Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:11][NH:10][C:9](=[O:12])[C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.[CH3:31]NN>>[CH3:31][N:10]1[C:9](=[O:12])[C:8]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:17][CH:18]=2)=[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[NH:11]1
Reactant: CNN
Reactant: O=c1[nH][nH]c(-c2ccncc2)c1-c1ccc(OCc2ccc3ccccc3n2)cc1
Product: Cn1[nH]c(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)c1=O
Yield: 15 %

Procedure:
Following the procedure for the preparation of 5-(pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrazol-3(2H)-one using methyl hydrazine provided the title compound. Yield: 15%. 1H NMR (500 MHz, d6-DMSO): δ 8.44-8.36 (m, 2H), 8.04-7.96 (m, 2H), 7.82-7.74 (m, 2H), 7.72-7.56 (m, 2H), 7.38-7.22 (m, 1H), 7.18-7.12 (m, 2H), 7.10-7.06 (m, 1H), 7.01-6.98 (m, 2H), 5.36 (s, 2H), 3.69 (s, 1H), 3.59 (s, 3H). MS: M+H: m/z=409.1.
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K].F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]([C:24]([O-:26])=[O:25])[NH2:23].[Na+].CO>COCCOC.Cl>[C:8]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:16]=2)([C:24]([OH:26])=[O:25])[NH2:23])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: NC(C(=O)[O-])c1ccccc1F
Agent: Cl
Agent: [K]
Agent: [Na+]
Solvent: COCCOC
Solvent: CO
Product: NC(C(=O)O)(c1ccccc1)P(c1ccccc1)c1ccccc1
Temperature: 80 °C

Procedure:
A solution of 3.07 g (16.5 mmol) of diphenylphosphine in 60 ml of 1,2-dimethoxyethane was admixed with 0.64 g (16.5 mmol) of potassium. After the metallation reaction was complete, 3.0 g (15.7 mmol) of sodium 2-(2-fluorophenyl)glycinate were added and the reaction mixture was heated at 80° C. for 3 hours. Subsequently, 10 ml of methanol were added and the volatile constituents were removed at 80° C. at a pressure of 10−2 bar. The residue obtained was suspended in 500 ml of dilute aqueous hydrochloric acid (pH=4) and filtered, and then dried at 20° C. and 10−2 bar. The yield was 4.7 g (89%). For the further work-up, the product was recrystallized from a 3:1 mixture of water and methanol. The 1H, 13C{1H} and 31P{1H} NMR spectra were recorded on a Bruker AC 250 spectrometer; the mass spectra were recorded on a Varian MAT 311 A instrument.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([O-])=[O:6])[CH:3]=1.Cl.[CH3:15][NH:16][CH3:17].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1>C(Cl)Cl>[CH3:15][N:16]([CH3:17])[C:5]([C:4]1[CH:3]=[C:2]([CH:10]=[CH:9][CH:8]=1)[C:1]([O:12][CH3:13])=[O:11])=[O:6]
Reactant: COC(=O)c1cccc(C(=O)[O-])c1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)c1cccc(C(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a methylene chloride (20 ml) solution of monomethyl isophthalate (317 mg, 1.76 mmol) were added dimethylamine hydrochloride (172 mg, 2.11 mmol), 1-hydroxybenzotriazole (287 mg, 1.76 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (404 mg, 2.11 mmol) and N-methylmorpholine (0.23 ml, 2.11 mmol) and the resulting mixture was stirred at room temperature for 21 hours. The reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue. The resulting mixture was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, and brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column and the fraction obtained from the methanol:methylene chloride (=1:50) eluate was concentrated under reduced pressure, whereby the title compound (290 mg, 80%) was obtained as a colorless oil.
Reaction SMILES: [O-][CH2:2]C.[Na+].[F:5][C:6]([F:23])([F:22])[C:7]1[CH:8]=[C:9]([CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1)[C:10]([CH2:12][C:13]#[N:14])=[O:11].CI>CCO>[F:5][C:6]([F:22])([F:23])[C:7]1[CH:8]=[C:9]([C:10](=[O:11])[CH:12]([CH3:2])[C:13]#[N:14])[CH:15]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:17]=1
Reactant: CC[O-]
Reactant: N#CCC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Na+]
Solvent: CI
Solvent: CCO
Product: CC(C#N)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
A solution of sodium ethoxide (0.127 g, 1.87 mmol) in EtOH (5 mL) was treated with 3,5-bis(trifluoromethyl)benzoyl acetonitrile (0.500 g, 1.78 mmol) portionwise over 5 min. The reaction was heated at reflux for 30 min before the addition of methyl iodide (0.41 mL, 6.6 mmol). Heating at reflux was continued for a further 2 h before the reaction mixture was allowed to cool and concentrated in vacuo. The residue was partitioned between H2O (10 mL) and EtOAC (20 mL) and the aqueous phase was separated and re-extracted with EtOAC (2×20 mL). The combined organic extracts were washed with brine (25 mL), dried (MgSO4), filtered and concentrated. The crude product was purified by flash chromatography on silica gel (0-20% EtOAc in hexanes gradient) to afford 3-[3,5-bis(trifluoromethyl)phenyl]-2-methyl-3-oxopropanenitrile. 1H NMR (500 MHz, CDCl3) δ 8.21 (s, 2H), 8.10 (s, 1H), 4.42 (q, J=7.1 Hz, 1H), 1.71 (d, J=7.1 Hz, 6H).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21]([Cl:22])=[CH:20][N:19]=[C:18](Cl)[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[C:24]([O:28][C:29](=[O:35])[NH:30][CH2:31][CH2:32][CH2:33][NH2:34])([CH3:27])([CH3:26])[CH3:25].C(N(CC)C(C)C)(C)C>O1CCOCC1.ClCCl>[C:24]([O:28][C:29](=[O:35])[NH:30][CH2:31][CH2:32][CH2:33][NH:34][C:18]1[N:17]=[C:16]([C:13]2[S:12][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([C:5](=[O:6])[NH:4][CH:1]4[CH2:3][CH2:2]4)[C:15]=3[CH:14]=2)[C:21]([Cl:22])=[CH:20][N:19]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCCNc1ncc(Cl)c(-c2cc3c(C(=O)NC4CC4)cccc3s2)n1
Temperature: 97 °C
Yield: 65.1 %

