Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH:35]1([CH2:38]Br)[CH2:37][CH2:36]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH2:38][CH:35]3[CH2:37][CH2:36]3)[C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:31])(=[O:32])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: BrCC1CC1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2CC1CC1)N1CCN(C2CCCC2)CC1
Yield: 70 %

Procedure:
The title compound was synthesized in analogy to example 51, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone (example 34), sodium hydride and cyclopropylmethyl bromide in N,N-dimethylformamide, to give the desired product as a light yellow solid (70%).
Reaction SMILES: C([O:8][C:9]([CH2:11][N:12]1[C:16]([SH:17])=[N:15][N:14]=[N:13]1)=O)C1C=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1>>[OH:8][CH2:9][CH2:11][N:12]1[C:16]([SH:17])=[N:15][N:14]=[N:13]1
Reactant: O=C(Cn1nnnc1S)OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCn1nnnc1S

Procedure:
1-Benzyloxycarbonylmethyl-1H-tetrazole-5-thiol was reduced with lithium aluminum hydride-tetrahydrofuran. m.p. 137°-139° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)=[CH:4][CH:3]=1.B([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=1[CH3:26])(O)O>>[CH3:26][C:18]1[CH:19]=[C:20]([C:21]([OH:23])=[O:22])[CH:24]=[CH:25][C:17]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2ccc(Br)cc2)no1
Reactant: Cc1cc(C(=O)O)ccc1B(O)O
Product: Cc1nc(-c2ccc(-c3ccc(C(=O)O)cc3C)cc2)no1

Procedure:
The title compound was prepared from 3-(4-bromophenyl)-5-methyl-1,2,4-oxadiazole (1 g) and 4-borono-3-methylbenzoic acid (D74, 0.75 g) as a white solid (0.3 g, 24%) by the method described in Description 15.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][S:6]([O:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][CH:16](O)[C:15]([CH3:20])([CH3:19])[C:14]=2[CH:21]=1)(=[O:8])=[O:7].N1C=CC=CC=1>C(Cl)Cl>[CH3:5][S:6]([O:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][CH:16]([Cl:3])[C:15]([CH3:20])([CH3:19])[C:14]=2[CH:21]=1)(=[O:8])=[O:7]
Reactant: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1O
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1Cl
Reaction time: 3 h
Yield: 97 %

Procedure:
A solution of thionyl chloride (72 parts) in methylene chloride (270 parts) was added dropwise over a period of 30 minutes to a mixture of 2,3-dihydro-2-hydroxy-3,3-dimethyl-5-benzofuranyl methanesulphonate (130 parts) and pyridine (48 parts) in methylene chloride (1,300 parts) cooled in an ice bath. After stirring for three hours, the solution was washed twice with water, dried over sodium sulphate and the solvent distilled off under reduced pressure. The brown liquid which remained solidified to form 2-chloro-2,3-dihydro-3,3-dimethyl-5-benzofuranyl methanesulphonate (135 parts, 97% yield), melting point 59°-61° C, confirmed by its elemental analysis:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[N:7][CH:8]=[C:9]([CH2:11][O:12][Si](C(C)C)(C(C)C)C(C)C)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CO>Cl>[C:1]([C:5]1[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[N:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[Si](OCc1cncc(C(C)(C)C)c1)(C(C)C)C(C)C
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1cncc(CO)c1
Reaction time: 8 h
Yield: 45.9 %

Procedure:
3-tert-butyl-5-((triisopropylsilyloxy)methyl)pyridine (0.7 g, 2.637 mmol) was dissolved in HCl in methanol (42 mL, 1.25M, 52.73 mmol) at room temperature and stirred for overnight. The solvent was removed under vacuum, dissolved in chloroform and washed with saturated aqueous Na2CO3. The resulting organic solvent was dried, concentrated to give a residue which was purified by flash column chromatography to give pure (5-tert-butylpyridin-3-yl)methanol (0.2 g). 1H NMR (CDCl3): d: 1.280 (s, 9H), 4.663 (s, 2H), 7.730 (s, 1H), 8.225 (s, 1H), 8.368 (s, 1H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[N+]([O-])(OCCC(C)C)=O.Cl.[N+:19]([CH:22]([S:26][C:27]1[S:31][C:30]([O:32][CH3:33])=[CH:29][CH:28]=1)C(O)=O)([O-:21])=[O:20]>O>[CH3:33][O:32][C:30]1[S:31][C:27]([S:26][CH2:22][N+:19]([O-:21])=[O:20])=[CH:28][CH:29]=1
Reactant: COc1ccc(SC(C(=O)O)[N+](=O)[O-])s1
Agent: CC(C)CCO[N+](=O)[O-]
Agent: CC(C)[N-]C(C)C
Agent: Cl
Solvent: O
Product: COc1ccc(SC[N+](=O)[O-])s1
Temperature: -40 °C
Reaction time: 2 h

