Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19](Br)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][NH:36][CH:37]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19]([C:33]4[CH:34]=[N:35][NH:36][CH:37]=4)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(Br)c2n1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(-c3cn[nH]c3)c2n1C
Temperature: 140 °C
Yield: 19.4 %

Procedure:
A mixture of 4-Amino-6-[(S)-1-(7-bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethylamino]-pyrimidine-5-carbonitrile, (0.10 g, 0.26 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.065 g, 0.33 mmol), tetrakis(triphenylphosphine)palladium(0) (0.015 g, 0.01 mmol) and caesium carbonate (0.17 g, 0.51 mmol) in dioxane (3 mL) and water (1.5 mL) was placed in a sealed tube and degassed with nitrogen for 5 minutes, then heated for 40 minutes at 140° C. by microwave irradiation. 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.10 g, 0.52 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.015 g, 0.01 mmol) were added and the resultant mixture heated for 80 minutes at 140° C. by microwave irradiation. The resulting mixture was loaded onto an Isolute® SCX-2 cartridge then washed with MeOH and the product eluted with 2M NH3/MeOH then concentrated in vacuo. The residue was purified by chromatography eluting with (SiO2, 0-10% (2M ammonia in methanol) in DCM) then by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 78 min gradient 20-98% 0.1% HCO2H in acetonitrile/water) to give 428 as a white solid (0.019 g, 20%). LCMS (Method K): RT 2.23 min [M+H]+ 378.0. 1H NMR (DMSO-d6, 400 MHz): δ 13.10 (1H, s), 8.28 (1H, s), 8.04 (1H, s), 7.83 (1H, s), 7.66-7.64 (1H, m), 7.60 (1H, dd, J=8.74, 4.77 Hz), 7.31 (2H, s), 7.12-7.06 (1H, m), 5.66-5.61 (1H, m), 3.66 (3H, s), 1.57 (3H, d, J=6.73 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.C1(N=C=NC2CCCCC2)CCCCC1.O.ON1C2C=CC=CC=2N=N1.[NH2:37][CH:38]1[CH:43]2[CH2:44][CH2:45][N:40]([CH2:41][CH2:42]2)[CH2:39]1>C(#N)C>[N:40]12[CH2:45][CH2:44][CH:43]([CH2:42][CH2:41]1)[CH:38]([NH:37][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=1)[CH2:39]2
Reactant: NC1CN2CCC1CC2
Reactant: O=C(O)c1cccc(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC1CN2CCC1CC2)c1cccc(Cl)c1
Reaction time: 20 h
Yield: 99.6 %

Procedure:
In 400 ml of acetonitrile was suspended 25 g of m-chlorobenzoic acid and while the suspension was stirred with ice-cooling, 39.5 g of N,N'-dicyclohexylcarbodiimide and 27.0 g of 1-hydroxybenzotriazole monohydrate were added. The mixture was stirred for 2 hours. Then, 20.2 g of 3-aminoquinuclidine was added and the mixture was further stirred with ice-cooling for 2 hours and, then, at room temperature for 20 hours. The reaction mixture was filtered to remove insolubles and the solvent was evaporated off. The residue was dissolved by addition of diluted hydrochloric acid and washed twice with ethyl acetate. The aqueous layer was neutralized with aqueous solution of sodium hydroxide and extracted with chloroform. The extract was washed with water and dried over anhydrous magnesium sulfate and the chloroform was evaporated off to give 42.1 g of the desired compound as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[N:5]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@H:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[NH:9][C@@H:8]([CH3:20])[CH2:7]1)[CH3:2].[C:29](Cl)([Cl:31])=[O:30]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:28])[N:5]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C@H:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]([C:29]([Cl:31])=[O:30])[C@@H:8]([CH3:20])[CH2:7]1)[CH3:2]
Reactant: CCOC(=O)N(Cc1ccccc1)[C@@H]1C[C@H](C)Nc2cc(OC)c(OC)cc21
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)N(Cc1ccccc1)[C@@H]1C[C@H](C)N(C(=O)Cl)c2cc(OC)c(OC)cc21
Yield: 92 %

