Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[C:17]([C:27](=[O:30])[NH:28][CH3:29])[C:16]=3[CH:31]=2)[C:10]=1[CH3:11])[C:5](O)=[O:6].[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]1([NH2:41])[CH2:40][CH2:39]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[C:10]([CH3:11])=[C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][C:18]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[C:17]([C:27]([NH:28][CH3:29])=[O:30])[C:16]=3[CH:31]=2)[CH:8]=[C:4]([C:5](=[O:6])[NH:41][C:38]2([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=3)[CH2:40][CH2:39]2)[CH:3]=1
Reactant: NC1(c2ccccn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)cc(F)c3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccccn5)CC4)cc(F)c3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-fluoro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methyl benzoic acid (0.2 g, 0.47 mmol, 1 eq), 1-(pyridin-2-yl)cyclopropanamine (0.075 g, 5.5 mmol, 1.2 eq) (60% purity), HOBT (0.81 g, 0.015 mmol, 1.7 eq), EDC.HCl (0.16 g, 00.83 mmol, 1.8 eq) in DCM at ambient temperature and under nitrogen was added Diisopropylethylamine (0.30 g, 2.3 mmol, 5.0 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer is further washed with water, dried over sodium sulphate and concentrated. The product obtained was further purified by column chromatography (neutral alumina) using 0.5% Methanol/DCM and further purification was done using preparative HPLC. Yield: 0.1 g (50%). 1H NMR (400 MHz, CDCl3): δ 1.39-1.42 (m, 2H), 1.67-1.70 (m, 2H), 2.21-2.22 (d, 3H, J=2.24 Hz), 2.9-3.0 (d, 3H, J=4.88 Hz), 5.98-5.99 (s, 1H), 7.06-7.09 (dd, 1H, J=5.2, 7.2 Hz), 7.18-7.36 (m, 5H), 7.53-7.62 (m, 4H), 7.76 (d, 1H, J=1.36 Hz), 7.94-7.97 (m, 2H), 8.4 (s, 1H). LCMS: (ES+) m/z=538.2 (M+H). LCMS Method: Column-Atlantis dC18 (50×4.6 mm-5 μm) A: 10 mM NH4OAc; B: acetonitrile
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=[O:4].[CH3:12][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1>C(OCC)C>[Br-:1].[CH3:12][NH+:13]1[CH:17]=[CH:16][N:15]([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=2)=[O:4])[CH2:14]1
Reactant: Cn1ccnc1
Reactant: Cc1ccc(C(=O)CBr)cc1
Solvent: CCOCC
Product: Cc1ccc(C(=O)CN2C=C[NH+](C)C2)cc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.4 %

Procedure:
To a solution of 10.6 g (0.05 mol) of 1-bromo-2-(4-methylphenyl)-2-oxoethane in 150 ml of diethyl ether was added 4.18 g (0.051 mol) of 1-methylimidazole (Aldrich Chemical Company, Milwaukee, Wis.). The reaction mixture was stirred for approximately 3 hours at room temperature and the precipitated solid was collected by filtration. The resulting hygroscopic solid was recrystallized from methanol/ethyl acetate to afford 4.82 g of 1-methyl-3-[2-(4-methylphenyl)-2-oxoethyl]-1H-imidazolium bromide as a solid. A second crop was obtained from the filtrate to provide an additional 5.8 g of product. (72% yield) mp=148°-151° C.
Reaction SMILES: [CH2:1]([PH:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].C([Mg]Br)CCC.C(OP([O-])OCC)C.[CH3:25][Si:26](Cl)([CH3:28])[CH3:27]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH2:1]([P:5]([CH2:6][CH2:7][CH2:8][CH3:9])[O:10][Si:26]([CH3:28])([CH3:27])[CH3:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[PH](=O)CCCC
Reactant: C[Si](C)(C)Cl
Agent: CCCC[Mg]Br
Agent: CCOP([O-])OCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCP(CCCC)O[Si](C)(C)C
Temperature: 80 °C
Yield: 86 %

