Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])=[C:6]([CH3:15])[CH:5]=1)(=[O:3])[CH3:2].S(=O)(=O)(O)O.O.[CH3:22]O>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([O:14][CH3:22])=[O:13])=[C:6]([CH3:15])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CO
Reactant: CC(=O)c1ccc(C=CC(=O)O)c(C)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)C=Cc1ccc(C(C)=O)cc1C
Temperature: 25 °C

Procedure:
The obtained 3-(4-acetyl-2-methylphenyl)acrylic acid (657 mg, 3.22 mmol) was dissolved in methanol (20 mL). Concentrated sulfuric acid (250 μL) was added to the solution. The mixture was refluxed for 2 hours, and cooled to room temperature. Water (50 mL) was added to the solution. Methanol was removed under reduced pressure. The solution was extracted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and saturated brine. The organic layer was dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography with hexane/ethyl acetate (9:1, v/v) to give the desired compound (665 mg) as yellow crystalline product (yield 95%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH:22]1[CH2:24][CH2:23]1)[CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][N:15]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]([C:45]2[C:46]([CH2:51]OS(C)(=O)=O)=[N:47][CH:48]=[CH:49][CH:50]=2)([CH3:44])[CH3:43])=[CH:38][CH:37]=1>CC#N>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:51][C:46]1[C:45]([C:42]([C:39]2[CH:38]=[CH:37][C:36]([Cl:35])=[CH:41][CH:40]=2)([CH3:44])[CH3:43])=[CH:50][CH:49]=[CH:48][N:47]=1)[CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][N:15]=1)[CH:22]1[CH2:23][CH2:24]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(c1ccc(Cl)cc1)c1cccnc1COS(C)(=O)=O
Reactant: Cc1cnc(CNCCCCN(C(=O)OC(C)(C)C)C2CC2)c(C)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(CN(CCCCN(C(=O)OC(C)(C)C)C2CC2)Cc2ncccc2C(C)(C)c2ccc(Cl)cc2)c(C)c1

Procedure:
Using General Procedure A: Reaction of cyclopropyl-{4-[(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester and DIPEA in CH3CN with methanesulfonic acid 3-[1-(4-chloro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl ester gave {4-[{3-[1-(4-chloro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl}-(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-butyl}-cyclopropyl-carbamic acid tert-butyl ester as an oil. 1H.NMR (CDCl3) δ 0.51-0.54 (m, 2H), 0.64-0.70 (m, 2H), 1.21-1.28 (m, 4H), 1.42 (s, 9H), 1.63 (s, 6H), 2.14 (s, 3H), 2.28 (s, 3H), 2.33-2.40 (m, 3H), 3.00-3.04 (m, 2H), 3.27 (s, 2H), 2.62 (s, 2H), 6.90 (d, 2H, J=8.6 Hz), 7.14 (d, 2H, J=8.5 Hz), 7.20-7.22 (m, 2H), 7.84 (d, 1H, J=7.4 Hz), 8.12 (s, 1H), 8.53 (d, 1H, J=3.3 Hz).
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=[O:4])=[O:3].[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([CH2:19]O)=[N:17][CH:18]=1)([O-:12])=[O:11].C(N(CC)CC)C>C(Cl)Cl>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([CH2:19][O:5][S:2]([CH3:1])(=[O:4])=[O:3])=[N:17][CH:18]=1)([O-:12])=[O:11]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: O=[N+]([O-])c1ccc(CO)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc([N+](=O)[O-])cn1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Methanesulfonic anhydride (1.79 g, 10.3 mmol, 1.1 equiv) was added portionwise to a cold (5° C.) mixture of (5-nitro-pyridin-2-yl)-methanol (Step 112.4) (1.44 g, 9.4 mmol) and triethylamine (1.57 mL, 11.3 mmol, 1.2 equiv) in DCM (20 mL), under an argon atmosphere. The reaction mixture was allowed to stir for 0.5 h at 5° C., quenched with H2O and extracted with DCM. The organic phase was washed with H2O, dried (Na2SO4), filtered and concentrated to provide 2.16 g of the title compound as a brown solid: ESI-MS: 231.1 [M−H]−; tR=2.85 min (System 1).
Reaction SMILES: [CH3:1][C:2]1([C:8]([NH:10][CH:11]([C:23](=[O:25])[CH3:24])[CH2:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:24][C:23]1[O:25][C:8]([C:2]2([CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)=[N:10][C:11]=1[CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: CC(=O)C(CC(=O)OCc1ccccc1)NC(=O)C1(C)CCCCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1oc(C2(C)CCCCC2)nc1CC(=O)OCc1ccccc1
Reaction time: 4 h