Procedure:
A hexane/THF solution of lithium diisopropylamide was obtained by adding butyllithium (1.55 M hexane solution, 86.45 ml) to a stirred solution of diisopropylamine (101 g) in THF (100 ml) at -70° C. under an argon atmosphere. After 1 hour at -70° C., a solution of 2-(2-methoxythien-5-ylthio)acetic acid (obtained as described in West German OLS no. 1512272; 10.91 g) was added to the diisopropylamide solution during 20 minutes at -70° C. After 2 hours at this temperature, it was allowed to warm up to -40° C. Isoamyl nitrate (21.2 ml) was then added. The mixture was stirred at -40° C. for 2 hours and then at ambient temperature for 16 hours. The mixture was acidified to pH 2 with 2 M hydrochloric acid and stirred for 1 hour, during which time the intermediate 2-nitro-2-(2-methoxythien-5-ylthio)acetic acid underwent decarboxylation. The mixture was added to water (100 ml) and extracted with ethyl acetate. The combined organic layers were washed first with saturated sodium bicarbonate solution (200 ml) (to remove unreacted acidic starting material) and then with 2 M sodium hydroxide (2×200 ml). The latter washings were acidified to pH 2 with 2 M hydrochloric acid and extracted with ether (2×300 ml). The combined extracts were dried (MgSO4) in the presence of activated charcoal and evaporated. The residual oil was purified by column chromatography on silica (300 g) using 15% v/v ethyl acetate/hexane as eluant to give 2-methoxy-5-(nitromethylthio)thiophene (2.9 g) as an oil; NMR (90 MHz): 3.9 (s,3H), 5.25 (s,2H), 6.1 (d,1H), 7.0 (d,1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[NH:11]1[CH:15]=[N:14][C:13]([C:16]([O:18]C)=[O:17])=[N:12]1.ClC1C=C(N2C=NC(C(O)=O)=N2)C=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[N:14][C:13]([C:16]([OH:18])=[O:17])=[N:12]1
Reactant: OB(O)c1ccccc1F
Reactant: COC(=O)c1nc[nH]n1
Agent: O=C(O)c1ncn(-c2cccc(Cl)c2)n1
Product: O=C(O)c1ncn(-c2ccccc2F)n1

Procedure:
This intermediate was prepared from 2-fluorophenylboronic acid and methyl 1,2,4-triazole-3-carboxylate in two steps according to the preparation of 1-(3-chloro-phenyl)-1H-[1,2,4]-triazole-3-carboxylic acid.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:24](=[O:25])[N:14]2[CH:15]([C:21]([OH:23])=[O:22])[C:16]([CH3:20])([CH2:18]Br)[S:17][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.C(OCC)(=O)C>C1C=CC=CC=1>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:24](=[O:25])[N:14]2[C:15]([C:21]([OH:23])=[O:22])=[C:16]([CH3:20])[CH2:18][S:17][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)O
Solvent: c1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.8 %

Procedure:
6-(2-phenoxyacetamido)-2-methyl-2-bromomethylpenam-3-carboxylic acid (429 mg.) was suspended in dry benzene (10 cc), and pyridine (400 mg.) and trimethylsilychloride (5 cc) were added thereto. The mixture was stirred for 1.5 hours at room temperature and pyridine (400 mg.) was added thereto. The mixture was heated under reflux for 3 hours, mixed with ethyl acetate (30 cc). washed with dilute phosphoric acid and further with an aqueous solution saturated with sodium chloride, dried and then concentrated. A small amount of ethyl acetate was added to the residue and the precipitate was collected by filtration to yield crystals (250 mg.) of 7-(2-phenoxyacetamido)-3-methyl-3-cephem-4-carboxylic acid, m.p. 170.5°-172° C.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[C:14](=O)[CH2:15]Br)C.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH2:30])=[O:29])=[CH:23][CH:22]=1>>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:18])=[C:8]([C:14]2[N:30]=[C:28]([CH2:27][C:24]3[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[O:29][CH:15]=2)[CH:9]=1
Reactant: COc1ccc(CC(N)=O)cc1
Reactant: CCOC(=O)COc1ccc(Br)cc1C(=O)CBr
Product: COc1ccc(Cc2nc(-c3cc(Br)ccc3OCC(=O)O)co2)cc1

