Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C([O:7][C:8](=[O:35])/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH3:20])=[C:13]([C:21]2[NH:22][C:23](=[O:34])[C:24]3[C:29]([CH3:30])=[N:28][N:27]([CH2:31][CH2:32][CH3:33])[C:25]=3[N:26]=2)[CH:12]=1)(C)(C)C>CO>[CH3:30][C:29]1[C:24]2[C:23](=[O:34])[NH:22][C:21]([C:13]3[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=3[O:17][CH2:18][CH2:19][CH3:20])/[CH:10]=[CH:9]/[C:8]([OH:35])=[O:7])=[N:26][C:25]=2[N:27]([CH2:31][CH2:32][CH3:33])[N:28]=1
Reactant: CCCOc1ccc(/C=C/C(=O)OC(C)(C)C)cc1-c1nc2c(c(C)nn2CCC)c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCOc1ccc(/C=C/C(=O)O)cc1-c1nc2c(c(C)nn2CCC)c(=O)[nH]1
Yield: 11.4 %

Procedure:
2N Aqueous sodium hydroxide solution (8.0 ml, 0.016 mol) was added to a solution of (E)-3-(3-methyl-4-oxo-1-n-propyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-6-yl)-4-n-propoxycinnamic acid t-butyl ester (Example 12; 1.8 g, 0.004 mol) in methanol (8 ml) and the mixture heated under reflux for 5 hours. The methanol was removed by evaporation under vacuum and the aqueous solution acidified to pH 1 with 2N hydrochloric acid. Exhaustive extraction of the product with 10% methanol in ethyl acetate was followed by drying of the combined extracts (Na2SO4) and evaporation of solvents under vacuum to furnish an off-white solid. Crystallisation from ethyl acetate-methanol afforded the title compound as white crystals (0.18 g, 12%), m.p. 231-232° C. Found: C, 63.52; H, 5.96; N, 14.00. C21H24N4O4 requires C, 63.62; H, 6.10; N, 14.13%.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][C:10]([CH2:15][CH3:16])([N:12]([CH3:14])[CH3:13])[CH2:9]2)C=CC=CC=1.[ClH:23]>C(O)C.[OH-].[OH-].[Pd+2]>[ClH:23].[ClH:23].[CH2:15]([C:10]1([N:12]([CH3:14])[CH3:13])[CH2:11][NH:8][CH2:9]1)[CH3:16]
Reactant: CCC1(N(C)C)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: CCC1(N(C)C)CNC1
Yield: 112.2 %

Procedure:
1-(Diphenylmethyl)-3-ethyl-N,N-dimethyl-3-azetidinamine (0.215 g, 0.73 mmol) in 1 N HCl (5 ml) and ethanol (30 ml) was treated with H2 at 60 psi in the presence of Pd(OH)2 on carbon (100 mg). Standard work-up afforded 3-ethyl-N,N-dimethyl-3-azetidinamine dihydrochloride (0.165 g, 112.2%). LCMS: (M+H)+ 129.1.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH-].[Na+].[CH3:16][CH2:17][N:18]([CH2:21][CH2:22]Cl)[CH2:19][CH3:20].Cl>O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])(=[O:13])=[O:12])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CCN(CC)CCCl
Reactant: CC(=O)Nc1ccc(S(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN(CC)CCS(=O)(=O)c1ccc(NC(C)=O)cc1
Reaction time: 5 h

