Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[N:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][N:10]=1>N1C=CC=CC=1>[NH:2]([C:5]1[N:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][N:10]=1)[NH2:3]
Reactant: NN
Reactant: Clc1ncc(-c2ccccc2)nn1
Solvent: c1ccncc1
Solvent: O
Product: NNc1ncc(-c2ccccc2)nn1
Temperature: 0 °C
Yield: 92.9 %

Procedure:
Hydrazine hydrate (1.50 mL, 0.0308 mol) was added to suspension of 3-chloro-6-phenyl-1,2,4-triazine (2.20 g, 0.0115 mol) in pyridine (12.0 mL) at 0° C. and stirred at 0° C. until a precipitate formed. The mixture was then heated at 65° C. for 30 min. The solvent was evaporated under reduced pressure. The residue was triturated with water, filtered, and washed with water. The crystalline formed was collected and dried under high vacuum to give the desired product (2.0 g, 93%). Analytical LCMS: (M+H)+=188.1.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([O:30][CH3:31])[C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[N:15][CH:16]=3)[CH:9]=2)[N:4]([S:32]([C:35]2[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[CH:3]=1.[F:42][C:43]1[CH:44]=[C:45]([CH:61]=[CH:62][CH:63]=1)[CH2:46][N:47]1[CH:51]=[C:50](B2OC(C)(C)C(C)(C)O2)[CH:49]=[N:48]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:42][C:43]1[CH:44]=[C:45]([CH:61]=[CH:62][CH:63]=1)[CH2:46][N:47]1[CH:51]=[C:50]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([O:30][CH3:31])[C:14]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)=[N:15][CH:16]=4)[CH:9]=3)[N:4]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:3]=2)[CH:49]=[N:48]1
Reactant: COc1cc(-c2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC1(C)OB(c2cnn(Cc3cccc(F)c3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(-c2cnc3c(c2)c(-c2cnn(Cc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 69.9 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 4-(5-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-methoxypyridin-2-yl)piperazine-1-carboxylate (Intermediate 66S) (175 mg, 0.254 mmol) was coupled with 1-(3-fluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 11) (115 mg, 0.380 mmol) using sodium carbonate (81 mg, 0.764 mmol) and Pd(dppf)Cl2 (9.4 mg, 0.012 mmol) in toluene/ethanol/water (20/10/4 mL) to afford 131 mg (70% yield) of the titled compound after purification by column (Silica gel 60/120) using 37% ethyl acetate in hexane as eluent.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[CH2:16]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]1[CH3:27])[CH3:17].[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[CH2:16]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([C:11]([C:6]2[C:5]([Cl:13])=[C:4]([Cl:14])[C:3]([Cl:15])=[C:2]([Cl:1])[C:7]=2[C:8]([OH:10])=[O:9])=[O:12])=[C:19]1[CH3:27])[CH3:17]
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: CCn1c(C)cc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CCn1c(C)c(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To a stirred suspension of 9.66 g (0.017 mole) of tetrachlorophthalic anhydride and 13.5 g (0.034 mole) of 80 percent active 1-ethyl-2-methylindole in 30 ml of benzene maintained at 0°-5° C. by means of an ice bath, 10.6 g (0.079 mole) of aluminum chloride was added in small increments. The reaction mixture was then maintained at 0° to 5° C. for an additional twenty minutes, allowed to warm to room temperature and stirred overnight. The mixture was transferred to a beaker and triturated successively with hexane, 10 percent hydrochloric acid, and lastly with 5 percent aqueous sodium hydroxide which had been heated to 70° C. The residual oil was filtered, acidified with dilutes hydrochloric acid and allowed to stand overnight. On standing, the oil gave way to a solid which was collected by filtration, washed with water and dried to yield 6.8 g of 2-[(1-ethyl-2-methyl-3-indolyl)carbonyl]-3,4,5,6-tetrachlorobenzoic acid (Formula VIII: Ro =R1 =R2 =R3 =Cl; R5 =CH3 ; R6 =CH3CH2 ; Y1 =H), an off white solid melting at 214°-216° C. Analysis by mass spectrum showed m/e peaks at 443 (M+, Cl=35) and 398 (M+ --COOH).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[N:13][C:14]([C:16](O)=[O:17])=[CH:15][C:10]=3[N:9]=[CH:8]2)=[CH:4][CH:3]=1.Cl.[CH3:22][O:23][NH2:24]>>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[N:13][C:14]([C:16]([NH:24][O:23][CH3:22])=[O:17])=[CH:15][C:10]=3[N:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc2ncn(Cc3ccc(F)cc3)c2cn1
Reactant: CON
Agent: Cl
Product: CONC(=O)c1cc2ncn(Cc3ccc(F)cc3)c2cn1

