Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]=[CH:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)=[O:6].[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:35][CH2:34][N:33]([CH2:2][CH2:3][CH2:4][C:5]([NH:7][CH:8]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[CH:12]=[CH:11][C:10]4[CH:19]=[CH:20][CH:21]=[CH:22][C:9]3=4)=[O:6])[CH2:32][CH2:31]2)=[CH:28][CH:29]=1
Reactant: O=C(CCCCl)NC1c2ccccc2C=Cc2ccccc21
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCCN1CCN(c2ccc(F)cc2)CC1)NC1c2ccccc2C=Cc2ccccc21
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 73.9 %

Procedure:
A mixture of 5.0 g of 5-(4-chlorobutyrylamino)-5H-dibenzo[a,d]cycloheptene, 5.8 g of 1-(4-fluorophenyl)piperazine, 5.0 g of sodium iodide and 50 ml of dimethylformamide is stirred at 100° C. for 1.5 hours. After the reaction mixture is cooled to room temperature, 100 ml of 10% aqueous potassium carbonate solution is added and the solution is extracted with three 300-ml portions of chloroform. The combined extracts are washed successively with water and saturated aqueous sodium chloride solution, and dried over magnesium sulfate, and the chloroform is distilled off. The residue is chromatographed on silica gel with chloroform-methanol (100:3) to give 5.4 g of the title compound. m.p. 233°-235° C. (recrystallized from chloroform-ethyl acetate);
Reaction SMILES: O1CC[O:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH2:11])=[O:10].CO[C:17](OC)([N:19](C)C)[CH3:18]>>[CH3:18][C:17]1[N:11]=[C:9]([C:8]2[CH:7]=[C:6]([CH:14]=[CH:13][CH:12]=2)[CH:2]=[O:3])[O:10][N:19]=1
Reactant: NC(=O)c1cccc(C2OCCO2)c1
Reactant: COC(C)(OC)N(C)C
Product: Cc1noc(-c2cccc(C=O)c2)n1
Temperature: 90 °C
Yield: 102.7 %

Procedure:
A mixture of 3-[1,3]dioxolan-2-yl-benzamide (2.3 g) and dimethylacetamide dimethylacetal (4 g) was heated under reflux for 1 hour and then evaporated to dryness. The oily residue was dissolved in dioxane (20 mL) and hydroxylamine hydrochloride (1.18 g), acetic acid (20 mL) and a 2N aqueous sodium hydroxide solution (9 mL) were added and the mixture was heated at 90° C. for 2 hours. After evaporation, the residue was dissolved in toluene (100 mL) and a 1N hydrochloric acid solution (50 mL) was added and the mixture was stirred at reflux for 2 hours. After cooling at room temperature the organic phase was decanted, washed with water, dried over Na2SO4, filtered and evaporated to give the title compound (2.3 g) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[CH:20]=[CH:19][C:18]3[N:17]([CH3:21])[C:16]4[CH2:22][CH:23]5[NH:27][CH:26]([C:15]=4[C:14]=3[C:13]=2[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25][CH2:24]5)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[BH4-].[Na+]>CO.[Co](Cl)Cl>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([S:9]([C:12]2[CH:20]=[CH:19][C:18]3[N:17]([CH3:21])[C:16]4[CH2:22][CH:23]5[NH:27][CH:26]([C:15]=4[C:14]=3[C:13]=2[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25][CH2:24]5)(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccc(C#N)cc4)ccc31)C1CCC(C2)N1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccc(CN)cc4)ccc31)C1CCC(C2)N1
Temperature: 0 °C
Reaction time: 2 h
Yield: 43.7 %