Procedure:
A stirred suspension of 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (5.59 g, 15.3 mmol) in 1.4-dioxane (60 mL), (3-amino-propyl)-carbamic acid tert-butyl ester (2.70 mL, 2.69 mg, 15.5 mmol) in N,N-diisopropylethylamine (5.20 mL, 3.86 g, 29.9 mmol) is heated at 97° C. for 120 hours. The mixture is then cooled to room temperature, diluted with dichloromethane (120 mL), filtered, washed with dichloromethane (2×25 mL), and dried to provide {3-[5-chloro-4-(4-cyclopropylcarbamoyl-benzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-propyl}-carbamic acid tert-butyl ester (5.00 g, 65%). This intermediate (4.99 g, 9.94 mmol) is suspended in methanol (120 mL) and treated with 10% aqueous HCl (10 mL) and the mixture is heated at 100° C. for 24 hours. The mixture is then cooled to room temperature, quenched with 2 N NaOH (20 mL), filtered, washed with H2O (60 mL), dichloromethane (60 mL), and diethyl ether (60 mL), and dried to provide the title compound (3.99 g, 99%).
Reaction SMILES: [C:1]([C:3]([C@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].[OH-:21].[Na+]>S(=O)(=O)(O)O.O>[C:1]([C:3]([C@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:21])[NH2:2]
Reactant: [OH-]
Reactant: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCNC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: NC(=O)C(c1ccccc1)(c1ccccc1)[C@H]1CCNC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
3 3-(R)-(-)-(1-cyano-1,1-diphenylmethyl)pyrrolidine (9.2 g--see Preparation 9(B)) was dissolved in 95% sulphuric acid (80 ml) and the mixture was heated at 80° C. for 4 hours and then at 90° C. for 1 hour. Ice (1 kg) was added and the mixture was basified (pH 12) by the addition of a cold solution of sodium hydroxide (120 g) in water (100 ml). The mixture was extracted with dichloromethane (4×100 ml) and the combined extracts were dried (MgSO4) then concentrated in vacuo to give a foam which was purified by column chromatography on alumina eluting with dichloromethane containing methanol (0% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a foam, yield, 4.5 g, [α]25D +16 9° (c 1.0, CH2Cl2).
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:12]([O-])=O)[C:4](=O)[O:3]1.O.[NH2:16][NH2:17]>C(O)C.[Pd]>[CH4:2].[NH2:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH:2]=[N:16][NH:17][C:4]2=[O:3]
Reactant: O=C1OC(O)c2c1cccc2[N+](=O)[O-]
Reactant: NN
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: C
Product: Nc1cccc2c(=O)[nH]ncc12
Reaction time: 0.5 h
Yield: 35 %

