Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[N+:10]([O-])=O>C(O)C.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[NH2:10]
Reactant: Cc1cc(C)c([N+](=O)[O-])cc1C
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C)c(N)cc1C
Yield: 97.2 %

Procedure:
19.70 g of 2,4,5-trimethylnitrobenzene are dissolved in 500 ml of ethanol and the solution is then hydrogenated at room temperature and pressure in the presence of 1 g of 5% Pd/C. The catalyst is filtered off on Celite® and the medium is then evaporated to give 15.67 g of the expected compound.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=1)(C)C.CO.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:6]([C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc(N)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1ccc(N)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
To a solution of 5-trimethylsilanylethynyl-pyridin-2-ylamine (26 mg, 137 μmol) described in Manufacturing Example 28-1-2 in tetrahydrofuran (1 mL) and methanol (1 mL) was added potassium carbonate (37.9 mg, 274 μmol) at room temperature, which was stirred for 1 hour at room temperature. The reaction solution was partitioned into water and ethyl acetate at 0° C. The organic layer was washed with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (16 mg, 99%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12].[OH-].[Na+].Cl[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:23])([CH3:22])[CH3:21]>CN(C)C=O>[OH:23][C:20]([CH3:22])([CH3:21])[CH2:19][CH2:18][CH2:17][CH2:16][N:7]1[C:6]2[C:5](=[O:11])[NH:4][C:3](=[O:12])[N:2]([CH3:1])[C:10]=2[N:9]=[CH:8]1
Reactant: CC(C)(O)CCCCCl
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c(=O)c2c1ncn2CCCCC(C)(C)O
Temperature: 110 °C

Procedure:
83 g (0.5 mol) of 3-methylxanthine are dissolved in 500 ml of 1N sodium hydroxide solution (0.5 mol) under the influence of heat. The mixture is filtered, the water is distilled off under reduced pressure and the sodium salt which remains is dried under a high vacuum. After addition of 1.5 liters of dimethylformamide and 75.3 g (0.5 mol) of 1-chloro-5-hydroxy-5-methylhexane, the mixture is heated at 110° C. for 6 hours, while stirring, filtered hot and evaporated under reduced pressure, the residue obtained is taken up in 1 liter of hot 1N sodium hydroxide solution, the hot solution is filtered and, after cooling to room temperature, 6N hydrochloric acid is added dropwise, with stirring, until a pH of 9 is reached. The precipitate is filtered off with suction, washed neutral and dried in vacuo.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[Br:12][CH2:13][CH2:14][CH:15](Br)[CH3:16].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: CC(Br)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)Nc1ccc(OCCCCBr)cc1

Procedure:
A solution of N-(4-hydroxyphenyl)acetamide (Paracetamol) (1) (1.50 g) and 1,3-dibromobutane (15) (10.0 ml) in acetonitrile (25.0 ml) containing potassium carbonate (5.0 g) was refluxed for 8 hrs. at room temperature. The reaction mixture was filtered and the filtrate was poured into ice cold water. The residue was filtered and washed with 5% NaOH solution (3×100 ml), water (3×50 ml), dried, filtered and crystallized from methanol to get the desired product N-[4-(4-bromobutoxy)phenyl]acetamide (17) (2.15 g, 77.06), mp 119-124° C.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[C:19]([CH:21]1[NH:26][CH2:25][CH2:24][NH:23][CH2:22]1)#[CH:20]>N1C=CC=CC=1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([N:23]3[CH2:24][CH2:25][NH:26][CH:21]([C:19]#[CH:20])[CH2:22]3)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: C#CC1CNCCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Solvent: c1ccncc1
Product: C#CC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3CC)CCN1
Temperature: 100 °C
Yield: 13.2 %

Procedure:
A mixture of 1.12 g of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.95 g of 3-ethynylpiperazine and 15 ml of pyridine is heated at 100° C. in a pressure bottle for 3 hours, then cooled and evaporated. The residue is purified by silica gel flash chromatography, eluting with chloroform:methanol:water:triethylamine (9:0.5:0.02:0.02), giving 200 mg of the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([O:19][CH2:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:25][CH2:24]1)=O)[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC(C)C)(C)C>O1CCCC1>[CH2:29]([CH:26]1[CH2:25][CH2:24][N:23]([CH2:21][CH2:20][O:19][C:14]2[CH:13]=[CH:12][C:11]3[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:10]=3)[CH:15]=2)[CH2:28][CH2:27]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(COc1ccc2cc(OCc3ccccc3)ccc2c1)N1CCC(Cc2ccccc2)CC1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: c1ccc(COc2ccc3cc(OCCN4CCC(Cc5ccccc5)CC4)ccc3c2)cc1
Yield: 99.9 %