Procedure:
A mixture of the product of Example 30, step A (92 mg, 0.19 mmol) and cobalt(II) chloride (25 mg, 0.19 mmol) in anhydrous methanol (1.5 mL), cooled to 0° C. was treated with sodium borohydride (22 mg, 0.58 mmol). The reaction mixture was stirred at 0° C. for 2 h then quenched with water and filtered through a celite bed. The filtrate was concentrated in vacuo and extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 80:18:2 chloroform/methanol/ammonium hydroxide) to give tert-butyl 2-(4-aminomethylphenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (40 mg, 43%) as a light-yellow solid: ESI MS m/z 382 [M+H]+
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5](CCC)[N:4]=1)#[N:2].[Na].[C:13](O)(=[O:15])C>C[O-].[Na+].CO>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1](=[NH:2])[O:15][CH3:13]
Reactant: CC(=O)O
Reactant: CCCc1cccc(C#N)n1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=N)c1ccccn1
Reaction time: 8 h
Yield: 618.6 %

Procedure:
2-Cyano-6-n-propylpyridine (10 g) was dissolved in a solution of sodium methoxide in methanol prepared from methanol (100 ml) and metallic sodium (0.32 g). After standing overnight, acetic acid (0.82 g) was added thereto, followed by concentration under reduced pressure. The resulting residue was dissolved in ether (200 ml) and insoluble materials were filtered out. The filtrate was concentrated under reduced pressure to obtain methyl 2-picoline-imidate (11.5 g, yield: 94%).
Reaction SMILES: [F:1][C:2]1[C:3]([O:19]C)=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][C:8]1[C:12]([F:18])=[C:13]([O:16]C)[CH:14]=[CH:15][C:7]2=1.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[C:3]([OH:19])=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][C:8]1[C:12]([F:18])=[C:13]([OH:16])[CH:14]=[CH:15][C:7]2=1
Reactant: COc1ccc2c(c1F)COc1c-2ccc(OC)c1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc2c(c1F)COc1c-2ccc(O)c1F
Temperature: 8 °C
Reaction time: 1 h

Procedure:
5.23 g (18.8 mmol) of 4,7-difluoro-3,8-dimethoxy-6H-benzo[c]chromene (prepared by the method of: Taugerbeck, Klasen-Memmer, WO 2004076438) are initially introduced in 70 ml of dichloromethane, and a solution of 5 ml (52.7 mmol) of boron tribromide in 10 ml of dichloromethane is added dropwise with ice cooling. After 1 h, the cooling is removed, and the batch is left to stir at room temp. for 3 h and added to ice-cold 1 M sodium hydroxide solution. The aqueous phase is separated off and extracted three times with ethyl acetate. The combined org. phases are washed with sat. sodium chloride soln. and dried over sodium sulfate. The solvent is removed in vacuo, the residue is filtered through silica gel with toluene/ethyl acetate (3:2), and the crude product is washed by stirring with hot heptane/ethyl acetate (2:1) and filtered off with suction after cooling to 8° C., giving 4,7-difluoro-6H-benzo[c]chromene-3,8-diol as colourless solid.
Reaction SMILES: [NH2:1][C:2]([C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[C:23]([O:30]C)[CH:22]=1)([CH2:6][CH:7]1[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]([OH:5])=[O:4].B(Br)(Br)Br>ClCCl.O>[NH2:1][C:2]([C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[C:23]([OH:30])[CH:22]=1)([CH2:6][CH:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[O:14][C:15]2[C:20]1=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3]([OH:5])=[O:4]
Reactant: COc1cc(C(N)(CC2c3ccccc3Oc3ccccc32)C(=O)O)ccc1C(=O)O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: NC(CC1c2ccccc2Oc2ccccc21)(C(=O)O)c1ccc(C(=O)O)c(O)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of 2-amino-2-(4-carboxy-3-methoxyphenyl)-3-(9H-xanthen-9-yl)propanoic acid (140 mg, 0.33 mmol) in dry dichloromethane (10 ml) was added a solution of boron tribromide in dichloromethane (1.0M, 0.7 ml). The resulting suspension was stirred at room temperature for 3 days, diluted with water and stirred a further 2 h. The dichloromethane layer was separated and the aqueous phase purified by ion exchange as described in Example 1 (vi). The water-tetrahydrofuran fractions were found to contain the desired product and were combined, evaporated and freeze-dried from water to give the title compound as a white powder, m.p. 191°-194° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][NH:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH3:13][N:14]([C:8](=[O:10])[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=1)[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)CCNC
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCN(C)C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a mixture of 4-nitrobenzoic acid (16.7 g), ethyl 3-(methylamino)propanoate (13.1 g), 1-hydroxybenzotriazole monohydrate (18.4 g), and N,N-dimethylformamide (200 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (23.0 g), and the mixture was stirred at room temperature for 8 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (28.0 g, 100%) as an oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16]CC)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([NH2:21])=O.C[O-].[Na+]>CN(C)C=O.CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:16])[NH2:21])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: NC(=O)C1CCN(Cc2ccccc2)CC1

