH2:3][CH:2]=[CH2:1])[CH2:13][S:14]2)=[CH:9][CH:8]=1
Reactant: C=CCBr
Reactant: COc1ccc(C2CSc3cc(OC)ccc3C2=O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCC1(c2ccc(OC)cc2)CSc2cc(OC)ccc2C1=O
Temperature: 10 °C
Reaction time: 15 h
Yield: 78.7 %

Procedure:
Allyl bromide (5.7 ml, 66.56 mmol) was added dropwise to a solution of 7-methoxy-3-(4-methoxyphenyl)thiochroman-4-one (2 g, 6.64 mmol) in dimethyl sulfoxide (34 ml). To this mixture, a solution of potassium tert-butoxide (5.22 g, 46.55 mmol) in dimethyl sulfoxide (70 ml) was slowly added dropwise at 10° C., followed by stirring for 2 hours at 10° C. and for 15 hours at room temperature. Water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent:ethyl acetate/hexane=1/9) to give 7-methoxy-3-(4-methoxyphenyl)-3-(2-propenyl)thiochroman-4-one (1.78 g, Yield 79%) as a colorless oil.