Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15])[CH:2]([CH3:4])[CH3:3].O>CO.[BH4-].[K+]>[OH:10][CH:9]1[C:8]2[C:7](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6](=[O:15])[N:5]1[CH2:1][CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN1C(=O)c2ccccc2C1=O
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)CN1C(=O)c2ccccc2C1O
Temperature: 20 °C
Reaction time: 20 h
Yield: 88.4 %

Procedure:
3-Hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one is prepared as described in Example 1, starting with 6.5 g of N-isobutylphthalimide in 60 cm3 of methanol and 1.7 g of potassium borohydride. The reaction mixture is stirred at a temperature in the region of 20° C. for 20 hours and is then cooled to a temperature in the region of 0° C., followed by dropwise addition of 50 cm3 of distilled water. The methanol is then partially evaporated off under reduced pressure (2 kPa) at a temperature in the region of 35° C., and the residue is extracted three times with 60 cm3 of dichloromethane. The organic extracts are combined, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 25° C. to give a pale yellow oil, which is purified by chromatography under argon pressure (60 kPa) on a column of silica gel (particle size 40-63 μm), eluting with a cyclohexane/ethyl acetate mixture (60/40 by volume). The fractions comprising the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 5.8 g of 3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one are thus obtained in the form of a white solid melting at 82° C.
Reaction SMILES: O.[OH-].[Li+].[C:4]([O:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]2[C:28]([C:29]([O:31]C)=[O:30])=[C:27]([C:33](OC)=[O:34])[N:26]=[C:25]2[CH2:37][CH2:38][CH2:39][CH3:40])=[CH:19][CH:18]=1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>O.O1CCOCC1>[C:4]([O:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]2[C:28]([C:29]([OH:31])=[O:30])=[C:27]([CH2:33][OH:34])[N:26]=[C:25]2[CH2:37][CH2:38][CH2:39][CH3:40])=[CH:19][CH:18]=1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CCCCc1nc(C(=O)OC)c(C(=O)OC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCCc1nc(CO)c(C(=O)O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.2 %

Procedure:
A solution of 2.01 g of lithium hydroxide monohydrate in 97 ml of water was added to a solution of 4.78 g of methyl 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-hydroxymethylimidazole-5-carboxylate (prepared as described in Example 1) in 48 ml of dioxane, and the resulting mixture was stirred at room temperature for 18 hours. At the end of this time, the reaction mixture was freed from dioxane by distillation under reduced pressure, and 47.6 ml of 1N aqueous hydrochloric acid were added to the aqueous residue. The crystals which precipitated were collected by filtration and then washed with water and with diethyl ether, in that order, to give 4.26 g of the title compound, melting at 187° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N:9]([OH:14])[C:10]([NH:12][CH3:13])=[O:11].Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N:9]([O:14][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]([NH:12][CH3:13])=[O:11]
Reactant: CCOC(=O)Cl
Reactant: CNC(=O)N(O)c1cc(Cl)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)ON(C(=O)NC)c1cc(Cl)ccc1Cl

Procedure:
A solution of 1-(2,5-dichlorophenyl)-1-hydroxy-3-methylurea (22 grams; 0.09 mol) in 2 N sodium hydroxide (50 ml) was charged into a glass reaction flask equipped with a mechanical stirrer. Ethyl chloroformate (9.6 ml; 0.1 mol) was added to the flask at a temperature of about 10° to 15°C. After the addition the reaction mixture was stirred for a period of about one-half hour, during which time a precipitate was formed. The precipitate was recovered by filtration and was recrystallized from isopropyl alcohol to yield 1-(2,5-dichlorophenyl)-1-ethoxycarbonyloxy-3-methylurea having a melting point of 130° to 132°C and having the following elemental analysis as calculated for C11H12Cl2N2O4 :
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:37])[N:10]([CH2:28][C@H:29]([NH2:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:11](=[O:27])[N:12]([CH2:15][C:16]2[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][C:17]=2[F:26])[C:13]=1[CH3:14].[CH2:38]([CH:43]=O)[CH2:39][C:40]([OH:42])=[O:41].N1C=CC=CC=1>CO>[OH:42][C:40]([CH2:39][CH2:38][CH2:43][NH:36][C@H:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:28][N:10]1[C:9](=[O:37])[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[C:13]([CH3:14])[N:12]([CH2:15][C:16]2[C:21]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:19]=[CH:18][C:17]=2[F:26])[C:11]1=[O:27])=[O:41]
Reactant: O=CCCC(=O)O
Reactant: Cc1c(-c2ccccc2Cl)c(=O)n(C[C@H](N)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Solvent: CO
Solvent: c1ccncc1
Product: Cc1c(-c2ccccc2Cl)c(=O)n(C[C@H](NCCCC(=O)O)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Reaction time: 8 h