Procedure:
The procedure described in Tetrahedron, 1967, 23, 1065 (M. Grayson et al.) was followed. Dibutylphosphine oxide, prepared from butyl magnesium bromide and diethylphosphite, (3.3 g, 20 mmol) and triethylamine (2.02 g, 20 mml) were dissolved in toluene (20 mL) and treated with a solution of trimethylsilyl chloride (2.17 g, 20 mmol) in toluene (5 mL) at room temperature. The solution got very warm and a precipitate formed immediately. The mixture was heated at 80° C. for two hours, then filtered, washed with toluene, and concentrated. Kugelrohr distillation at 80° C. (1.5 mmHg) afforded 4.1 g (86%) of the desired product. 1H NMR (CDCl3) δ1.8-1.2 (m, 6H), 1.1-0.7 (m, 3H), 0.17 (s, 9H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[CH:13][C:14]([CH2:19][CH3:20])=[C:15]([CH:18]=1)[CH:16]=[O:17]>>[CH2:19]([C:14]1[CH:13]=[CH:12][C:11]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:18][C:15]=1[CH:16]=[O:17])[CH3:20]
Reactant: OB(O)c1ccncc1
Reactant: CCc1ccc(Br)cc1C=O
Product: CCc1ccc(-c2ccncc2)cc1C=O

Procedure:
Pyridine-4-boronic acid (75 mg, 0.52 mmol) is coupled to aryl bromide 235 (111 mg, 0.52 mmol) using Method A to give the title compound.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH:7]=[CH:8][C:9]1=[N:10][CH2:11][CH2:12][N:13]([CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]1=2>CO>[ClH:3].[ClH:3].[Cl:3][C:4]1[CH:5]=[C:6]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH:7]=[CH:8][C:9]1=[N:10][CH2:11][CH2:12][N:13]([CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]1=2
Reactant: COC(=O)c1ccc(CN2CCN=C(C=Cc3ccc(Cl)c(Cl)c3)c3ccccc32)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cl
Product: O=C(O)c1ccc(CN2CCN=C(C=Cc3ccc(Cl)c(Cl)c3)c3ccccc32)cc1
Temperature: 60 °C
Reaction time: 72 h
Yield: 185.1 %

Procedure:
0.4 ml of 1M potassium hydroxide solution were added to a solution of 80 mg (0.17 mmol) of methyl (E)-4-[[5-(3,4-dichlorostyryl)-2,3-dihydro-1H-1,4-benzodiazepin-1-yl]methyl]benzoate in 8 ml of methanol. The mixture was heated at 60° C. for 4 hours then left at room temperature for 3 days. A further 0.2 ml of 1M potassium hydroxide solution were added followed by heating at 60° C. for 4 hours. The solvent was removed by evaporation and the residue dissolved in diethyl ether and water. The aqueous phase was separated, acidified with acetic acid and extracted three times with ethyl acetate. The combined organic extracts were dried over magnesium sulphate, filtered and evaporated to dryness. The residue was chromatographed on silica gel using dichloromethane/methanol/acetic acid/water (120:15:3:2) for the elution. The product was dissolved in a mixture of 10 ml of acetone and 0.2 ml of concentrated hydrochloric acid, evaporated to dryness and the residue triturated with diethyl ether. There was obtained 55 mg of (E)-4-[[5-(3,4-dichlorostyryl)-2,3-dihydro-1H-1,4-benzodiazepin-1-yl]methyl]benzoic acid dihydrochloride MS: m/e 451 [M+H]+.
Reaction SMILES: [CH3:1]N.[N+:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[N+:15]([O-])=O)[C:9]([OH:11])=[O:10])([O-:5])=[O:4]>CCO>[CH3:1][NH:15][C:14]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[N+:3]([O-:5])=[O:4]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: CN
Solvent: CCO
Product: CNc1ccc(C(=O)O)cc1[N+](=O)[O-]

