Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Br.N[C:4]1[C:5]([CH:18]([CH3:20])[CH3:19])=[C:6]([S:14]([NH2:17])(=[O:16])=[O:15])[CH:7]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:9]=1[Br:10].[Br:21]C1C(C(C)C)=CC(S(N)(=O)=O)=C(C(C)C)C=1C#N>>[Br:21][C:4]1[C:5]([CH:18]([CH3:20])[CH3:19])=[C:6]([S:14]([NH2:17])(=[O:16])=[O:15])[CH:7]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:9]=1[Br:10]
Reactant: CC(C)c1cc(S(N)(=O)=O)c(C(C)C)c(N)c1Br
Reactant: CC(C)c1cc(S(N)(=O)=O)c(C(C)C)c(C#N)c1Br
Agent: Br
Agent: Cl
Product: CC(C)c1cc(S(N)(=O)=O)c(C(C)C)c(Br)c1Br

Procedure:
If hydrochloric acid is substituted for hydrobromic acid and cuprous cyanide for cuprous bromide, the 3-amino-4-bromo-2,5-diisopropylbenzenesulfonamide may be converted to 4-bromo-3-cyano-2,5-diisopropylbenzenesulfonamide.
Reaction SMILES: [C:1]([N:4]1[CH:13](C(O)=O)[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)(=O)[CH3:2].[C:17]([C:23]([O:25][CH3:26])=[O:24])#[C:18][C:19]([O:21][CH3:22])=[O:20]>C(OC(=O)C)(=O)C>[CH3:22][O:21][C:19]([C:18]1[C:17]([C:23]([O:25][CH3:26])=[O:24])=[C:1]([CH3:2])[N:4]2[C:13]=1[CH2:12][C:11]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:5]2)=[O:20]
Reactant: COC(=O)C#CC(=O)OC
Reactant: CC(=O)N1Cc2ccccc2CC1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1c(C(=O)OC)c2n(c1C)Cc1ccccc1C2
Temperature: 65 °C
Yield: 123.3 %

Procedure:
A mixture of 2-acetyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (6.22 g, 20 mmol) and dimethyl acetylenedicarboxylate (4.26 g, 30 mmol) in acetic anhydride (50 mL) was heated at 60-70° C. for 3.5 hours. The reaction mixture was then cooled to room temperature and then evaporated under reduced pressure to dryness. The solid residue was recrystallized from ethanol to give 3-methyl-5,10-dihydropyrrolo[1,2-b]isoquinoline-1,2-dicarboxylic acid dimethyl ester 7.38 g, (94.4%); mp 155-158° C.; 1H NMR (DMSO-d6) δ δ 3.70 (3H, s, OMe), 3.86 (3H, s, COOMe), 3.89 (3H, s, COOMe), 4.41 (2H, s, CH2), 4.86 (2H, s, CH2), 7.01 (2H, d, J=8.5 Hz, ArH), 7.12 (1H, m, ArH), 7.22-7.25 (1H, m, ArH), 7.30-7.32 (1H, m, ArH), 7.37 (2H, d, J=8.5 Hz, ArH), 7.37-7.38 (1H, m, ArH); m/z 391.0 (M+H)+ Anal. Calcld. for C23H21NO5. 0.1H2O: C, 70.25; H, 5.43; N, 3.56. Found: C, 70.15; H, 5.44; N, 3.49.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][NH:3][CH:2]1[C:6]([OH:8])=[O:7].[N:9]([O-])=[O:10].[Na+]>C(O)(=O)C.O>[N:9]([N:3]1[CH2:4][CH2:5][S:1][CH:2]1[C:6]([OH:8])=[O:7])=[O:10]
Reactant: O=C(O)C1NCCS1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=NN1CCSC1C(=O)O
Reaction time: 5 h

Procedure:
To a suspension of thiazolidine-2-carboxylic acid (39.9 g, 0.30 mol) in 1,000 ml of acetic acid was added a solution of 31.0 g (0.45 mol) of sodium nitrite in 500 ml of water over 13 minutes at room temperature and stirred for 5 hours. The reaction solution was concentrated under reduced pressure. Acetone (500 ml) was added to the residue and the precipitate was filtered through a pad of Celite. The pad was washed with acetone (500 ml). The filtrate was concentrated under reduced pressure to dryness and crude 3-nitrosothiazolidin-2-carboxylic acid was obtained as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]([NH2:17])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>C(Cl)Cl>[C:13]([NH:17][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)N
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 76.9 %