Procedure:
To compound 2b (0.03 mmol) in 1 mL MeOH, succinic semialdehyde (0.03 mmol) was added followed by addition of 8 M BH3: Pyridine (0.03 mmol). After overnight shaking, the compound 2-1 was purified by prep. LC-MS. MS (CI) m/z 618.2 (MH+) tR=1.005 (method 1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22]C)=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[NH:24][C:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26].[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[NH:24][C:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(Cl)c(NC(=O)C3CCCCC3)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(Cl)c(NC(=O)C2CCCCC2)c1
Yield: 13.6 %

Procedure:
To a solution of methyl 2-(4-chloro-3-(cyclohexanecarboxamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (380 mg, 0.835 mmol) in methanol (15 mL) was added a solution of sodium hydroxide (270 mg, 6.68 mmol) in water (6.8 mL). The mixture was stirred and heated to reflux for 5 h. The mixture was evaporated, and the residue was dissolved in 15 mL of water. The aqueous solution was acidified to pH=3 with 1M hydrochloric acid. The precipitated solid was collected by filtration, and dissolved in ethyl acetate. The organic layer was dried over sodium sulfate. After evaporation, the mixture was purified on silica gel to afford 50 mg of 2-(4-chloro-3-(cyclohexanecarboxamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as an off white solid. (Yield: 14%) MS (ESI+APCI) M+1=423.2, M−1=441.0.
Reaction SMILES: [C:1]1([NH:11][C:12](=[S:15])[NH:13][NH2:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH:16][C:17]1[CH:24]=[C:23]([OH:25])[CH:22]=[C:21]([OH:26])[C:18]=1[CH:19]=O>C(O)(=O)C>[C:1]1([NH:11][C:12](=[S:15])[NH:13][N:14]=[CH:19][C:18]2[C:17]([OH:16])=[CH:24][C:23]([OH:25])=[CH:22][C:21]=2[OH:26])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NNC(=S)Nc1cccc2ccccc12
Reactant: O=Cc1c(O)cc(O)cc1O
Solvent: CC(=O)O
Product: Oc1cc(O)c(C=NNC(=S)Nc2cccc3ccccc23)c(O)c1
Yield: 47.9 %

Procedure:
A solution of 4-(naphth-1-yl)thiosemicarbazide (572 mg, 2.63 mmol) and 2,4,6-trihydroxybenzaldehyde (405 mg, 2.63 mmol) in acetic acid (5 mL) was heated under reflux for 20 min, then cooled. The precipitate was filtered, washed (acetic acid) and dried to give the title compound (445 mg, 54%) as a solid. MS (ES+) m/e 354 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:20]3[CH:28]=[CH:27][C:23]4[O:24][CH2:25][O:26][C:22]=4[CH:21]=3)[CH:11]([N+:17]([O-])=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[NH2:17][CH:11]([CH:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)[C:20]1[CH:28]=[CH:27][C:23]2[O:24][CH2:25][O:26][C:22]=2[CH:21]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: [H][H]
Reactant: CCOC(=O)C(C(c1ccc2c(c1)OCO2)c1ccc2c(c1)OCO2)[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)C(N)C(c1ccc2c(c1)OCO2)c1ccc2c(c1)OCO2
Yield: 67.1 %