Procedure:
9.0 g of 4-acetamido-phenylsulphinic acid are dissolved in 10 ml of water and 45 ml of 1N sodium hydroxide solution and 9.47 g of 2-chlorotriethylamine hydrochloride are added. The mixture is stirred for 5 hours at reflux temperature. After cooling, sodium hydroxide solution is added until an alkaline reaction is obtained, the mixture is extracted with ethyl acetate, dried over magnesium sulphate and finally the solvent is eliminated.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([OH:27])=O)=[N:23][CH:24]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.[CH2:35]([CH2:37][NH2:38])[OH:36]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([NH:38][CH2:37][CH2:35][OH:36])=[O:27])=[N:23][CH:24]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]2)[N:3]=1
Reactant: NCCO
Reactant: CC1Cc2ccc(-c3ccc(C(=O)O)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Product: CC1Cc2ccc(-c3ccc(C(=O)NCCO)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 50B starting from 5-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid (Example 50B, Step 1) and ethanolamine (Aldrich, Cat. No. 411000). LCMS (M+H)+: m/z=503.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:37]1[CH:42]=[N:41][CH:40]=[CH:39][N:38]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:37]4[CH:42]=[N:41][CH:40]=[CH:39][N:38]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: Brc1cnccn1
Product: C[C@@H](c1ccc(-c2cnccn2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 2-bromopyrazine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.157, m/z=458; 1H NMR (CDCl3) 1.31 (m, 1H), 1.52 (d, 3H), 1.63 (m, 1H), 1.81-1.95 (m, 2H), 2.09-2.32 (m, 3H), 2.91 (m, 1H), 3.68 (t, 2H), 5.69 (m, 1H), 6.91 (m, 4H), 7.21 (m, 2H), 7.73 (m, 2H), 8.43 (s, 1H), 8.56 (s, 1H), 8.89 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[F:11].FC(F)(F)S(O[C:18]1[CH:23]=[CH:22][C:21]([C@H:24]2[C:29]3=[N:30][S:31](=[O:35])(=[O:34])[CH2:32][CH2:33][N:28]3[CH2:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CCO.O.CN(C=O)C.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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]2[CH:19]=[CH:20][C:21]([C@H:24]3[C:29]4=[N:30][S:31](=[O:35])(=[O:34])[CH2:32][CH2:33][N:28]4[CH2:27][CH2:26][CH2:25]3)=[CH:22][CH:23]=2)=[CH:4][C:3]=1[F:11]
Reactant: O=S1(=O)CCN2CCC[C@@H](c3ccc(OS(=O)(=O)C(F)(F)F)cc3)C2=N1
Reactant: OB(O)c1ccc(Cl)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: O=S1(=O)CCN2CCC[C@@H](c3ccc(-c4ccc(Cl)c(F)c4)cc3)C2=N1
Temperature: 50 °C
Reaction time: 16 h
Yield: 5.2 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (16.0 mg) was added to a mixture of (4-chloro-3-fluorophenyl)boronic acid (85.0 mg), 4-[(9S)-2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl]phenyl trifluoromethanesulfonate (100 mg) and sodium carbonate (51.4 mg) in EtOH (3 mL), water (1.5 mL) and DMF (dry) (2 mL). The mixture was stirred at 50° C. under nitrogen for 16 hr. Silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) and concentrated. The residue was dissolved in MeCN/DMSO (1900/100 μM) and purified by preparative HPLC (C18, eluted with water in acetonitrile containing 0.1% TFA). The desired fractions were neutralized with sat. NaHCO3 aq., extracted with EtOAc and washed with brine. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound (5.00 mg) as a white solid.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[NH2:24][C:25]1([CH2:29][OH:30])[CH2:28][NH:27][CH2:26]1>>[NH2:24][C:25]1([CH2:29][OH:30])[CH2:28][N:27]([C:2]2[CH:23]=[CH:22][C:5]3[C:6]4[N:7]([CH:11]=[C:12]([C:14]5[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=5)[N:13]=4)[CH2:8][CH2:9][O:10][C:4]=3[CH:3]=2)[CH2:26]1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: NC1(CO)CNC1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N3CC(N)(CO)C3)cc1OCC2

Procedure:
Following the procedures of Example 551, 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 194 and (3-aminoazetidin-3-yl)methanol were reacted to give 525. LC/MS (ESI+): m/z 396.2 (M+H)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[O:16][C:17]1[CH:18]=[N:19][C:20]([N+:23]([O-])=O)=[CH:21][CH:22]=1>CO.[C].[Pd]>[NH2:23][C:20]1[N:19]=[CH:18][C:17]([O:16][C:3]2[CH:4]=[C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:22][CH:21]=1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1Oc1ccc([N+](=O)[O-])nc1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(NC(=O)OC(C)(C)C)cc1Oc1ccc(N)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
To a solution of tert-butyl {4-methyl-3-[(6-nitropyridin-3-yl)oxy]phenyl}carbamate (1.85 g, 5.35 mmol) in methanol (10 mL) was added palladium carbon (50% water-containing product, 100 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was dried to give the title compound (1.69 g, 99%) as a colorless oil.
Reaction SMILES: C([S:4][CH2:5][C@@H:6]1[CH2:10][C@@H:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:8][N:7]1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])(=O)C.C[O-].[Na+].CO.I[CH2:38][C:39]([NH2:41])=[O:40]>CO>[Si:12]([O:11][C@H:9]1[CH2:8][N:7]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])[C@H:6]([CH2:5][S:4][CH2:38][C:39](=[O:40])[NH2:41])[CH2:10]1)([C:15]([CH3:18])([CH3:16])[CH3:17])([CH3:13])[CH3:14]
Reactant: CC(=O)SC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)CI
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CSCC(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.17 h
Yield: 102.2 %

