Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.CC#N.N1C=CC=CC=1.[C:19]1([O:25][C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH3:9][O:8][C:5]1[N:4]=[N:3][C:2]([NH:1][C:26](=[O:27])[O:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:7][CH:6]=1
Reactant: COc1ccc(N)nn1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ccc(NC(=O)Oc2ccccc2)nn1
Reaction time: 3 h
Yield: 81.6 %

Procedure:
A solution of 3-amino-6-methoxypyridazine (1.25 g, 10.0 mmol) in a mix of 1:1 THF:MeCN (20 mL), and pyridine (0.83 g, 1.5 mmol) was treated dropwise with phenylchloroformate (1.65 g, 10.5 mmol) in THF (10 mL). After stirring for 3 h, the resulting solid was collected and dried to provide the title compound (2 g, 81%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[F:12][C:13]1[CH:29]=[CH:28][C:16]2[NH:17][C:18]([S:20][C:21]3[O:25][C:24]([CH:26]=O)=[CH:23][CH:22]=3)=[N:19][C:15]=2[CH:14]=1.[C:30]1(=O)[CH2:35][CH2:34][CH2:33][C:32](=[O:36])[CH2:31]1>C(O)CCC>[CH2:10]([O:9][C:7]([C:3]1[NH:4][CH:5]=[C:6]2[CH:26]([C:24]3[O:25][C:21]([S:20][C:18]4[NH:17][C:16]5[CH:28]=[CH:29][C:13]([F:12])=[CH:14][C:15]=5[N:19]=4)=[CH:22][CH:23]=3)[C:31]3[C:32](=[O:36])[CH2:33][CH2:34][CH2:35][C:30]=3[NH:1][C:2]=12)=[O:8])[CH3:11]
Reactant: O=C1CCCC(=O)C1
Reactant: O=Cc1ccc(Sc2nc3cc(F)ccc3[nH]2)o1
Reactant: CCOC(=O)c1[nH]ccc1N
Solvent: CCCCO
Product: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CCC1)C2c1ccc(Sc2nc3cc(F)ccc3[nH]2)o1
Temperature: 25 °C
Yield: 50.4 %

Procedure:
A mixture of 3-amino-2-ethoxycarbonyl-pyrrole (0.235 g, 1.52 mmol), 5-(5-fluoro-1H-benzoimidazol-2-ylsulfanyl)-furan-2-carbaldehyde (0.40 g, 1.52 mmol) and 1,3-cyclohexanedione (0.171 g, 1.52 mmol) in 5 ml of 1-butanol is heated at reflux temperature for 2 hours. The reaction mixture is then concentrated under reduced pressure. The residue is resuspended in 5 ml of acetonitrile and the mixture is heated at reflux temperature for 30 minutes. The mixture is allowed to cool to room temperature and the insoluble material is collected by filtration, washed with diisopropylether (20 ml), pentane (20 ml) and dried under vacuum to yield 377 mg of 9-[5-(5-fluoro-1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylic acid ethyl ester as a white powder. Yield=50%. Analytical LC/MS (method B): m/z=491 (negative ion mode, [M−H]−), m/z=493 (positive ion mode [M+H]+).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C(O)C>[CH3:8][C:6]1[N:7]=[C:2]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1nc(Br)ccc1[N+](=O)[O-]
Reactant: C1COCCN1
Solvent: CCO
Product: Cc1nc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 5 h
Yield: 69.7 %

Procedure:
To a solution of 6-bromo-2-methyl-3-nitropyridine (2.05 g, 9.45 mmol) in ethanol (10 mL) was added morpholine (1.728 mL, 19.84 mmol) and the reaction mixture was stirred at 70° C. for 5 hours. The reaction mixture was allowed to cool to room temperature causing a precipitate. The solid was collected by filtration and washed with ethanol (5 mL), then dried in vacuo. The crude was redissolved in a mixture of saturated sodium carbonate solution and ethyl acetate. The organic phase was separated, washed with further saturated sodium carbonate solution, then dried over magnesium sulphate and evaporated in vacuo to give the title compound (1.47 g) as a yellow solid. LCMS (2 min, formic) Rt 0.92 min, m/z (ES+) 224 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:12]=O)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[O:20]1[CH2:23][CH:22]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:27]3[CH2:28][CH2:29][CH:24]([CH:22]4[CH2:23][O:20][CH2:21]4)[CH2:25][CH2:26]3)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1
Reactant: Cn1c(C=O)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: C1CC(C2COC2)CCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(CN2CCC(C3COC3)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reaction time: 18 h
Yield: 56.8 %