Procedure:
The nitro compound of Example 18 (2.1 g, 5.42 mmol) is dissolved in 50 mL of ethyl acetate aided by a few drops of methanol. A catalytic amount of 20% palladium-on-carbon is added and the reaction mixture is stirred under one atmosphere of hydrogen at room temperature for 2 hours. The catalyst is removed by filtration through Celite and washed with ethyl acetate. The solvent is evaporated to provide 1.3 g (67%) of product as a thick oil;
Reaction SMILES: [C:1]([Si:5]([CH3:28])([CH3:27])[O:6][CH:7]([CH2:25][CH3:26])[C:8]([N:10]1[CH2:15][CH2:14][C:13]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:18][C:12]=2[CH2:11]1)=O)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>C1(C)C=CC=CC=1>[C:1]([Si:5]([CH3:28])([CH3:27])[O:6][CH:7]([CH2:25][CH3:26])[C:8]([N:10]1[CH2:15][CH2:14][C:13]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:18][C:12]=2[CH2:11]1)=[S:38])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(O[Si](C)(C)C(C)(C)C)C(=O)N1CCc2nc(-c3ccccc3)oc2C1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCC(O[Si](C)(C)C(C)(C)C)C(=S)N1CCc2nc(-c3ccccc3)oc2C1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
680.00 mg (1.70 mmol) 2-(tert-butyl-dimethyl-silanyloxy)-1-(2-phenyl-6,7-dihydro-4H-oxazolo[5,4-c]pyridin-5-yl)-butan-1-one and 1.40 g (3.46 mmol) Lawesson's reagent are placed in 35 mL toluene and stirred overnight at 90° C. The solvent of the reaction mixture is eliminated in vacuo and the residue is purified on silica gel. (Eluant: cyclohexane/EA).
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=5[NH:38][C:39](=[O:50])[CH2:40][CH2:41][NH:42]C(OC(C)(C)C)=O)=[CH:27][CH:26]=4)=[O:24])(=[O:21])=[O:20])=[CH:15][C:14]=3[N+:51]([O-:53])=[O:52])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl>ClCCl.O1CCOCC1>[C:1]12([CH2:11][NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]([C:25]4[CH:26]=[CH:27][C:28]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=5[NH:38][C:39](=[O:50])[CH2:40][CH2:41][NH2:42])=[CH:29][CH:30]=4)=[O:24])(=[O:20])=[O:21])=[CH:15][C:14]=3[N+:51]([O-:53])=[O:52])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CC(C)(C)OC(=O)NCCC(=O)Nc1cc(F)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(NCC34CC5CC(CC(C5)C3)C4)c([N+](=O)[O-])c2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCCC(=O)Nc1cc(F)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(NCC34CC5CC(CC(C5)C3)C4)c([N+](=O)[O-])c2)cc1
Reaction time: 4 h

Procedure:
A room temperature solution of Example 49A (19 mg, 0.03 mmol) in dichloromethane (1 mL) was treated with 4M HCl in dioxane, stirred for 4 hours, and concentrated to provide the desired product. MS (ESI(+)) m/e 650 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 9.12 (br s, 1H), 8.65 (d, 1H), 8.56 (t, 1H), 7.95 (dd, 1H), 7.94 (m, 3H), 7.65 (br s, 3H), 7.50-7.35 (m, 4H), 7.15 (dt, 1H), 3.18 (d, 2H), 2.75 (s, 6H), 1.98 (m, 3H), 1.72-1.55 (m, 12H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)#[N:19]>>[CH3:11][C:10]1[O:9][N:8]=[C:7]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:6]=1[C:4]1[N:3]=[CH:2][N:1]([C:24]2[CH:25]=[C:20]([CH:21]=[CH:22][CH:23]=2)[C:18]#[N:19])[CH:5]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2cccc(C#N)c2)cn1
Yield: 30 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (112.6 mg, 0.5 mmol) was converted, using 3-cyanophenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (49 mg, 30%) which was obtained as a white solid. MS (ESI): m/e=327.0 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[C:15]([F:16])=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=3[F:17])[N:7]=[C:6]([C:18]([F:21])([F:20])[F:19])[CH:5]=2)[CH2:3][CH2:2]1.C([O:26][C:27](=O)[CH2:28][C:29]([CH3:31])=[O:30])(C)(C)C>C1(C)C(C)=CC=CC=1>[CH:1]1([C:4]2[N:8]([C:9]3[C:10]([F:17])=[CH:11][C:12]([NH:13][C:27](=[O:26])[CH2:28][C:29](=[O:30])[CH3:31])=[CH:14][C:15]=3[F:16])[N:7]=[C:6]([C:18]([F:20])([F:19])[F:21])[CH:5]=2)[CH2:2][CH2:3]1
Reactant: Nc1cc(F)c(-n2nc(C(F)(F)F)cc2C2CC2)c(F)c1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Solvent: Cc1ccccc1C
Product: CC(=O)CC(=O)Nc1cc(F)c(-n2nc(C(F)(F)F)cc2C2CC2)c(F)c1
Temperature: 145 °C
Yield: 78.2 %