Procedure:
A mixture of benzyl 3-(1-methylcyclohexylcarbonylamino)-4-oxovalerate (1.2 g), toluene (20 ml) and phosphorus oxychloride (2.0 ml) was refluxed with stirring for 4 hours. The solvent was distilled off and aqueous sodium hydrogen carbonate was added. The mixture was extracted with ethyl ether and the ethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the residue was purified by chromatography on silica gel (13 g) [eluent: hexaneacetone (9:1)] to give benzyl 5-methyl-2-(1-methylcyclohexyl)- 4-oxazoleacetate; yield 1.0 g (87.7%).
Reaction SMILES: [CH2:1]([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[N:7]1)[CH2:2][CH:3]([CH3:5])[CH3:4].Br[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].CC(C)(C)C(O)=O>CN(C)C(=O)C.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:21][C:19]1[CH:18]=[CH:17][C:16]([O:22][CH3:23])=[C:15]([C:10]2[N:6]([CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])[N:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[CH:20]=1
Reactant: CC(C)CCn1cc([N+](=O)[O-])cn1
Reactant: COc1ccc(Cl)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)C(=O)O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(Cl)cc1-c1c([N+](=O)[O-])cnn1CCC(C)C
Temperature: 120 °C
Reaction time: 12 h

Procedure:
A mixture of 1-Isopentyl-4-nitro-1H-pyrazole (356.9 mg, 1.95 mmol, 1.00 eq), 2-Bromo-4-chloroanisole (0.37 ml, 2.72 mmol, 1.40 eq), Palladium (II) acetate (88 mg, 0.39 mmol, 0.20 eq), Di(1-adanmtyl)-n-butylphosphine (209 mg, 0.58 mmol, 0.30 eq), potassium carbonate (807 mg, 5.84 mmol, 3.00 eq) and trimethylacetic acid (52 mg, 0.50 mmol, 0.26 eq) in 5.0 mL N,N-Dimethylacetamide was stirred at 120° C. for 12 hours. The reaction mixture was cooled to room temperature and diluted with 20 mL ethyl acetate and filtered. The filtrate was then concentrated and used as is for the next step. LCMS (ESI) m+H=324.3
Reaction SMILES: NC(N)=[S:3].[ClH:5].Cl.[CH3:7][C:8]1[CH:24]=[CH:23][C:11]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][Cl:22])[CH2:15][CH2:14]2)=[CH:10][CH:9]=1.C(N(CC)CC)C.[OH-].[Na+]>O.C(O)C>[ClH:22].[ClH:5].[CH3:7][C:8]1[CH:24]=[CH:23][C:11]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][SH:3])[CH2:15][CH2:14]2)=[CH:10][CH:9]=1
Reactant: NC(N)=S
Reactant: Cc1ccc(CN2CCN(CCCCl)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: Cc1ccc(CN2CCN(CCCS)CC2)cc1
Yield: 71.8 %

Procedure:
A mixture of 14.0 g of 1-(4-methylbenzyl)piperazine, 8.0 g of potassium hydroxide and 125 ml of dimethyl sulfoxide was stirred for 45 minutes. 11.8 g of 1-bromo-3-chloropropane were then added, and the mixture was stirred for an additional hour. Water was added, and the product was extracted with ether, and the extract was dried (sodium sulfate) and treated with ethereal hydrochloric acid to give 23.3 g (94% of theory) of 1-(4-methylbenzyl)-4-(3-chloropropyl)piperazine dihydrochloride as a white crystalline solid. (b) The procedure described in Example 1(b) was followed, using 7.7 g of thiourea, 23.0 g of 1-(4-methylbenzyl)-4-(3-chloropropyl)piperazine dihydrochloride, 6.5 g of triethylamine and 250 ml of reagent ethanol. The hydrolysis was effected with 6.0 g of sodium hydroxide in 40 ml of water. Work-up, as described above, gave 16.4 g (72% of theory) of 3-[4-(4-methylbenzyl)piperazin-1-yl] propanethiol dihydrochloride as a white crystalline solid, M.p. 273°-277° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[N+:11]([C:14]1[CH:15]=[N:16][NH:17][CH:18]=1)([O-:13])=[O:12].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:16]2[CH:15]=[C:14]([N+:11]([O-:13])=[O:12])[CH:18]=[N:17]2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cnn(-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
A mixture of 4-fluorobenzeneboronic acid (2.47 g, 17.7 mmol), 4-nitro-1H-pyrazole (1.00 g, 8.84 mmol), copper (II) acetate (2.41 g, 13.3 mmol) and pyridine (2.86 mL, 35.4 mmol) in CH2Cl2 (40 mL) was stirred at room temperature overnight. The reaction mixture was filtered and diluted with water (40 mL). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography (SiO2, 0-20% EtOAc/hexanes gradient elution) to give 1-(4-fluorophenyl)-4-nitropyrazole as a white solid (0.820 g, 22%).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12].[N:24]1[CH:29]=[CH:28][N:27]=[C:26]2[NH:30][CH:31]=[CH:32][C:25]=12.[OH-].[K+].O>CO>[F:1][C:2]1[C:7]([CH:8]([OH:9])[C:32]2[C:25]3[C:26](=[N:27][CH:28]=[CH:29][N:24]=3)[NH:30][CH:31]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: c1cnc2[nH]ccc2n1
Reactant: O=Cc1cccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=S(=O)(Nc1cccc(C(O)c2c[nH]c3nccnc23)c1F)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.4 %