Procedure:
To a solution of (2S,4R)-2-acetylthiomethyl-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.0 g) in methanol (20 ml) was added 28% sodium methoxide-methanol solution (0.98 ml) under an atmosphere of nitrogen at 0° C. After stirring at the same temperature for 10 minutes, to this reaction mixture was added 2-iodoacetamide (1.02 g) under the same condition. The mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (100 ml). The solution was washed with saturated aqueous sodium hydrogen carbonate and saturated sodium chloride successively, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give (2S,4R)-4-t-butyldimethylsilyloxy-2-(carbamoylmethyl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.11 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]3[O:16][CH2:15][O:14][C:11]=3[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:17]([O:19]CC)=[O:18])[CH3:2]>[OH-].[Na+]>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]3[O:16][CH2:15][O:14][C:11]=3[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:17]([OH:19])=[O:18])[CH3:2]
Reactant: CCOC(=O)c1cnc2cc3c(cc2c1OCC)OCO3
Agent: [Na+]
Agent: [OH-]
Product: CCOc1c(C(=O)O)cnc2cc3c(cc12)OCO3

Procedure:
To 120 ml of 5% ethanolic sodium hydroxide solution was added 6 g of ethyl 4-ethoxy-6,7-methylenedioxyquinoline-3-carboxylate with stirring, and the mixture was stirred further for 15 minutes at room temperature then concentrated to a small volume under reduced pressure. A small amount of water was added to the residue, the pH of the solution was adjusted to 5 by the addition of hydrochloric acid, and the precipitate thus formed was filtered, washed with water and dried to provide 5.2 g of almost pure 4-ethoxy-6,7-methylenedioxyquinoline-3-caboxylic acid having a melting point of 250°-253°C. Recrystallization from dimethyl sulfoxide gave colorless needles having a melting point of 252°C (decomposed).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:27]3[O:26][CH2:25][CH2:24][O:23][C:22]=3[CH:21]=[CH:20][CH:19]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[O:23]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([C:16]([NH:15][C:6]3([C:4]([OH:5])=[O:3])[CH2:7][C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:14]3)=[O:17])[C:27]=2[O:26][CH2:25][CH2:24]1
Reactant: CCOC(=O)C1(NC(=O)c2cccc3c2OCCO3)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1cccc2c1OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
The mixture of 2-[(2,3-dihydro-benzo[1,4]dioxine-5-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (59) (495 mg, 1.35 mmol) and KOH (1 g, 17.9 mmol) is dissolved in EtOH (10 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (30 mL) and acidified with conc. HCl until no more white precipitate came out of the water. The precipitate is filtered to give a pure product (60) as white solid (440 mg, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[OH:13].C(N(CC)C(C)C)(C)C.Br[CH2:24][CH2:25][CH:26]=[CH2:27]>CN(C)C=O>[CH2:27]([O:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[NH:8][C:7](=[O:12])[CH:6]=1)[CH2:26][CH:25]=[CH2:24]
Reactant: C=CCCBr
Reactant: O=c1cc(O)c2cc(Cl)ccc2[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCCOc1cc(=O)[nH]c2ccc(Cl)cc12
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of 6-chloro-4-hydroxyquinolin-2(1H)-one (800 mg, 4.09 mmol) and N,N-diisopropylethylamine (1415 μl, 8.18 mmol) in dimethylformamide (13.6 ml) was added 4-bromo-1-butene (415 μl, 4.09 mmol). The solution was heated to 60° C. and stirred for 18 hours. The reaction mixture was purified by column chromatography to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6]C(C#N)=CC=1.[CH3:10][Mg]Br.[CH2:13]1[CH2:17][O:16][CH2:15][CH2:14]1>>[Cl:1][C:2]1[N:7]=[N:6][C:13]([C:17](=[O:16])[CH3:10])=[CH:14][CH:15]=1
Reactant: C[Mg]Br
Reactant: C1CCOC1
Reactant: N#Cc1ccc(Cl)nn1
Product: CC(=O)c1ccc(Cl)nn1
Reaction time: 1.5 h

