Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([NH2:11])[CH:5]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21]Br>CN(C=O)C.C(OCC)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:21][CH2:20][NH:11][C:6]=2[CH:5]=1)=[O:12]
Reactant: BrCCBr
Reactant: COC(=O)c1ccc(O)c(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1ccc2c(c1)NCCO2
Temperature: 70 °C
Reaction time: 12 h
Yield: 40 %

Procedure:
To a 2000 ml three-necked flask under N2 containing 3-Amino-4-hydroxy-benzoic acid methyl ester (31.35 g, 187 mmol) in anhydrous DMF (630 ml; 20 vols) at RT, was added K2CO3 (103 g, 4 eq.) in one portion followed by 1,2dibromoethane (65 ml, 4 eq.) in one portion. The reaction mixture was stirred at 70° C. for 12 h. Temperature was allowed to cool down to RT, and HCl1N was added until pH=8, and extraction was performed using diethyl ether (3*200 ml). The organic phase was washed with water (2*200 ml) and dried over MgSO4 and concentrated to afford a brown red oil with solid, which was taken up again in diethyl ether (450 ml) and THF (50 ml) and filtered to remove a white solid. To the filtrate was added HCl1N, and diethyl ether (130 ml) was added, suspension was stirred at RT for 5 minutes and filtered to give 27.6 g of crude product. The aqueous phases were again extracted with ethyl acetate to afford additional 6.23 g of product. The combined fractions (32 g) were recrystallised from EtOH (420 ml; 13 vols) to give after filtration and drying a white powder (19.47 g (16.37 g free base)), yield=40%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[C:4]([CH3:14])[CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([F:11])([F:12])[F:10])=[C:4]([CH3:14])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(O)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: ClCCl
Product: Cc1cc(Br)ccc1C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethanol (1.8 g, 6.7 mmol) in CH2Cl2 (20 mL) was added Dess-Martin Periodinane (3.4 g, 8.1 mmol) at 0° C. The mixture was stirred at RT for 2 h, then diluted with water (10 mL) and filtered. The filtrate was extracted with CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by normal phase silica gel column provided 1-(4-bromo-2-methylphenyl)-2,2,2-trifluoroethanone as a yellow oil.
Reaction SMILES: C(O[C:6]([N:8](C)[CH2:9][CH2:10][NH2:11])=O)(C)(C)C.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>>[CH3:6][NH:8][CH2:9][CH2:10][NH:11][S:14]([CH3:13])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: CN(CCN)C(=O)OC(C)(C)C
Product: CNCCNS(C)(=O)=O

Procedure:
By using N-t-butoxycarbonyl-N-methylethylenediamine (500 mg) and methanesulfonyl chloride (289 μl) as starting materials, the title compound (260 mg) was obtained in the same manner as that of Reference Example 58.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C@@H:9]1[CH2:11][C@H:10]1[CH:12]([NH:14][O:15][CH3:16])[CH3:13].C(N(CC)CC)C.[F:24][CH:25]([F:35])[C:26]1[C:30]([C:31](Cl)=[O:32])=[CH:29][N:28]([CH3:34])[N:27]=1>ClCCl.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C@@H:9]1[CH2:11][C@H:10]1[CH:12]([N:14]([O:15][CH3:16])[C:31]([C:30]1[C:26]([CH:25]([F:35])[F:24])=[N:27][N:28]([CH3:34])[CH:29]=1)=[O:32])[CH3:13]
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: CONC(C)[C@@H]1C[C@H]1c1c(F)cccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(C)[C@@H]1C[C@H]1c1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
To a stirred solution of trans N-{1-[2-(2-Chloro-6-fluoro-phenyl)-cyclopropyl]-ethyl}-O-methyl-hydroxylamine (0.80 g; 3.3 mmol) prepared as described in example P14 and triethylamine (0.60 ml; 4.3 mmol) in dichloromethane (10 ml) at ambient temperature was added dropwise 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (0.64 g; 3.3 mmol). The reaction mixture was stirred for 16 hours at ambient temperature then poured in water (60 ml) and extracted with dichloromethane (3×25 ml). Combined organic layers were washed with water (10 ml), brine and dried over anhydrous sodium sulphate. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel (elution gradient: cyclohexane/ethyl acetate 99:1 to 1:99) to afford 1.30 g (100% of theory) of trans 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid {1-[2-(2-chloro-6-fluoro-phenyl)-cyclopropyl]-ethyl}-methoxy-amide as a clear viscous oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](Cl)=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.OC(C(F)(F)F)=O.[NH2:20][CH:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:30][CH:29]([NH:31][C:32]([CH2:34][NH:35][C:36](=[O:47])[C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=3)=[O:33])[CH2:28]2)[CH2:23][CH2:22]1>C(Cl)Cl>[F:46][C:43]([F:44])([F:45])[C:39]1[CH:38]=[C:37]([CH:42]=[CH:41][CH:40]=1)[C:36]([NH:35][CH2:34][C:32]([NH:31][CH:29]1[CH2:28][N:27]([CH:24]2[CH2:23][CH2:22][CH:21]([NH:20][C:10]([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)=[O:11])[CH2:26][CH2:25]2)[CH2:30]1)=[O:33])=[O:47]
Reactant: NC1CCC(N2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(NC(=O)c3ccc4c(c3)OCO4)CC2)C1
Reaction time: 2 h