Procedure:
To N-(2-fluoro-3-formyl-phenyl)-4-trifluoromethyl-benzenesulfonamide (26, 162 mg, 0.47 mmol) in 1 mL of methanol, 5H-pyrrolo[2,3-b]pyrazine (3, 67 mg, 0.56 mmol) and potassium hydroxide (79 mg, 1.4 mmol) were added under an atmosphere of nitrogen. The reaction was stirred at room temperature for 24 hours, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with 70% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a solid (27, 150 mg, 69%). MS (ESI) [M+H+]+=465.4.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:35]=[C:34]([O:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:33]=[CH:32][C:22]=4[O:23][CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].CS(O)(=O)=O>C(#N)C.CC(C)=O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:35]=[C:34]([O:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:33]=[CH:32][C:22]=4[O:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCCOc1ccc(OCC(=O)OC(C)(C)C)c(COc2ccc3oc(-c4nc(C(C)(C)C)cs4)cc3c2)c1
Agent: CS(=O)(=O)O
Solvent: CC#N
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1ccc(OCC(=O)O)c(COc2ccc3oc(-c4nc(C(C)(C)C)cs4)cc3c2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
tert-Butyl 2-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yloxy]methyl}-4-[3-(ethoxycarbonyl)propoxy]phenoxyacetate (200 mg) was dissolved in a mixed solvent of acetnitrile (10 ml) and acetone (1 ml) and methanesulfonic acid (62 mg) was added. The resulting solution was stirred at 80° C. for two hours. The reaction mixture was concentrated and diluted with water and neutralized with sodium hydrogen carbonate solution. The mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine and was dried over magnesium sulfate. After concentration, the product was crystallized with a mixed solvent of diisopropyl ether and n-hexane (1:2), filtered and dried to give 2-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yloxy]methyl}-4-[3-(ethoxycarbonyl)propoxy]-phenoxyacetic acid (117 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[C:17]=1I.C([Mg]Cl)(C)C.I[C:25]1[CH:26]=[CH:27][C:28]2[N:29]([C:31]([CH:34]([CH3:36])[CH3:35])=[N:32][N:33]=2)[N:30]=1.CN(C=O)C>C1COCC1.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[O-]S([O-])(=O)=O.[Zn+2]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[C:17]=1[C:25]1[CH:26]=[CH:27][C:28]2[N:29]([C:31]([CH:34]([CH3:36])[CH3:35])=[N:32][N:33]=2)[N:30]=1
Reactant: Fc1ccc(-c2nc3n(c2I)CCCC3)c(F)c1
Reactant: CC(C)c1nnc2ccc(I)nn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[Mg]Cl
Agent: O=S(=O)([O-])[O-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4n3CCCC4)nn12
Temperature: 30 °C
Reaction time: 0.25 h
Yield: 7.1 %