Procedure:
TEA (13 mL) and methylamine (2 M in MeOH, 35 mL, 70 mmol) was added to 3,4-dinitrobenzoic acid (10 g, 47.2 mmol) in EtOH (50 mL) at rt. After 24 h at rt the mixture was concentrated and H2O was added to the residue. The mixture was filtered and acidified with AcOH. The solids were collected and dried to give the sub-title compound. Yield: 7.5 g (81%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[N:7][N:6]=[CH:5]2.[CH:18]1([NH:21][C:22](=[O:39])[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25](B3OC(C)(C)C(C)(C)O3)[CH:24]=2)[CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCO.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>[CH:18]1([NH:21][C:22](=[O:39])[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[N:7][N:6]=[CH:5]4)[CH:24]=2)[CH2:19][CH2:20]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccc2c(N3CCNCC3)nncc2c1
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: [K+]
Solvent: CCO
Solvent: COCCOC
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CCNCC3)nncc2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
A mixture of 6-bromo-1-(piperazin-1-yl)phthalazine (0.12g, 0.41 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.12g, 0.41 mmol), tetrakis(triphenylphosphine)palladium (24mg, 0.0205 mmol) and 2 M potassium carbonate (0.7 mL, 1.4 mmol) in 5 mL DME/EtOH (4:1) was stirred at 90° C. for 2 h. The mixture was directly purified via flash chromatography (silica gel) with a gradient of 2% 2 M ammonia in MeOH/DCM to 10% 2 M ammonia in MeOH/DCM to give the title compound (0.14g) as a yellow solid. Found MS (ES+): 388(M+H)+.
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11][NH2:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](N1C=CN=C1)(N1C=CN=C1)=[O:14].[CH2:25]([N:27]([CH2:33][CH3:34])[CH2:28][CH2:29][NH:30][CH2:31][CH3:32])[CH3:26].[C:35]([OH:47])(=[O:46])[CH2:36][C:37]([CH2:42][C:43]([OH:45])=[O:44])([C:39]([OH:41])=[O:40])[OH:38]>O1CCCC1.CO.CCOCC>[C:35]([OH:47])(=[O:46])[CH2:36][C:37]([CH2:42][C:43]([OH:45])=[O:44])([C:39]([OH:41])=[O:40])[OH:38].[CH2:25]([N:27]([CH2:33][CH3:34])[CH2:28][CH2:29][N:30]([CH2:31][CH3:32])[C:13]([NH:12][CH2:11][CH2:10][S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:8])=[O:9])=[O:14])[CH3:26]
Reactant: CCNCCN(CC)CC
Reactant: NCCS(=O)(=O)c1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: CCN(CC)CCN(CC)C(=O)NCCS(=O)(=O)c1ccccc1
Yield: 52 %

Procedure:
A solution of 5.55 g (0.030 mole) of 2-(phenylsulfonyl)ethanamine and 5.35 g (0.033 mole) of 1,1'-carbonyldiimidazole in 400 ml of tetrahydrofuran was stirred at room temperature for 1 hr. A solution of 4.62 g (0.032 mole) of N,N,N'-triethylethylenediamine in 50 ml of tetrahydrofuran was added, and the mixture was refluxed for 16 hr. The solvent was removed in vacuo, and the residue was partitioned between a mixture of 300 ml of methylene chloride and 500 ml of ether and water. The organic phase was dried over magnesium sulfate, and the solvent was removed in vacuo to give an oil. A solution of the oil in methanol was treated with an equivalent of citric acid and ether was added. A white precipitate formed to give 8.54 g (52.0%) of white crystalline solid, m.p. 105°-107° C.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[C:12]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)(=[O:14])[NH2:13]>>[CH3:8][C:7]1[C:2]([C:19]2[CH:20]=[C:15]([CH:16]=[CH:17][CH:18]=2)[C:12]([NH2:13])=[O:14])=[N:3][CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: NC(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc([N+](=O)[O-])cnc1Br
Product: Cc1cc([N+](=O)[O-])cnc1-c1cccc(C(N)=O)c1
Yield: 95 %