Procedure:
Benzo[1,3]dioxole-5-carbonyl chloride (Aldrich, 74 mg, 0.404 mmol) was added into a solution of N-{[1-(4-amino-cyclohexyl)-azetidin-3-ylcarbamoyl]-methyl}-3-trifluoromethyl-benzamide TFA salt (as prepared in the previous step 200 mg, 0.404 mmol) and TEA (170 μL, 1.21 mmol) in DCM (5 mL) at 0° C. The reaction was stirred for an additional 2 hours and quenched with saturated sodium bicarbonate. The reaction was then partitioned between DCM and water. The organic layer was separated and the aqueous layer was extracted 3 times with a chloroform/IPA “cocktail” (˜3:1, v/v). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was then purified by a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as white solid.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][NH:22][C@H:21]([C:24]([NH2:26])=[O:25])[C:20]([CH3:27])=[CH:19]1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].C1(S)C=CC=CC=1>C(#N)C>[CH2:1]([O:4][NH:5][C@H:18]1[CH2:23][NH:22][C@H:21]([C:24]([NH2:26])=[O:25])[C:20]([CH3:27])=[CH:19]1)[CH:2]=[CH2:3]
Reactant: C=CCON([C@@H]1C=C(C)[C@@H](C(N)=O)NC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CC#N
Product: C=CCON[C@@H]1C=C(C)[C@@H](C(N)=O)NC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.9 %

Procedure:
To (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-3-methyl-1,2,5,6-tetrahydropyridine-2-carboxamide (Intermediate 84, 2.01 g, 5.07 mmol) and potassium carbonate (2.172 g, 15.72 mmol) in acetonitrile (10 mL) was added benzenethiol (1.557 mL, 15.21 mmol) and stirred at rt for 2 h. The solvent was evaporated at 30° C., redissolved in DCM and a little bit MeOH, filtered and loaded onto silica gel at 30° C. The crude mixture was purified via flash chromatography (220 g column, 0-20% MeOH/DCM), the fractions were concentrated at 35° C. and dried under high-vacuum to obtain the desired product (0.759 g, 70.9%) as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C(O)C.Cl[CH:13]([CH:19]=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:19][N:8]=[C:4]2[CH:3]=1
Reactant: CCOC(=O)C(Cl)C=O
Reactant: Nc1cc(Br)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2cc(Br)ccn12
Temperature: 60 °C