Procedure:
To a mixture of 1-benzyl-4-ethoxycarbonylpiperidine (6.88 g) and formamide (3.71 ml) in N,N-dimethylformamide (30 ml) was added 28% sodium methoxide solution in methanol (4.0 ml) at 100° C. under stirring. After stirring at 100° C. for 1 hour, the mixture was evaporated in vacuo. The residue was dissolved in ethyl acetate and washed with water and brine and dried over magnesium sulfate, and evaporated in vacuo. The residue was recrystallized from ether to give 1-benzyl-4-carbamoylpiperidine (2.8 g).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C=O)C>[CH2:14]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1C(=O)N(Cc2ccccc2)c2ccccc21
Reaction time: 0.33 h
Yield: 84.9 %

Procedure:
Prepared according to literature procedure (C. Martin and E. M. Carreira, J. Am. Chem. Soc., 2005, 127, 11505-11515). A stirred solution of isatin (10.0 g, 68 mmol) in dry DMF (125 mL) was cooled in an ice bath before addition of sodium hydride (60 wt % in mineral oil, 2.86 g, 71.5 mmol) in 10 portions, the orange solution turning quickly purple. When no further evolution of gas was observed, benzyl bromide (13.4 g, 78.0 mmol) was added by syringe. A colour change back to orange was observed within 20 min. Water (300 mL) was added with stirring, and the resulting orange-red precipitate collected by filtration and washed with water and a little cold ethanol. The solid was then recrystallized from boiling ethanol (300 mL) to afford N-benzylisatin (13.7 g, 85%) as long, red needles.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]3[CH:23]=[C:22]([Sn](CCCC)(CCCC)CCCC)[N:21]=[CH:20]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:37][C:38]([NH:41][S:42]([C:45]1[S:49][C:48](Br)=[CH:47][CH:46]=1)(=[O:44])=[O:43])([CH3:40])[CH3:39].CCCCCC>C1(C)C=CC=CC=1>[C:38]([NH:41][S:42]([C:45]1[S:49][C:48]([C:22]2[N:21]=[CH:20][N:19]([C:11]3[N:10]=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[CH:14]=[C:13]([C:15]([F:18])([F:16])[F:17])[N:12]=3)[CH:23]=2)=[CH:47][CH:46]=1)(=[O:43])=[O:44])([CH3:40])([CH3:37])[CH3:39]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(-c3ccc(Cl)c(Cl)c3)cc(C(F)(F)F)n2)cn1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
A stirred mixture of 4-(3,4-dichloro-phenyl)-2-(4-tributylstannanyl-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (Example G.6) (0.46 g, 0.71 mmol), commercially available 5-bromothiophene-2-N-tert-butylsulfonamide (0.23 g, 0.78 mmol), tetrakis(triphenyl-phosphine)palladium (0.049 g, 0.042 mmol) in toluene (8 mL) was heated under reflux conditions for 15 h, hexane (10 mL) was added and the mixture was stirred at RT for 1 h. The precipitate was collected by filtration and dried to yield 5-{1-[4-(3,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.34 g) as a white solid.
Reaction SMILES: [OH:1]O.[CH2:3]([N:6]1[C@H:11]([CH3:12])[CH2:10][N:9]([C@H:13]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]#[N:25])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[C@@H:8]([CH3:29])[CH2:7]1)[CH:4]=[CH2:5].[OH-].[Na+].Cl>C(O)C>[CH2:3]([N:6]1[C@H:11]([CH3:12])[CH2:10][N:9]([C@H:13]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]([NH2:25])=[O:1])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[C@@H:8]([CH3:29])[CH2:7]1)[CH:4]=[CH2:5]
Reactant: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C#N)c2)C[C@H]1C
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(N)=O)c2)C[C@H]1C
Temperature: 60 °C
Yield: 79 %