Procedure:
Obtained (0.225 g, yield 95%) following the procedure described in Intermediate 27, starting with 2-bromo-3-methyl-5-nitropyridine (0.92 mmol, 0.200 g), 3-carbamoylphenyl boronic acid (0.92 mmol, 0.152 g).
Reaction SMILES: [Br:1][CH2:2][C:3](OCC)([O:38]CC)[C:4](=[N:35][O:36][CH3:37])[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:12]([CH:15]=[CH2:16])[CH2:13][S:14][C@H:9]12)=[O:6].Cl.O>C(Cl)Cl>[Br:1][CH2:2][C:3](=[O:38])[C:4](=[N:35][O:36][CH3:37])[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])=[C:12]([CH:15]=[CH2:16])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)C(CBr)(OCC)OCC)[C@H]2SC1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)C(=O)CBr)[C@H]2SC1
Temperature: 25 °C
Yield: 60.5 %

Procedure:
To a solution of benzhydryl 7-(4-bromo-3,3-diethoxy-2-methoxyiminobutyramido)-3-vinyl-3-cephem-4-carboxylate (syn isomer) (6.5 g) in methylene chloride (60 ml) was added conc. hydrochloric acid (6 ml) at 3° to 5° C., and the mixture was stirred from under ice-cooling to at ambient temperature for 8 hours. After methylene chloride (100 ml) was added to the reaction mixture, it was heated with water and then dried over anhydrous magnesium sulfate. Removal of the solvent gave a residue, which was washed with diethyl ether to obtain benzhydryl 7-(4-bromo-2-methoxyiminoacetoacetamido)-3-vinyl-3-cephem-4-carboxylate (syn isomer) (3.5 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][N:10]([CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:11]1[N:16]=[C:15]([N:17]([CH3:19])[CH3:18])[CH:14]=[CH:13][N:12]=1.C(N(CC)CC)C>CN(C)C(=O)C>[CH3:9][N:10]([CH:20]1[CH2:25][CH2:24][N:23]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:22][CH2:21]1)[C:11]1[N:16]=[C:15]([N:17]([CH3:18])[CH3:19])[CH:14]=[CH:13][N:12]=1
Reactant: ClCc1ccccc1
Reactant: CN(C)c1ccnc(N(C)C2CCNCC2)n1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CN(C)c1ccnc(N(C)C2CCN(Cc3ccccc3)CC2)n1
Temperature: 75 °C
Reaction time: 2 h
Yield: 55.4 %

Procedure:
A mixture of chloromethylbenzene (1.9 g), intermediate 2 (3 g) and triethylamine (2.62 g) in N,N-dimethylacetamide (55 ml) was stirred for 2 hours at 75° C. The reaction mixture was poured out into ice-water and extracted with toluene. The separated organic layer was washed three times with water, dried, filtered and the solvent evaporated. The residue was dissolved in boiling petroleum ether and treated with activated charcoal. The mixture was filtered warm over dicalite, and the filtrate was concentrated. The concentrate was cooled on an ice-bath and the resulting precipitate was filtered off and dried, yielding 2.3 g (54.4%) of N2,N4,N4-trimethyl-N2-[1-(phenylmethyl)-4-piperidinyl]-2,4-pyrimidinediamine (comp. 8).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O-])=[O:14])=[CH:11][C:10]=1[CH:18]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:19][CH2:20][N:21]([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COCCO[AlH2-]OCCOC.[Na+].CO.O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][OH:14])=[CH:11][C:10]=1[C@@H:18]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:19][CH2:20][N:21]([CH:22]([CH3:23])[CH3:24])[CH:25]([CH3:26])[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N(CCC(c1ccccc1)c1cc(C(=O)[O-])ccc1OCc1ccccc1)C(C)C
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CO)ccc1OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5 gm (R)-[4-benzyloxy-3-(3-diisopropylamino-1-phenyl propyl)benzoate and 25 ml toluene was added under nitrogen atmosphere to a solution of 5.5 g Vitride in 50 ml toluene at 0° C. to 5° C. After stirring at room temperature for 5 hours, methanol was added drop wise at 0° C. to 5° C. After raising the temperature to room temperature, water and toluene was added and stirred for 30 minutes at 25° C. to 35° C. Layers were separated. Toluene layer after complete distillation afforded the title compound as (R)-[4-benzyloxy-3-(3-diisopropylamino-1-phenyl propyl)-phenyl]-methanol of formula (H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.C[C:13]1[NH:14][CH:15]=[CH:16][N:17]=1.[CH:18](N(CC)C(C)C)(C)C>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:17]1[CH:16]=[C:15]([CH3:18])[N:14]=[CH:13]1
Reactant: Cc1ncc[nH]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CC#N
Product: Cc1cn(-c2ccc([N+](=O)[O-])cc2F)cn1
Yield: 42.1 %