Procedure:
4-Nitrobenzoyl chloride (18.9 g, 0.1 mol) dissolved in 60 ml of methylene chloride is added, over 30 minutes at a temperature of 0-5° C., to a solution of tert-butylamine (8.3 g, 0.112 mol) and of triethylamine (15.6 ml, 0.112 mol) dissolved in 170 ml of dichloromethane in a reactor. The reaction mixture is brought back to laboratory temperature and left stirring for 2 hours. The organic phase is washed twice with water and dried. After removing the solvent under reduced pressure, the solid obtained is recrystallized from isopropanol. 17.1 g (Yield: 77%) of N-(tert-butyl)-4-nitrobenzamide are obtained in the form of a pale yellow powder (m.p. 161-2° C.) which is used as is in the following stage.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[CH2:14][O:15][CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][S:18]([CH3:17])(=[O:20])=[O:19])[CH2:10][C@H:9]1[CH2:14][O:15][CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: COC[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-2-methoxymethylpyrrolidine (2.8 g) and methanesulfonyl chloride (1.12 ml) in dichloromethane (30 ml) was added dropwise triethylamine (2.38 ml) at 0° C. After 30 minutes, the reaction mixture was washed in turn with 1N-hydrochloric acid, water and brine. The organic layer was dried over magnesium sulfate and evaporated to give an oil, which was chromatographed on silica gel (300 ml) eluting with a mixture of hexane and ethyl acetate (1:1, V/V) to give (2S,4R)-1-(tert-butoxycarbonyl)-4-methanesulfonyloxy-2-methoxymethylpyrrolidine (3.61 g).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH3:6])=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CN(CCN(C)C)C.[CH3:25][O:26][C:27]1[CH:28]=[CH:29][C:30]2[CH2:36][C:35](=[O:37])[C:34]3[CH:38]=[CH:39][CH:40]=[CH:41][C:33]=3[O:32][C:31]=2[CH:42]=1>C1COCC1>[OH:37][C:35]1([CH2:6][C:4]([O:3][CH2:2][CH3:1])=[O:5])[C:34]2[CH:38]=[CH:39][CH:40]=[CH:41][C:33]=2[O:32][C:31]2[CH:42]=[C:27]([O:26][CH3:25])[CH:28]=[CH:29][C:30]=2[CH2:36]1
Reactant: COc1ccc2c(c1)Oc1ccccc1C(=O)C2
Reactant: CCOC(C)=O
Agent: CN(C)CCN(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)Cc2ccc(OC)cc2Oc2ccccc21
Reaction time: 0.5 h

Procedure:
Anhydrous EtOAc (0.94 mL, 9.6 mmole) was added dropwise to a solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 7 mL, 7 mmole) in dry THF (7 mL) in a flame-dried flask at −78° C. under argon. After 0.5 hr, TMEDA (2.4 mL, 16 mmole) was added. After another 5 min, a solution of 3-methoxydibenzo[b,f]oxepin-10-one (760 mg, 3.2 mmole) in THF (2 mL) was added dropwise over 3 min. Additional dry THF (0.4 mL) was used in transfer. The reaction was stirred at −78° C. to −40° C. for 1 hr, then was quenched with saturated NH4Cl (10 mL). The mixture was wanned to RT and extracted with EtOAc. Drying (MgSO4), concentration, and flash chromatography on silica gel (10% EtOAc/hexanes) gave the title compound as a clear oil: 1H NMR (300 MHz, CDCl3) δ1.14-1.20 (t, 3 H), 1.21-1.30 (m, 1 H), 2.62-2.68 (dd, 1 H), 2.94-3.02 (dd, 1 H), 3.24-3.30 (dd, 1 H), 3.40-3.46 (dd, 1 H), 3.40-3.46 (dd, 1 H), 3.78 (s, 3 H), 4.08-4.18 (m, 2 H), 6.60-7.26 (m, 6 H), 7.64-7.68 (dd, 1 H).
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:13]=[C:12]([O:14][CH2:15][O:16][CH3:17])[C:11]([CH:18]([CH3:20])[CH3:19])=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7]>CO.O>[OH:3][C:4]1[CH:13]=[C:12]([O:14][CH2:15][O:16][CH3:17])[C:11]([CH:18]([CH3:20])[CH3:19])=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COCOc1cc(O)c(C(=O)OC)cc1C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCOc1cc(O)c(C(=O)O)cc1C(C)C
Temperature: 25 °C
Yield: 83.2 %

