Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[NH:4][C:5](=[O:9])[NH:6][C:7]=1[CH3:8].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1.O.O.[F-].[K+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:2]3[C:3](=[O:10])[NH:4][C:5](=[O:9])[NH:6][C:7]=3[CH3:8])[CH2:20][CH2:19]2)=[CH:16][CH:17]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: Cc1[nH]c(=O)[nH]c(=O)c1Br
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1[nH]c(=O)[nH]c(=O)c1N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 0 °C
Yield: 18.9 %

Procedure:
A mixture of 20.50 g (0.100 mole) of 5-bromo-6-methyl-2,4(1H, 3H)pyrimidinedione, 26.96 g (0.100 mole of 1-(4-chlorophenyl)-piperazine, 10.35 g (0.110 mole) of potassium fluoride dihydrate and 41.40 g (0.300 mole) of potassium carbonate in 200 ml of dimethylsulfoxide was heated at 80° for 72 hours. The reaction mixture was cooled and poured into 1 l of ice water. The solid was collected, washed with water, and recrystallized from ethanol to give 6.05 g of the product as a dull yellow solid.
Reaction SMILES: [OH-].[Na+:2].[C:3]([OH:10])(=[O:9])/[CH:4]=[CH:5]/[CH:6]=[CH:7]/[CH3:8]>>[C:3]([O-:10])(=[O:9])/[CH:4]=[CH:5]/[CH:6]=[CH:7]/[CH3:8].[Na+:2]
Reactant: C/C=C/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: C/C=C/C=C/C(=O)[O-]

Procedure:
To 135 parts of the above-prepared polyester, 110 parts of a concentrated hydrochloric acid was added, and the resulting mixture was heated to 80° C. to decompose the polyester. The resulting mixture was separated by filtration, and was washed to yield 123 parts of a crude sorbic acid. A sodium hydroxide aqueous solution was added to the crude sorbic acid to yield a sodium sorbate aqueous solution, and to the solution 6 parts of active carbon was added, and the resulting mixture was stirred for 30 minutes. The mixture was filtrated to remove the active carbon, and a neutralization amount of a concentrated hydrochloric acid was added to the filtrate and the mixture was cooled to precipitate sorbic acid. The precipitated sorbic acid was separated by filtration, was washed, and was dried in vacuo to yield 114 parts of sorbic acid. The yield of sorbic acid was 84.7% on the basis of the polyester.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[C:10]=2[CH:11]=1.S(Cl)(Cl)=O.[CH3:19]O>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:19])=[O:13])[C:10]=2[CH:11]=1
Reactant: O=C(O)c1cccc2cnc(Cl)cc12
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc2cnc(Cl)cc12
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A 20 mL microwave vial was charged with 3-chloroisoquinoline-5-carboxylic acid (1 g, 4.82 mmol) in 5 mL of MeOH and then was added with thionyl chloride (0.703 mL, 9.63 mmol). Stirred at 65° C. overnight and then concentrated in vacuo. Purified by silica gel chromatography (0-50% EtOAc in hexane) yielded Methyl 3-chloroisoquinoline-5-carboxylate (26-1).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:29]=[CH:28][C:27]([C:30]([O:32]C)=[O:31])=[CH:26][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[O:13][CH:12]([C:21](=[O:25])[N:22]([CH3:24])[CH3:23])[CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>O1CCCC1.CO>[CH:1]1([C:7]2[C:8]3[CH:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[O:13][CH:12]([C:21](=[O:25])[N:22]([CH3:23])[CH3:24])[CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N(C)C)Oc1ccccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)C(=O)C1Cn2c(c(C3CCCCC3)c3ccc(C(=O)O)cc32)-c2ccccc2O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 9.5 %