Procedure:
3,4-Difluoronitrobenzene (7.97 g, 50 mmol), 2-methylimidazole (4.51 g, 55 mmol) and N,N-diisopropylethylamine (16.16 g, 125 mmol) were dissolved in acetonitrile (80 mL) and the reaction was heated to reflux for 24 hours under an atmosphere of nitrogen. The solvent was evaporated under reduced pressure and the residue was crystallized from a mixture of ethyl acetate and heptane to yield the title compound (4.66 g, 42%) as a pale-yellow solid. MS ISP (m/e): 222.1 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=8.42 (d, 1H), 8.21 (d, 1H), 8.11 (s, 1H), 7.95 (t, 1H), 7.43 (s, 1H), 2.19 (s, 3H).
Reaction SMILES: CS([O:5][CH:6]([C:26]([NH:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:27])[CH2:7][CH2:8][S:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:14]=1)(=[O:11])=[O:10])(=O)=O.[C:37]([O-])(=[S:39])[CH3:38].[K+]>CN(C=O)C>[C:37](=[S:39])([O:5][CH:6]([C:26]([NH:28][CH2:29][CH2:30][N:31]1[CH2:32][CH2:33][O:34][CH2:35][CH2:36]1)=[O:27])[CH2:7][CH2:8][S:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:14]=1)(=[O:10])=[O:11])[CH3:38]
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)OC(CCS(=O)(=O)Cc1cccc(Oc2ccccc2)c1)C(=O)NCCN1CCOCC1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=S)OC(CCS(=O)(=O)Cc1cccc(Oc2ccccc2)c1)C(=O)NCCN1CCOCC1
Reaction time: 1 h
Yield: 69.1 %

Procedure:
Part I: A solution of 2.5 g (5 mmol) of 1-[(2-morpholinoethyl)amino]carbonyl-3-[(3-phenoxybenzyl)sulfonyl]propyl methanesulfonate from Part H in 20 mL of anhydrous DMF was treated with 0.8 g (7 mM) of potassium thioacetate. After 1 hour, the reaction was partitioned between ethyl acetate and sodium bicarbonate solution. The layers were separated and the organic layer was washed with brine (3×), dried (MgSo4) and concentrated to yield 2.4 g of crude product. This was chromatographed on silica gel using 1-3% methanol/ethyl acetate to yield 1.8 g of 1-[(2-morpholinoethyl)amino]carbonyl-3-[(3-phenoxybenzyl)sulfonyl]propyl ethanethioate suitable for the next reaction.
Reaction SMILES: [CH:1]([CH:4]([C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1)[C:5]#N)([CH3:3])[CH3:2].[OH-:18].[Na+].C(O)C[OH:22]>>[CH:1]([CH:4]([C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1)[C:5]([OH:22])=[O:18])([CH3:3])[CH3:2]
Reactant: CC(C)C(C#N)c1ccc(SC(F)(F)F)cc1
Reactant: OCCO
Reactant: [OH-]
Agent: [Na+]
Product: CC(C)C(C(=O)O)c1ccc(SC(F)(F)F)cc1
Temperature: 0 °C