Procedure:
Aqueous potassium hydroxide (50% w/v, 1 ml) was added to a mixture of methyl 2-hydroxy-5-isopropyl-4-(methoxymethyloxy)benzoate (508 mg, 2.0 mmol) in methanol (10 ml) and water (4 ml) and the mixture was stirred and held at reflux for 6 hours. Upon cooling to room temperature the organic solvent was removed in vacuo and the residue acidified by the addition of 2M hydrochloric acid (30 ml). The solid material was collected by suction filtration, rinsed with water (2×20 ml) and sucked dry under reduced pressure to afford 2-hydroxy-5-isopropyl-4-(methoxymethyloxy)benzoic acid (400 mg, 83%) as a colourless solid. 1H NMR (DMSO-d6) 13.60 (1H, br s), 11.30 (1H, br s), 7.58 (1H, s), 6.58 (1H, s), 5.30 (2H, s), 3.42 (3H, s), 3.15 (1H, m), 1.18 (6H, d). MS: [M+H]+ 241.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][OH:6])[CH3:2].[C:7](#[N:10])[CH:8]=[CH2:9].Cl>CO>[CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:9][CH2:8][C:7]#[N:10])[CH3:2]
Reactant: CCOCCO
Reactant: C=CC#N
Agent: Cl
Solvent: CO
Product: CCOCCOCCC#N
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.5 %

Procedure:
To an ice-water cooled mixture of 2-ethoxyethanol (1 g, 11.1 mmol) and Triton B (40% in MeOH, 0.138 g, 0.33 mmol) was added acrylonitrile (0.618 g, 11.6 mmol). The mixture was stirred at room temperature for 24 hours. It was then neutralized with 0.1 M HCl (3.3 cm3) and extracted with CH2Cl2 (2×10 cm3). The extracts were concentrated under reduced pressure and the residue was Kugelrohr-distilled to give the product 3-(2-ethoxyethoxy)propanenitrile (1.20 g, 75.5%) as a colourless oil, bp 100-130° C./20 Torr.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.[Cl-].[OH:16][NH3+:17].C([O-])(=O)C.[Na+]>C(O)C.O>[F:1][C:2]([F:14])([F:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[N:17][OH:16]
Reactant: [NH3+]O
Reactant: COc1ccc(C(=O)C(F)(F)F)cc1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=NO)C(F)(F)F)cc1
Temperature: 0 °C
Yield: 75.2 %

Procedure:
37.2 g (0.182 mol) of 2,2,2-trifluoro-1-(4-methoxyphenyl)-ethanone are dissolved in 150 ml of ethanol at 80° C. To the solution are added dropwise 13.3 g (0.191 mol) of hydroxylammonium chloride and 25.4 g (0.309 mol) of sodium acetate dissolved in 75 ml of water. The reaction mixture is refluxed for 4 hours. The mixture is poured into ice water, the precipitate is filtered, yielding 30.0 g of 2,2,2-trifluoro-1-(4-methoxyphenyl)-ethanone oxime as a pale yellow solid. The crude product is used in the next reaction step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:12])[CH2:4][CH2:5][C:6]1[N:7]([CH3:11])[CH:8]=[CH:9][N:10]=1.Cl>>[CH3:11][N:7]1[CH:8]=[CH:9][N:10]=[C:6]1[CH2:5][CH2:4][C:3]([OH:12])=[O:2]
Reactant: COC(=O)CCc1nccn1C
Agent: Cl
Product: Cn1ccnc1CCC(=O)O