Procedure:
To 2-(6-benzyloxy-naphthalen-2-yloxy)-1-(4-benzyl-piperidin-1-yl)-ethanone (0.71 g, 1.53 mmol) in anhydrous tetrahydofuran (25 ml) was added BH3 ·SMe2 (0.62 ml, 6.20 mmol) and diisopropyl amine (0.214 ml, 1.53 mmol), and the solution was refluxed for 18 h under N2. The reaction was cooled in an ice bath and quenched with dropwise addition of methanol (15 ml). The solvent was evaporated, the solid washed with hexanes and evaporated. The solid was washed with hexanes, filtered, and air dried to give 0.69 g (100%) of 4-benzyl-1-[2-(6-benzyloxy-naphthalen-2-yloxy)-ethyl]-piperidine. 1H NMR (CDCl3) 7.64-7.56 (2H, m), 7.45 (2H, d, J=7.3), 7.39-7.003 (12H, m), 5.12 (2H, d, J=3.6), 4.55 (1H, t, J=5.4), 4.51 (1H, t, J=5.4), 3.62 (1H, t, J=5.4), 3.18-3.14 (3H, m), 2.92 (1H, m), 2.60-2.54 (3H, m), 2.15-2.0 (1H, m), 1.66-1.51 (4H, m).
Reaction SMILES: [N:1]1C=CC=CC=1C(C)C=O.[CH:11]1([C:17](=[O:29])[C:18]([CH3:28])([C:22]2C=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:19][CH:20]=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([C:17](=[O:29])[C:18]([CH3:28])([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:1]=2)[CH2:19][CH:20]=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(CC=O)(C(=O)C1CCCCC1)c1ccccc1
Reactant: CC(C=O)c1ccccn1
Product: CC(CC=O)(C(=O)C1CCCCC1)c1ccccn1

Procedure:
Scheme VI, steps A-D: 4-Cyclohexyl-3-methyl-4-oxo-3-(2-pyridyl)butyraldehyde is prepared from 2-(2-pyridyl)-propanaldehyde in a manner analogous to the procedure described in example 7 for the preparation of 4-cyclohexyl-3-methyl-4-oxo-3-phenylbutyraldehyde.
Reaction SMILES: O1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7].[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Al+3].[Cl-].[Cl-].[Cl-]>CCOCC>[CH3:9][O:8][C:6]([C:2]1[C:15]2[C:14](=[CH:13][CH:12]=[C:11]([Cl:10])[CH:16]=2)[CH:5]=[CH:4][CH:3]=1)=[O:7]
Reactant: Clc1ccccc1
Reactant: COC(=O)c1ccco1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: COC(=O)c1cccc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 50 ml of methyl 2-furoate and 400 ml of chlorobenzene is stirred at 0° for 30 minutes, at RT for 1.5 hours and at 100° for 16 hours. 121 g of anhydrous AlCl3 are added by portion at 0°. The solution obtained is cooled, poured in an ice-bath and stirred for 30 minutes before extraction of the aq. phase with ether. The organic phase obtained is washed with aq. 10% NaHCO3 solution and brine, dried and solvent is evaporated. The residue obtained is purified by flash chromatography on silica gel (eluent: cyclohexane/EtOAc 99/1 to 95/5) to obtain the title compound.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:16]=[CH:15][C:8]([O:9][CH:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH2:17](O)[CH2:18][OH:19]>O>[OH:19][CH2:18][CH2:17][O:12][C:11](=[O:13])[CH:10]([O:9][C:8]1[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:16][CH:15]=1)[CH3:14]
Reactant: OCCO
Reactant: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: Cl
Solvent: O
Product: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)OCCO
Yield: 56.8 %

Procedure:
Dry HCl gas was passed through a mixture of 2-(4-nitrophenoxy)-propionic acid 29 (45 g, 213 mol) and ethylene glycol (135 ml) for 1½ hours. During HCl gas bubbling the temperature rose to 60° C. The crude reaction mass was poured onto cold water (600 ml). Crude 30 was extracted into chloroform, dried over Na2SO4, distilled and purified by column chromatography on silica gel using hexane as eluant to give pure 30 (28 g, 56.8%) as a syrup.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH:10]([CH2:21][OH:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[CH:10]([CH2:21][OH:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC1CN(Cc2ccccc2)CC=C1c1ccc(F)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: OCC1CN(Cc2ccccc2)CCC1c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 22.3 %