Procedure:
A solution of 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (1.0 g, 3.55 mmol), 4-oxetan-3-ylpiperidine (600 mg, 4.25 mmol) and molecular sieves (4 Å, powdered, 5 g) in anhydrous THF (25 mL) was stirred at ambient temperature for 5 h. Sodium triacetoxyborohydride (1.5 g, 7.08 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; 100:0 to 99:1 to 98:2 to 95:5 to 90:10) to afford the title compound as a white foam (0.82 g, 57%). LCMS (Method H): RT=2.38 min, M+H+=408.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:8][C:7]=1[CH3:31])=[O:5])C.[OH-].[Na+].C(OCC)(=O)C>C(O)C.O>[CH3:31][C:7]1[N:8]=[C:9]([NH:11][C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[S:10][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1sc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1nc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)sc1C(=O)O
Temperature: 50 °C
Yield: 11.9 %

Procedure:
A mixture of 4-methyl-2-(trityl-amino)-thiazole-5-carboxylic acid ethyl ester (500 mg, 1.17 mmol) in ethanol (10 mL) at 25° C. was treated with a 1N aqueous sodium hydroxide solution (3.51 mL, 3.51 mmol). The resulting mixture was heated to 50° C. for 18 h. At this time, the reaction was treated with an additional amount of a 1N aqueous sodium hydroxide solution (3.6 mL, 3.6 mmol). This mixture was heated at 50° C. for an additional 8 days. At this time, the reaction was diluted with water (100 mL), acidified to pH=5, and treated with ethyl acetate. The resulting white solid was collected by filtration and dried in vacuo. The filtrate was extracted with ethyl acetate. The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 4-methyl-2-(trityl-amino)-thiazole-5-carboxylic acid (55.7 mg, 11.9%) as a white solid: 1H NMR (DMSO-d6, 300 MHz) δ9.09 (broad s, 1H), 7.22 (m, 15 H), 2.22 (s, 3H).
Reaction SMILES: [H-].[Na+].[C:3]([N:6]1[CH2:11][CH2:10][C:9]([OH:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])[CH3:4].F[C:20]1[CH:21]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:24][CH:25]=1>CN(C)C=O>[C:3]([N:6]1[CH2:11][CH2:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([O:18][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[CH2:8][CH2:7]1)(=[O:5])[CH3:4]
Reactant: Fc1cccc(C(F)(F)F)c1
Reactant: CC(=O)N1CCC(O)(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)(c2ccccc2)CC1
Temperature: 70 °C
Reaction time: 20 h
Yield: 20.9 %

Procedure:
A stirred suspension of sodium hydride (60% in oil, 1.8 g) in 35 ml of dimethylformamide was treated with a solution of 9.00 g of 1-acetyl-4-hydroxy-4-phenylpiperidine in 100 ml of dimethylformamide and heated at 70° C. until evolution of gas had ceased. A solution of 7.38 g of 3-fluorobenzotrifluoride in 20 ml of dimethylformamide was added, dropwise, and the reaction allowed to proceed at 70° C. for 20 hours. The reaction mixture was then poured into an ice/water mixture and the aqueous suspension extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. High pressure liquid chromatography of the oil (silica gel; elution with 50% ethyl acetate/dichloromethane) afforded 3.11 g (20.90%) of 1-acetyl-4-phenyl-4-(3-trifluoromethylphenoxy)piperidine, m.p. 100°-103° C.
Reaction SMILES: C(O[C:4]([C:6]1[C:7](Cl)=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])C.[NH2:18][C:19]1[NH:23][N:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.CN(C)C=O>O>[CH2:15]([N:12]1[C:9]2[N:10]=[CH:11][C:6]3[C:4](=[O:5])[N:23]4[N:22]=[CH:21][CH:20]=[C:19]4[NH:18][C:7]=3[C:8]=2[CH:14]=[N:13]1)[CH3:16]
Reactant: Nc1ccn[nH]1
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCn1ncc2c3[nH]c4ccnn4c(=O)c3cnc21