Procedure:
3-(1-Methyl-1H-imidazol-2-yl)-propionic acid methyl ester (0.87 g) is treated with hydrochloric acid (6 N; 5 ml) at RT for 20 h. After evaporation of the solvent the compound (0.86 g) is obtained as hydrochloric salt.
Reaction SMILES: [C:1]([NH:3][CH3:4])#[CH:2].[Cl:5][C:6]1[C:11]([CH:12]=O)=[C:10]([F:14])[C:9]([CH3:15])=[CH:8][CH:7]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[Cl:5][C:6]1[C:11]([CH2:12][N:3]([C:1]#[CH:2])[CH3:4])=[C:10]([F:14])[C:9]([CH3:15])=[CH:8][CH:7]=1
Reactant: C#CNC
Reactant: Cc1ccc(Cl)c(C=O)c1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: C#CN(C)Cc1c(Cl)ccc(C)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethynyl-methylamine (98 uL, 1.16 mmol) and 6-chloro-2-fluoro-3-methyl-benzaldehyde (200 mg, 1.16 mmol) in CH2Cl2 (3 mL) was added sodium triacetoxyborohydride (369 mg, 1.74 mmol) and acetic acid (7 uL, 0.12 mmol). The reaction mixture was stirred at room temperature for 2 hours, quenched with saturated aqueous NaHCO3, and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate, and concentrated to afford the title compound as yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]([CH3:17])([CH3:16])[C:14]#[N:15])[CH:5]=[C:6]([CH:8]2OCC[O:9]2)[CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:13]([CH3:17])([CH3:16])[C:14]#[N:15])[CH:5]=[C:6]([CH:8]=[O:9])[CH:7]=1
Reactant: CC(C)(C#N)c1cc(Br)cc(C2OCCO2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C#N)c1cc(Br)cc(C=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 123.1 %

Procedure:
To a solution of 2-(3-bromo-5-(1,3-dioxolan-2-yl)phenyl)-2-methylpropanenitrile (1.9836 g, 6.70 mmol) in acetone (25 mL) was added p-toluenesulfonic acid hydrate (0.26 g, 1.36 mmol) and the reaction mixture was stirred at room temperature overnight to give an orange-red solution. The solvent was evaporated in vacuo to give an orange-brown residue. The residue was partitioned between aqueous saturated NaHCO3 solution (25 mL) and ethyl acetate (50 mL), the organic layer was removed, washed with brine (1×25 mL), dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give an orange viscous liquid (2.08 g). Purification of the crude product by silica-gel flash chromatography on silica gel column and elution with 5-40% ethyl acetate in n-hexane afforded the desired product as a pale yellow crystalline solid (0.89 g). LC-MS analysis of the solid shows the desired product's mass: m/z 252 (79BrM+H), m/z 254 (81BrM+H); Calcd for C11H10BrNO: 252.11
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]2[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=2)=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[C:25]([CH:27]1[CH2:29][CH2:28]1)=[O:26]>C1COCC1>[CH:27]1([C:25](=[O:26])[C:2]2[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]3[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=3)=[CH:4][CH:3]=2)[CH2:29][CH2:28]1
Reactant: CN(C)C(=O)C1CC1
Reactant: CC1(C)COC(C(C)(C)c2ccc(Br)cc2)=N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)COC(C(C)(C)c2ccc(C(=O)C3CC3)cc2)=N1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
A solution of 4-bromo-α,α-dimethyl-α-(4,4-dimethyloxazolin-2-yl)toluene, prepared according to Example 2, (10.0 g. 0.0338 mole) in 400 mL THF was cooled to −78° C., n-butyllithium (16 mL, 0.042 mole) was added via syringe, and the mixture was stirred at −78° C. for 30 minutes. While keeping the temperature below −75° C., N,N-dimethyl cyclopropylcarboxylic acid amide (11.5 g, 0.102 mole) in 30 mL THF was added dropwise, and the mixture was stirred at −78° C. for 30 minutes. The mixture was allowed to warm to −15° C., and was quenched with water. The product was extracted with methylene chloride, washed with saturated NaCl solution, dried over Na2SO4, and concentrated. The residue was cooled to 0° C., treated with minimal acetonitrile, and filtered, to afford 6.95 g of 4-(cyclopropyl-oxo-methyl)-α,α-dimethyl-α-(4,4-dimethyloxazolin-2-yl)toluene as a white solid (72%).
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10]CC)=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])[O-:14].[Cs+].[Cs+]>CN(C)C=O>[CH2:6]([O:5][C:3](=[O:4])[C:2]([OH:14])([CH3:1])[C:8]([OH:10])=[O:9])[CH3:7]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(O)C(=O)O
Temperature: 25 °C
Yield: 70.3 %