Procedure:
58 ml (203 mmol) of sodium dihydrido-bis-(2-methoxy-ethoxy)aluminate (70% in toluene) were added dropwise under argon at room temperature while stirring to a solution of 17.4 g (58.5 mmol) of (RS)-[1-benzyl-4-(4-fluoro-phenyl)-1,2,3,6-tetrahydro-pyridin-3-yl]-methanol in 580 ml of absolute toluene. Subsequently, the mixture was stirred at 80° C. for 4 hours. 100 ml of water were added dropwise to the reaction mixture at room temperature, with working-up thereafter being carried out by extraction with water and ethyl acetate. The crude product was chromatographed on silica gel with hexane and ethyl acetate as the eluent. There were obtained 3.90 g (44% of theory) of (3RS,4SR)-[1-benzyl-4-(4-fluoro-phenyl)-piperidin-3-yl]-methanol; MS: 300 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][CH2:4][C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:6].Cl.[O-:15][C:16]#[N:17].[K+]>O>[F:1][CH:2]([F:13])[O:3][CH2:4][C@@H:5]([NH:6][C:16]([NH2:17])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N#C[O-]
Reactant: N[C@H](COC(F)F)c1ccccc1
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)N[C@H](COC(F)F)c1ccccc1
Temperature: 80 °C

Procedure:
To a solution of (S)-2-(difluoromethoxy)-1-phenylethanamine (169 mg, 0.903 mmol) in water (6 ml), was added HCl (3.6 ml, 3.61 mmol) 1N and potassium cyanate (366 mg, 4.51 mmol). The reaction was heated at 80° C. for 2 hrs, then allowed to cool to ambient temperature overnight. The precipitate formed was filtered, washed with water, and dried under high vacuum to provide (S)-1-(2-(difluoromethoxy)-1-phenylethyl)urea MS: [M+H]+ m/z 231. 1H NMR (500 MHz, DMSO-d6) δ 7.42-7.30 (m, 4H), 7.29-7.17 (m, 1H), 6.84-6.45 (m, 2H), 5.61 (s, 2H), 4.97-4.83 (m, 1H), 4.08-3.89 (m, 2H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[CH3:28][SiH:29]([CH3:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1.Cl>C(OCC)C>[CH3:28][Si:29]([CH3:36])([CH:20]=[CH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1
Reactant: C[SiH](C)c1ccccn1
Reactant: C#CCCCCCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CCCCCCC=C[Si](C)(C)c1ccccn1
Temperature: 40 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To 1.0 ml of diethyl ether were added 10 mg (0.25 μmol) of bis(cyclooctadiene)platinum, 13 mg (0.50 μmol) of triphenylphosphine and 165 mg (1.5 mmol) of 1-octyne, and 69 mg (0.5 mmol) of dimethyl(2-pyridyl)silane was added dropwise thereto at room temperature over 1 hour. Further, the mixture was continued to be stirred for 6 hours at an inner temperature of 40° C., followed by the addition of 6 ml of 1N hydrochloric acid and 5 ml of diethyl ether. After the mixture was stirred for 30 minutes, it was left stand and separated into the organic and aqueous layers. The organic layer was extracted with five portions of 6 ml of 1N hydrochloric acid, and the resulting aqueous layers were combined together and turned basic with the addition of sodium hydroxide pellets. This aqueous layer was extracted with three portions of 10 ml of diethyl ether. The resulting organic layer was dried over magnesium sulfate and the solvent was evaporated off under reduced pressure to give 112 mg of dimethyl(1-octenyl)(2-pyridyl)silane. Yield: 90%
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[C:10]1([N:16]=[C:17]=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[OH:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[NH:1][C:17]([NH:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:18]
Reactant: Nc1ccc(F)cc1O
Reactant: O=C=Nc1ccccc1
Product: O=C(Nc1ccccc1)Nc1ccc(F)cc1O
Yield: 91 %

Procedure:
N-(2-Hydroxy-4-fluorophenyl)-N'-phenyl urea was prepared from 2-amino-5-fluoro phenol (200 mg, 1.57 mmol) and phenyl isocyanate according to the procedure in General Method A The product was purified by precipitation from toluene and filtering to afford the titled compound (352 mg, 91%). mp: 195.5°-195.7° C.; 1H NMR (CD3OD/CDCl3): δ7.70 (m, 1H), 7.3 (d, 2H, J=8.25 Hz), 7.15 (t, 2H, J=8.25 Hz), 6.89 (t, 1H, J=8.25 Hz), 6.50-6.38 (m, 2H); EI-MS m/z 246 (M+H)+ ; Anal. (C13H11N2O2F) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[NH:10][C:11](=O)[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:4]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[C:9]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][N:6]=2)[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccnc(-c2cc3ccccc3c(=O)[nH]2)c1
Product: COc1ccnc(-c2cc3ccccc3c(Cl)n2)c1

