Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]([CH3:25])[CH2:20][C:21](=[O:24])[NH:22][N:23]=2)=[CH:14][C:13]=1[N+:26]([O-:28])=[O:27].ClCCl>C(O)(=O)C>[C:1]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]([CH3:25])[CH2:20][C:21](=[O:24])[NH:22][N:23]=2)=[CH:14][C:13]=1[N+:26]([O-:28])=[O:27])(=[O:3])[CH3:2]
Reactant: CC1CC(=O)NN=C1c1ccc(NCCN)c([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)NCCNc1ccc(C2=NNC(=O)CC2C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.40 ml (4.23 mmol) of acetic anhydride is added to a solution of 1.00 g (3.43 mmol) of 6-[4-(2-aminoethyl)amino-3-nitro-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone in 10 ml of glacial acetic acid and the solution is stirred at room temperature for 20 hours. The precipitated solid is suction filtered and washed with 5 ml of dichloromethane. The mother liquor is concentrated by evaporation under vacuum and the residue obtained is stirred up with 5 ml of dichloromethane and filtered. The two crystal fractions are recrystallized together from ethanol (99.7%). 0.86 g (75%) of orange coloured crystals, m.p. 222° C., are obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([CH2:27][C:28]#[N:29])[CH:24]=[C:23]([O:30][CH3:31])[CH:22]=1>CC(O)C.CO>[CH3:31][O:30][C:23]1[CH:24]=[C:25](/[C:27](=[CH:15]/[C:14]2[CH:17]=[CH:18][C:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[CH:12][CH:13]=2)/[C:28]#[N:29])[CH:26]=[C:21]([O:20][CH3:19])[CH:22]=1
Reactant: COc1cc(CC#N)cc(OC)c1
Reactant: O=Cc1ccc(OCCCCCCCCO)cc1
Solvent: CO
Solvent: CC(C)O
Product: COc1cc(OC)cc(/C(C#N)=C/c2ccc(OCCCCCCCCO)cc2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 43.2 %

Procedure:
5.0 g (20.0 mmol) of 4-[(8-hydroxyoctyl)oxy]benzaldehyde, 3.5 g (19.8 mmol) of 3,5-(dimethoxyphenyl)acetonitrile are dissolved in 50 mL of propan-2-ol. The solution is heated to 60° C. and 2.0 mL (2.0 mmol) of a one molar solution of tetrabuthylamoniumhydroxyde in methanol are added drop wise. After 2 h at 60° C., the reaction mixture is cooled to 0° C. The precipitate is filtered off, washed with cold propan-2-ol and recristalized in propan-2-ol. 3.5 g of (2Z)-2-(3,5-dimethoxyphenyl)-3-{4-[(8-hydroxyoctyl)oxy]phenyl}prop-2-enenitrile are obtained as a white solid (42% yield). This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH:6]([CH:11]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]2=[O:19])[CH2:7][N+:8]([O-])=O)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:8][CH2:7][C@H:6]([CH:11]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[OH:19])[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:21][CH:20]=1
Reactant: O=C1CCCCCCC1C(C[N+](=O)[O-])c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC[C@@H](c1ccc(Cl)cc1)C1CCCCCCC1O

Procedure:
A solution of 7.4 g (23.9 mmol) of rac-(2S*)-2-[4-chloro-α-(nitromethyl)benzyl]cyclooctanone in 100 ml of dry tetrahydrofuran is added dropwise at 40° while stirring to a suspension of 2.3 g (59.7 mmol) of lithium aluminium hydride in 75 ml of dry tetrahydrofuran under argon and the mixture is stirred under reflux temperature overnight. The mixture is cooled, excess lithium aluminium hydride is destroyed with tetrahydrofuran/water (1:1), the separated precipitate is filtered off under suction while washing with methylene chloride and the filtrate is evaporated. The residue is dissolved in ether, the ethereal phase is extracted with 1N hydrochloric acid, the acidic phase is made alkaline with conc. ammonia and extracted with methylene chloride. The organic phase is washed with water, dried over magnesium sulphate and evaporated. After crystallization from methylene chloride/isopropyl ether there is obtained rac-(2S*)-2-[(R*)-α-(aminomethyl)-4-chlorobenzyl]cyclooctanol in the form of colourless crystals of m.p. 110°-111°.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:12]([CH3:18])([CH3:17])[C:13]([O:15]C)=[O:14])[C:7](=[O:19])[C:6]3([CH3:24])[CH2:20][O:21][CH2:22][CH2:23][N:5]3[C:4]=2[N:3]=1.[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:12]([CH3:18])([CH3:17])[C:13]([OH:15])=[O:14])[C:7](=[O:19])[C:6]3([CH3:24])[CH2:20][O:21][CH2:22][CH2:23][N:5]3[C:4]=2[N:3]=1
Reactant: COC(=O)C(C)(C)N1C(=O)C2(C)COCCN2c2nc(Cl)ncc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)N1C(=O)C2(C)COCCN2c2nc(Cl)ncc21
Reaction time: 48 h