Procedure:
To a solution of methyl 12-cyclohexyl-6-dimethylcarbamoyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (100 mg, 0.22 mmol) in tetrahydrofuran (1 ml) and methanol (1 ml) was added 4N aqueous sodium hydroxide solution (1 ml), and the mixture was stirred at room temperature for 18 hr. 1N Hydrochloric acid was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (chloroform:methanol=30:1-20:1) to give 12-cyclohexyl-6-dimethylcarbamoyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid (9 mg, yield 9.4%).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][C:11]1=[O:19]>[SH-].[C+4].[SH-].[SH-].[SH-]>[Cl:1][CH2:2][C:3]([C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[NH:10][C:11](=[O:19])[CH2:12]2)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: O=C1Cc2ccccc2N1
Agent: [Al+3]
Agent: [C+4]
Agent: [Cl-]
Product: O=C1Cc2cc(C(=O)CCl)ccc2N1
Yield: 35.8 %

Procedure:
α-Chloroacetyl chloride (47.4 g) and 80.0 g of finely-ground anhydrous aluminum chloride were suspended in 100 ml of carbon bisulfide under ice-cooling. Oxindol (26.6 g) was added thereto with vigorous stirring and the mixture was refluxed for about 3 hours. Then the solvent was removed under reduced pressure, and the residue was poured into 1 l of ice-water and allowed to cool for a while. Crystals which precipitated were collected by filtration, washed successively with water, methanol, and diethyl ether, and dried to give 15 g of 5-(α-chloroacetyl)oxindol.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[C:15]2[CH2:14][CH2:13][N:12]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][C:6]=1[Cl:22].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[C:23]([NH:1][CH2:2][CH2:3][NH:4][C:5]1[C:15]2[CH2:14][CH2:13][N:12]([C:16](=[O:21])[C:17]([F:19])([F:18])[F:20])[CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][C:6]=1[Cl:22])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCNc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCNc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)c1ccccc1

Procedure:
Dissolve 6-(2-amino-ethylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (70 mg, 0.208 mmol) in DCM (4 mL). Add benzoyl chloride (24 μL, 0.208 mmol), and triethylamine (44 μL, 0.312 mmol) and stir at ambient temperature for 24 h under nitrogen atmosphere. Dilute with DCM and add 1M aqueous HCl. Extract the aqueous layer with DCM. Dry the organic layer over MgSO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 7:3 and 1:1) to obtain 6-(2-benzoylamino-ethylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]([C:11]([NH2:13])=[O:12])=[C:9]([N+:14]([O-])=O)[C:8]([CH2:17][CH3:18])=[N:7]1)[CH3:2].[H][H]>[Pt].C(OC(C)C)(=O)C>[NH2:14][C:9]1[C:8]([CH2:17][CH3:18])=[N:7][N:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[C:10]=1[C:11]([NH2:13])=[O:12]
Reactant: [H][H]
Reactant: CCOCCn1nc(CC)c([N+](=O)[O-])c1C(N)=O
Agent: [Pt]
Solvent: CC(=O)OC(C)C
Product: CCOCCn1nc(CC)c(N)c1C(N)=O

Procedure:
1-(2-ethoxyethyl)-3-ethyl-4-nitro-1H-pyrazole-5-carboxamide from step 1 (15.0 g, 58 mmol), 5% Platinum-on-carbon (0.75 g), and isopropyl acetate (150 mL) were combined and the mixture was stirred under 80 psi of hydrogen for about 50 hours. The mixture was then filtered through celite, the celite was rinsed with acetonitrile, and the filtrate was concentrated. The material eventually crystallized to give 13.7 g as a hydrate of the title compound.
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[C:7]1([C:13](Cl)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.O>CN(C)C=O>[I:1][C:2]1[N:3]=[CH:4][N:5]([C:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Ic1c[nH]cn1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 59.9 %