Procedure:
Hydrogen peroxide (0.5 mL of a 30% by weight solution) was added to a mixture of the benzonitrile (0.50 g, 1.4 mmol), 0.7 mL of 10N aqueous sodium hydroxide and 3 mL of ethanol. The reaction was exothermic with gas evolution and formation of a white precipitate. After a few minutes, the mixture was carefully heated under a reflux condenser in an oil bath at 60° C. for three hours. After cooling to room temperature, 6N aqueous hydrochloric acid was added to adjust the pH to 8. The mixture was evaporated to dryness under vacuum, and the residue was extracted between ethyl acetate and pH 8 buffer solution. The organic layer was washed with pH 8 buffer and brine, dried over sodium sulfate, and the solvent was evaporated to give 0.42 g (79%) of (±)-3-((αR*)-α-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzamide as a bright yellow solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][N:20]3[C:29](=[O:30])[CH2:28][C:23]4([CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:22](C(OOCC4C=CC([N+]([O-])=O)=CC=4)=O)[C:21]3=[O:45])[CH2:12][CH2:11]2)=[N:2]1.CO.C1C[O:51]CC1>[Pd]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][N:20]3[C:29](=[O:30])[CH2:28][C:23]4([CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:22]([OH:51])[C:21]3=[O:45])[CH2:14][CH2:15]2)=[N:2]1
Reactant: C1CCOC1
Reactant: O=C(OOCc1ccc([N+](=O)[O-])cc1)C1C(=O)N(CCCCN2CCN(c3nsc4ccccc34)CC2)C(=O)CC12CCCC2
Agent: [Pd]
Solvent: CO
Product: O=C1CC2(CCCC2)C(O)C(=O)N1CCCCN1CCN(c2nsc3ccccc23)CC1
Reaction time: 1.5 h
Yield: 69 %

Procedure:
A mixture of 8-[4-[4-(1,2-benzisothiazol-3-yl)-1piperazinyl]butyl]-6-(4-nitro-benzyloxycarboxy)-8-azaspiro [4.5]decane-7,9-dione (1.98 g, 3.12 mmol) and 10% Pd/C (0.75 g) in MeOH-THF (2:1, 30 mL) was hydrogenated in a Parr shaker at 55 psi for 1.5 h. An additional 1.25 g of 10% Pd/C was added and hydrogenation was continued at 55 psi for 1 h. The resulting mixture was filtered through a pad of Celite and the pad was washed with EtOAc. The filtrate was evaporated to give a gum which was purified by flash chromatography (EtOAc) to give the title compound (0.98 g, 69%) as a solid. An analytical sample was crystallized from EtOAc/hexane to give pale yellow crystals, m.p. 151° C.; IR (neat) 3430, 1728, 1673 cm-1 ; 1H NMR (CDCl3) δ 7.90-7.76 (m, 2H), 7.49-7.29 (m, 2H), 4.18 (s, 1H), 3.82-3.69 (m, 2H), 3.59-3.54 (m, 5H), 2.79, 2.52 (AB q, J=17.4 Hz, 2H), 2.75-2.66 (m, 4H), 2.49-2.44 (m, 2H), 2.11-1.98 (m, 1H), 1.74-1.19 (b m, llH);
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[CH:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CS(O[CH2:27][C:28]1[C:33]([Cl:34])=[CH:32][CH:31]=[C:30]([N+:35]([O-:37])=[O:36])[C:29]=1[Cl:38])(=O)=O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[CH:14]2)[CH2:27][C:28]1[C:33]([Cl:34])=[CH:32][CH:31]=[C:30]([N+:35]([O-:37])=[O:36])[C:29]=1[Cl:38])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc2cccc(NC(=O)OC(C)(C)C)c2n1
Reactant: CS(=O)(=O)OCc1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2cccc(N(Cc3c(Cl)ccc([N+](=O)[O-])c3Cl)C(=O)OC(C)(C)C)c2n1
Reaction time: 0.33 h
Yield: 76.2 %