Procedure:
To a suspension of methyl 2-(2-chloro-6a-methyl-6-oxo-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-2-methylpropanoate (82.6 mg, 0.233 mmol) in THF (6 ml) and MeOH (3 ml) was added 1 N NaOH aqueous solution (0.698 ml, 0.698 mmol), and the mixture was stirred for 2 days. After further addition of THF (20 ml) and MeOH (10 ml), the mixture was stirred for 16 hours and concentrated in vacuo to give a crude 2-(2-chloro-6a-methyl-6-oxo-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-2-methylpropanoic acid which was used in the next step without further purification. MS [M+H] found 341.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:33]=[CH:32][C:6]([C:7]([N:9]([C@@H:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:13][C@H:12]2[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)[CH3:10])=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:41](Cl)(=[O:43])[CH3:42].O>C1COCC1>[C:41]([N:21]1[CH2:22][CH2:23][CH:18]([CH2:17][N:14]2[CH2:15][CH2:16][C@@H:11]([N:9]([CH3:10])[C:7](=[O:8])[C:6]3[CH:5]=[CH:4][C:3]([Cl:2])=[CH:33][CH:32]=3)[C@H:12]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=3)[CH2:13]2)[CH2:19][CH2:20]1)(=[O:43])[CH3:42]
Reactant: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCN(CC2CCNCC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(CN2CC[C@@H](N(C)C(=O)c3ccc(Cl)cc3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1
Reaction time: 14 h
Yield: 12 %

Procedure:
To a solution of 4-chloro-N-[(3R,4R)-3-(3,4-dichlorophenyl)-1-(piperidin-4-ylmethyl)piperidin-4-yl]-N-methylbenzamide monohydrochloride (100 mg) obtained in Example 463 and triethylamine (78 μL) in THF (3 mL) was added acetyl chloride (40 μL) at room temperature, and the mixture was stirred for 14 hr. To the reaction mixture was added water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (12.5 mg, 12%) as a white powder.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>C(O)C>[CH2:13]1[CH:14]2[N:10]([CH2:2][CH:3]=[C:4]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[N:6][CH:5]=4)[NH:1][CH:2]=3)[CH2:5]2)[CH2:11][CH2:12]1
Reactant: C1CCNC1
Reactant: c1cc2[nH]ccc2cn1
Solvent: CCO
Product: C1=C(c2c[nH]c3ccncc23)CC2CCCN2C1
Yield: 102.9 %

Procedure:
A mixture of 5-azaindole (0.5 g, 4.23 mmol), 1,2,3,5,6,8,8a-heptahydrohydro-7-oxo-indolizine (589 mg, 4.23 mmol) and pyrrolidine (3.0 g, 42.3 mmol) in ethanol (4 mL) were heated to reflux for 6 hrs. The reaction mixture was cooled, filtered, and the collected solid washed with ether to give 3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-5-Azaindole (0.521 g, 51.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[N:13][N:14]=[C:7]1[C:6]([O:15]C)=[N:5]2.Cl>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[N:13][N:14]=[C:7]1[C:6]([OH:15])=[N:5]2
Reactant: COc1nc2cc(Cl)ccc2n2cnnc12
Agent: Cl
Solvent: CC(=O)O
Product: Oc1nc2cc(Cl)ccc2n2cnnc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture consisting of 3.4 g. (0.014 mole) of 7-chloro-4-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline, 35 ml. of 1N hydrochloric acid and 105 ml. of glacial acetic acid was refluxed for a period of 2.5 hours. Upon completion of this step, the reaction mixture was cooled to room temperature and poured over ice/water. The resulting mixture was then stirred for a period of 20 minutes, filtered and the recovered solid product washed with water and air-dried to constant weight to ultimately afford 2.6 g. (87%) of pure 7-chloro-4-hydroxy-[1,2,4]triazolo[4,3-a]quinoxaline, m.p.>300° C.
Reaction SMILES: [CH2:1]([Si:4]1([CH3:17])[CH2:9][CH2:8][CH:7](C2CCC(=O)CC2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Cl-].[NH4+]>C1COCC1>[CH2:1]([Si:4]1([CH3:17])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[Si]1(C)CCC(C2CCC(=O)CC2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC[Si]1(C)CCCCC1
Temperature: 25 °C