Procedure:
To 4-iodo-1H-imidazole (Preparation 71, 3.0 g, 15.3 mmol) in N,N-dimethylformamide (25 ml) was added triphenylmethyl chloride (4.72 g, 16.9 mmol) and then triethylamine (2.5 ml, 18.4 mmol). After stirring at room temperature for 2.5 h, water (200 ml) was added and the reaction mixture was filtered and washed with water. The crude solid was chromatographed on silica gel eluting with hexane:ethyl acetate (5:1 and then 2:1). The material was then recrystallised from hexane and dichloromethane to give the title compound as a white solid (4.0 g, 59%).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]([S:41]([CH3:44])(=[O:43])=[O:42])[CH:10]1[CH2:15][CH2:14][CH:13]([NH:16][C:17]2[N:22]=[C:21]([N:23]3[C:31]4[C:26](=[C:27]([N:32]5[CH2:37][CH2:36][N:35]([C:38](=[O:40])[CH3:39])[CH2:34][CH2:33]5)[CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24]3)[CH:20]=[CH:19][N:18]=2)[CH2:12][CH2:11]1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[C:38]([N:35]1[CH2:36][CH2:37][N:32]([C:27]2[CH:28]=[CH:29][CH:30]=[C:31]3[C:26]=2[CH:25]=[CH:24][N:23]3[C:21]2[CH:20]=[CH:19][N:18]=[C:17]([NH:16][CH:13]3[CH2:12][CH2:11][CH:10]([N:9]([CH2:8][CH2:7][OH:6])[S:41]([CH3:44])(=[O:43])=[O:42])[CH2:15][CH2:14]3)[N:22]=2)[CH2:33][CH2:34]1)(=[O:40])[CH3:39]
Reactant: CC(=O)N1CCN(c2cccc3c2ccn3-c2ccnc(NC3CCC(N(CCO[Si](C)(C)C(C)(C)C)S(C)(=O)=O)CC3)n2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N1CCN(c2cccc3c2ccn3-c2ccnc(NC3CCC(N(CCO)S(C)(=O)=O)CC3)n2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 62.1 %

Procedure:
1-{1-[2-(4-{[2-(t-Butyl-dimethyl-silanyloxy)-ethyl]-methanesulfonylamino}-cyclo-hexylamino)-pyrimidin-4-yl]-1H-indol-4-yl}-4-acetyl-piperazine (0.119 g, 0.178 mmol) in THF (2.5 mL) was cooled in an ice bath under N2, and TBAF (0.18 mL, 1.01 eq) slowly added. The reaction mixture was allowed to warm to RT slowly, and stirred at RT for 15 h. The product was taken up in water and EtOAc, extracted with EtOAc, and the organic fractions washed with water, dried over Na2SO4, concentrated, and chromatographed (0% to 5% MeOH/DCM) to provide N-(4-{4-[4-(4-acetyl-piperazin-1-yl)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-N-(2-hydroxy-ethyl)-methanesulfonamide (Compound 320, 61.4 mg, 62%).
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)=O.[OH-].[Na+]>C(O)C>[N:6]1([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:20]=[CH:21][C:22]([S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])=[CH:23][CH:24]=3)[N:10]=2)[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]1
Reactant: CCCS(=O)(=O)c1ccc(-c2cc3ccccc3c(N3CCN(C=O)CC3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCS(=O)(=O)c1ccc(-c2cc3ccccc3c(N3CCNCC3)n2)cc1
Yield: 90.7 %