Procedure:
A dried round bottom flask was charged with 2-(2,4-difluorophenyl)-3-iodo-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (1.50 g, 4.17 mmol, Example #C.1.1) and THF (20 mL) under an atmosphere of nitrogen to give a brown suspension. The reaction mixture was cooled to about 30° C. and then i-PrMgCl (2.0 M in THF, 2.5 mL, 5.0 mmol) was added dropwise. The reaction mixture was stirred at about −25° C. for about 15 min. In a separate dry flask, zinc chloride (0.70 g, 5.1 mmol) was dissolved in THF (20 mL). The zinc chloride solution was added dropwise to the heteroaryl Grignard solution and formed a brown suspension. The reaction mixture was stirred for about 30 min. In a separate flask, a mixture 6-iodo-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (1.14 g, 3.96 mmol; Preparation #H.1) and DMF (20 mL) was heated until all of the solids were in solution and then cooled down to about 30° C. To the DMF solution, Pd(Ph3P)4 (Strem, 0.19 g, 0.164 mmol) was added. This solution was poured into the zincate suspension and the mixture was immediately heated to about 80° C. in an oil bath. After heating at about 80° C. for about 3 h, the mixture was cooled to ambient temperature. The reaction was concentrated in vacuo and the residue was partitioned between in DCM (50 mL) and 1N HCl (100 mL). The layers were separated and the aqueous layer was washed with additional DCM (50 mL) and basified with solid Na2CO3. Upon basification, a yellow precipitate formed that was collected by vacuum filtration. The crude material was purified by silica gel chromatography using DCM/MeOH/NH4OH 990/9/1 to give a glass-like solid that was triturated and washed with Et2O to give the title compound (0.111 g, 7%): LC/MS (Table 1, Method a) Rt=2.75 min; MS m/z: 395.5 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][NH2:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1([CH:22]([C:28]([CH3:30])=O)[C:23](OCC)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:23](=[O:24])[C:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:28]([CH3:30])[NH:15]2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(C)=O)c1ccccc1
Reactant: NNC1CCN(Cc2ccccc2)CC1
Product: Cc1[nH]n(C2CCN(Cc3ccccc3)CC2)c(=O)c1-c1ccccc1
Yield: 77.7 %

Procedure:
When 1.4 g of 1-benzyl-4-hydrazinopiperidine and 2.0 g of ethyl 2-phenylacetoacetate were used in the procedure of Example 124, Step A, there was obtained 1.84 g of 1-benzyl-4-(5-methyl-4-phenyl-1H-pyrazol-3(2H)-on-2-yl)-piperidine. ESI-MS 348.2 (M+H); HPLC A: 1.95 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:11]([C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1)#[N:12].C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=2)[C:11]#[N:12])=[C:6]([CH:7]=[O:8])[CH:9]=1
Reactant: N#Cc1cccc(O)c1
Reactant: O=Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: N#Cc1cccc(Oc2ccc(Br)cc2C=O)c1
Yield: 90.3 %

Procedure:
In a manner similar to the method described in Example 50a, 5-bromo-2-fluorobenzaldehyde (2.2 g, 11 mmol) (Alfa) was reacted with 3-cyanophenol (1.4 g, 12 mmol)(Aldrich) and K2CO3 in N,N-dimethylacetamide to give 3-(4-bromo-2-formyl-phenoxy)-benzonitrile as a brown solid (Yield 3 g, 100%).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][S:7][CH2:8][CH:9]([C:14](=[O:21])[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2].[CH:22]1(O)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1>>[C:1]([NH:4][CH2:5][CH2:6][S:7][CH2:8][CH:9]([C:14](=[O:21])[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:10][C:11]([O:13][CH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1)=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCSCC(CC(=O)O)C(=O)c1cccnc1
Reactant: OC1CCc2ccccc21
Product: CC(=O)NCCSCC(CC(=O)OC1CCc2ccccc21)C(=O)c1cccnc1
Yield: 55 %

Procedure:
The title compound was prepared from 3-{[2-(acetylamino)ethylthio]methyl}-4-oxo-4-(3-pyridyl)butanoic acid and indanol as described in the above Example 26 in 55% yield; ESMS (M+1+) 427.
Reaction SMILES: [CH:1]([N:4]([CH:25]([CH3:27])[CH3:26])[C:5](=[O:24])[CH:6]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:8][C:9]([NH2:11])=O)([CH3:3])[CH3:2].O=S(Cl)Cl>CN(C=O)C>[C:9]([CH2:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[C:5]([N:4]([CH:25]([CH3:27])[CH3:26])[CH:1]([CH3:3])[CH3:2])=[O:24])#[N:11]
Reactant: CC(C)N(C(=O)C(c1cccnc1)C(CC(N)=O)c1ccccc1)C(C)C
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)N(C(=O)C(c1cccnc1)C(CC#N)c1ccccc1)C(C)C