Procedure:
To a solution of cis-benzyl-(6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid ethyl ester (Example 66) (103 mg, 0.268 mmol) in toluene (2.5 mL) was added phosgene (1.0 mL of a 1.93M solution in toluene) and the reaction mixure was heated at reflux for 2 h. The reaction mixture was then concentrated in vacuo to give the desired carbamoyl chloride (110 mg, 92%).
Reaction SMILES: [C:1]([C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])=CN(C)C)(=[O:3])[CH3:2].O>O1CCOCC1>[N+:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:4][C:1](=[O:3])[CH3:2])([O-:17])=[O:16]
Reactant: CC(=O)C(=CN(C)C)c1ccccc1[N+](=O)[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Cc1ccccc1[N+](=O)[O-]

Procedure:
The product of Example 8, i.e., α-acetyl-β-dimethylamino-2-nitrostyrene was refluxed with a mixture of 8 ml. of water and 25 ml. of dioxane for 24 hours. After cooling, the mixture was concentrated in vacuo and the residue partitioned between methylene chloride and water. The organic phase was washed with brine, dried and concentrated. The crude product was chromatographed on silica gel using benzene, followed by methylene chloride as the eluent to give 926 mg. (26 percent based on β-dimethylamino-2-nitrostyrene) of 1-o-nitrophenyl-2-propanone as an oil. A small amount was recrystallized from hexane to give pale yellow plates of 1-o-nitrophenyl-2-propanone, having a melting point of 24°-25°. The nmr spectrum was in agreement with the proposed structure.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([N+:14]([O-:16])=[O:15])[C:8]=1[NH2:17])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[NH2:1][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([N+:14]([O-:16])=[O:15])[C:8]=1[NH2:17]
Reactant: [N-]=[N+]=NCCOc1cc(Cl)cc([N+](=O)[O-])c1N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCCOc1cc(Cl)cc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 2-(2-azido-ethoxy)-4-chloro-6-nitro-phenylamine (1.9 g, 7.36 mmol) and triphenylphosphine (2.27 g, 8.65 mmol) in tetrahydrofuran (80 ml) and water (2 ml) was allowed to stir for 24 hours at room temperature. The solvent was removed under vacuum and the solid washed with methylene chloride (30 ml) to afford an orange solid: mp 156-157° C.
Reaction SMILES: C1C=CC=CC=1.[C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:9])[CH3:8].[CH2:16](O)[CH2:17][OH:18]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:16]1[CH2:17][O:18][C:7]([CH3:8])([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[O:9]1
Reactant: OCCO
Reactant: CCOC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)CC1(C)OCCO1
Yield: 92 %

Procedure:
Benzene (50 cc), ethyl acetylacetate (30 g, 231 mmol) and ethylene glycol (16 g), followed by p-toluenesulphonic acid (0.5 g), are introduced into a round-bottomed flask fitted with a Dean and Stark apparatus. The mixture is heated under reflux while the azeotrope is distilled off for 2 hours 30 minutes. After the removal of benzene, ethyl 3,3-ethylenedioxybutanoate (37 g) is obtained (B.P.12 =98° C.).
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:7]=1[CH:8]=[O:9])([O-:5])=[O:4]>[OH-].[Na+].CO>[N+:3]([C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:7]=1[CH2:8][OH:9])([O-:5])=[O:4]
Reactant: O=Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
A solution of 1.1 grams of sodium borohydride dissolved in 16 ml of 0.2N sodium hydroxide (temperature 10-23 degrees Centigrade) was dropwise added to a solution of 10 grams of 2,6-dinitrobenzaldehyde in 75 ml of methanol. The reaction mixture was stirred at room temperature for 30 minutes. The methanol was then removed under vacuum and the water residue extracted several times with ether. The ether washings were dried over anhydrous magnesium sulfate and filtered. After solvents were removed on a rotary evaporator under reduced pressure, the residue was recrystallized 3 times from a chloroform/carbon tetrachloride composition yielding 9.17 grams of 2,6-dinitrobenzyl alcohol.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].CC(C)([O-])C.[K+].[Cl:12][C:13]1[C:14]([O:30][C:31]2[CH:32]=[N:33][C:34]([O:38][C@H:39]([CH3:44])[C:40]([F:43])([F:42])[F:41])=[C:35]([Cl:37])[CH:36]=2)=[CH:15][C:16]([F:29])=[C:17]([CH:28]=1)[C:18](OC1C=CC(C)=CC=1)=[O:19]>C1COCC1>[Cl:12][C:13]1[C:14]([O:30][C:31]2[CH:32]=[N:33][C:34]([O:38][C@H:39]([CH3:44])[C:40]([F:42])([F:43])[F:41])=[C:35]([Cl:37])[CH:36]=2)=[CH:15][C:16]([F:29])=[C:17]([CH:28]=1)[C:18]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:19]
Reactant: Cc1ccc(OC(=O)c2cc(Cl)c(Oc3cnc(O[C@H](C)C(F)(F)F)c(Cl)c3)cc2F)cc1
Reactant: CS(N)(=O)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C[C@@H](Oc1ncc(Oc2cc(F)c(C(=O)NS(C)(=O)=O)cc2Cl)cc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.7 %