Procedure:
4-bromopyridin-2-amine (10.0 g, 0.06 mol) was mixed with ethanol (50 mL) in a reaction flask, under an atmosphere of dry nitrogen. A solution of ethyl 2-chloro-3-oxopropanoate (5% in benzene; 222 mL; Commercial solution from Toronto Research Chemicals Inc.) was added. The mixture was heated to 60° C. under nitrogen for 5 hours. After allowing the mixture to cool the solvent was removed under vacuum to give a brown solid. The solid was mixed with ethyl acetate (500 mL) and sodium bicarbonate solution (200 mL) and stirred to dissolve. The phases were separated and the bicarbonate solution was extracted further with ethyl acetate (100 mL). The combined ethyl acetate extracts were dried over sodium sulfate, filtered and concentrated under vacuum to give a solid. The crude material was dissolved in ethyl acetate and passed through a short column of silica, eluting with ethyl acetate to give ethyl 7-bromoimidazo[1,2-a]pyridine-3-carboxylate as a pale yellow solid (15 g).
Reaction SMILES: [CH:1]([NH:3][C@@H:4]1[C:9](=[O:10])[O:8][C:6](=O)C1)=[O:2].C=O.[C:13]([OH:16])(=[O:15])[CH3:14]>>[C:13]([CH2:14][CH:4]1[C:9](=[O:10])[O:8][CH2:6][N:3]1[CH:1]=[O:2])([OH:16])=[O:15]
Reactant: O=CN[C@H]1CC(=O)OC1=O
Reactant: CC(=O)O
Agent: C=O
Product: O=CN1COC(=O)C1CC(=O)O
Temperature: 50 °C

Procedure:
14.3 g (100 mmol) of formyl aspartic acid anhydride are charged into a 100° C. solution of 9 g (300 mmol) paraformaldehyde in 200 ml glacial acetic acid. After 30 min the mixture is cooled to 50° C. and the acetic acid removed in a vacuum. Then, the yellowish oily residue is taken up in a little saturated sodium hydrogen carbonate solution and extracted several times after acidification of the aqueous solution to pH 1.5 with ethyl acetate. The collected organic phases are dried over magnesium sulfate and then filtered. After removal of the solvent in a vacuum a yellowish oil is obtained.
Reaction SMILES: [OH:1][C:2]1([C@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14])[CH2:5][N:4](CC2C=CC=CC=2)[CH2:3]1.[H][H]>CO.[Pd]>[OH:1][C:2]1([C@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14])[CH2:3][NH:4][CH2:5]1
Reactant: [H][H]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C1(O)CN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: C[C@@H](NC(=O)OC(C)(C)C)C1(O)CNC1
Yield: 105.7 %

Procedure:
To a solution of 1,1-dimethylethyl {(1R)-1-[3-hydroxy-1-(phenylmethyl)azetidin-3-yl]ethyl}carbamate (1.07 g, 3.5 mmol) in methanol was added wet 10% palladium on carbon (50% by mass, 250 mg). The resulting suspension was subjected to 1 atmosphere of hydrogen for 7 h, and an additional 250 mg of catalyst was added over the course of the reaction. The catalyst was then removed by filtration through celite. The filtrate was then concentrated in vacuo to provide 1,1-dimethylethyl [(1R)-1-(3-hydroxyazetidin-3-yl)ethyl]carbamate as a colorless syrup (800 mg, quantitative yield). MS (EI) for C10H20N2O3: 161 (M-tert-butyl+H).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].Cl[CH2:11][C:12]([NH:14][C:15]([NH:17][CH2:18][CH2:19][CH3:20])=[O:16])=[O:13].C(=O)([O-])O.[Cs+]>CN1C(=O)CCC1>[C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O:6][CH2:11][C:12](=[O:13])[NH:14][C:15]([NH:17][CH2:18][CH2:19][CH3:20])=[O:16])=[O:5]
Reactant: COC(=O)/C=C/C(=O)O
Reactant: CCCNC(=O)NC(=O)CCl
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCCNC(=O)NC(=O)COC(=O)/C=C/C(=O)OC
Yield: 1.9 %