Procedure:
To a solution of 8-tert-butoxycarbonylamino-2-methylquinoline (258 mg) in N,N-dimethylformamide (3 ml) was added sodium hydride (44 mg) in an ice-water bath cooling, and the mixture was stirred for 20 minutes at the same temperature. To the reaction mixture was added 2,6-dichloro-3-nitrobenzyl methanesulfonate (300 mg) in an ice water bath cooling, and the mixture was stirred for 80 minutes at the same temperature and then for 15 minutes at ambient temperature. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography eluting with methylene chloride, and crystallized with n-hexane to give 8-[N-tert-butoxycarbonyl-N-(2,6-dichloro-3-nitrobenzyl)amino]-2-methylquinoline (352 mg). mp: 130-131° C.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:28])[CH2:4][CH2:5][N:6]1[C:25](=[O:26])[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:15]4[C:16]5[O:23][CH2:22][C:21](=[O:24])[C:17]=5[CH:18]=[CH:19][C:20]=4[N:8]([C:9]=23)[C:7]1=[O:27]>C(O)(=O)C>[CH3:2][N:3]([CH3:28])[CH2:4][CH2:5][N:6]1[C:25](=[O:26])[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:15]4[C:16]5[O:23][CH2:22][CH:21]([OH:24])[C:17]=5[CH:18]=[CH:19][C:20]=4[N:8]([C:9]=23)[C:7]1=[O:27]
Reactant: CN(C)CCn1c(=O)c2cccc3c4c5c(ccc4n(c1=O)c23)C(=O)CO5
Agent: Cl
Solvent: CC(=O)O
Product: CN(C)CCn1c(=O)c2cccc3c4c5c(ccc4n(c1=O)c23)C(O)CO5
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.3 %

Procedure:
105.5 mg (0.29 mmol) of the compound of Example 8 was dissolved in acetic acid (1 ml). Then 36 μl of an 8 M borane/pyridine complex was added thereto under stirring at room temperature. The obtained mixture was stirred for 4.5 hours. After adding 30 μl of an 8 M borane/pyridine complex thereto, the obtained mixture was further stirred overnight and concentrated. Then it was extracted by adding thereto water, a saturated aqueous solution of sodium hydrogencarbonate and chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography. The product thus obtained was recrystallized from ethanol/diisopropyl ether to thereby give 22.6 mg of the title compound.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:9]=[N:10][N:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:12]=2[CH3:13])[C:3]1=[O:21].[Cl:22][C:23]1[C:24]([C:29]([F:32])([F:31])[F:30])=[N:25][NH:26][C:27]=1[CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:22][C:23]1[C:24]([C:29]([F:31])([F:30])[F:32])=[N:25][N:26]([CH:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]3[CH:9]=[N:10][N:11]([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=4)[C:12]=3[CH3:13])[C:3]2=[O:21])[C:27]=1[CH3:28]
Reactant: Cc1[nH]nc(C(F)(F)F)c1Cl
Reactant: Cc1c(N2CCCC(Br)C2=O)cnn1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(N2CCCC(n3nc(C(F)(F)F)c(Cl)c3C)C2=O)cnn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.9 %

Procedure:
To a solution of 3-bromo-1-[1-(4-fluorophenyl)-5-methylpyrazol-4-yl]piperidin-2-one (0.05 g, 0.14 mmol) in DMF (1.0 mL) was added 4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazole (0.031 g, 0.17 mmol), followed by potassium carbonate (0.029 g, 0.21 mmol). After stirring at room temperature for 1 h, the reaction was quenched with water. The aqueous layer was then extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude product was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.015 g, 0.025 mmol, 23%). 1H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 7.44-7.35 (m, 2H), 7.22-7.13 (m, 2H), 4.94 (dd, J=9.9, 6.3 Hz, 1H), 3.90-3.70 (m, 2H), 2.73 (dddd, J=13.2, 11.5, 9.8, 3.3 Hz, I H), 2.47-2.38 (m, 1H), 2.36 (s, 3H), 2.31 (ddd, J=10.6, 5.4, 2.4 Hz, 1H), 2.17-2.12 (m, 1H), 2.13 (s, 3H); MS: (ES) m/z calculated for C20H18ClF4N5O [M+H]+ 456.1. found 456.1.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=1.O.[NH2:17][NH2:18]>O>[NH:17]([C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=1)[NH2:18]
Reactant: Clc1cc(OCc2cccnc2)ccn1
Reactant: NN
Solvent: O
Product: NNc1cc(OCc2cccnc2)ccn1
Temperature: 80 °C
Yield: 40.1 %