Procedure:
32 g of 1-bromo-4-(t-butyldimethylsiloxy)benzene was dropped in a mixture of 2.55 g of magnesium and 100 ml of THF, followed by refluxing for 3 hours to obtain a Grignard reagent. A solution of 31.4 g of 4-(4-n-propyl-4-methyl-4-silacyclohexyl)cyclohexanone in 50 ml of THF was added to the reagent. After refluxing for 2 hours, the reaction mixture was cooled down to room temperature and poured into an ammonium chloride aqueous solution and extracted with benzene. 1 g of p-toluenesulfonic acid was added to the resultant benzene solution. While refluxing, generated water was separated and removed. At the time when water was not distilled off at all, the mixture was cooled down to room temperature. The reaction mixture was poured into a sodium hydrogencarbonate aqueous solution. After ordinary washing, drying and concentration, the resulting residue was purified through silica gel chromatography to obtain 4-(4-(t-butyldimethylsiloxy)phenyl)-3-cyclohexenyl)-1-propyl-1-methyl-silacyclohexane. This product was dissolved in 200 ml of ethyl acetate and hydrogenated in the presence of a catalyst composed of 200 mg of palladium-carbon at a pressure of 0.5 MPa. After a theoretical amount of hydrogen had been consumed, the catalyst was removed by filtration and the resultant filtrate was concentrated. 100 ml of a THF solution of 1 mol/liter of tetrabutylammonium fluoride was added to the concentrate and agitated for 3 hours at room temperature. The reaction mixture was poured into 10% hydrochloric acid. After ordinary washing, drying and concentration, the residue was purified through silica gel chromatography.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[F:11][C:12]([F:20])([F:19])[C:13]([C:15]([F:18])([F:17])[F:16])=[O:14]>[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)Cl>[F:11][C:12]([F:20])([F:19])[C:13]([C:15]([F:18])([F:17])[F:16])([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:1][CH2:2][CH2:3][CH2:4]2)[OH:14]
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: OC(c1ccc2c(c1)CCCN2)(C(F)(F)F)C(F)(F)F
Temperature: 120 °C
Yield: 69.3 %

Procedure:
Two hundred grams of 1,2,3,4-tetrahydroquinoline and 2 g anhydrous aluminum chloride are added to a one liter stainless steel reactor. The reactor is cooled and evacuated, 265 g (1.60 moles) hexafluoroacetone is added, and it is sealed and heated to 120° C. with shaking for ten hours. The reactor is then cooled to room temperature and vented. The contents are decanted to give a red semicrystalline solid, which is treated with 250 ml of methylene chloride and filtered. The filter cake is washed with three additional 250 ml portions of methylene chloride. The residual orange solid is treated with decolorizing carbon in hot chlorobutane and filtered. From the filtrate is obtained 310 g (1.04 moles) α,α-bis(trifluoromethyl)-1,2,3,4-tetrahydro-6-quinolinemethanol, as a pale yellow crystalline solid, m.p. 115°-116° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[C:9](I)[N:8]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.O1CCCC1.O.[CH3:27][S:28]([N:31]1[CH2:36][CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH2:33][CH2:32]1)(=[O:30])=[O:29].C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([C:34]3[CH2:35][CH2:36][N:31]([S:28]([CH3:27])(=[O:30])=[O:29])[CH2:32][CH:33]=3)[N:8]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC1(C)OB(C2=CCN(S(C)(=O)=O)CC2)OC1(C)C
Reactant: O=S(=O)(c1ccccc1)n1c(I)cc2c(Cl)ncnc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)N1CC=C(c2cc3c(Cl)ncnc3n2S(=O)(=O)c2ccccc2)CC1
Temperature: 50 °C