Procedure:
Intermediate 35 (1 g, 3.3 mmol) and t-Butylacetoacetate (782 mg, 4.94 mmol) were dissolved in xylene (3 ml) and heated to 145° C. for 90 mins Reaction mixture was cooled to rt to obtain a solid. Solid that formed was filtered, washed with petether and dried to obtain N-{4-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-3,5-difluorophenyl}-3-oxobutanamide (1.0 g).
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:22][NH:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:22][N:23]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: CNCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N(C)CCc3ccccc3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL sealed tube, was placed a solution of methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL), N-methyl-2-phenylethanamine (177.6 mg, 1.32 mmol, 3.00 equiv), potassium carbonate (181.6 mg, 1.32 mmol, 3.00 equiv). The resulting solution was stirred overnight at 100° C. in an oil bath. The reaction was then quenched by the addition of water. The resulting solution was extracted with 3×20 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (100:1). This resulted in 153.3 mg (85%) of methyl 3-(methyl(phenethyl)amino)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]([CH:15]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH:16]=[CH2:17])=[CH:13][C:12]([CH3:27])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:28])[NH:10]2)(=[O:3])[CH3:2].S([O-])([O-])=[O:30].[Na+].[Na+]>C(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[C:14]([CH:15]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH:16]2[O:30][CH2:17]2)=[CH:13][C:12]([CH3:27])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:28])[NH:10]2)(=[O:3])[CH3:2]
Reactant: O=S([O-])[O-]
Reactant: C=CC(CO[Si](C)(C)C(C)(C)C)c1cc(C)c2[nH]c(=O)ccc2c1OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1c(C(CO[Si](C)(C)C(C)(C)C)C2CO2)cc(C)c2[nH]c(=O)ccc12

Procedure:
5-Acetoxy-6-[1-(tert-butyldimethylsilyloxy)methyl-2propenyl]-8-methylcarbostyril (6.00 g, 15.0 mmol) was dissolved in chloroform (100 ml), to which m-perbenzoic acid (13.0 g, 52.7 mmol) was added. The mixture was stirred for hours. Saturated aqueous sodium sulfite solution was added to the reaction mixture, followed by stirring for 90 minutes. The organic phase was washed with saturated NaCl solution, dried over sodium sulfate and condensed under reduced pressure. The resultant residue was recrystallized from chloroform--n-hexane. As a result, 6.10 g of the title compound (mixtures of diastereomers, 3:1) was obtained as colorless powdery crystals (97.8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:20][C:21](O)=[O:22])[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11].[CH2:24]([NH:31][CH2:32][C:33]#[N:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([N:31]([CH2:32][C:33]#[N:34])[C:21](=[O:22])[CH2:20][N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ccccc1C
Reactant: N#CCNCc1ccccc1
Product: COc1ccccc1N(CC(=O)N(CC#N)Cc1ccccc1)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-acetic acid with benzylamino-acetonitrile
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[Cl:10][C:11]([F:22])([F:21])[C:12]([N:14]=[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][NH:16]1)=[O:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:10][C:11]([F:21])([F:22])[C:12]([N:14]=[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]1[CH2:8][C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=1)=[O:13]
Reactant: O=C(N=c1cccc[nH]1)C(F)(F)Cl
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(N=c1ccccn1Cc1ccc(Cl)nc1)C(F)(F)Cl
Reaction time: 1 h