Procedure:
The resulting 3-(4-methoxypyridin-2-yl)isoquinolin-1-one (0.85 g) was reacted with phosphorus oxychloride (10 ml) according to the method of Example 10-2, to give 1-chloro-3-(4-methoxypyridin-2-yl)isoquinoline. The resulting compound was reacted, as it was, with N-ethylpiperazine (2.5 ml) at 100° C. overnight. The reaction solution was evaporated, and to the resulting residue were added ethyl acetate and purified water. The resulting ethyl acetate layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 0.40 g of the free compound of the title compound as a pale yellow oil.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=O)=[CH:9][N:8]=1.[CH3:19][C:20]1[C:21]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:22][C:23]([CH3:27])=[C:24]([CH3:26])[CH:25]=1>>[O:18]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:8]=[CH:9][C:10]([C:11]([N:31]2[CH2:32][CH2:33][N:28]([C:21]3[C:20]([CH3:19])=[CH:25][C:24]([CH3:26])=[C:23]([CH3:27])[N:22]=3)[CH2:29][CH2:30]2)=[O:13])=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1ccc(N2CCCS2(=O)=O)nc1
Reactant: Cc1cc(C)c(N2CCNCC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)nc3)CC2)nc1C
Yield: 41.5 %

Procedure:
Using ethyl 6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)nicotinate (135 mg) described in Preparation Example 25 and 1-(3,5,6-trimethylpyridin-2-yl)piperazine (103 mg) described in Preparation Example 92 and by the reaction and treatment in the same manner as in Example 109, the title compound (89 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=2)=[CH:4][C:3]=1[Cl:18].[CH3:19][N:20]1[C:24]([CH3:25])=[C:23]([C:26](O)=[O:27])[C:22](=[O:29])[N:21]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl.O>[Cl:18][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:2]=1[NH:1][C:26]([C:23]1[C:22](=[O:29])[N:21]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:20]([CH3:19])[C:24]=1[CH3:25])=[O:27])[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=1
Reactant: NC(=O)c1cc(Oc2ccc(N)c(Cl)c2)ccn1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: O
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)cc2Cl)c(=O)n(-c2ccccc2)n1C
Temperature: 46 °C
Reaction time: 6 h
Yield: 46.5 %

Procedure:
To a suspension of 4-(4-amino-3-chlorophenoxy)picolinamide (191 mg, 0.72 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (168 mg, 0.72 mmol) in DCM (10 mL) was added EDCI (166 mg, 0.86 mmol) and HOAT (20 mg, 0.14 mmol). The reaction was stirred at 46° C. for 6 hours, followed by the addition of 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (32 mg, 0.14 mmol) and EDCI (27 mg, 0.14 mmol). The mixture was further stirred at 46° C. for 13 hours, then cooled to rt and diluted with water (10 mL). The resulted mixture was extracted with ethyl acetate (10 mL×3), and the combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v)=50/1) to give the title compound as a pale yellow solid (160 mg, 46.5%).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1.Cl.[NH:18]1[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]1>CN(C=O)C>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:18]2[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]2)=[CH:11][CH:10]=1
Reactant: O=S1(=O)CCNCC1
Reactant: BrCc1ccc(Br)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=S1(=O)CCN(Cc2ccc(Br)cc2)CC1
Reaction time: 3 h