Procedure:
Following general procedure A, methyl hydrogen fumarate (MHF) (0.50 g, 3.84 mmol) dissolved in NMP was reacted at ca. 55° C. with 1-(2-chloroacetyl)-3-propyl urea (0.82 g, 4.60 mmol) in the presence of CsHCO3 (0.89 g, 4.61 mmol) to provide 0.02 g (2% yield) of the title compound (19) as a white solid. Addition of methanol (MeOH) afforded 0.49 g (48% yield) of white solid. 1H NMR (CDCl3, 400 MHz): δ 6.90-6.99 (m, 2H), 4.77 (s, 2H), 3.82 (s, 3H), 3.25-3.24 (q, 2H, J=5.6 Hz), 1.57-1.55 (q, 2H, J=7.2 Hz), 0.95-0.91 (t, 3H, J=7.6 Hz). MS (ESI): m/z 273.08 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][N:5]=1.[CH2:18]=[O:19]>CO>[OH:1][CH2:2][CH:3]([CH2:18][OH:19])[C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][N:5]=1
Reactant: C=O
Reactant: COc1cc2c(cc1OC)C(CCO)=NCC2
Solvent: CO
Product: COc1cc2c(cc1OC)C(C(CO)CO)=NCC2

Procedure:
To 0.01 mole of 1-(β-hydroxyethyl)-6,7-dimethoxy-3,4-dihydroisoquinoline 2 ml of a 37% aqueous formaldehyde solution are added, and the mixture is boiled in 30 ml of methanol for 2 hours. After evaporation the obtained oily residue is triturated with ether. Crystallization of the obtained product from a mixture of acetone and ether affords the desired compound, which has the same spectral characteristics as the product of Example 1. Melting point: 129° to 131 C.°
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[N:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCOCC1>[N+:11]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[N:3]=[C:2]2[C:36]1[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=1)([O-:13])=[O:12]
Reactant: OB(O)c1ccncc1
Reactant: O=[N+]([O-])c1ccc2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Yield: 92.8 %

Procedure:
3-Bromo-5-nitro-1-trityl-1H-indazole (1 g, 0.002 mol) was added to a vial containing pyridin-4-ylboronic acid (0.279 g, 0.00227 mol) and tetrakis(triphenylphosphine)-palladium (0.1155 g, 0.0001 mol). After purging the vial with nitrogen gas, dioxane (6 L) and 2M sodium carbonate (0.006 mol) was added to the vial respectively. The reaction mixture was stirred and was heated to 80° C. for 16 h. Upon completion, the mixture was concentrated under vacuo. Water (3 mL) was added and was extracted using dichloromethane (3×3 mL). The extracts were combined and dried using anhydrous sodium sulfate. The resulting suspension was filtered and concentrated. The crude product was purified using flash chromatography (1:1 Hexane:Ethyl Acetate). Pure product (0.8954 g, 92.8% yield) was recovered.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([SH:9])=[C:4]([Cl:10])[CH:3]=1.[Cl:11][C:12]1[N:13]=[N:14][C:15](Cl)=[CH:16][C:17]=1[CH:18]([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[Cl:8][C:6]1[CH:7]=[C:2]([NH2:1])[CH:3]=[C:4]([Cl:10])[C:5]=1[S:9][C:15]1[N:14]=[N:13][C:12]([Cl:11])=[C:17]([CH:18]([CH3:20])[CH3:19])[CH:16]=1
Reactant: Nc1cc(Cl)c(S)c(Cl)c1
Reactant: CC(C)c1cc(Cl)nnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1cc(Sc2c(Cl)cc(N)cc2Cl)nnc1Cl
Temperature: 90 °C
Yield: 71.1 %