Procedure:
To a solution of methanesulfonamide (105 mg, 1.1 mmol) in THF (4 mL) was added potassium tert-butoxide (126 mg, 1.1 mmol) and the mixture was stirred for 10 minutes at room temperature. A solution of 4-methylphenyl 5-chloro-4-({5-chloro-6-[(1R)-2,2,2-trifluoro-1-methylethoxy]pyridin-3-yl}oxy)-2-fluorobenzoate (Preparation 234, 429 mg, 0.85 mmol) in THF (4 mL) was added and the resulting mixture was stirred at 50° C. for 3 hours. The reaction mixture was allowed to cool to room temperature. The reaction was quenched with water and acidified with 1N aqueous citric acid solution. The mixture was partitioned between water and DCM (3×5 mL) and filtered through a phase separation cartridge. The filtrate was concentrated in vacuo to give a crude solid that was purified using trituration with heptanes/acetone 9/1 to give the title compound (199 mg, 48%) as a white solid.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:19]([NH:21][C:22]1[CH:23]=[C:24]([CH2:29][C@@H:30]([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:25]=[CH:26][C:27]=1[F:28])=[O:20])[CH:13]([C:15]([F:18])([F:17])[F:16])[CH3:14])=O)C1C=CC=CC=1>C(O)C.C1COCC1.[Pd]>[F:28][C:27]1[CH:26]=[CH:25][C:24]([CH2:29][C@@H:30]([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:23][C:22]=1[NH:21][C:19](=[O:20])[C@H:12]([CH:13]([C:15]([F:18])([F:17])[F:16])[CH3:14])[NH2:11]
Reactant: CCOC(=O)[C@H](C)Cc1ccc(F)c(NC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C)Cc1ccc(F)c(NC(=O)[C@@H](N)C(C)C(F)(F)F)c1
Reaction time: 8 h

Procedure:
2.36 g (4.61 mmol) of ethyl (2R)-3-[3-({N-[(benzyloxy)carbonyl]-4,4,4-trifluorovalyl}amino)-4-fluorophenyl]-2-methylpropanoate (Example 37A, mixture of 4 isomers) were dissolved in a mixture of 9.8 ml of ethanol and 9.8 ml of THF. The solution was inertized with argon, and 293 mg of palladium on carbon (10%) were added. The reaction mixture was stirred vigorously at standard pressure under an atmosphere of hydrogen overnight. Following filtration through kieselguhr and washing with dichloromethane/methanol, the filtrate was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1→4:1) and separated. This gave 1.35 g of the target compound as diastereomer mixture 1 (77.2% of theory).
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:18]=[CH:17][S:16][C:4]=2[N:5]([CH:13]([CH3:15])[CH3:14])[C:6](=[O:12])[C:7]=1[C:8]([O:10]C)=O.[CH2:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1)[CH3:20].C(N(C(C)C)CC)(C)C>C1(C)C(C)=CC=CC=1>[CH2:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:8]([C:7]2[C:6](=[O:12])[N:5]([CH:13]([CH3:15])[CH3:14])[C:4]3[S:16][CH:17]=[CH:18][C:3]=3[C:2]=2[OH:1])=[O:10])[CH2:23][CH2:22]1)[CH3:20]
Reactant: COC(=O)c1c(O)c2ccsc2n(C(C)C)c1=O
Reactant: CCN1CCC(N)CC1
Solvent: Cc1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCC(NC(=O)c2c(O)c3ccsc3n(C(C)C)c2=O)CC1
Temperature: 25 °C
Yield: 67.1 %