Procedure:
To a solution of 4-chloro-6-iodo-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (1.9 g, 4.53 mmol) in 6:1 tetrahydrofuran/water (60 mL) was added 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (1.56 g, 5.43 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane complex (0.37 g, 0.453 mmol) and cesium carbonate (3.54 g, 10.87 mmol). The mixture was heated at 50° C. overnight, cooled and diluted with 50 mL ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water, and brine, dried over magnesium sulfate, filtered, and concentrated. Purification by flash chromatography on silica (Analogix 280) eluting with a gradient of 10% to 60% ethyl acetate/hexanes gave the title compound. MS (ESI+) m/z 452.5 (M)+.
Reaction SMILES: [OH-].[Na+].[C@@H:3]1([C:11]([O:13]CC)=[O:12])[CH2:5][C@H:4]1[C:6]([O:8]CC)=[O:7]>O.C(O)C>[C@@H:3]1([C:11]([OH:13])=[O:12])[CH2:5][C@H:4]1[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)[C@@H]1C[C@H]1C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)[C@@H]1C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium hydroxide (86.0 g, 2.15 mol) in water (400 mL) was added drop-wise to a stirred solution of diethyl rel-(1R,2R)-cyclopropane-1,2-dicarboxylate (200.0 g, 1.075 mol) in ethanol (400 mL) at 0° C. The reaction mixture was allowed to warm to ambient temperature. After 16 hours, the reaction mixture was concentrated under reduced pressure. The residue was diluted with cold water (500 mL) and extracted with ethyl acetate (2×500 mL). The organic layers were separated, and the aqueous layer was adjusted to pH˜2 using 1 N aqueous hydrochloric acid. The aqueous layer was extracted with ethyl acetate (2×1.0 L). The organic layers were combined, washed with water (1.0 L) and brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford rel-(1R,2R)-cyclopropane-1,2-dicarboxylic acid. 1H NMR (400 MHz, DMSO-d6): δ 12.57 (s, 2H), 1.95-1.85 (m, 2H), 1.30-1.20 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH:12]([OH:15])[CH2:13][OH:14])=[CH:6][C:5]=1[CH3:16])([O-])=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:29].Cl>[Zn].[Cl-].[NH4+].O.C(O)C>[ClH:29].[ClH:29].[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH:12]([OH:15])[CH2:13][OH:14])=[CH:6][C:5]=1[CH3:16]
Reactant: Cc1cc(NCC(O)CO)ccc1[N+](=O)[O-]
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Cc1cc(NCC(O)CO)ccc1N

Procedure:
The 3-(4-nitro-3-methylphenylamino)propane-1,2-diol (9) obtained above was reduced with a boiling zinc/ammonium chloride/water/ethanol mixture. The corresponding amine was isolated in dihydrochloride form.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][NH:9][C:10](=[O:13])[CH2:11][CH3:12])=[CH:6][CH:5]=[C:4]([N:14]2[CH2:18][CH2:17][C:16]([C:23]3[CH:28]=[C:27]([Cl:29])[C:26]([Cl:30])=[C:25]([Cl:31])[CH:24]=3)([C:19]([F:22])([F:21])[F:20])[CH2:15]2)[N:3]=1.ClCCl.C(O)(=[O:37])C>[O-2].[O-2].[Mn+4]>[OH:37][CH:15]1[C:16]([C:23]2[CH:24]=[C:25]([Cl:31])[C:26]([Cl:30])=[C:27]([Cl:29])[CH:28]=2)([C:19]([F:22])([F:20])[F:21])[CH2:17][CH2:18][N:14]1[C:4]1[N:3]=[C:2]([CH3:1])[C:7]([CH2:8][NH:9][C:10](=[O:13])[CH2:11][CH3:12])=[CH:6][CH:5]=1
Reactant: CCC(=O)NCc1ccc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C
Reactant: CC(=O)O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCC(=O)NCc1ccc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2O)nc1C
Temperature: 25 °C
Reaction time: 100 h