Procedure:
A solution of 4-amino-2,6-dichloro-benzenethiol (82) (1.0 g, 5.2 mmol) in N,N-dimethylformamide at 25° C. was treated with 3,6-dichloro-4-isopropyl-pyridazine (7) (990 mg, 5.2 mmol) and potassium carbonate (2.16 g, 15.6 mmol). The resulting mixture was heated to 90° C. for 18 h. At this time, the reaction was cooled to 25° C., poured onto a mixture of ice water and a 1N aqueous hydrochloric acid solution (10 mL). The resulting solution was brought to pH=7 with additional 1N aqueous hydrochloric acid solution and then was extracted with ethyl acetate (2×100 mL). The organics were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried with magnesium sulfate, filtered and concentrated under vacuum. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 petroleum ether/ethyl acetate) afforded 3,5-dichloro-4-(6-chloro-5-isopropyl-pyridazin-3-ylsulfanyl)-phenylamine (83) (1.29 g, 72%) as an off-white foam; ES(+)-HRMS m/e calcd for C13H12Cl3N3S (M+H)+ 347.9891, found 347.9889. Exact Mass=346.9817; Molecular weight=348.68
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@@H:6]([O:8][C@H]2[C@H](O)[C@@](O)(CO)O[C@@H]2CO)[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@H:3]1[OH:22].C1(C)CCC(C(C)C)C(O)C1>>[OH:8][CH2:6][C@@H:5]([C@H:4]([C@@H:3]([C@@H:2]([CH2:1][OH:23])[OH:7])[OH:22])[OH:21])[OH:20]
Reactant: OC[C@H]1O[C@@H](O[C@@H]2[C@@H](CO)O[C@](O)(CO)[C@H]2O)[C@H](O)[C@@H](O)[C@H]1O
Agent: CC1CCC(C(C)C)C(O)C1
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Yield: 31.3 %

Procedure:
After softening 2 kg of gum base by heating, the gum base was added with 6 kg of a crystalline lactitol powder, 160 g of a sweetener, obtained similarly as in EXAMPLE 2, 1 kg of crystalline sorbitol powder, and small amounts of menthol and coloring agent. Thereafter, the mixture was kneaded sufficiently with the use of a roller, and the resultant was shaped into the titled product, in the usual way.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][C:10]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:28]([CH:29]([F:40])[C:30]5[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=5)=[C:27]([CH:41]5[CH2:46][CH2:45][C:44]([F:48])([F:47])[CH2:43][CH2:42]5)[C:26]5[CH:25]([O:49]CC6C=CC(OC)=CC=6)[CH2:24][C:23]([CH3:60])([CH3:59])[CH2:22][C:21]=5[N:20]=4)[CH2:15][CH2:14]3)=[N:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.Cl.C(=O)([O-])O.[Na+]>O1CCOCC1>[C:1]1([C:7]2[CH:12]=[N:11][C:10]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:28]([CH:29]([F:40])[C:30]5[CH:35]=[CH:34][C:33]([C:36]([F:37])([F:38])[F:39])=[CH:32][CH:31]=5)=[C:27]([CH:41]5[CH2:46][CH2:45][C:44]([F:47])([F:48])[CH2:43][CH2:42]5)[C:26]5[CH:25]([OH:49])[CH2:24][C:23]([CH3:60])([CH3:59])[CH2:22][C:21]=5[N:20]=4)[CH2:15][CH2:14]3)=[N:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(C6=CCCCC6)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)Cc2nc(C3CCN(c4ncc(C5=CCCCC5)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 67.2 %

Procedure:
To 78 mg (0.094 mmol) of 2-{1-[5-(Cyclohex-1-en-1-yl)pyrimidin-2-yl]piperidin-4-yl}-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 18, 0.4 ml of 6 N hydrochloric acid and 2 ml of 1,4-dioxane were added, and the reaction solution was stirred at 80° C. for 3 hours. After completion of the reaction, the reaction solution was poured into saturated sodium hydrogencarbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=95/5-80/20 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure. Diethyl ether was added to the obtained residue and the precipitate was obtained by filtration to provide 45 mg of the title compound as a white solid (yield: 67%).
Reaction SMILES: Cl[C:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]=1.[Br:9][C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([NH:14][NH2:15])=[O:13].[OH-].[Na+].C(OCC)C>C1C=CC=CC=1>[N:8]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=1[NH:15][NH:14][C:12](=[O:13])[C:11]1[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=1[Br:9]
Reactant: ClC1=NCCCCC1
Reactant: NNC(=O)c1ccccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: c1ccccc1
Product: O=C(NNC1=NCCCCC1)c1ccccc1Br
Yield: 38.7 %