Procedure:
The title compound was prepared by coupling of 3-(4-fluorobenzyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid and N-methoxyamine hydrochloride under the same conditions as those in step (c) of example 1. 1H NMR (300 MHz, MeOH-d4) δ: 8.71 (s, 1H), 8.53 (s, 1H), 8.32 (s, 1H), 7.36-7.33 (m, 2H), 7.07-7.05 (m, 2H), 5.57 (s, 2H), 3.75 (s, 3H). LCMS (API-ES, M+H+): 301.1. HRMS calcd for C15H14FN4O2 (M+H) 301.1 101, found 301.1105. HPLC: >84% purity.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([NH:6][C:7]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][OH:27])[CH:21]=3)[CH:17]=[CH:16][C:8]=2[C:9]([O:11]C(C)(C)C)=[O:10])=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][C:7]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][OH:27])[CH:21]=3)[CH:17]=[CH:16][C:8]=2[C:9]([OH:11])=[O:10])=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cccc(CO)c2)cc1Nc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-c2cccc(CO)c2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid 10 mL was added to the obtained tert-butyl 2-(4-fluoroanilino)-4-(3-(hydroxymethyl)phenyl)benzoate, and it was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 70-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 2-(4-fluoroanilino)-4-(3-(hydroxymethyl)phenyl)benzoic acid 7.7 mg of a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH2:6][NH:7][CH2:8][CH:9](OC)OC.CO/N=[CH:22]/[C:23]1[CH:31]=[CH:30][C:26]2[O:27][CH2:28][O:29][C:25]=2[C:24]=1[CH2:32][N:33]([CH3:35])[CH3:34].Cl.[NH4+].[OH-]>O>[CH3:18][O:17][C:16]1[CH:15]=[C:14]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[CH:6]=[N:7][C:8]1[C:31]3[CH:30]=[C:26]4[O:27][CH2:28][O:29][C:25]4=[C:24]([CH2:32][N:33]([CH3:34])[CH3:35])[C:23]=3[CH2:22][C:9]2=1
Reactant: COc1ccc(CNCC(OC)OC)cc1OC
Reactant: CO/N=C/c1ccc2c(c1CN(C)C)OCO2
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COc1cc2cnc3c(c2cc1OC)Cc1c-3cc2c(c1CN(C)C)OCO2
Temperature: 100 °C
Reaction time: 18 h
Yield: 8 %