Procedure:
A mixture of 0.5 g (2.27 mmol) of 2-chloro-4-(pyridin-3-ylmethoxy)pyridine and 2 mL (40.5 mmol) of hydrazine hydrate is heated at 80° C. for 12 hours. The reaction medium is then taken up in 30 mL of water and extracted with EtOAc (3×30 mL). The organic phases are combined, washed with brine (20 mL) and then dried over Na2SO4, filtered, concentrated under reduced pressure and purified on silica gel, eluting with a 95/5 DCM/MeOH mixture. 197 mg of 2-hydrazinyl-4-(pyridin-3-ylmethoxy)pyridine are obtained in the form of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:5](/[CH:7]=[CH:8]/[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>>[Cl:1][C:2]1[S:3][C:4]([C:15](=[CH:22][N:23]([CH3:25])[CH3:24])[C:16]([O:18][CH3:19])=[O:17])=[C:5](/[CH:7]=[CH:8]/[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=1
Reactant: COC(OC)N(C)C
Reactant: COC(=O)Cc1sc(Cl)nc1/C=C/c1ccccc1
Product: COC(=O)C(=CN(C)C)c1sc(Cl)nc1/C=C/c1ccccc1
Temperature: 50 °C

Procedure:
A mixture of 5.9 g of the product of Step B and 55 ml of dimethylformamide dimethyl acetal was heated to 50° C. and after 4 hours at this temperature, the mixture was allowed to return to 25° C. The reaction mixture was evaporated to dryness and the residue was chromatographed on silica, eluting with a hexane-ethyl acetate mixture (7-3) to obtain 3.3 g of the desired product. Thin layer chromatography; Rf=0.18 [eluant: hexane-ethyl acetate (7-3)].
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.Cl[C:14]([CH:17]1[CH:21]([O:22]CC2C=CC=C(OC3C=CC=CC=3)C=2)[O:20][C:19](=[O:37])[CH2:18]1)([CH3:16])[CH3:15].Cl>C1CCCCC1.O1CCCC1>[CH3:16][C:14]1([CH3:15])[CH:18]2[CH:17]1[CH:21]([OH:22])[O:20][C:19]2=[O:37]
Reactant: CC(C)(Cl)C1CC(=O)OC1OCc1cccc(Oc2ccccc2)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: CC(C)NC(C)C
Product: CC1(C)C2C(=O)OC(O)C21
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.3 %

Procedure:
0.25 ml of a solution of 2M butyllithium in cyclohexane was added at -20° C. to 0.55 ml of a molar solution of diisopropylamine in tetrahydrofuran and 5 ml of tetrahydrofuran and the temperature was allowed to rise to 0° C. and was then cooled to -60° to -70° C. 180 mg of the product of Step B were added all at once to the mixture at -60° to -70° C. and the mixture was heated over 2 hours at 0° C. The mixture was held at 0° C. for one hour and was poured into 2N hydrochloric acid. The mixture was stirred for 17 hours at 20° C. and the decanted aqueous phase was extracted with chloroform. The organic phase was dried and evaporated to dryness and the residue was taken up in a mixture of isopropyl ether and petroleum ether. The solution was extracted with water and the aqueous extract was evaporated to dryness under reduced pressure to obtain 30 mg of crystalline dl 6,6-dimethyl-4-hydroxy-3-oxabicyclo-[3,1,0]-hexan-2-one melting at 80° C.