Procedure:
2.18 ml (15.5 mmol) of triethylamine are added to a colorless suspension of 1.28 g (5 mmol) of 4-bromobenzyl bromide and 944 mg (5.5 mmol) thiomorpholine-1,1-dioxide hydrochloride in 15 ml DMF. After 3 h at RT, the reaction mixture is partitioned between CH2Cl2 and H2O. The aqueous phase is re-extracted four times with CH2Cl2. The combined organic extracts are washed with water, saturated brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo to afford, after drying in HV, the title compound which is used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:21])[CH2:9]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:5]=[CH:6][CH:7]=1.[N-:22]=[N+:23]=[N-:24].[Na+].CS(C)=O>O>[N:22]([CH2:9][C@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[OH:21])=[N+:23]=[N-:24]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](O)c2cccc(Cl)c2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NC[C@@H](O)c1cccc(Cl)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of toluene-4-sulfonic acid (S)-2-(3-chlorophenyl)-2-hydroxyethyl ester (16.34 g, 0.050 mol), sodium azide (6.50 g, 0.10 mol) and DMSO (50 mL) was stirred for 2 h at 80° C. Water (100 mL) was added, extracted with hexane-ether (1:1) mixture (2×150 mL). Combined extract was dried over Na2SO4, evaporated. The residue was separated on SiO2 (100 g), hexane-EtOAc, 0 to 20%. Colorless oil, 7.0 g, (0.035 mol, 71%).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([C:12](=O)[CH:13]([CH:21]([C:25]2[CH:42]=[CH:41][C:28]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36]C(C)(C)C)=[O:35])=[O:30])=[CH:27][CH:26]=2)[CH2:22][CH2:23][CH3:24])[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:45]1([NH:51][NH2:52])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>N1C=CC=CC=1.CCOC(C)=O>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([CH:13]([C:12]2[N:51]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:52]=[C:3]3[C:4]=2[CH:5]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:7]=[C:2]3[Cl:1])[CH:21]([C:25]2[CH:42]=[CH:41][C:28]([C:29]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])=[CH:27][CH:26]=2)[CH2:22][CH2:23][CH3:24])=[CH:19][CH:18]=1
Reactant: CCCC(c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)C(C(=O)c1cc(C(F)(F)F)cc(Cl)c1F)c1ccc(Cl)cc1
Reactant: NNc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCC(c1ccc(C(=O)NCCC(=O)O)cc1)C(c1ccc(Cl)cc1)c1c2cc(C(F)(F)F)cc(Cl)c2nn1-c1ccccc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of the major diastereomer of tert-butyl N-(4-{1-[2-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-1-(4-chlorophenyl)-2-oxoethyl]butyl}benzoyl)-β-alaninate (EXAMPLE 2, Step A, 100 mg, 0.153 mmol) in pyridine (1.5 mL) was added phenylhydrazine (0.083 mL, 0.076 mmol). The mixture was stirred at 80° C. for 18 hours in a sealed tube. The mixture was diluted with EtOAc then washed with 2 N HCl (aq) then saturated NaCl (aq). The organic layer was dried over sodium sulfate, filtered, then concentrated. The resulting residue was purified by silica gel chromatography eluting with 0-50% EtOAc/hexanes to afford the title compound. This diastereomer was resolved to provide enantiopure material by HPLC on a ChiralPak IA column (2 cm×25 cm) eluting with 9 mL/min of 5% EtOH/n-heptane. LC1 2.98 min. (M-tBu+H)+ 668.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[F:4][C:5]([F:16])([F:15])[C:6](=O)[CH:7]([CH3:13])[C:8](OCC)=[O:9].Cl>C(O)C>[CH3:1][N:2]1[C:8]([OH:9])=[C:7]([CH3:13])[C:6]([C:5]([F:16])([F:15])[F:4])=[N:3]1
Reactant: CCOC(=O)C(C)C(=O)C(F)(F)F
Reactant: CNN
Agent: Cl
Solvent: CCO
Product: Cc1c(C(F)(F)F)nn(C)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
To a solution of 20.9 g (454.2 mmol) of methylhydrazine in 500 ml of ethanol was added dropwise under stirring 90.0 g (454.2 mmol) of ethyl 4,4,4-trifluoro-2-methyl-3-oxobutanoate under ice-cooling so that the temperature did not exceed 10° C. After the completion of the dropwise addition, the whole was stirred at room temperature for 30 minutes. Then, 10 ml of concentrated hydrochloric acid was added into the reaction solution, followed by 2 days of stirring under refluxing. After the completion of the reaction was confirmed, the solvent was removed by evaporation under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and saline, successively, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was washed with n-hexane to obtain 61.0 g (yield: 74.6%) of 1,4-dimethyl-5-hydroxy-3-trifluoromethyl-1H-pyrazole as white crystals (melting point: 148 to 151° C.).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][C:16]=1[C:22]([F:25])([F:24])[F:23]>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:7]([NH:6][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:12][CH:11]=[CH:10][C:9]=2[F:13])=[O:8])=[CH:17][C:16]=1[C:22]([F:23])([F:24])[F:25]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
A solution of 9.2 g (0.05 mole) of 2,6-difluorobenzoylisocyanate in 50 ml of toluene was added dropwise at 40° C to a solution of 9.8 g (0.05 mole) of 4-chloro-3-trifluoromethylaniline in 100 ml of toluene. The batch was stirred for 1 hour at 40° C. The substance which separated out was filtered off after cooling the reaction mixture to 20° C, and washed with toluene and petroleum ether. After drying, 18.0 g (95% of theory) of N-(4-chloro-3-trifluoromethylphenyl)-N'-(2,6-difluorobenzoyl)-urea of melting point 220° C were obtained.