Procedure:
The amine 8 (0.30 g, 1.18 mmol) and oxime ether 13a (0.126 g, 0.534 mmol) were mixed with concentrated hydrochloric acid (7 mL) and the mixture was stirred at 100° C. for 18 h. The reaction mixture was cooled and washed with ether (3×20 mL). It was then brought to basic pH with NH4OH. The mixture was extracted with chloroform (40 mL×3) and the solution was washed with brine (50 mL), dried (Na2SO4) and concentrated. The residue was diluted in chloroform (40 mL) and filtered. Hydrochloric acid (2 M HCl in ether, 5 mL) was added to the filtrate. The precipitate that formed was recrystallized from methanol to provide a yellow solid. The solid was dissolved in water, basified with NH4OH and extracted with chloroform. The organic layer was concentrated to dryness. The residue was purified by preparative flash chromatography (SiO2, methanol-chloroform-TEA=3:97:2) to afford the final product 14a as a light yellow solid (0.0162 g, 7.8%): mp 205-207° C. IR (KBr) 2940, 1449, 1408, 1326, 1246, 1159, 1061 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.98 (s, 1H), 7.62 (s, 1H), 7.23 (s, 1H), 7.16 (s, 1H), 6.11 (s, 2H), 4.21 (s, 2H), 4.10 (s, 3 H), 4.05 (s, 3H), 2.77 (s, 6H); low resolution ESIMS m/z (rel intensity) 379 (MH+, 100), 334 (90). Anal. (C22H22N2O4.1.25H2O) C, H, N.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@@H:5]([S:7]C(=O)C)[CH2:4][C@H:3]1[C:11]([N:13]([CH3:15])[CH3:14])=[O:12].C[O-].[Na+].[ClH:19]>CO>[ClH:19].[CH3:1][N:2]1[CH2:6][C@@H:5]([SH:7])[CH2:4][C@H:3]1[C:11]([N:13]([CH3:15])[CH3:14])=[O:12]
Reactant: CC(=O)S[C@H]1C[C@@H](C(=O)N(C)C)N(C)C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN(C)C(=O)[C@@H]1C[C@H](S)CN1C
Reaction time: 0.05 h

Procedure:
(2S,4S)-1-Methyl-2-dimethylaminocarbonyl-4-acetylthiopyrrolidine (660 mg) was dissolved in methanol (6.6 ml), and a solution of sodium methoxide (155 mg) in methanol (2.2 ml) was added thereto at room temperature under nitrogen stream, followed by stirring at the same temperature for 3 minutes. To the reaction mixture, 6N hydrochloric acid (1.05 ml) was added, and the solvent was removed by distillation. The residue was dissolved in ethanol (10.5 ml), and active carbon (99 mg) was added thereto under reflux. After refluxing for 15 minutes, the resultant mixture was filtered while hot, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane and dried over magnesium sulfate. Removal of the solvent gave (2S,4S)-1-methyl-2-dimethylaminocarbonyl-4-mercaptopyrrolidine hydrochloride.
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[C:19]([CH3:20])=[C:18]([CH:21]=[CH2:22])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]>[Rh].CCO>[C:1]([O:5][CH:6]([C:10]1[C:19]([CH3:20])=[C:18]([CH2:21][CH3:22])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=Cc1c(C)c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc12
Agent: [Rh]
Solvent: CCO
Product: CCc1c(C)c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc12
Reaction time: 6 h

Procedure:
A suspension of 2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-4-vinylnaphthalen-2-yl)acetic acid (5.0 mg, 12 μmol), 5% w/w Rh/Al2O3 (10 mg), and EtOH (absolute, 2.0 mL) was evacuated and purged several times (vaccuum/H2 balloon). The suspension was rapidly stirred under a balloon of H2 for 6 h. H2O (500 μL) was added and the reaction was filtered through a 0.45 micron filter. The filtrate was directly purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA). The product-containing fractions were combined and lyophilized, giving the title compound (parent form) 1H NMR (400 MHz, DMSO-d6) δ 12.71 (s, broad, 1H), 8.13 (d, J=8.2 Hz, 1H), 7.70-7.62 (m, 2H), 7.60-7.47 (m, 2H), 7.34-7.33 (m, 2H), 7.20 (d, J=8.2 Hz, 1H), 5.06 (s, 1H), 3.40-3.20 (m, 2H), 1.25 (t, J=7.4 Hz, 3H), 0.93 (s, 9H). LCMS-ESI− (m/z): [2M-2H+Na]− calcd for C50H52Cl2NaO6: 841.3; Found: 841.3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([C@@H:9]([CH2:17][NH2:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[C:1]([O:5][C:6](=[O:19])[N:7]([C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:17][NH:18][S:28]([CH3:27])(=[O:30])=[O:29])[CH3:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CN)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)[C@@H](CNS(C)(=O)=O)Cc1ccccc1
Temperature: -78 °C
Reaction time: 16 h
Yield: 92.1 %