Procedure:
To a solution of N1,N1-diisopropyl-3-phenyl-2-pyridin-3-ylpentanediamide (90 mg, 0.245 mmol) in 1 mL DMF was added SOCl2 (0.5 mL) and heated at 90 C for 45 min. Concentrated (azeotroped 2× from benzene) and purified by r.p. HPLC. Desired fractions from HPLC were combined and the product was isolated as free base. White solid, single diastereomer.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3=[N:16][CH:17]=[CH:18][C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)=[C:14]3[NH:13][C:12]=2[CH3:32])=[O:10])[CH2:4][CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3=[N:16][CH:17]=[CH:18][C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)=[C:14]3[NH:13][C:12]=2[CH3:32])=[O:10])[CH2:4][CH2:3]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (example D.f5) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[H-].[Na+].FC(F)(F)S([O-])(=O)=O.Br[CH2:35][CH2:36][S+](C1C=CC=CC=1)C1C=CC=CC=1.[Cl-].[NH4+]>C(Cl)Cl.O.C(OCC)(=O)C>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([CH:2]2[O:1][CH2:36][CH2:35][N:4]([S:5]([C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=3)(=[O:7])=[O:6])[CH2:3]2)=[CH:16][CH:17]=1)([O-:23])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)NCC(O)c2ccc([N+](=O)[O-])cc2)cc1
Reactant: BrCC[S+](c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Cl-]
Agent: [H-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCOC(c3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 0 °C
Reaction time: 17 h

Procedure:
N-(2-Hydroxy-2-(4-nitrophenyl)ethyl)-4-methylbenzenesulfonamide (I84) (0.610 g, 1.34 mmol) was sonicated in DCM (20 mL) for five minutes and cooled to 0° C. under nitrogen. A 60% dispersion of NaH (0.220 g, 5.44 mmol) was added and the mixture stirred for five minutes before (2-bromoethyl)diphenylsulfonium trifluoromethanesulfonate (1.21 g, 2.72 mmol) was added. The mixture was stirred for 17 hours, allowing the cooling bath to come to room temperature over this time. Ethyl acetate (200 mL), saturated ammonium chloride (80 mL) and water (20 mL) were added and the layers separated. The aqueous phase was extracted with ethyl acetate (2×100 mL) and the combined ethyl acetate phases were washed with brine, dried (sodium sulfate) and evaporated. The residue was chromatographed (Isolera, 40 g silica cartridge, 0-40% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I85) (433 mg, 88%) as a white solid; 1H NMR (400 MHz, CDCl3) b 8.22-8.18 (m, 2H), 7.63-7.59 (m, 2H), 7.52-7.48 (m, 2H), 7.33 (dd, J=8.5, 0.6 Hz, 2H), 4.71 (dd, J=10.2, 2.6 Hz, 1H), 4.10 (ddd, J=11.6, 3.4, 1.4 Hz, 1H), 3.87 (td, J=11.6, 2.7 Hz, 1H), 3.82-3.77 (m, 1H), 3.65 (ddt, J=11.6, 2.8, 1.6 Hz, 1H), 2.51 (td, J=11.6, 3.4 Hz, 1H), 2.43 (s, 3H), 2.18 (dd, J=11.5, 10.3 Hz, 1H). LCMS Method C: rt 6.20 min; m/z 363.0 [M+H]+.
Reaction SMILES: [C:1]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+].N[C:15]1([O:24]O)[CH2:20][CH:19]([CH3:21])[CH2:18][C:17]([CH3:23])([CH3:22])[CH2:16]1>C(O)C>[C:1]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21][CH:19]1[CH2:18][C:17]([CH3:23])([CH3:22])[CH2:16][C:15](=[O:24])[CH2:20]1
Reactant: CC1CC(C)(C)CC(N)(OO)C1
Agent: CC(=O)[O-]
Agent: O=C1CCCCCC1
Agent: [NH4+]
Solvent: CCO
Product: CC1CC(=O)CC(C)(C)C1
Reaction time: 8 h

Procedure:
To a stirred mixture of cycloheptanone (73.2 g.) and ethanol (200 cc.), containing ammonium acetate (6.4 g.) and kept at or below 0°C was added 1-amino-3,3,5-trimethylcyclohexyl hydroperoxide (69.2 g.; 76% pure). After the solid had dissolved (5 hours) the solution was stored at 0°C overnight and the product worked up as in the previous Examples. There were obtained unreacted cycloheptanone, and dihydroisophorone, and fractions (57.5 g.) b.p. 124° - 130°C/0.3 mm.Hg., peroxide equivalent 283, perchloric acid equivalent 278 shown by mass spectroscopy to contain the peroxide ##SPC63##