Procedure:
To a solution of 3.52 g (20 mmol) diethyl methylmalonate in 40 ml dimethylformamide were added 13.1 g (40 mmol) cesium carbonate. The suspension was stirred at room temperature and air was bubbled in for 1 hour. The mixture was poured into water and extracted with ethylacetate. Extraction at pH 1 with ethylacetate yielded 2.28 g (70%) 2-hydroxy-2-methyl-malonic acid monoethyl ester, light yellow liquid, MS m/e (%): 161.0 (M−H, 100).
Reaction SMILES: [C:1]([N:4]1[C:17]2[C:12]3=[C:13]([C:18](=[O:28])[C:19]([CH2:21][C:22]4[CH:23]=N[CH:25]=[CH:26][CH:27]=4)=[CH:20][N:11]3[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=3)[CH:14]=[CH:15][CH:16]=2)(=[O:3])[CH3:2].[CH:29](=O)C1C=CC=CC=1>>[C:1]([N:4]1[C:17]2[C:12]3=[C:13]([C:18](=[O:28])[C:19]([CH2:21][C:22]4[CH:23]=[CH:29][CH:25]=[CH:26][CH:27]=4)=[CH:20][N:11]3[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=3)[CH:14]=[CH:15][CH:16]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2-n2cc(Cc3cccnc3)c(=O)c3cccc1c32
Reactant: O=Cc1ccccc1
Product: CC(=O)N1c2ccccc2-n2cc(Cc3ccccc3)c(=O)c3cccc1c32
Yield: 36 %

Procedure:
According to Example 9<step 4>, the compound (5 g) produced in Example 9<step 3>was reacted with benzaldehyde (3 mL) to obtain the title compound (2.4 g; 36%).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:13][C:14](SC)=[C:15]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:32]1([NH2:37])[CH2:36][CH2:35][CH2:34][CH2:33]1>>[F:31][C:2]([F:30])([F:1])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([NH:37][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[C:15]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:19])=[O:20])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: NC1CCCC1
Reactant: CSC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Product: N#CC(=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)NC1CCCC1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 71 %

Procedure:
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-(4-chloro-phenylsulfonyl)-3-methylsulfanyl-2-propenenitrile (0.400 g, 0.8 mmol) was stirred in cyclopentylamine (2 ml) at 80° C. for 2 h and at room temperature for 16 h under nitrogen. Work up as descriped in Example 1, 2) gave 305 mg (71%) of the title compound as pale yellow crystals. Mp 199-200° C. 1H NMR (300 MHz, CDCl3): δ=1.4-1.65 (m, 4H), 1.65-1.85 (m, 4H), 3.56 (sextet, 1H), 7.42 (s, 2H), 7.49 (d, 2H), 7.67 (s, 1 H), 7.78 (d, 2H); MA calc for C22H18ClF6N3O2S: C, 49.12%; H, 3.37%; N, 7.18%. Found: C, 48.93%; H, 3.31%; N, 7.58%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[NH:20]1[CH2:23][CH2:22][CH2:21]1.CCN(CC)CC>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:20]2[CH2:23][CH2:22][CH2:21]2)[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: C1CNC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cc(N2CCC2)c(Cl)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (4,5-dichloro-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example B2) (6.14 g, 20 mmol), azetidine (2.33 mL, 34 mmol) and Et3N (8.4 mL, 60 mmol) in DMSO (40 mL) at 23° C. according to the general procedure C. Obtained as an orange solid (5.85 g).
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([O:11][CH2:12][CH:13]([C:20]2[N:21]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[N:22]=[C:23]3[C:28]=2[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:6]([CH3:36])[CH:5]=1.[OH-].[Li+]>C1COCC1.CO>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([N:21]2[C:20]([CH:13]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:12][O:11][C:7]3[C:8]([CH3:10])=[CH:9][C:4]([C:3]([OH:37])=[O:2])=[CH:5][C:6]=3[CH3:36])=[C:28]3[C:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)=[N:22]2)=[CH:34][CH:33]=1
Reactant: COC(=O)c1cc(C)c(OCC(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(=O)O)cc(C)c1OCC(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1