Procedure:
N-((1R)-1-Aminomethyl-2-phenylethyl)-N-methylcarbamic acid tert-butylester (830 mg, 3.14 mmol) was dissolved in dichloromethane (15 ml). Triethylamine (0.44 ml, 3.14 mmol) was added. The solution was cooled to -78° C. A solution of methanesulfonyl chloride (0.24 ml, 3.14 mmol) in dichloromethane (2 ml) was added dropwise. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was diluted with dichloromethane (100 ml) and washed with saturated sodium chloride solution (100 ml). It was dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (65 g), using ethyl acetate/heptane (2:1) as eluent, to give 990 mg of N-((1R)-1-Benzyl-2-((methylsulfonyl)amino)ethyl)-N-methylcarbamic acid tert-butylester.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25][CH:26]=[C:27]([CH3:32])[C:28](=[O:31])[CH:29]=[CH2:30].B(F)(F)F.CCOCC>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25][C:26]1[CH2:30][CH2:29][C:28](=[O:31])[C:27]=1[CH3:32]
Reactant: C=CC(=O)C(C)=CCc1c(OC)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2
Agent: FB(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCOCC
Product: COc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1CC1=C(C)C(=O)CC1)C(=O)OC2
Reaction time: 0.5 h

Procedure:
The solid product prepared in Example ZC-1C, 6-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy-5-isobenzofuranyl)-4-methylhexa-1,4-dien-3-one was dissolved in methylene chloride (15 mL) and treated with boron trifluoride etherate (0.5 mL). After 0.5 hours, the reaction was diluted with ethyl acetate and washed with brine, then dried over magnesium sulfate. Filtration, solvent removal and chromatography (silica gel, hexanes/methylene chloride/ether, 4/4/2) gave the product, 3-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy-5 -isobenzofuranylmethyl)-2-methylcyclopent-2-en-1-one (0.18 g) as a colorless solid m.p. 65.4-66.8
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[N:15]1([CH2:22][C:23]2[CH:31]=[C:30]([O:32]C)[CH:29]=[C:28]3[C:24]=2[CH:25]=[CH:26][N:27]3[S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.Br.C([O-])(O)=O.[Na+]>C(O)(=O)C>[N:15]1([CH2:22][C:23]2[CH:31]=[C:30]([OH:32])[CH:29]=[C:28]3[C:24]=2[CH:25]=[CH:26][N:27]3[S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: COc1cc(CN2CCCNCC2)c2ccn(S(=O)(=O)c3ccccc3)c2c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccccc1)n1ccc2c(CN3CCCNCC3)cc(O)cc21
Temperature: 125 °C
Yield: 82.1 %