Procedure:
126 g. of 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (0.5 mol.), 41.5 g. of 5-amino-pyrazole (0.5 mol.) and 50.6 g. of triethylamine (0.5 mol.) are heated at reflux temperature with stirring in 250 ml. of dimethylformamide for 16 hours. After cooling, about 300 ml. of water are added and the white precipitated product, 3-ethyl-3,11-dihydro-6H-pyrazolo[1,5-a]pyrazolo-[4',3':5,6]pyrido[4,3-d]pyrimidin-6-one is filtered off, yield 57.7 g (45.4%); m.p. >300° (DMF).
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]2[CH2:16][CH:15]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:14][N:13]=2)=[C:10]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>CO.O>[Cl:1][C:2]1[C:11]([C:12]2[CH2:16][CH:15]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:14][N:13]=2)=[C:10]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C2=NOC(Cc3ccccc3)C2)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1C1=NOC(Cc2ccccc2)C1
Reaction time: 16 h
Yield: 86.3 %

Procedure:
1.02 g (2.5 mmol) of methyl 2-chloro-3-(5-benzylisoxazolin-3-yl)-4-methylsulfonylbenzoate are dissolved in 20 ml of methanol and combined with 0.15 g (3.7 mmol) of sodium hydroxide—dissolved in 10 ml of water—at room temperature. After 16 hours, the methanol is removed by distillation, the residue is diluted with water and, after acidifying to pH 2, the mixture is extracted with dichloromethane. After concentrating in a rotary evaporator, 0.85 g (87% of theory) of 2-chloro-3-(5-benzylisoxazolin-3-yl)4-methylsulfonylbenzoic acid is obtained as a yellowish resin.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([C:13](=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].C(N(CC)CC)C.[C:30](Cl)(=[O:48])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47].O>C(Cl)Cl>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:22])[C:13](=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:30](=[O:48])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:15]=1)[CH3:12]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCOC(=O)CN(CC(=O)OCC)C(=O)c1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)Nc1cccc(C(=O)N(CC(=O)OCC)CC(=O)OCC)c1
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
To an ice bath cooled solution of 3.1 g (10.06 mmol) of N-(3-aminobenzoyl)-N-(2-ethoxy-2-oxoethyl)glycine ethyl ester and 2.6 ml (19 mmol) of triethylamine in 60 ml of methylene chloride was added dropwise 3.2 ml (9.6 mmol) of stearoyl chloride. The reaction mixture was stirred in the cold for 30 minutes and then at room temperature for 5 hours. The mixture was poured into water containing 1N HCl and the product was extracted with ethyl acetate. The dried extract was concentrated to a solid which was purified by chromatography on 70 g of silica gel using 35% ethyl acetate: 10% methylene chloride: 55% hexane and then recrystallization from ethyl acetate-hexane to give 4.5 g (78% yield, mp 76°-79°) of N-(2-ethoxy-2-oxoethyl)-N-[3-(1-oxooctadecylamino)benzoyl]glycine ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)(CC#C[Si](C)(C)C)[C:8]2=[O:12])=[CH:4][C:3]=1[O:27][CH2:28][C:29]([O:31]CC)=[O:30].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][CH:7]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[C:8]2=[O:12])=[CH:4][C:3]=1[O:27][CH2:28][C:29]([OH:31])=[O:30]
Reactant: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(CC#C[Si](C)(C)C)(c1ccc(F)cc1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1cc2c(c(Cl)c1Cl)C(=O)C(c1ccc(F)cc1)C2