Procedure:
N-({2-Methyl-6-[3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-pyridin-3-yl}-methyl)propanamide (0.15 g) and manganese dioxide (1.2 g) were added to dichloromethane (20 ml), and acetic acid (2 ml) was added thereto in small portions at room temperature. The reaction mixture was stirred for 100 hours at room temperature, and filtered by suction on Celite. The filtrate was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to obtain N-({6-[2-hydroxy-3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-methylpyridin-3-yl}methyl)propanamide (0.06 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[C:11]([F:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[I-:23].[Na+].CNCCNC>[Cu](I)I.C(OCC)(=O)C.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([I:23])=[C:11]([F:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cc(OCc2ccccc2)ccc1Br
Reactant: [I-]
Agent: I[Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1cc(OCc2ccccc2)ccc1I
Temperature: 25 °C
Yield: 89.4 %

Procedure:
To a mixed solution of 4-(benzyloxy)-1-bromo-2-fluorobenzene (187 g, 665 mmol) described in Production Example 1-2-4 and 1,4-dioxane (300 mL) were added copper iodide (I) (12.6 g, 66.1 mmol), sodium iodide (200 g, 1.33 mol) and N,N′-dimethylethylenediamine (14.0 mL, 132 mmol) at room temperature, and the resultant mixture was stirred under a nitrogen atmosphere at 110 to 115° C. for 19 hours. The reaction mixture was cooled to room temperature, then water and ethyl acetate were added to the reaction mixture, the resultant mixture was filtrated using Celite, and a filtrate was partitioned between aqueous layer and organic layer. The aqueous layer was extracted with ethyl acetate. The combined organic layers were filtrated using a glass filter having silica gel laid thereon. The silica gel was washed with ethyl acetate, organic layers obtained were combined, and the solvent was evaporated under a reduced pressure. The resultant residue was purified by silica gel column chromatography (heptane:ethyl acetate=7:1 and then 4:1) to give the title compound (195 g, yield: 89%).
Reaction SMILES: Br[CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH2:3][C:4]([OH:6])=[O:5].[C:15]([O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[S:24])=[CH:21][CH:20]=1)(=[O:17])[CH3:16]>CN(C)C=O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[N:25]=[C:23]([C:22]3[CH:26]=[CH:27][C:19]([O:18][C:15](=[O:17])[CH3:16])=[CH:20][CH:21]=3)[S:24][C:2]=2[CH2:3][C:4]([OH:6])=[O:5])=[CH:9][CH:10]=1
Reactant: CC(=O)Oc1ccc(C(N)=S)cc1
Reactant: O=C(O)CC(Br)Cc1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(-c2nc(-c3ccc(Cl)cc3)c(CC(=O)O)s2)cc1

Procedure:
In a similar manner to Example 1(a), 3-Bromo-3-(4-chlorobenzyl)propionic acid and 4-acetoxy-thiobenzamide are reacted in dimethylformamide solvent to give the title compound.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[OH:21][CH:22]1[CH2:26][CH2:25][NH:24][CH2:23]1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:24]4[CH2:25][CH2:26][CH:22]([OH:21])[CH2:23]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: OC1CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC(O)C3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.2 %

Procedure:
A mixture of 2.1 g (7.8 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid, 20 ml acetonitrile, 1.2 g (7.8 mmole) 1,8-diazobicyclo[5.4.0]undec-7-ene and 0.7 g (7.8 mmole) of 3-hydroxypyrrolidine was refluxed for 2.5 hours. The reaction was allowed to cool and stirred at room temperature for 48 hours. The resulting precipitate was filtered, washed with diethyl ether, then taken up in isopropyl alcohol. The solid was filtered and washed with ether until dry to give 2.0 g of the title compound, mp 276°-278° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH2:7][CH:6]=[C:5]2[CH3:12].ClC1C(=O)C(=O)C(Cl)=C(Cl)C=1Cl>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9]([CH:8]=[CH:7][CH:6]=[C:5]2[CH3:12])=[CH:10][CH:11]=1
Reactant: CC1=CCCc2ccc(Cl)cc21
Agent: O=C1C(=O)C(Cl)=C(Cl)C(Cl)=C1Cl
Product: Cc1cccc2ccc(Cl)cc12