Procedure:
A solution of methyl 6,7-dihydro-4-hydroxy-7-isopropyl-6-oxothieno-[2,3-b]pyridine-5-carboxylate (0.22 g, 0.82 mmol), 1-ethylpiperidin-4-amine (0.44 g, 1.24 mmol) and diisopropylethylamine (0.35 mL, 2.48 mmol) in xylene (3 mL) was heated at 120° C. for 2 h. The reaction mixture was cooled to room temperature, washed with water and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography eluted with 3% methanol-dichloromethane to give the title compound (0.20 g, 67% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 10.34 (br s, 1 H, 7.37 (d, 1 H, 6.95 (d, 1 H, 4.01 (m, 2 H, 3.03 (m, 2 H, 2.63 (d, 2 H, 2.41 (m, 2 H, 2.12 (d, 2 H, 1.81 (q, 2 H, 1.62 (d, 6 H, 1.18 (t, 3 H; MS: m/e 364 (M+H+).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)[CH3:10]>>[C:1]1([NH:7][N:8]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1ccccc1
Reactant: NNc1ccccc1
Product: CC(=NNc1ccccc1)c1ccccc1
Temperature: 15 °C

Procedure:
Phenylhydrazine (10.8 g, 0.10 mole) is added to 20 g (0.10 mole) of acetophenone with stirring at about 15° C. The reaction produces a slight exotherm and the solution solidifies. The title product is allowed to sit for about 12 hours at room temperature and is then used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][C@@H:19]3[CH3:24])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:25]([O:27][CH3:28])=[O:26])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:35][CH2:36]I>CN(C)C=O.O>[CH2:35]([N:21]1[CH2:22][CH2:23][N:18]([C:17]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:25]([O:27][CH3:28])=[O:26])=[CH:12][CH:11]=3)[C@@H:19]([CH3:24])[CH2:20]1)[CH3:36]
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCNC[C@@H]3C)nc2c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CCN(c2nc3cc(C(=O)OC)ccc3nc2-c2ccc(F)cc2)[C@@H](C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-methyl 2-(4-fluorophenyl)-3-(2-methylpiperazin-1-yl)quinoxaline-6-carboxylate (160 mg, 0.42 mmol) in N,N-dimethylformamide (30 mL) was added potassium carbonate (174 mg, 1.26 mmol) and CH3CH2I (68.8 mg, 0.44 mmol), and the reaction was stirred overnight at room temperature. The reaction solution was diluted with water (150 mL), extracted with dichloromethane (3×30 mL), and the organic layers combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (1% methanol in dichloromethane) to afford (S)-methyl 3-(4-ethyl-2-methylpiperazin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as light yellow oil (80 mg, crude).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=3[O:33][CH3:34])(=[O:25])=[O:24])=[C:16]([O:35][CH3:36])[CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:38]1C=CC(OC)=C(S(Cl)(=O)=O)C=1>>[CH3:38][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=3[O:33][CH3:34])(=[O:24])=[O:25])=[C:16]([O:35][CH3:36])[CH:15]=2)=[O:13])=[CH:10][C:2]=1[Cl:1]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCc2c(OC)cc(C(=O)Nc3ccc(C(=O)O)c(Cl)c3)cc21
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Product: COC(=O)c1ccc(NC(=O)c2cc(OC)c3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CC3)cc1Cl