Procedure:
- Desilylation and hydrolysis of ethyl [6,7-dichloro-1-oxo-2-(p-fluorophenyl)-2-(3-(trimethylsilyl)-2-propynyl)-5-indanyloxy]acetate with sodium hydroxide in ethanol according to the procedure of Example 1, STEP (c), affords the title compound, m.p. 189°-190°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:23]3[C:18]([CH2:19][CH2:20][CH2:21][CH2:22]3)=[C:17]([C:24](O)=[O:25])[CH:16]=2)=[C:11]([C:27]([N:29]2[C@H:38]([CH2:39][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30]2)=[O:28])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(N(C)C)=C(C)C.C1(C)C=CC=CC=1.[Si:61]([O:68][C:69]1[CH:74]=[CH:73][C:72]([NH:75][C:76]2[CH:77]=[C:78]3[CH:84]=[CH:83][N:82]([CH3:85])[C:79]3=[N:80][CH:81]=2)=[CH:71][CH:70]=1)([C:64]([CH3:67])([CH3:66])[CH3:65])([CH3:63])[CH3:62]>ClCCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:23]3[C:18]([CH2:19][CH2:20][CH2:21][CH2:22]3)=[C:17]([C:24]([N:75]([C:72]3[CH:71]=[CH:70][C:69]([O:68][Si:61]([C:64]([CH3:67])([CH3:65])[CH3:66])([CH3:63])[CH3:62])=[CH:74][CH:73]=3)[C:76]3[CH:77]=[C:78]4[CH:84]=[CH:83][N:82]([CH3:85])[C:79]4=[N:80][CH:81]=3)=[O:25])[CH:16]=2)=[C:11]([C:27]([N:29]2[C@H:38]([CH2:39][N:40]3[CH2:41][CH2:42][O:43][CH2:44][CH2:45]3)[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30]2)=[O:28])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ccc2cc(Nc3ccc(O[Si](C)(C)C(C)(C)C)cc3)cnc21
Reactant: O=C(O)c1cc(-c2ccc(OCc3ccccc3)cc2C(=O)N2Cc3ccccc3C[C@H]2CN2CCOCC2)n2c1CCCC2
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCCl
Solvent: Cc1ccccc1
Product: Cn1ccc2cc(N(C(=O)c3cc(-c4ccc(OCc5ccccc5)cc4C(=O)N4Cc5ccccc5C[C@H]4CN4CCOCC4)n4c3CCCC4)c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The acid obtained in Step B (9 g, 11.8 mmol) is dissolved in 90 mL of 1,2-dichloroethane. 1.9 mL of 1-chloro-N,N,2-trimethylpropenylamine (14 mmol) are added thereto. After stirring for 3 hours at ambient temperature, 90 mL of toluene and 4.62 g of N-[4-[tert-butyl(dimethyl)silyl]oxyphenyl]-1-methyl-1H-pyrrolo[2,3-b]pyridin-5-amine (Preparation 3″, 13 mmol) are added. The reaction mixture is heated at 110° C. for 20 hours. After returning to ambient temperature, the reaction mixture is washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue obtained is purified by chromatography over silica gel (dichloromethane/ethanol gradient) to yield the expected product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[N:30]([C:33]1[CH:42]=[CH:41][CH:40]=[CH:39][C:34]=1[C:35]([O:37][CH3:38])=[O:36])=[C:31]=[O:32]>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][C:31]([NH:30][C:33]3[CH:42]=[CH:41][CH:40]=[CH:39][C:34]=3[C:35]([O:37][CH3:38])=[O:36])=[O:32])[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccccc1N=C=O
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: COC(=O)c1ccccc1NC(=O)Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and methyl 2-isocyanatobenzoate according to the procedure of Example 65. MS (ES) m/z 567.9.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1.[C:17]([Cl:25])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[ClH:25].[C:17]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[N:9]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CCC(c2n[nH]c3ccccc23)CC1
Product: CN1CCC(c2nn(C(=O)c3ccccc3)c3ccccc23)CC1
Product: Cl
Yield: 62.2 %