Procedure:
To 4-(1,4-Diazepan-1-ylmethyl)-6-methoxy-1-(phenylsulfonyl)-1H-indole (0.12 g, 0.03 mmol; Example 58) was 33% HBr in acetic acid (2 mL) added and the mixture was refluxed in STEM-block at 125° C. for 20 h which gave 70% conversion to product. Additional HBr in acetic acid (1 mL) was added and the mixture was refluxed for additional 20 h which gave 90% conversion product. Additional HBr in acetic acid (1 mL) was added and the mixture was refluxed for additional 21 h. The mixture was cooled to rt and sat. NaHCO3-solution was added (foaming) until neutral pH. The mixture was extracted with 3*EtOAc/ethanol (10:1). The organic layers were dried (Na2SO4), filtrated and the solvent was evaporated yielding 9.5 mg (82%) of a brownish-red solid. MS (ESI+) for C20H23N3O3S m/z 386 (M+H)+.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.C(O)(=O)C.[F:10][C:11]([F:39])([F:38])[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[NH:22][C:23]1[N:28]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:27](=[O:33])[CH:26]=[C:25]([C:34]([F:37])([F:36])[F:35])[N:24]=1.C(=O)(O)[O-].[Na+]>CCOCC>[F:39][C:11]([F:38])([F:10])[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=1[NH:22][C:23]1[N:28]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:27](=[O:33])[C:26]([Cl:4])=[C:25]([C:34]([F:35])([F:36])[F:37])[N:24]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C)Cn1c(Nc2cc(C(F)(F)F)ccc2C(F)(F)F)nc(C(F)(F)F)cc1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(C)Cn1c(Nc2cc(C(F)(F)F)ccc2C(F)(F)F)nc(C(F)(F)F)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
Sulfuryl chloride (0.16 ml) was added to acetic acid (14 ml) solution of 2-{2,5-bis(trifluoromethyl)phenyl}amino-3-isobutyl-6-trifluoromethyl-4(3H)-pyrimidinone (630 mg, 1.41 mmol), followed by stirring at room temperature for 3 hours. After completion of the reaction, ether (50 ml) and saturated sodium bicarbonate aqueous solution (50 ml) were added to the reaction solution to separate the organic layer, and the resulting aqueous layer was extracted with ether (30 ml×2). The thus obtained ether layers were combined, washed with sodium bicarbonate aqueous solution (50 ml) and saturated brine (50 ml) and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. By purifying the thus obtained crude product by a column chromatography (dichloromethane:hexane=7:3), white solid of 2-{2,5-bis(trifluoromethyl)phenyl}amino-5-chloro-3-isobutyl-6-trifluoromethyl-4(3H)-pyrimidinone [Compound No. 57] was obtained.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[C:9]([C:17](Cl)=[O:18])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:17](=[O:18])[C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(N)cn1
Reactant: O=C(Cl)C(=O)c1ccccc1
Product: Cc1ccc(NC(=O)C(=O)c2ccccc2)cn1

Procedure:
In analogy to the procedure described for the synthesis example 41 (step 1), the title compound N-(6-methyl-pyridin-3-yl)-2-oxo-2-phenyl-acetamide (MS m/e: 241.2 [M+H]+) was prepared from 6-methyl-pyridin-3-ylamine and benzoylformic acid chloride.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:11])=[N:7][CH:8]=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3].[OH:12]O>CC(O)=O>[CH2:1]([C:5]1[C:6]([CH3:11])=[N+:7]([O-:12])[CH:8]=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: OO
Reactant: Cc1ncccc1CC(C)C
Solvent: CC(=O)O
Product: Cc1c(CC(C)C)ccc[n+]1[O-]
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 76 %

Procedure:
3-Isobutyl-2-methyl-pyridine (Ishiguro et al. Yakugaku Zasshi 1958, 78, 220) (970 mg, 6.51 mmol) was suspended in a mixture of hydrogen peroxide (5 mL) and HOAc (45 mL) and the resulting mixture was stirred at 100° C. for 2.5 hours. The solvent was removed under reduced pressure and the resulting oily mixture was quenched with saturated NaHCO3 (60 mL) and extracted with CH2Cl2 (10×100 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo to yield 3-isobutyl-2-methyl-pyridine-1-oxide as a colorless oil (821 mg, 76%). 1H NMR (CDCl3) δ 0.93 (d, 6H, J=6.0 Hz), 1.84 (m, 1H), 2.51 (d, 2H, J=6.0 Hz), 2.52 (s, 3H), 7.03 (m, 2H), 8.18 (d, 1H, J=6.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[NH:10][C:11](=[O:19])[CH:12]([CH3:18])[C:13]([O:15]CC)=[O:14]>C1COCC1>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[NH:10][C:11](=[O:19])[CH:12]([CH3:18])[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)C(C)C(=O)Nc1cc(F)cc(F)c1Cl
Solvent: C1CCOC1
Product: CC(C(=O)O)C(=O)Nc1cc(F)cc(F)c1Cl