Procedure:
A stirred solution of 3-hydroxy-4-nitrophthalide (43.4 g, 0.22 mole) and hydrazine hydrate (11.6 ml) in ethanol (1830 ml) was heated under reflux for 1 hour. The heating was discontinued and palladium on carbon (10%, 2.44 g) was added (with caution) over 15 minutes. A solution of hydrazine hydrate (24.2 ml) in ethanol (304 ml) was then added, dropwise, over 30 minutes and the mixture was heated under reflux for a further 2.5 hours. Filtration of the hot reaction mixture followed by the addition of a saturated solution of hydrogen chloride in ethanol (80 ml) to the filtrate gave a solid precipitate which was collected and washed with ethanol and ether. Evaporation of the filtrate gave a solid residue which was washed several times with boiling ethanol. The combined solids were recrystallised from water, after charcoal treatment, to give 5-amino-1(2H)-phthalazinone (12.7 g, 35%, m.p. 289°-291°).
Reaction SMILES: [N+:1]([C:4]1[C:9]2[O:10][CH2:11][O:12][C:8]=2[C:7]([C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[C:9]2[O:10][CH2:11][O:12][C:8]=2[C:7]([C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c2c1OCO2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(C(=O)O)c2c1OCO2
Yield: 98.7 %

Procedure:
8.05 g of 7-nitro-benzo[1,3]dioxole-4-carboxylic acid is reacted with hydrogen in 650 ml of ethanol with 800 mg of palladium/carbon catalyst under normal pressure at room temperature. It is filtered through diatomaceous earth and concentrated by evaporation in a vacuum. 6.82 g of 7-amino-benzo[1,3]dioxole-4-carboxylic acid is obtained as a brown solid, flash point 196-197° C.
Reaction SMILES: CS[C:3](=[NH:17])[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[CH3:18][NH:19][CH3:20]>C(N(CC)CC)C>[CH3:18][N:19]([CH3:20])[C:3]([NH2:17])=[N:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: CNC
Reactant: CSC(=N)Nc1ccccc1N1CCOCC1
Solvent: CCN(CC)CC
Product: CN(C)C(N)=Nc1ccccc1N1CCOCC1

Procedure:
A mixture of 2-methyl-1-(2-morpholinophenyl)-2-thiopseudourea hydroidide (3.8 g), a 33% ethanolic solution of dimethylamine (5 ml) and triethylamine (25 ml) was heated at 80° C. for 8 hours. Triethylamine was removed by evaporation under reduced pressure and the residue treated with a mixture of ice and water to give 1,1-dimethyl-2-(2-morpholinophenyl)guanidine (m.p. 141°-143° C.) which was recrystallised from hexane.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O.C(OCC)(=O)C>ClCCl>[NH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(C#N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1ccc(CCN)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.90 g commercially available [2-(4-Cyano-phenyl)-ethyl]-carbamic acid tert-butyl ester were dissolved in 100 ml dichloromethane. 10 ml trifluoroacetic acid were added and the reaction mixture was stirred at room temperature for one hour. 250 ml ethyl acetate were added and the mixture was washed three times with saturated NaHCO3 solution. The organic layer was dried over MgSO4 and then the solvent was removed in vacuo to obtain 700 mg 4-(2-Amino-ethyl)-benzonitrile as pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:24]([OH:26])=O)=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.Cl.CN.[CH2:30]([N:32]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.CCOC(C)=O.O>[NH2:1][C:2]1[C:3]([C:24]([NH:32][CH3:30])=[O:26])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: CC(C)n1cc(-c2nc(C(=O)O)c(N)nc2-c2ccccc2)ccc1=O
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CNC(=O)c1nc(-c2ccc(=O)n(C(C)C)c2)c(-c2ccccc2)nc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.1 %