Procedure:
In analogy to the procedure described in example 7.2, [rac]-4-{2-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-2-cyclohexyl-ethoxy}-3,5-dimethyl-benzoic acid methyl ester (example 39) was treated with 1 N aqueous lithium hydroxide solution in THF and MeOH to give the title compound as off-white solid. MS: m/e=507.2 [M+H+].
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:26][CH2:27][C@H:28]([N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C:29]([O:31][CH3:32])=[O:30]>ClCCl>[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:26][CH2:27][C@H:28]([N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[C:29]([O:31][CH3:32])=[O:30])(=[O:24])=[O:23])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)[C@H](CN)N1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CNS(=O)(=O)c1ccc(OCc2ccccc2)cc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.6 %

Procedure:
1.2 ml (8.5 mmol) of triethylamine and then 800 mg (2.8 mmol) of 4-benzyloxybenzenesulfonyl chloride in 8 ml of dichloromethane are added to a solution of 670 mg (2.6 mmol) of methyl(S)-3-amino-2-piperidin-1-ylpropanoate in 10 ml of dichloromethane. The reaction medium is stirred at ambient temperature for 18 h, hydrolyzed and then diluted with dichloromethane. The product is extracted with dichloromethane. The organic phase is washed with water and then with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue obtained is purified by chromatography on silica gel, elution being carried out with a 70/30 heptane/ethyl acetate mixture. 940 mg (85%) of methyl(S)-3-(4-benzyloxybenzenesulfonylamino)-2-piperidin-1-ylpropanoate are obtained in the form of a white solid.
Reaction SMILES: [Zn](CC)[CH2:2][CH3:3].[CH:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>C1(C)C=CC=CC=1>[OH:13][CH:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:2][CH3:3]
Reactant: O=Cc1ccccc1
Reactant: CC[Zn]CC
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(O)c1ccccc1
Reaction time: 0.5 h
Yield: 31.4 %

Procedure:
(+)-Me-IAN amine (19.0 mg, 66.8 μmol) was dissolved in toluene (0.85 mL) in a 10 mL flask. Et2Zn (1.22 mL, 1.1 M in toluene, 1.34 mmol) was added in one portion via syringe. Immediately, a clear red-orange solution formed. After stirring for 30 min., benzaldehyde (0.068 mL, 0.669 mmol) was added. This addition immediately lightened the solution to a pale orange-yellow. After 19 h, the solution returned to its red-orange color. Water was added and the mixture was extracted three times with CH2Cl2. The combined organic phases were dried over MgSO4, filtered, and concentrated iii vacuo. Purification of the crude product via flash column chromatography on silica gel gave 1-hydroxy-1-phenylpropane as a light yellow liquid (28.6 mg, 31.4%). HPLC analysis of the product (OD column, 1.0 mL/min, 2% iPrOH in hexanes) gave 85.2% ee (retention time of major peak=13.7 min, retention time of minor peak=16.3 min) and a decrease in the ee of (+)-Me-IAN amine (from 99% to 93.2% ee).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:26]=[CH:25][CH:24]=[CH:23][C:8]=3[CH2:9][CH2:10][CH:11]([NH:12]C(=O)OCC3C=CC=CC=3)[C:5]2=[N:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1[N:6]2[C:7]3[CH:26]=[CH:25][CH:24]=[CH:23][C:8]=3[CH2:9][CH2:10][CH:11]([NH2:12])[C:5]2=[N:4][CH:3]=1
Reactant: Cc1cnc2n1-c1ccccc1CCC2NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1cnc2n1-c1ccccc1CCC2N
Reaction time: 7 h
Yield: 87.2 %

Procedure:
Combine benzyl N-(1-methyl-5,6-dihydro-4H-imidazo[1,2-a][1]benzazepin-4-yl)carbamate (0.99 g, 2.85 mmol) and 10% Pd/C (200 mg, 1.88 mmol) in absolute ethanol (50 mL). Place the mixture on a Parr shaker for 7 hours (hydrogen (H2) 60 psi, ambient temperature). Remove the catalyst by filtration, add 10% Pd/C (200 mg, 1.88 mmol) to the filtrate, and place the mixture on a Parr shaker for 7 additional hours (60 psi, ambient temperature). After 7 hours, add more 10% Pd/C (189 mg, 1.78 mmol) and shake for 7 additional hours. Remove the catalyst by filtration and concentrate the filtrate under reduced pressure to give the title compound (0.53 g, 87%): MS (m/z): 214 (M+1).