Procedure:
2-Chloro-4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid, m/z (ES+): 551.28 (M+H+.), was prepared in analogy to example 21, steps 1 to 6. Step 5 was performed using 5-chloro-2-methoxy-benzenesulfonyl chloride, yielding 2-chloro-4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid methyl ester, which was hydrolyzed in step 6.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:6](O)=O)[CH3:2].C=O.N1CCCCC1>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:22])[C:5](=[CH2:6])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[CH3:2]
Reactant: CCOC(=O)C(CCCCCCCC1CCCCC1)C(=O)O
Agent: C=O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: C=C(CCCCCCCC1CCCCC1)C(=O)OCC

Procedure:
9.2 g of 9-cyclohexyl-2-methylenenonanoic acid ethyl ester, in the form of a colourless oil, which is purified by chromatography on silica gel (migrating agent: 95:5 petroleum ether/ethyl acetate), are obtained by the procedure described in Example (1b) from 16.2 g of (7-cyclohexylheptyl)-malonic acid ethyl ester, 1.86 g of paraformaldehyde, 11.5 ml of pyridine and 0.6 ml of piperidine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[O:11])[C:5]([CH:23]=O)=[C:4]([S:25][CH3:26])[N:3]=1.C(=O)(O)[O-].[K+].Cl.[NH2:33][OH:34]>CO>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[O:11])[C:5]([CH:23]=[N:33][OH:34])=[C:4]([S:25][CH3:26])[N:3]=1
Reactant: NO
Reactant: CSc1nc(N)nc(NCC(=O)Nc2cccc(C(F)(F)F)c2)c1C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Product: CSc1nc(N)nc(NCC(=O)Nc2cccc(C(F)(F)F)c2)c1C=NO
Temperature: 60 °C
Yield: 28.8 %

Procedure:
To a round bottom flask was added 2-(2-amino-5-formyl-6-methylsulfanyl-pyrimidin-4-ylamino)-N-(3-trifluoromethyl-phenyl)-acetamide (50.0 mg, 0.13 mmol, 1.0 mmol), MeOH (2.0 mL), potassium bicarbonate (51.0 mg, 0.51 mmol, 4.0 eq.), and hydroxylamine HCl (35.6 mg, 0.51 mmol, 4.0 eq.). The reaction was heated to 60° C. for 72 hrs before quenching with H2O (10 mL) and EtOAc (50 mL). The EtOAc layer washed with brine, dried with Na2SO4, and concentrated to give crude 2-[2-amino-5-(hydroxyimino-methyl)-6-methylsulfanyl-pyrimidin-4-ylamino]-N-(3-trifluoromethyl-phenyl)-acetamide as an oil. The product was then precipitated out with 3 mL water and 0.5 mL of ACN, filtered and rinsed with 2 mL of (1:2 ACN: H2O) to give pure 2-[2-amino-5-(hydroxyimino-methyl)-6-methylsulfanyl-pyrimidin-4-ylamino]-N-(3-trifluoromethyl-phenyl)-acetamide as a solid (15.0 mg, 29%). LC/MSD (HP Series 1100 MSD): Expected MW: 400, Observed M+H, 401.1, Retention time: 1.48 min. ANALYTICAL HPLC: >80%, Retention time: 2.89 min (8 minute run). 1H-NMR (d6-DMSO): 10.98 (s, 1H), 10.50 (s, 1H), 8.40 (t, 1H), 8.15 (s, 1H), 8.09 (s, 1H), 7.77 (d, 1H), 7.58 (t, 1H), 7.40 (d, 1H), 5.90 (br s, 2H), 4.36 (d, 2H), 2.40 (s, 3H) ppm.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].Br[CH2:13][CH:14](OCC)OCC.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:11][C:2]([F:1])([F:10])[C:3]1[C:4]2[S:9][CH:13]=[CH:14][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(CBr)OCC
Reactant: FC(F)(F)c1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: FC(F)(F)c1cccc2ccsc12
Temperature: 45 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-(trifluoromethyl)benzenethiol (5.000 g, 0.028 mol) in acetone (50 mL) was added 2-bromo-1,1-diethoxyethane (6.08 g, 0.030 mol) and potassium carbonate (7.757 g, 0.056 mol). The resulting mixture was then stirred at 45° C. for 2 hours prior to removal of the solvent in vacuo and suspension of the residue in EtOAc. The inorganic salts were filtered off and the organic phase was concentrated to give crude product, which was used in next step without further purification. This residue was dissolved in toluene (50 mL), and to this solution was added PPA (10 g) and the resulting mixture stirred at 95-100° C. for 2 hours. The mixture was allowed to cool to rt, was poured into ice-water, then extracted with EtOAc (3×50 mL). The combined extracts were washed with aqueous sodium bicarbonate followed by brine, then dried over anhydrous sodium sulfate and evaporated under reduced pressure to yield an oil. This was purified by column chromatography over silica gel eluting with hexane to give 7-trifluoromethyl-benzo[b]thiophene. 1H NMR (400 MHz, MeOD) δ ppm 7.49-7.57 (m, 2H), 7.70 (d, J=7.33 Hz, 1H), 7.74 (d, J=5.56 Hz, 1H) and 8.10 (d, J=8.08 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]=[CH:13]OCC)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[NH:21][CH3:22]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([N:12]=[CH:13][N:21]([C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[O:18][CH3:17])[CH3:22])=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CNc1ccccc1OC
Reactant: CCOC=Nc1ccc(C(=O)OCC)cc1
Solvent: CCO
Product: CCOC(=O)c1ccc(N=CN(C)c2ccccc2OC)cc1