Procedure:
An amount of 53 mg (0.33 mmol) of 2-chloro-5-chloromethylpyridine dissolved in 6 mL of anhydrous acetonitrile was added to 68 mg (0.33 mmol) of 2-chloro-2,2-difluoro-N-(pyridin-2(1H)-ylidene)acetamide synthesized by the above method, following which 50 mg (0.36 mmol) of potassium carbonate was added and refluxing under heating was carried out for 1 hour. Following reaction completion, the reaction mixture was returned to room temperature then concentrated under reduced pressure. Diethyl ether was added to the concentrate, whereupon a solid separated out. The solid was collected by filtration and dried, affording the target compound in an amount of 49 mg (yield, 45%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9](=O)[CH:10]([F:19])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[F:19][CH:10]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][OH:8]
Reactant: COC(=O)C(F)CCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC(F)CCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a 0° C. suspension of LiAlH4 (0.4 g, 10.6 mmol) in dry THF (5 ml) was added dropwise a solution of (RS)-2-fluoro-4-phenyl-butyric acid methyl ester (1 g, 5.3 mmol) in dry THF (10 ml). After 1 hour stirring at 0° C., the reaction mixture was quenched successively with H2O (0.4 ml), 5N NaOH (0.4 ml) and again H2O (1.2 ml). The resulting solid was filtered and the filtrate was concentrated to provide (RS)-2-fluoro-4-phenyl-butan-1-ol (0.89 g, 99%) as a colorless oil, MS: m/e=168.1 (M+).
Reaction SMILES: CS[C:3]([N:14]1[CH2:18][CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[N:15]1)=[N:4][S:5]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)(=[O:7])=[O:6].[CH3:32][NH2:33]>CO>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:16]2[CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:18][N:14]([C:3]([NH:33][CH3:32])=[N:4][S:5]([N:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)(=[O:7])=[O:6])[N:15]=2)=[CH:26][CH:27]=1
Reactant: CN
Reactant: CSC(=NS(=O)(=O)N1CCCCC1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Solvent: CO
Product: CNC(=NS(=O)(=O)N1CCCCC1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Temperature: 50 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
To a cooled mixture (<0° C.) of 3-(4-chlorophenyl)-N-((piperidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidothioic acid methyl ester (10.0 gram, 21 mmol) in methanol (75 mL) is added cold methylamine (15 mL). The resulting mixture is allowed to attain room temperature and stirred for 3 hours at 50° C. After cooling to room temperature the mixture is concentrated in vacuo, dissolved in dichloromethane, washed twice with water, dried over Na2SO4, filtered and concentrated in vacuo. Subsequent flash chromatography (EtOAc/MeOH/NH4OH (25% aq.)=95/5/0.5 (v/v)), followed by recrystallisation from diisopropyl ether gives 3-(4-chlorophenyl)-N-methyl-4-phenyl-N′-((piperidin-1-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamidine (7.87 gram, 81% yield) as a white solid. MP: 175-177° C.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][C:32]([N:34]([CH2:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40](O)=[O:41])[CH3:35])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:40](=[O:41])[C:39]3[CH:43]=[CH:44][CH:45]=[C:37]([CH2:36][N:34]([C:32]([O:31][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:33])[CH3:35])[CH:38]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(CCN1CC[C@H](Cc2ccccc2)[C@H](O)C1)c1ccc(O)cc1
Reactant: CN(Cc1cccc(C(=O)O)c1)C(=O)OC(C)(C)C
Product: CN(Cc1cccc(C(=O)Oc2ccc(S(=O)(=O)CCN3CC[C@H](Cc4ccccc4)[C@H](O)C3)cc2)c1)C(=O)OC(C)(C)C
Yield: 70 %

Procedure:
The title compound was prepared from (3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenol and 3-[(tert-butoxycarbonyl-methyl-amino)-methyl]-benzoic acid in 70% yield as a colorless gum.
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:15]1[CH:32]=[CH:31][C:18]([O:19][CH2:20][C@H:21]([OH:30])[CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:17][CH:16]=1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1>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.C(O)C>[F:33][C:34]([F:45])([F:44])[C:35]1[CH:40]=[C:39]([C:15]2[CH:32]=[CH:31][C:18]([O:19][CH2:20][C@H:21]([OH:30])[CH2:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:17][CH:16]=2)[CH:38]=[CH:37][CH:36]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O[C@H](CCc1cccnc1)COc1ccc(Br)cc1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O[C@H](CCc1cccnc1)COc1ccc(-c2cccc(C(F)(F)F)c2)cc1
Yield: 59.9 %

Procedure:
Prepared according to the method described in Example 33a) from toluene (5 ml), aqueous sodium carbonate (2 M, 1 ml), (2R)-1-(4-bromophenoxy)-4-(3-pyridyl)-2-butanol (0.25 g), ethanol (1 ml), 3-trifluoromethylbenzeneboronic acid (0.161 g) and tetrakis(triphenylphosphine)palladium(0) (22 mg) with heating at reflux for 6 hours. The residue obtained after work-up was purified by column chromatography over silica eluting with ethyl acetate to give (2R)-1-(3'-trifluoromethylbiphenyl-4-yloxy)-4-(3-pyridyl)-2-butanol as a colourless oil (0.180 g). Conversion to the oxalate salt upon treatment with excess saturated ethereal oxalic acid gave the title compound as a hygroscopic gum. (0.150 g)