Procedure:
A solution of 6-chloro-pyridazine-3-carbonitrile (prepared according to MacDonald et al., WO/2008/068277) (100 mg, 0.71 mmol) in dry THF (3.6 mL) was cooled to −50° C. in a dry ice/acetone bath. Methylmagnesium bromide (1.0 M in MePh/THF, 0.54 mL, 0.75 mmol) was added via syringe in one portion. The cold bath was removed and the reaction was stirred for 1.5 h. To the reaction mixture was added saturated aqueous NH4Cl and this mixture was extracted with EtOAc (3×). The combined organics were dried over MgSO4 and concentrated. The resulting residue was purified by flash chromatography (silica, 0→4% MeOH/CH2Cl2) to give 34 mg of 1-(6-chloro-pyridazin-3-yl)-ethanone as a brown semi-solid, m/z 157.3 [M+H]+.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:45])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:41][CH3:42])([C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([OH:39])([C:35]([F:38])([F:37])[F:36])[C:31]([F:34])([F:33])[F:32])=[C:24]([CH3:40])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:43])=[CH:9][C:8]=1[F:44]>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([OH:45])=[O:4])=[C:8]([F:44])[CH:9]=2)=[C:14]([CH3:43])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([OH:39])([C:35]([F:36])([F:37])[F:38])[C:31]([F:33])([F:34])[F:32])=[C:24]([CH3:40])[CH:23]=1)[CH2:41][CH3:42])[CH3:21]
Reactant: CCC(CC)(c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(F)c2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)O)c(F)c2)c(C)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.145 mL, 0.145 mmol) was added to a solution of (4′-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-1-butenyl)-phenyl]-propyl}-3-fluoro-2′-methyl-biphenyl-4-yl)acetic acid methyl ester (Example 72-(1); 29.6 mg, 0.049 mmol) in methanol-tetrahydrofuran (1:1, 1 mL), and the mixture was stirred at 60° C. for one hour. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=8:3, saturated with water) to give the target compound as a colorless oil (27.5 mg, 95%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([OH:13])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:14])[N:5]=[C:4]2[S:15][C:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[C:3]=12.C(O[C:26]([CH3:29])([CH3:28])[CH3:27])(=O)C.Cl(O)(=O)(=O)=O>>[Cl:1][C:2]1[C:7]([CH:8]([O:13][C:26]([CH3:29])([CH3:28])[CH3:27])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:14])[N:5]=[C:4]2[S:15][C:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[C:3]=12
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)C(O)c1c(C)nc2sc3c(c2c1Cl)CCCC3
Agent: [O-][Cl+3]([O-])([O-])O
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1Cl)CCCC3
Temperature: 25 °C
Reaction time: 5 h
Yield: 58.8 %

Procedure:
To a solution of methyl 2-[4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-hydroxyacetate (0.100 g, 0.307 mmol) in tert-butyl acetate (1.5 mL; 11.23 mmol) under a nitrogen atmosphere was added perchloric acid 70% (0.029 mL; 0.338 mmol). The reaction was stirred at room temperature for 5 h and quenched by adding a saturated solution of sodium bicarbonate. The mixture was diluted with dichloromethane and the phases were separated. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethylacetate (5-40%) in heptane furnished 0.069 g (59%) of the title compound as a solid.
Reaction SMILES: [CH2:1]([C@H:8]([NH:26]C(=O)OC(C)(C)C)[C@H:9]([OH:25])[CH2:10][NH:11][C:12]1([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:34]>ClCCl.O1CCOCC1>[ClH:34].[NH2:26][C@@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@H:9]([OH:25])[CH2:10][NH:11][C:12]1([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:16]=2)[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CNC1(c2cccc(C(F)(F)F)c2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccccc1)[C@H](O)CNC1(c2cccc(C(F)(F)F)c2)CC1
Reaction time: 0.5 h