Procedure:
Title compound was prepared from [4-bromo-2-(2-bromoacetyl)phenoxy]acetic acid ethyl ester and 2-(4-methoxyphenyl)acetamide according to GP5 and GP3: LC/MS (an10p8) Rt 2.40 min, m/z 418 [M+H]+; 1H NMR (CDCl3): δ 3.72 (s, 3H), 4.14 (s, 1H), 4.85 (s, 1H), 6.92 (m, 2H), 7.02 (d, 1H), 7.2 (d, 1H), 7.23 (d, 1H), 7.44 (d, 1H), 8.05 (s, 1H), 8.67 (s, 1H), 13.2 (br s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]([C:13]1([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)[CH3:3].[CH:20]([OH:22])=[O:21]>CC(C)=O>[CH3:1][N:2]([CH2:4][CH:5]([C:13]1([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)[CH3:3].[CH:20]([O-:22])=[O:21]
Reactant: O=CO
Agent: CN(C)CC(c1ccc(O)cc1)C1(O)CCCCC1
Solvent: CC(C)=O
Product: O=C[O-]
Temperature: 45 °C
Reaction time: 0.08 h

Procedure:
To a stirred suspension of O-desmethylvenlafaxine (39.51 g, 0.150 mol) in acetone (1500 mL) at 55–60° C., under a nitrogen atmosphere, was added a solution of 96% formic acid (13.5 mL, d=1.22, 2.29 molar excess) in acetone (150 mL) over a period of 10 min. The stirred mixture was kept at 55–60° C. for a further 5 min. to complete the dissolution. The warm solution was filtered through a pad of Celite filter aid (prewashed with warm acetone) and the filter pad was washed with warm acetone (150 mL). The filtrate and washings (temperature ˜35° C.) were warmed to 45° C. under a nitrogen atmosphere and seeded with crystals of O-desmethyl-venlafaxine formate. The stirred solution was allowed to cool. Crystallization ensued and was copious after 1 hour (when the temperature had fallen to 30° C.). The slurry of crystals at 27° C. was chilled to −10° C. over a period of half an hour and maintained at −5–−10° C. for 15 min. The crystals were then collected on a filter and washed with chilled (−5 to −10° C.) acetone (2×100 mL). After drying in a vacuum oven at room temperature under oil pump vacuum for 24 hours, the product, O-desmethyl-venlafaxine formate, weighed 38.5 g, (83% yield) and it had mp=148° C.–149.5° C. It was characterized by DSC (sharp endotherm at 152.4° C.).
Reaction SMILES: CN(C)[C:3](Cl)=[O:4].[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]([NH:24][NH2:25])=[O:23])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)([O-:9])=[O:8]>N1C=CC=CC=1>[N+:7]([C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:17][CH2:18][CH:19]([C:22]3[O:23][C:3](=[O:4])[NH:25][N:24]=3)[CH2:20][CH2:21]2)=[CH:14][CH:15]=1)([O-:9])=[O:8]
Reactant: CN(C)C(=O)Cl
Reactant: NNC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Solvent: c1ccncc1
Product: O=c1[nH]nc(C2CCN(c3ccc([N+](=O)[O-])cc3)CC2)o1
Temperature: 85 °C
Yield: 39.9 %

Procedure:
To a stirred solution of 4-fluoro nitrobenzene (1a, 3.1 g, 22 mmol) and methyl 4-piperidine carboxylate (2, 3.15 g, 22 mmol) in DMF solvent and K2CO3 (7.6 g, 55 mmol) as base and heated at 80° C. for 10 h, after completion of the reaction, reaction is poured into ice water and extracted into ethyl acetate finally purification by column chromatography to afford pure compound methyl 1-(4-nitrophenyl)-4-piperidinecarboxy-late (3a, 4.93 g, 85%). To a stirred solution of ester (3a, 4.75 g, 18 mmol) in ethanol, NH2NH2. H2O (2.25 g, 45 mmol) is added and refluxed for 24 h. After completion of the reaction ethanol is evaporated under vacuum and water is added and extracted into ethyl acetate finally purification by column chromatography to afford pure compound 1-(4-nitrophenyl)-4-piperidinecarbohydrazide (4a, 3.99 g, 84%). Addition N,N-dimethyl carbamyl chloride (1.29 g, 12 mmol) to hydrazide (4a, 3.17 g, 12 mmol) in pyridine at room temperature (27° C.) and followed by reflux at temperature 85° C. for 2.5 h. After completion of the reaction, the reaction mixture is cooled and filtered. The residue is recrystallized from water to get 5-[1-(4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (5a, 1.39 g, 40%). Nitro compound (5a, 1.16 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65° C. for 4 h, after completion of reaction methanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5-[1-(4-aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (7a, 884 mg, 85%). To a stirred solution of 5-nitro2-furanoic acid (0.16 g, 1 mmol) in DMF add HOBT (Hydroxybenzotriazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide)) (0.19 g, 1 mmol) and amine compound (7a, 0.26 g, 1 mmol) and stirred for 2 h at room temperature (27° C.), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-4-[4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidino]phenyl-5-nitro-2-furamide (8a, 323 mg, 81%).
Reaction SMILES: [CH3:1][C:2]1([C:8](Cl)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C[O:12][P:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][C:2]1([C:8]([P:13](=[O:12])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC1(C(=O)Cl)CCCCC1
Reactant: COP(c1ccccc1)c1ccccc1
Product: CC1(C(=O)P(=O)(c2ccccc2)c2ccccc2)CCCCC1