Procedure:
To the resulting 1-(4-formylpiperazin-1-yl)-3-[4-(propylsulfonyl)phenyl]isoquinoline (0.72 g) were added ethanol (25 ml) and a 8N aqueous solution of sodium hydroxide (1.06 ml), and the mixture was heated under reflux in nitrogen atmosphere for 1.5 hr. The solvent was evaporated, and to the resulting residue were added water and ethyl acetate. The organic layer was separated. Then, it was washed with brine, and dried over magnesium sulfate. The solvent was evaporated, to give 1-(piperazin-1-yl)-3-[4-(propylsulfonyl)phenyl]isoquinoline (0.61 g) as a colorless powder.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18].O[C@@H:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[N+:17]([C:9]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=1[C@H:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])([O-:19])=[O:18]
Reactant: CCOC(=O)[C@H](C)O
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)[C@@H](C)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
In the presence of potassium carbonate, 1-fluoro-2,4-dinitrobenzen was treated with ethyl (2S)-(−)-2-hydroxypropanoate to obtain ethyl (2S)-2-(2,4-dinitrophenyl)propionate.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]([O:15][CH3:16])=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[C:7]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH:6]=1)([CH3:3])[CH3:2].CO.[OH-].[Na+]>O1CCCC1>[CH:1]([O:4][C:5]1[C:14]([O:15][CH3:16])=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[C:7]([NH:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH:6]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(OC)c(OC(C)C)cc1NCc1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CNc2cc(OC(C)C)c(OC)cc2C(=O)O)cc1
Yield: 99.1 %

Procedure:
A mixture of methyl 4-isopropoxy-5-methoxy-2-(4-methoxybenzyl)aminobenzoate (18.9 g), methanol (50 ml), tetrahydrofuran (150 ml) and a 1N aqueous sodium hydroxide solution (80 ml) was stirred at room temperature for 1 night, heated under reflux for 12 hours. The solvent was distilled off under reduced pressure, the reaction mixture was adjusted to about pH 6 by adding 1N hydrochloric acid and 5% citric acid. The precipitated solid was collected by filtration, washed and dried to obtain the target compound (18.0 g).
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(O)C.Cl[CH2:8][CH2:9][CH:10]1[CH2:16][N:15]([CH3:17])[C:14](=[S:18])[C:13]2[CH:19]=[CH:20][CH:21]=[N:22][C:12]=2[O:11]1.[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27]>C(Cl)Cl.C(O)(C)C.CO>[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27].[CH3:1][N:2]([CH3:3])[CH2:8][CH2:9][CH:10]1[CH2:16][N:15]([CH3:17])[C:14](=[S:18])[C:13]2[CH:19]=[CH:20][CH:21]=[N:22][C:12]=2[O:11]1
Reactant: CNC
Reactant: CN1CC(CCCl)Oc2ncccc2C1=S
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CC(C)O
Solvent: CO
Product: CN(C)CCC1CN(C)C(=S)c2cccnc2O1
Temperature: 100 °C

Procedure:
To a solution of 113 ml (1.0 mole) of 40% aqueous dimethylamine and 326 ml of ethanol in a steel bomb was added 48.4 g (0.189 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepine-5(4H)-thione. The mixture was heated at 100° C. for 14 hr. The ethanol was removed in a rotary evaporator leaving some water in the residue. The residue was dissolved in 200 ml of methylene chloride and washed with three 100 ml portions of 20% aqueous potassium carbonate solution. The combined aqueous layers were extracted with three 150 ml portions of methylene chloride. Methylene chloride solutions were combined and treated with charcoal. Charcoal was filtered off and the filtrate was evaporated to give an oil. The oil was dissolved in 215 ml isopropyl alcohol and the solution was heated to a slow boil. A solution of 21.9 g (0.19 mole) of fumaric acid in 150 ml of boiling methanol was added to the isopropyl alcohol solution. Crystalline solid was obtained weighing 63.4 g (88%). The solid was recrystallized from hot 200 proof ethyl alcohol. The crystals were filtered off and triturated in isopropyl ether at room temperature and again separated by filtering. After drying in a vacuum oven overnight at 85° C., crystals in the amount of 72.45 g (79%), m.p. 130°-133° C., were obtained.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:16][C:17]1[CH:18]=[C:19]([OH:24])[CH:20]=[CH:21][C:22]=1[F:23].[BH4-].[Na+].Cl>CN(C)C=O.O.C(O)C>[F:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][C:22]=1[F:23])[O:24][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)c(F)c1
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: OCc1ccc(Oc2ccc(F)c(F)c2)cc1
Temperature: 135 °C
Reaction time: 2.5 h
Yield: 92.7 %