Procedure:
The acid was prepared according to Procedure B using ethyl 3-(2-chloro-3,5-difluorophenylamino)-2-methyl-3-oxopropanoate (5.0 g, 17.14 mmol) in THF (17.1 mL) to give 3-(2-chloro-3,5-difluorophenylamino)-2-methyl-3-oxopropanoic acid. Mass Spectrum (ESI) m/e=264.0 (M+1).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl>O>[CH2:17]([O:16][C:14]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])=[O:15])[CH3:18]
Reactant: C[C@H](N)C(=O)O
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)N[C@@H](C)C(=O)O
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Production of 3-(methyl ONN azoxy)-2,2-propylene dioxy-butane [Compound (IV):R3 =H, R4 =-CH2CH2CH2 -]: (a) In 700 ml of water were dissolved 40 g of L-alanine and 127 g of sodium carbonate. Then 64 ml of ethyl chloroformate was added dropwise to the mixture under ice-cooling and its stirring was conducted at room temperature for 30 minutes. A 35% hydrochloric acid was added to the reaction liquid to make this acidic and the reaction liquid was adsorbed on the column (6.5×60 cm) of diaion HP-20. After washing with water this was eluted with 70% methanol. The eluate was condensed under vacuum thereby to obtain 69 g (yield of 96%) of N-ethoxycarbonyl alanine as an oily substance.
Reaction SMILES: O.P([O-])([O-])(O)=O.[Na+].[Na+].OO.[Cl-].[Na+].[Cl:13][C:14]1[C:23]([CH:24]=[O:25])=[C:22]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17].Cl.S([O-])(O)=[O:32].[Na+]>O.C(#N)C>[Cl:13][C:14]1[C:23]([C:24]([OH:32])=[O:25])=[C:22]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: O=S([O-])O
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C=O)c1Cl
Agent: Cl
Agent: O=P([O-])([O-])O
Agent: OO
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C(=O)O)c1Cl
Temperature: 5 °C
Reaction time: 1 h

Procedure:
At 5° C., 13.8 g (0.11 mol) of sodium hydrogen phosphate monohydrate in 170 ml of water, 49.3 g (0.43 mol) of a 30% strength solution of hydrogen peroxide and 66.2 g (0.59 mol) of an 80% strength aqueous sodium chloride solution were added successively to a solution of 115.3 g (0.42 mol) of methyl 2-chloro-3-formyl-4-methylsulfonylbenzoate and 2000 ml of acetonitrile. The reaction solution was subsequently stirred at 5° C. for 1 hour and then at room temperature for 12 hours. The pH was then adjusted to 1 using 10% strength hydrochloric acid, and 1500 ml of aqueous 40% strength sodium hydrogen sulfite solution were added. The mixture was stirred at room temperature for 1 hour and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with sodium hydrogen sulfite solution and dried. The solvent was distilled off, yielding 102.0 g of methyl 2-chloro-3-hydroxycarbonyl-4-methylsulfonylbenzoate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([O:40]CC2C=CC=CC=2)[C@@H:15]([N:25](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C@@H:10]([CH2:48][O:49][CH:50]2[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:40])[C@@H:15]([NH2:25])[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C@@H:10]([CH2:48][O:49][CH:50]2[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](COC2CCCCC2)OC[C@@H]1[C@@H](OCc1ccccc1)[C@H](Cc1cc(F)cc(F)c1)N(Cc1ccccc1)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C[C@H](COC2CCCCC2)OC[C@@H]1[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1
Yield: 97 %

Procedure:
Add 20% palladium hydroxide on carbon (0.772 g) to a solution of (2R,5R)-5-[(1S,2S)-1-benzyloxy-2-dibenzylamino-3-(3,5-difluorophenyl)-propyl]-2-cyclohexyloxymethyl-morpholine-4-carboxylic acid tert-butyl ester (0.772 g, 1.023 mmol) in ethanol (10.2 mL). Stir vigorously under 1 atmosphere of hydrogen gas for 60 hours. Filter through a filtering agent, wash with ethanol and concentrate to give the desired compound (0.481 g, 97.1%).