Procedure:
A mixture of ethyl N-(4-ethoxycarbonylphenyl)formimidate (Example Ia) (4.9 g, 0.022 mol) and 2-methoxy-N-methylaniline (3.2 g, 0.022 mol) were heated at 180° until 1.3 ml of ethanol had been collected by distillation. The resulting yellow oil was flash distilled to yield the desired product, bp≈200° C. (0.05 mm). ##STR14##
Reaction SMILES: [CH:1]1([CH2:6][N:7]([C:10]2[CH:18]=[C:17]3[C:13]([CH2:14][CH2:15][CH2:16]3)=[CH:12][C:11]=2[CH:19]=O)[CH2:8][CH3:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:21][C:22]([F:36])([F:35])[C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:26][NH2:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:1]1([CH2:6][N:7]([CH2:8][CH3:9])[C:10]2[CH:18]=[C:17]3[C:13](=[CH:12][C:11]=2[CH2:19][NH:27][CH2:26][C:25]2[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=[C:23]([C:22]([F:21])([F:35])[F:36])[CH:24]=2)[CH2:14][CH2:15][CH2:16]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCN(CC1CCCC1)c1cc2c(cc1C=O)CCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCN(CC1CCCC1)c1cc2c(cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCC2
Temperature: 25 °C
Yield: 82.4 %

Procedure:
To a solution (20 ml) of 6-(N-cyclopentylmethyl-N-ethylamino)indane-5-carbaldehyde (1.09 g) and 3,5-bis(trifluoromethyl)benzylamine (1.26 g) in dichloromethane was added sodium triacetoxyborohydride (1.70 g) with stirring at room temperature. The reaction solution was stirred overnight. The reaction solution was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine, and the organic layer was dried over sodium sulfate. Sodium sulfate was filtered off and the filtrate was concentrated. The obtained residue was purified by column chromatography (n-hexane:ethyl acetate=6:1) to give the title compound (1.65 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:5]2.[H][H]>C(O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:5]2
Reactant: CCCCC=Cc1cc2cc(Cl)ccc2[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCCc1cc2cc(Cl)ccc2[nH]1
Reaction time: 5 h

Procedure:
5-Chloro-2-hex-1-enyl-1H-indole was dissolved in ethanol and 10% palladium on carbon was added to the solution. The reaction flask was sealed and exposed to hydrogen gas under pressure and was stirred for 5 hours. Then the reaction mixture was filtered through Celite. The solvent was evaporated to give 5-chloro-2-hexyl-1H-indole.