Procedure:
To a solution of 4-fluorobenzaldehyde (2.50 g, 20.1 mmol) in N,N-dimethylformamide (13 mL) were added potassium carbonate (3.33 g, 24.1 mmol) and 3,4-difluorophenol (2.61 g, 20.1 mmol) in turn, and the mixture was stirred for 2.5 hours at 135° C. Water was added to the reaction mixture, which was extracted with ethyl acetate. Then the ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. To the residue were added ethanol (50 mL) and sodium borohydride (760 mg, 20.1 mmol) in turn, and the mixture was stirred for 4 hours at room temperature. Water was added to the reaction mixture, which was brought to pH 4 with 3 mol/L hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1→3:1) to afford 4.40 g of pale yellow liquid title compound. Yield 93%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:4]=1[CH:5]=O.C([O-])(=O)C.[NH4+:16].CO.Cl>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:4]=1[CH2:5][NH2:16]
Reactant: COc1ccc(I)cc1C=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CO
Product: COc1ccc(I)cc1CN
Temperature: 25 °C
Reaction time: 48 h
Yield: 40 %

Procedure:
To a stirred solution of 67 (500 mg, 1.9 mmol) and ammonium acetate (1.5 g, 19.4 mmol) in dry methanol (6 mL) NaCNBH3 (170 mg, 2.66 mmol) was added in one portion. The resulting mixture was stirred at room temperature for 48 h. Concentrated HCl was added until pH<2. The methanol was evaporated and the resulting white residue was dissolved in water (10 mL) and washed with Et2O (2×10 mL). The aqueous phase was then basified with aqueous KOH (45%), saturated with NaCl and extracted with CH2Cl2 (10 mL×4). The combined organic phases were dried over Na2SO4, filtered and concentrated to give 68 as a yellow oil (200 mg, 40%). 1H NMR (CDCl3, 300 MHz) δ 7.55-7.45 (m, 2H), 6.46-6.58 (m, 1H), 3.82-3.72 (m, 5H), 1.63 (br s, 2H). MS (m/e) (positive FAB) 264.1 (M+H)+, m.p. 95-97° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:23]2[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=2)[CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:21]=2[CH3:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:21]=2[CH3:22])[C:23]2[CH:28]=[CH:27][C:26]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[CH:25][CH:24]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccncc1CN(c1ccc(Br)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C1COCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: Cc1ccncc1CN(c1ccc(N2CCOCC2)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 71.4 %

Procedure:
A solution of 4-[(4-bromo-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 352) (300 mg, 0.630 mmol), Pd(OAc)2 (7.10 mg, 0.0315 mmol), potassium tert-butoxide (106 mg, 0.945 mmol), morpholine (50.0 μL, 0.573 mmol) and tri(tert-butyl)phosphine (128 mg, 0.0315 mmol) in degassed toluene (2.2 mL) was stirred at 100° C. for 16 hours under nitrogen. Standard work-up and purification gave 4-[(4-methyl-pyridin-3-ylmethyl)-(4-morpholin-4-yl-phenyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (191 mg, 74%).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[CH2:10][C:11]1[NH:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1>>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([CH2:10][C:11]2[NH:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:4][CH2:3]1
Reactant: CN1CCCNCC1
Reactant: ClCc1nc2ccccc2[nH]1
Product: CN1CCCN(Cc2nc3ccccc3[nH]2)CC1
Yield: 26 %