Procedure:
Using a method similar to that of Example 2, 80 parts of 1-methyl-1-cyclohexanecarboxylic acid chloride and 108 parts of methoxydiphenylphosphine, in the absence of a solvent, give 100 parts of 1-methyl-cyclohexylcarbonyl-diphenylphosphine oxide as an oily crude product, which is purified by chromatography over silica gel (using toluene as the eluant).
Reaction SMILES: CS(O[CH:6]1[CH2:10][O:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C.CCOCC>[N:17]([CH:6]1[CH2:10][O:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC1COC(c2ccccc2)C1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: [N-]=[N+]=NC1COC(c2ccccc2)C1

Procedure:
14.7 g (61 mmol) of 4-methanesulfonyloxy-2-phenyltetrahydrofuran and 5.13 g (79 mmol) of sodium azide were heated for 3 hours in 120 ml of DMF at 90° C. After the mixture had cooled, it was diluted with ether, washed with water and saturated NaCl solution, dried and concentrated in vacuo. This gave 9.4 g (quant.) of a colorless oil, which was further reacted directly.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[C:16]([O:27][CH3:28])=[N:17][C:18]([N:21]2[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22]2)=[CH:19][CH:20]=1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[C:16]([O:27][CH3:28])=[N:17][C:18]([N:21]2[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22]2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(N4CCC(O)C4)nc3OC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1nc(N2CCC(O)C2)ccc1-c1cc2c(C(=O)O)c[nH]c2cc1Cl
Temperature: 80 °C
Yield: 37.5 %

Procedure:
A vial was charged with methyl 6-chloro-5-[6-(3-hydroxypyrrolidin-1-yl)-2-methoxypyridin-3-yl]-1H-indole-3-carboxylate (52.5 mg, 0.130 mmol), NaOH aqueous (2 mL, 2M) and methanol (2 mL). The mixture was heated at 80° C. for 3 hrs. The mixture was cooled to room temperature and neutralized with conc. HCl aqueous to pH=6. The mixture was evaporated to dryness, and the resulting residue was purified through prep. HPLC to give the title compound (18.9 mg, 37.3%) as off-white solid.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][C:11]([O:15][C@H:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C@@H:17]([NH2:19])[CH3:18])=[CH:12][CH:13]=3)[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:26]1([S:29](Cl)(=[O:31])=[O:30])[CH2:28][CH2:27]1>>[CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][C:11]([O:15][C@H:16]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[C@@H:17]([NH:19][S:29]([CH:26]4[CH2:28][CH2:27]4)(=[O:31])=[O:30])[CH3:18])=[CH:12][CH:13]=3)[CH:8]=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2C2CCCC2)c1)c1ccccc1
Product: C[C@H](NS(=O)(=O)C1CC1)[C@H](Oc1ccc2c(cnn2C2CCCC2)c1)c1ccccc1

Procedure:
The title compound was prepared from (1R,2S)-1-[(1-cyclopentyl-1H-indazol-5-yl)oxy]-1-phenylpropan-2-amine (32b, 17 mg, 51 μmol) and cyclopropanesulfonyl chloride (34 mg, 153 μmol) as described in Example 2b. Yield 10 mg (45%).
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=[CH:3]1.Br[CH2:12][CH2:13][CH2:14][CH3:15].[OH-].[K+].O>CN1CCCC1=O.C(OCC)(=O)C>[CH2:12]([C:3]1[C:2](=[O:1])[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]=1[CH3:10])[CH2:13][CH2:14][CH3:15]
Reactant: CC1=CC(=O)CC(C)(C)C1
Reactant: CCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCC1=C(C)CC(C)(C)CC1=O
Temperature: 70 °C
Yield: 44.9 %