Procedure:
A mixture of 3.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole and 3.2 ml of benzoyl chloride was heated at 100° for 2 hrs. The resultant solid was triturated with ether and collected. The salt was twice recrystallized from ethanol-ether to yield 3.1 g (62.2%) of product, mp 234°-236° C.
Reaction SMILES: [CH3:1][N:2](S(C)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[F:18][C:19]([F:36])([F:35])[O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:34]=C[C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.ClC1C=CC=CC=1.[CH:44]([Cl:47])(Cl)Cl>[Fe](Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:32]=[C:31]([C:30]2[CH:29]=[CH:28][C:27]([C:24]3[CH:23]=[CH:22][C:21]([O:20][C:19]([F:18])([F:35])[F:36])=[CH:26][CH:25]=3)=[CH:34][C:44]=2[Cl:47])[N:2]([CH3:1])[N:3]=1
Reactant: CN(N=C(Cl)c1c(F)cccc1Cl)S(C)(=O)=O
Reactant: N#Cc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Reactant: ClC(Cl)Cl
Agent: Cl[Fe](Cl)Cl
Solvent: Clc1ccccc1
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1Cl
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A mixture of N-methyl-N-(methanesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (1.50 g), 4-(4-trifluoromethoxyphenyl)benzonitrile (1.56 g), anhydrous iron (III) chloride (0.90 g) and chlorobenzene (20 ml) is stirred at an oil bath temperature of 140° C. for 1 hour. After cooling, the reaction mixture is dissolved in chloroform (300 ml), washed with dilute hydrochrolic acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 1.80 g of desired compound (refractive index: 1.5925).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[F:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=1.[F:31][C:32]([F:42])([F:41])[CH2:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:9]2[CH2:8][CH2:7][C:6]3([C:4](=[O:5])[N:38]([C:37]4[CH:39]=[CH:40][C:34]([CH2:33][C:32]([F:31])([F:41])[F:42])=[CH:35][CH:36]=4)[CH2:13][CH2:12]3)[CH2:11][CH2:10]2)(=[O:25])=[O:24])=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: Nc1ccc(CC(F)(F)F)cc1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1C(F)(F)F
Product: O=C1N(c2ccc(CC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1ccc(F)cc1C(F)(F)F)CC2

Procedure:
Off-white solid. MS (ESI): 539.12 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 4-fluoro-2-trifluoromethyl-benzenesulfonyl chloride and 4-(2,2,2-trifluoroethyl)-aniline.
Reaction SMILES: [Mg].[CH3:2][N:3]1[CH2:8][CH2:7][CH:6](Cl)[CH2:5][CH2:4]1.[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[C:13]#N.[Cl-].[NH4+].[O:21]1CCCC1>C(Br)C>[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[C:13]([CH:6]1[CH2:7][CH2:8][N:3]([CH3:2])[CH2:4][CH2:5]1)=[O:21]
Reactant: C1CCOC1
Reactant: CN1CCC(Cl)CC1
Reactant: N#Cc1ccccc1F
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCBr
Product: CN1CCC(C(=O)c2ccccc2F)CC1
Temperature: 0 °C
Yield: 91 %