Procedure:
6.8 g of tert-butyl [(1S,2R)-1-benzyl-2-hydroxy-3-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]carbamate are then dissolved in 250 cm3 of dichloromethane at a temperature close to 20° C. 36.6 cm3 of a 4M solution of hydrochloric acid in dioxane are added. The reaction mixture is kept stirring for 1 h 30 min at a temperature close to 20° C. The reaction mixture is concentrated using a rotary evaporator under reduced pressure (5 kPa). The beige solid obtained is triturated in diisopropyl ether then filtered. 5.4 g of (2R,3S)-3-amino-4-phenyl-1-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)butan-2-ol hydrochloride (2:1) are obtained.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([NH2:8])[CH:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH:9]([C@@H:5]1[CH2:4][CH2:3][C@@H:2]([CH3:1])[CH2:7][C@@H:6]1[NH:8][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:11])[CH3:10].[CH:9]([C@H:5]1[CH2:4][CH2:3][C@H:2]([CH3:1])[CH2:7][C@H:6]1[NH:8][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:11])[CH3:10]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1CCC(C(C)C)C(N)C1
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1NC(=O)c1ccccc1
Product: CC(C)[C@H]1CC[C@H](C)C[C@H]1NC(=O)c1ccccc1

Procedure:
The aforementioned product is obtained as a colorless solid containing in total 97.6% of the desired neomenthylamine derivatives from racemic neomenthylamine, as in the GP, by reaction with benzoylchloride. Furthermore, two further isomeric menthylamine derivatives are present at 1.3% and 1.0%, corresponding to a purity of isomeric N-(-2-isopropyl-5-methylcyclohexyl)benzamides of 99.9%.
Reaction SMILES: [C:1]([NH:4][C:5]#[N:6])(=[O:3])[CH3:2].[Na].[CH2:8](Cl)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C)C=O>[CH2:8]([N:4]([C:5]#[N:6])[C:1](=[O:3])[CH3:2])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)NC#N
Reactant: ClCc1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(=O)N(C#N)Cc1ccccc1

Procedure:
106.1 g (1.0 mol) of sodium acetylcyanamide and 151.9 g (1.0 mol+20% excess) of benzyl chloride are reacted in 500 ml of dimethylformamide at 100°-112° C. for 4 hours and 20 minutes and the mixture is then filtered. The filtrate is evaporated completly in vacuo on a rotary evaporator at 60° C. to give 146.7 g (88.7% of theory) of a brown viscous residue, which is recrystallised from 290 ml of diisopropyl ether. The yield of pure product of melting point 42° C. is 111.0 g (63.7% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].Br[CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([F:31])[CH:29]=2)[CH:24]=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([F:31])[CH:29]=3)[CH:24]=[CH:23][CH:22]=2)[C:7]2[C:12]([C:13]=1[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4]
Reactant: COC(=O)Cc1c(C(=O)OC)[nH]c2ccccc12
Reactant: Fc1ccc2cccc(CBr)c2c1
Product: COC(=O)Cc1c(C(=O)OC)n(Cc2cccc3ccc(F)cc23)c2ccccc12

Procedure:
Using general procedure B, 3-methoxycarbonylmethyl-1H-indole-2-carboxylic acid methyl ester (prepared according to Lit. 2) was coupled with 1-bromomethyl-7-fluoro-naphthalene (from Example 49.3.) to give 1-(7-fluoro-naphthalen-1-ylmethyl)-3-methoxycarbonylmethyl-1H-indole-2-carboxylic acid methyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to the title compound as a white solid. MS: 375.9 ([M−H]−).
Reaction SMILES: [CH3:1][S:2]([C:5]1[C:14]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8])(=[O:4])=[O:3].C(O)C.[OH-].[Na+]>O>[CH3:1][S:2]([C:5]1[C:14]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([OH:9])=[O:8])(=[O:4])=[O:3]
Reactant: COC(=O)c1cccc(Sc2ccccc2)c1S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1c(Sc2ccccc2)cccc1C(=O)O
Yield: 99.5 %

Procedure:
A mixture of methyl 2 -methylsulphonyl-3-phenylsulphenylbenzoate (8.3 g), ethanol (50 ml) and 2N sodium hydroxide (25 ml) was heated at reflux for one hour and then added to water. The inorganic phase was washed with ethyl acetate, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. This organic phase was dried over sodium sulphate, filtered and evaporated giving 7.9 g of 2-methylsulphonyl-3-phenylsulphenylbenzoic acid as a white solid, m.p. 185.4°-186.0° C.