Procedure:
A mixture of 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarboxylic acid (70 mg), methylamine hydrochloride (14.8 mg), 1-ethyl-3-[3′-(dimethylamino)propyl]-carbodiimide (34.1 mg), and 1-hydroxy-benzotriazole (29.7 mg) in CH2Cl2 (0.7 ml) was stirred at 25° C. for 4 hours. Water and EtOAc were poured into the mixture. The organic layer was separated, washed with water, sat. aq. NaHCO3, and brine, and dried over MgSO4. The solvent was removed under reduced pressure. The residue was purified by silica-gel column chromatography (n-hexane-EtOAc then CH2Cl2—MeOH) and then crystallized from MeOH-IPE to give 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-N-methyl-5-phenyl-2-pyrazinecarboxamide (40 mg).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]1(C)[CH:14]=[CH:13][C:12](S(O)(=O)=O)=[CH:11][CH:10]=1.C1(=O)CCCCC1>C(O)C>[F:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][CH:3]=1)[NH:6][C:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C:9]2=1
Reactant: Nc1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O=C1CCCCC1
Product: Fc1ccc2[nH]c3c(c2c1)CCCC3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
12.6 g of p-fluoroaniline was dissolved in 100 ml of ethanol and a catalytic amount of p-toluenesulfonic acid was added thereto. 9.8 g of cyclohexanone was then added dropwise to the mixture at room temperature. After completion of the addition, the mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. Dilute sulfuric acid prepared from 190 ml of water and 20 ml of concentrated sulfuric acid was added to the residue and the mixture was heated at 110° C. for 15 minutes on an oil bath to precipitate light orange crystals. The crystals thus formed were filtered, washed 3 times with water and dried to obtain 17.4 g of 6-fluoro-1,2,3,4-tetrahydrocarbazole which was identified by NMR spectrum.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12](O)=[O:13])[C:6]=2[CH2:5][CH2:4][N:3]1[CH:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18].Cl.[NH2:23][C@@H:24]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C@H:25]([OH:41])[CH2:26][NH:27][C:28]1([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)[CH2:30][CH2:29]1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>ClCCl.O>[CH2:42]([C@H:24]([NH:23][C:12]([C:7]1[C:6]2[CH2:5][CH2:4][N:3]([CH:15]([CH2:16][CH2:17][CH3:18])[CH2:19][CH2:20][CH3:21])[C:2](=[O:1])[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:13])[C@H:25]([OH:41])[CH2:26][NH:27][C:28]1([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[CH:32]=2)[CH2:29][CH2:30]1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CCCC(CCC)N1CCc2c(C(=O)O)cccc2C1=O
Reactant: N[C@@H](Cc1ccccc1)[C@H](O)CNC1(c2cccc(C(F)(F)F)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCCC(CCC)N1CCc2c(C(=O)N[C@@H](Cc3ccccc3)[C@H](O)CNC3(c4cccc(C(F)(F)F)c4)CC3)cccc2C1=O
Reaction time: 24 h
Yield: 129.8 %

Procedure:
Poured into a suspension of 125 mg of 1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid, 170 mg of (2R,3S)-3-amino-4-phenyl-1-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)butan-2-ol hydrochloride (2:1), 9 mg of hydroxybenzotriazole and 104 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 15 cm3 of dichloromethane is 0.444 cm3 of N,N-diisopropylethylamine at a temperature close to 20° C. The solution is kept stirring for 24 h. 15 cm3 of dichloromethane and 15 cm3 of water are added to the reaction medium. The aqueous phase is extracted with 15 cm3 of dichloromethane. The organic phases are combined, washed with 10 cm3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). The 350 mg of oil obtained are purified by flash chromatography over silica (column: 50 g; particle size: 120-40 μm, spherical; eluent: 100% ethyl acetate). After concentrating the fractions under reduced pressure, 79 mg of N-[(1S,2R)-1-benzyl-2-hydroxy-3-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide are obtained.
Reaction SMILES: C[C:2]([C:4]([C:14]([CH3:16])=[O:15])=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[Cl:13])=O.C1(C)C=CC(S([CH2:26][N+:27]#[C-])(=O)=O)=CC=1.C[O-].[Na+].O>CO>[CH3:16][C:14]([C:4]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=2[Cl:13])=[CH:26][NH:27][CH:2]=1)=[O:15]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CC(=O)C(=Cc1cccc(Cl)c1Cl)C(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)c1c[nH]cc1-c1cccc(Cl)c1Cl
Yield: 50 %

Procedure:
With stirring, 20 g of 1,1-di(methylcarbonyl)-2-(2,3-dichlorophenyl)ethene are added at 0° C. to 65 g of a 23.2% by weight solution of (p-tolylsulfonyl)methyl isocyanide prepared according to Example P1 (a). Then 28.1 g of a 30 % solution of sodium methylate in methanol are added dropwise over 3 hours. The mixture is stirred for 60 minutes at a temperature of +10° C. and then 170 ml of water are added dropwise and the product is subsequently isolated by filtration. The filter residue is recrystallised from a 1:1 mixture of methanol/ethanol and dried under vacuum, affording 8.3 g (50% of theory) of 4-methylcarbonyl-3-(2,3-dichlorophenyl)pyrrole which melts at 192°-194° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5](/[C:9](/[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[N:10]\[NH:11]C(OC(C)(C)C)=O)=[C:4](F)[CH:3]=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:9]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[N:10][NH:11]2)=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N/N=C(/c1ccncc1)c1cc(F)c(Br)cc1F
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Fc1cc2c(-c3ccncc3)n[nH]c2cc1Br
Yield: 84.7 %