Procedure:
α-Isopropyl-4-trifluoromethylthiophenylacetonitrile (6.9 g real, 0.0265 mol) and 50% sodium hydroxide (25 g, 0.312 mol) are combined in 53 ml of ethylene glycol and heated at gentle reflux for 18 hours. The reaction is poured into ice water and extracted with ether. The aqueous phase is acidified with concentrated HCl, then re-extracted with ether which is washed with water and dried over sodium sulfate. Evaporation in vacuo gives 2.05 g of an oil product.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH3:15])[C:9]=1[NH2:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:17]([O-])=O.[Na+]>C(O)(=O)C.O>[CH3:15][O:14][C:10]1[N:11]=[CH:12][CH:13]=[C:8]2[C:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:17][NH:16][C:9]=12
Reactant: O=N[O-]
Reactant: COc1nccc(Cc2ccccc2)c1N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1nccc2c(-c3ccccc3)n[nH]c12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 56.3 %

Procedure:
To a solution of 4-benzyl-2-methoxypyridin-3-amine (8.8 g) in acetic acid (310 mL) was added an aqueous solution prepared by dissolving sodium nitrite (2.83 g) in water (15.5 mL) at 0° C., and the mixture was stirred at 0° C. for 10 min, and then overnight at room temperature. The reaction mixture was concentrated under reduced pressure, to the residue was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethanol and hexane to give the title compound (5.2 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:12]([C:22]([F:25])([F:24])[F:23])=[N:11][N:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Br:26]NC(=O)CCC(N)=O>C(OCC)(=O)C>[Br:26][CH2:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:19])([CH3:20])[CH3:21])[C:12]([C:22]([F:24])([F:25])[F:23])=[N:11][N:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(-c2nnc(C(F)(F)F)n2COCC[Si](C)(C)C)c1
Reactant: NC(=O)CCC(=O)NBr
Solvent: CCOC(C)=O
Product: Cc1cc(CBr)cc(-c2nnc(C(F)(F)F)n2COCC[Si](C)(C)C)c1

Procedure:
The product from step (x) (2 g), N-bromosuccinamide (1 g) in dry ethyl acetate (25 ml) was irradiated at reflux with a 500 Watt halogen lamp for 1 h. The cooled reaction mixture was partitioned with dilute sodium bicarbonate solution. The organic layer collected, dried (MgSO4) and solvent removed by evaporation under reduced pressure. Yield:2.5 g The product was not purified but used directly in the next step.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1([CH3:25])[CH2:23][N:11]2[CH2:12][CH2:13][CH2:14][CH:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[N:10]2[C:9]1=[O:24])(=O)=O.[I-].[Na+].[C:28]([O-:31])(=[S:30])[CH3:29].[K+]>CC(C)=O>[C:28]([S:30][CH2:6][CH2:7][C:8]1([CH3:25])[CH2:23][N:11]2[CH2:12][CH2:13][CH2:14][CH:15]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[N:10]2[C:9]1=[O:24])(=[O:31])[CH3:29]
Reactant: CC(C)(C)OC(=O)C1CCCN2CC(C)(CCOS(C)(=O)=O)C(=O)N12
Reactant: CC([O-])=S
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(=O)SCCC1(C)CN2CCCC(C(=O)OC(C)(C)C)N2C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.9 %

Procedure:
A solution of 0.77 g tert.butyl hexahydro-2(2-methanesulfonyloxyethyl)-2-methyl-3-oxo-1H-pyrazolo[1,2-a]-pyridazine-5-carboxylate (diastereomer A) in 20 ml of acetone was treated with 0.3 g of sodium iodide and 0.23 g of potassium thioacetate. The mixture was then stirred at room temperature for 24 hours and subsequently evaporated. After chromatography of the residue on silica gel, there was obtained 0.43 g (59%) of tert.butyl hexahydro-2-(2-acetylthioethyl)-2-methyl-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate (diastereomer A) in the form of an oil.