Procedure:
In 60 ml of 1-methyl-2-pyrrolidone were dissolved 10.0 g (72.36 mmol) of isophorone and 14.9 g (95.6 mmol) of 1-bromobutane. To this mixture was added 8.1 g (144.4 mmol) of powdered potassium hydroxide and the mixture was stirred with heating at 70° C. for 6 hours. After the reaction mixture was added to water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residual liquid was purified by silica gel column chromatography to give 6.31 g of a yellow oily matter (yield: 44.9%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@:11]2([CH2:19][C:20](O)=[O:21])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([N:8]1[CH2:12][C@:11]2([CH2:19][CH2:20][OH:21])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C@@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C[C@]12CN(Cc3ccccc3)C[C@H]1c1ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC[C@]12CN(Cc3ccccc3)C[C@H]1c1ccccc12
Reaction time: 2 h

Procedure:
3.32 g of the product obtained in Step C are introduced, in portions, into a suspension composed of 0.73 g of lithium aluminium hydride and 53 ml of tetrahydrofuran. After 2 hours at ambient temperature, the medium is hydrolysed in the cold state and the precipitate formed is filtered off. After evaporating off the solvent, the expected product is isolated.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]([CH2:12]O)=[N:10][CH:11]=2)[CH2:3][CH2:2]1.[Br-].[K+].C(=O)(O)[O-].Cl[O-].[Na+].[CH3:23][C:24]([S@:27]([NH2:29])=[O:28])([CH3:26])[CH3:25]>ClCCl.S([O-])([O-])(=O)=O.[Cu+2].CC1(C)N([O])C(C)(C)CCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9](/[CH:12]=[N:29]/[S@@:27]([C:24]([CH3:26])([CH3:25])[CH3:23])=[O:28])=[N:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)[S@](N)=O
Reactant: OCc1ccc(OCC2CC2)cn1
Agent: [Cu+2]
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)/N=C/c1ccc(OCC2CC2)cn1
Reaction time: 0.17 h
Yield: 88.4 %

Procedure:
To a solution of (5-(cyclopropylmethoxy)pyridin-2-yl)methanol (4.5 g, 25 mmol) in dichloromethane (50 ml), was added a 15% potassium bromide aqueous solution (20 mL) followed by a saturated bicarbonate solution (20 ml). The biphasic mixture was cooled in an ice bath and TEMPO (200 mg, 1.3 mmol) was added. After stirring for 10 min, 5% sodium hypochlorite (30 ml) was dropwised. The reaction mixture was stirred for 10 min. The solution was poured into a separatory funnel and the organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in dichloromethane (50 mL). Copper(II) sulfate (10.1 g, 63 mmol) followed by (R)-(+)-2-methyl-2-propanesulfinamide (3.1 g, 25 mmol) were added to the mixture respectively and the mixture was stirred for 18 hours at room temperature. The reaction mixture was filtrated off and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (1:1 (v/v)) to give 6.2 g (87% yield) of the title compound as a flaky solid:
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)[N:21]=3)[CH:19]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:26][C:24]1[CH:23]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][CH:28]=2)[N:21]=[C:20]([N:18]2[CH:19]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=3)[N:16]=[CH:17]2)[N:25]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(-c3cccc(S(N)(=O)=O)c3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.8 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{1-[4-methyl-6-(4-trifluoromethylphenyl)-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.19 g) in dichloromethane (4 mL) was added TFA (4 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (3 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried to yield the title compound as an off-white solid (0.13 g, 28%). MS (ISP) 460.2 [(M+H)+]; mp 186° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([C@H]1COC(=O)N1[C:20](=[O:35])[C@@H:21]([CH3:34])[CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)C1C=CC=CC=1>C1COCC1>[CH2:27]([O:26][CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]([CH3:34])[CH2:20][OH:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C[C@@H](CCCCOCc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](CO)CCCCOCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of 13.2 g (0.35 mol) of LiAlH4 in 380 ml of THF was added a solution of amide VI in 250 ml of THF at 0° C. The mixture was stirred for 2 h at 0° C. and quenched with 14 ml of H2O, 14 ml of 15% NaOH and 25 ml of H2O. The precipitated aluminum salts were removed by filtration. After concentration of the filtrate, the crude product was purified by silica gel filtration (570 g of SiO2, toluene/EtOAc=90:10, 3 l and toluene/EtOAc=80:20 1 l). The product VII was obtained as a colorless oil (54.5 g, 81% over two steps). Rf=0.24 (SiO2, 1:1 heptane-TBME); HPLC: 87% de (Chiralcel OD, n-hexane/i-PrOH=95:5, 1.0 ml/min, 30° C.) tR=10.07 min.