Procedure:
Using general procedure A (Exp. 1.2.), 6-chloro-4-methyl-1,2-dihydro-naphthalene was reacted with 3,4,5,6-tetrachloro-1,2-benzoquinone to give 7-chloro-1-methyl-naphthalene as a colorless oil.
Reaction SMILES: [C:1]([N:4]1[N:8]=[C:7]([C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])[O:6][C:5]1([CH2:23][CH2:24][CH2:25]O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C([O-])(O)=O.[Na+].C(C1C(CCC=O)(C2C=CC=CC=2)[CH:67]2COC3C=CC(Cl)=C[C:71]=3[N:66]2N=1)(=O)C.CNC.C(N(CC)CC)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.ClC(Cl)C.CCOC(C)=O.CCCCCC>[C:1]([N:4]1[N:8]=[C:7]([C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])[O:6][C:5]1([CH2:23][CH2:24][CH2:25][N:66]([CH3:71])[CH3:67])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1N=C(c2cc(F)ccc2F)OC1(CCCO)c1ccccc1
Reactant: CC(=O)C1=NN2c3cc(Cl)ccc3OCC2C1(CCC=O)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CNC
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(=O)N1N=C(c2cc(F)ccc2F)OC1(CCCN(C)C)c1ccccc1
Reaction time: 1.5 h

Procedure:
3-[3-acetyl-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-oxadiazol-2-yl]propan-1-ol (3-5, 25 mg, 69 umol) was dissolved in anhydrous CH2Cl2 (1 mL) and was treated with Dess-Martin periodinane (50 mg, 118 umol) and the resulting cloudy yellow solution was stirred 1.5 h. Upon completion, the cloudy solution was treated with 1 mL sat. sodium thiosulfate/NaHCO3 solution (1:1) and stirred 30 min. The mixture was extracted with EtOAc (3×5 mL), and the combined organics were dried (MgSO4), filtered and concentrated. The crude residue 3-[3-acetyl-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-oxadiazol-2-yl]propanal was carried directly into the next transformation. 3-(2-Acetyl-8-chloro-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazin-3-yl)propanal (25 mg, 39 mmol) was dissolved in anhydrous dichloroethane (1 mL) and treated sequentially with dimethylamine (2.0 M in THF, 42 μL, 84 mmol), triethylamine (19 μL, 140 umol) and Na(OAc)3BH (22 mg, 105 μmol). The reaction stirred 1 h at ambient temperature and was loaded directly onto a hexane flushed ISCO Redisep Column. Flash chromatography (Redisep® 12 g, 0-100% (3:1 EtOAc/(20:1:1 EtOH/NH4OH/H2O))/hexanes gradient) provided 3-[3-acetyl-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-oxadiazol-2-yl]-N,N-dimethylpropan-1-amine (3-6) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 7.58 (m, 2H), 7.51 (m, 1H), 7.37 (m, 3H), 7.16 (m, 2H), 2.91 (m, 1H), 2.54 (m, 1H), 2.36 (m, 2H), 2.35 (s, 3H), 2.21 (s, 6H), 1.61 (m, 2H); MS (M+H+, C21H23F2N3O2) 388.4 found 388.4 required.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([NH2:14])[N:11]=[C:10]([NH2:15])[N:9]=2)=[CH:4][CH:3]=1.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[NH2:14][C:12]1[N:11]=[C:10]([NH2:15])[N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:22]([C:16]3[CH:21]=[CH:20][C:19]4[C:18](=[CH:7][CH:2]=[CH:3][CH:4]=4)[CH:17]=3)(=[O:24])=[O:23])=[CH:7][CH:6]=2)[N:13]=1
Reactant: Nc1ccc(-c2nc(N)nc(N)n2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: Nc1nc(N)nc(-c2ccc(NS(=O)(=O)c3ccc4ccccc4c3)cc2)n1

Procedure:
6-(4-Aminophenyl)-1,3,5-triazine-2,4-diamine was processed as in Example 23 but substituting 2-naphthalenesulfonyl chloride for benzenesulfonyl chloride to provide the title compound.