Procedure:
A solution of 1,1-dimethylethyl (2Z)-2-[(4-bromo-2,5-difluorophenyl)(4-pyridinyl)methylidene]hydrazinecarboxylate (Intermediate 3, 250 mg) and DBU (95 μ) in THF (3 ml) was stirred at 150° C. in a microwave oven. After 30 min the mixture was partitioned between water and ethyl acetate and the organic layer was washed with water and brine, dried using a hydrophobic filter tube and concentrated under vacuum to give the title compound as an orange solid (150 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[NH2:45][C:46]([CH3:50])([CH3:49])[CH2:47][OH:48].[Cl-].[Na+]>C1COCC1>[OH:48][CH2:47][C:46]([NH:45][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:16]=1)=[O:23])([CH3:50])[CH3:49]
Reactant: CC(C)(N)CO
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)O)n(C)n1
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)NC(C)(C)CO)n(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
To a solution of 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (100 mg, 0.3 mmol) in THF (2.7 mL) was added 1-hydroxybenzotriazole hydrate (47.2 mg, 0.3 mmol), N-ethyldiisopropylamine (131.9 μL, 0.76 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidazole hydrochloride (59.1 mg, 0.3 mmol) and 2-amino-2-methyl-1-propanol (27.8 mg, 0.3 mmol) and the resulting mixture stirred overnight at room temperature. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and saturated sodium hydrogen carbonate solution and then dried over sodium sulfate, filtered and evaporated. Concentration and purification by chromatography (silica, dichloromethane:methanol=99:1 to 95:5) afforded the title compound (115 mg, 94%) as a white solid. MS: m/e=403.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([F:21])[CH:10]=2)[CH3:8])[N:6]=1.[C:22]1([N:28]=[C:29]=[S:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O.C(=O)([O-])O.[Na+]>[C:22]1([NH:28][C:29]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)=[C:11]([F:21])[CH:10]=3)[CH3:8])[N:6]=2)=[S:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1csc(N)n1
Reactant: S=C=Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1csc(NC(=S)Nc2ccccc2)n1
Yield: 15.8 %

Procedure:
To 2-amino-4-(1-(2-fluoro-4-biphenylyl)ethyl) thiazole (0.50 g, 1.68 mmol) in acetone (10 ml) were added phenylisothiocyanate (0.25 g, 1.85 mmol) in acetone (5 ml) and sodium hydrogen carbonate (0.30 g). After the mixture was refluxed to 10 h, phenyisothiocyanate (0.50 g, 3.70 mmol) was added to the mixture, and then the mixture was refluxed for 2 h. The mixture was evaporated under reduced pressure to a residue, which was chromatographed and recrystallized to afford N-phenyl-N'-(4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazol-2-yl)thiourea (0.115 g, 16% yield) as crystalline material: mp 176°-177.0° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][C:6]([CH3:11])([CH3:10])[C:7](O)=[O:8].[Cl:15]SCl.N#N>>[F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][C:6]([CH3:11])([CH3:10])[C:7]([Cl:15])=[O:8]
Reactant: CC(C)(Oc1cccc(F)c1)C(=O)O
Reactant: ClSCl
Agent: N#N
Product: CC(C)(Oc1cccc(F)c1)C(=O)Cl
Temperature: 25 °C

Procedure:
To 2-(3-fluorophenoxy)-2-methylpropanoic acid (1.70 g, 8.58 mmol) was added dichlorosulfane (15 mL) dropwise under N2 and the mixture was refluxed for 3 h. The mixture was cooled to rt and concentrated in vacuo to give the title compound as yellow oil, which was used for next step without further purification.
Reaction SMILES: [C:1](#[N:4])[CH2:2][OH:3].[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1.COCCOC.[OH-].[Na+]>O>[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([S:11]([O:3][CH2:2][C:1]#[N:4])(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#CCO
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC#N)cc1
Reaction time: 6.5 h

Procedure:
Method of preparation: 8.1 g (0.1 mole of glycolonitrile (70% aqueous solution) is added to a cooled (15° -20° C.) mixture of 9.5 g (0.05 mole) of p-toluenesulfonyl chloride in 20 ml. of 1,2-dimethoxyethane and 50 ml. distilled water. A solution of 2.1 g (0.05 mole) of NaOH in 50 ml. distilled water is added slowly with stirring at 20°-25° C. over a period of 6.5 hours, maintaining the pH of the reaction mixture at about 8. The insoluble material is filtered off, washed with cold water, and dried at 40° C. under vacuum to yield 6.8 g (64% conversion) of the product, a light brown solid, m.p. 48°-50.5° C.