Procedure:
To a suspension of 7.6 g of magnesium turnings in 25 ml of tetrahydrofuran was added a few drops of ethyl bromide, with stirring under nitrogen. After the reaction began, approximately 50.0 g of N-methyl-4-chloropiperidine in 125 ml of tetrahydrofuran was added dropwise at a rate such as to maintain moderate reflux. The reaction mixture was heated under reflux an additional hr, and 37.2 g of 2-fluorobenzonitrile in 50 ml of tetrahydrofuran was added dropwise. After completion of the addition, the reaction mixture was refluxed for two hrs, and stirred overnight at room temperature. The reaction mixture was poured into a solution of 85 g of ammonium chloride in 1200 ml of ice water and heated on a steam bath for 3 hrs. The mixture was cooled, extracted with benzene (3×250 ml), dried over anhydrous sodium sulfate, and the excess solvent was removed under reduced pressure to give 62.72 g (91%) of 4-(2-fluorobenzoyl)-1-methyl piperidine as an oil. A small amount of 4-(2-fluorobenzoyl)-1-methyl piperidine (1.0 g) was removed, dissolved in ether and a solution of ethereal hydrochloric acid was added. The precipitate was collected, dried and recrystallized from ethanol-ether (2×) to give 0.5 g of 4-(2-fluorobenzoyl)-1-methyl piperidine hydrochloride, mp, 167°-169°.
Reaction SMILES: CO[C:3]1[CH:4]([CH2:10][CH2:11][C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([O:16][CH3:17])=[O:15])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]=1.[Cl-:22].[NH4+:23]>CO>[ClH:22].[NH:23]=[C:3]1[CH:4]([CH2:10][CH2:11][C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([O:16][CH3:17])=[O:15])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9]1
Reactant: [Cl-]
Reactant: [NH4+]
Reactant: COC(=O)c1ccccc1CCC1CCCCN=C1OC
Solvent: CO
Product: COC(=O)c1ccccc1CCC1CCCCNC1=N
Product: Cl

Procedure:
The title product of Example 89 in MeOH is reacted with ammonium chloride by the method of Example 5 to generate the title material.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20](=O)[C:21](F)(F)F)[CH2:16][CH2:15]2)[CH:10]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH2:9]1)=[O:7].[CH:42]1(CBr)C[CH2:43]1>C(Cl)(Cl)Cl>[F:38][C:36]([F:39])([F:37])[C:34]1[CH:33]=[C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:15][CH2:16][N:17]([CH2:20][CH:21]4[CH2:43][CH2:42]4)[CH2:18][CH2:19]3)[CH:10]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)[CH2:9]2)=[O:7])[CH:4]=[C:3]([C:2]([F:41])([F:1])[F:40])[CH:35]=1
Reactant: BrCC1CC1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC(N2CCN(C(=O)C(F)(F)F)CC2)C(c2ccc(Cl)cc2)C1
Solvent: ClC(Cl)Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC(N2CCN(CC3CC3)CC2)C(c2ccc(Cl)cc2)C1

Procedure:
The title compound, MS: m/e=574.1 (M+H+), [α]58920=−18.46, [α]54620=−27.04, (c=0.3846, chloroform), was prepared in accordance with the general method of example 102 from (−)-1-{4-[1-(3,5-bis-trifluoromethyl-benzoyl)-3-(4-chloro-phenyl)-piperidin-4-yl]-piperazin-1-yl}-2,2,2-trifluoro-ethanone and cyclopropylmethylbromide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].Cl.[NH2:14][OH:15].C([O-])([O-])=O.[K+].[K+].Cl>C(O)C>[OH:15][NH:14][C:5](=[NH:6])[C:4]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:3]=1[O:2][CH3:1]
Reactant: NO
Reactant: COc1ccc(C#N)c(OC)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc(C(=N)NO)c(OC)c1
Temperature: 85 °C
Reaction time: 27 h
Yield: 34.4 %

Procedure:
A mixture of 2,4-dimethoxybenzonitrile (3.25 g, 20 mmol), hydroxylamine hydrochloride (2.92 g, 42 mmol) and K2CO3 (5.80 g, 42 mmol) in ethanol (80 mL) is stirred at 85° C. for 27 h before it is poured onto water (250 mL). The solution is acidified by adding 1 N aq. HCl (75 mL) and extracted once with DCM (100 mL). The aq. layer is basified with 1 N aq. NaOH (90 mL) and extracted three times with DCM (3×150 mL). The organic extracts are dried over MgSO4, the solvent is evaporated and the residue is dried under high vacuum to leave N-hydroxy-2,4-dimethoxy-benzamidine (1.35 g) as a beige solid. LC-MS: tR=0.68 min, [M+1]+=197.11.