Procedure:
To a solution of 7-chloro-3,4,5,6-tetrahydro-2H-azepine (1.32 g, 10 mmol, J. Med. Chem. 30, 1543-49) in benzene (20 ml) was added 2-bromo-benzoic acid hydrazide (1.08 g, 5 mmol) and the mixture was stirred at reflux temperature for 5 hrs. To the cooled reaction mixture was added 10% sodium hydroxide (10 ml) and diethyl ether (20 ml). The mixture was stirred for 30 min., the precipitate filtered off and dried in vacuo at 50° C. for 1 hr. affording 0.6 g of 2-bromo-benzoic acid-N′-(4,5,6,7-tetrahydro-3H-azepin-2-yl)-hydrazide which was dissolved in ethanol (20 ml) followed by addition of TEA (5 ml) and refluxed for 16 hrs. The volatiles were evaporated in vacuo and to the residue was added diethyl ether (10 ml) and ethyl acetate (5 ml). The precipitate was filtered off and dried in vacuo at 50° C. for 1 hr affording 0.35 g (24%) of the title compound as a solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=O)=O.O[CH2:7][CH:8]1[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]1.CCN(C(C)C)C(C)C.C[S-].[Na+].CS(OCC1CN(C(OC(C)(C)C)=O)C1)(=O)=O>C(Cl)Cl.CN(C=O)C.C1(C)C=CC=CC=1>[CH3:1][S:2][CH2:7][CH:8]1[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Reactant: CS(=O)(=O)Cl
Agent: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C1
Agent: C[S-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CSCC1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.7 %

Procedure:
Methanesulfonyl chloride (0.53 mL, 6.8 mmol) was added dropwise to a stirred solution of 9 (530 mg, 2.8 mmol) and Hunig's base (0.986 mL, 5.6 mmol) in CH2Cl2 (10 mL) and left overnight at room temperature. The reaction was then diluted with CH2Cl2 (100 mL) and washed with water (25 mL), brine (25 mL), dried (MgSO4) and concentrated in vacuo. Sodium thiomethoxide (218 mg, 3109 μmol) was added portionwise to a solution of the residue, presumably tert-butyl 3-(methanesulfonyloxymethyl)azetidine-1-carboxylate (550 mg, 73%), in DMF (5 mL) and stirred at room temperature overnight. The reaction was diluted with toluene (100 mL) and washed with water (25 mL), brine (25 mL), dried (MgSO4) and concentrated in vacuo. Chromatography (MeOH/CH2Cl2=5:95) of the resulting residue afforded 13 as an oil (120 mg, 27%). 1H NMR (CDCl3): δ 3.98 (m, 2H), 3.54 (m, 2H), 2.65 (brs, 3H), 2.03 (s, 3H), 1.37 (s, 9H). 13C NMR (CDCl3): δ 155.3, 78.3, 53.1, 37.4, 27.4, 14.5.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1)([CH3:3])[CH3:2].[F:18][C:19]([F:30])([F:29])[C:20]1[C:25]([CH:26]=[CH2:27])=[CH:24][N:23]=[C:22]([CH3:28])[CH:21]=1.[OH-].[K+]>CN1C(=O)CCC1>[F:30][C:19]([F:18])([F:29])[C:20]1[CH:21]=[C:22]([CH3:28])[N:23]=[CH:24][C:25]=1[CH2:26][CH2:27][N:9]1[C:10]2[CH:11]=[CH:12][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][C:6]=2[C:7]2[CH2:16][N:15]([CH3:17])[CH2:14][CH2:13][C:8]1=2
Reactant: CC(C)c1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1cnc(C)cc1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1cc(C(F)(F)F)c(CCn2c3c(c4cc(C(C)C)ccc42)CN(C)CC3)cn1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-8-isopropyl-2-methyl-1H-pyrido[4,3-b]indole, 4-(trifluoromethyl)-2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.