Procedure:
In the same manner as described in Reference Example 4, N-methylhomopiperazine (15 g) and 2-chloromethylbenzimidazole (10 g) are reacted, and the crude crystal thus obtained is recrystallized from toluene to give 2-(4-methyl-1-homopiperazinyl)methylbenzimidazole (3.81 g) as pale yellow prisms, m.p. 152°-155° C.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[C:6]([CH2:12][CH:13]([OH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][N:4]=1)[CH3:2].C(O)(=O)C>[O-2].[O-2].[O-2].[Cr+6].O>[CH2:1]([C:3]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[C:6]([CH2:12][C:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:20])[O:5][N:4]=1)[CH3:2]
Reactant: CCc1noc(CC(O)c2ccccc2)c1C(=O)NC
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: O
Product: CCc1noc(CC(=O)c2ccccc2)c1C(=O)NC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 29.0 g. (0.105 mole) of 3-ethyl-5-(β-hydroxyphenethyl)-N-methyl-isoxazole-4-carboxamide and 500 ml. acetic acid at room temperature is treated dropwise rapidly with 12.5 g. (0.125 mole) of chromium trioxide in 125 ml. water. The resulting solution is stirred for 2 hours at room temperature and a portion of the acetic acid is removed in vacuo. The remainder is poured onto ice water and extracted with methylene chloride. The methylene chloride layer is washed with 2 N sodium hydroxide, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The solid residue is triturated with ether and recrystallized from ethanol to give 3-ethyl-N-methyl-5-phenacyl-4-isoxazole carboxamide, m.p. 134° to 136° C.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([CH3:31])=[C:25]([CH3:32])[C:4]=1[CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:33]([O:35][C:36](=[O:47])[CH:37]=[C:38]([CH3:46])[CH:39]=[CH:40][CH:41]=[C:42]([CH:44]=O)[CH3:43])[CH3:34]>>[CH2:33]([O:35][C:36](=[O:47])[CH:37]=[C:38]([CH3:46])[CH:39]=[CH:40][CH:41]=[C:42]([CH3:44])[CH:43]=[CH:5][C:4]1[C:25]([CH3:32])=[C:26]([CH3:31])[C:27]([O:29][CH3:30])=[CH:28][C:3]=1[Cl:2])[CH3:34]
Reactant: COc1cc(Cl)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1C
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C=O
Agent: [Cl-]
Product: CCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(Cl)cc(OC)c(C)c1C

Procedure:
By the procedure of Example 1, 2-chloro-4-methoxy-5,6-dimethyl-benzyl-triphenylphosphonium chloride is reacted with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid ethyl ester to obtain 9-(2-chloro-4-methoxy-5,6-dimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid ethyl ester, a yellow-red oil.
Reaction SMILES: [Br:1][C:2](Br)([Br:12])[CH:3]1[CH:8]2[CH:6]([C:7]2([CH3:10])[CH3:9])[C:5](=[O:11])[O:4]1.O>C(O)(=O)C.CCOCC.[Zn]>[Br:1][C:2]([Br:12])=[CH:3][C@@H:8]1[C@H:6]([C:5]([OH:11])=[O:4])[C:7]1([CH3:9])[CH3:10]
Reactant: CC1(C)C2C(=O)OC(C(Br)(Br)Br)C21
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOCC
Product: CC1(C)[C@H](C=C(Br)Br)[C@@H]1C(=O)O
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a chilled suspension of zinc powder (0.494 g, 0.0076 mole) in 0.57 ml of acetic acid and 3 ml of ether was added dropwise over a period of 20 minutes a solution of 4-tribromomethyl-6,6-dimethyl-2-oxo-3-oxabicyclo[3.1.0]hexane (0.72 g, 0.0019 mole) in 5 ml of ether. The mixture was stirred at 0° for one hour. After adding 30 ml of ether and 5 ml of water, the mixture was filtered through Celite filter aid. The organic layer was separated, washed three times with saturated aqueous sodium chloride, dried magnesium sulfate, and the ether was removed by evaporation to give crystalline cis-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylic acid (0.489 g, 86% yield); mp, 112°-114° after recrystallization from n-hexane.