Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([NH:31][CH2:32][CH2:33][CH2:34][NH2:35])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][NH:35][CH2:34][CH2:33][CH2:32][NH:31][C:25]3[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[CH:24]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Reactant: COc1ccc(NCCCN)cc1OC
Product: COc1ccc(NCCCNCCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC

Procedure:
The title compound is prepared from 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane and 3-(3,4-dimethoxyphenylamino)-propylamine analogously to Example 1. M.p.: 206°-212° C. (decomp.)
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[N:5][N:4]([CH2:7][C:8]2[O:9][CH:10]=[C:11]([C:13](=[O:15])[CH3:14])[N:12]=2)[N:3]=1.[C:16]1([C:22]2[O:26][CH:25]=[N:24][C:23]=2[C:27](O)=[O:28])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:13]([C:11]1[N:12]=[C:8]([CH2:7][N:4]2[N:3]=[C:2]([NH:1][C:27]([C:23]3[N:24]=[CH:25][O:26][C:22]=3[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:28])[CH:6]=[N:5]2)[O:9][CH:10]=1)(=[O:15])[CH3:14]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC(=O)c1coc(Cn2ncc(N)n2)n1
Product: CC(=O)c1coc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)n1

Procedure:
Following general procedure A, starting from 1-[2-(4-amino-[1,2,3]triazol-2-ylmethyl)-oxazol-4-yl]-ethanone and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[N+:6]([O-:8])[CH:7]=1.S(=O)(=O)(O)O.[N+:15]([O-])([OH:17])=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>>[Br:1][C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[CH:4][C:5]([CH3:9])=[N+:6]([O-:8])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(Br)c[n+]1[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1cc([N+](=O)[O-])c(Br)c[n+]1[O-]
Temperature: 0 °C
Yield: 90.3 %

Procedure:
5-bromo-2-methylpyridine 1-oxide (2.269 g, 12.07 mmol, 1 eq) was dissolved in sulfuric acid (4 mL, 80 mmol, 6 eq) and cooled at 0° C. Fuming nitric acid (3 mL, 60 mmol, 5 eq) was added dropwise. After addition of the nitric acid was complete, the reaction mixture was first warmed to room temperature and then heated to 90° C. After 2 hours the reaction was cooled in an ice bath and slowly adjusted to pH 10 with 2 M aqueous sodium carbonate. This solution was extracted twice with dichloromethane. The combined organic extracts were dried over magnesium sulfate and concentrated to yield 2.54 g (90%) of 5-bromo-2-methyl-4-nitropyridine 1-oxide. LMCS (ESI) m+H=233.0.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]=[N:9][S:10][CH:11]=1.[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)Cl>[Br:13][CH2:12][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]=[N:9][S:10][CH:11]=1
Reactant: Cc1ccccc1-c1csnn1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: BrCc1ccccc1-c1csnn1

Procedure:
A solution of 4-o-tolyl-[1,2,3]thiadiazole (100 mg, 0.57 mmol), N-bromosuccinimide (100 mg, 0.57 mmol) and 2,2′-azobisisobutyronitrile (9.4 mg, 0.057 mmol) in chloroform (10 ml) was heated at reflux temperature for ˜18 h. Additional chloroform was added and the mixture was washed with water, 5% sodium thiosulfate solution and brine. Drying and solvent evaporation gave 4-(2-bromomethyl-phenyl)-[1,2,3]thiadiazole; 1H NMR (CDCl3, 300 MHz) δ8.87 (s, 1H), 7.67-7.39 (m, 4H), 4.71 (s, 2H). cls Step D: 4-(2-Azidomethyl-phenyl)-[1,2,3]thiadiazole (I-13-4)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.[F:11][C:12]([F:25])([F:24])[C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[NH2:16]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:7]=[N:16][C:15]2[CH:17]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:19]=[C:13]([C:12]([F:11])([F:24])[F:25])[CH:14]=2)[CH:9]=1
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: Oc1ccc(Cl)cc1C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 76.6 %

Procedure:
Using 5-chlorosalicylaldehyde and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 14(1) gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19]CC)=[O:18])=[CH:5]2.[OH-].[Na+].Cl>CCO.O>[Cl:1][C:2]1[C:3]([CH3:22])=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[O:8][CH:7]([C:13]([F:16])([F:14])[F:15])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2c(cc(C)c(Cl)c2C)OC1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc2c(c(C)c1Cl)C=C(C(=O)O)C(C(F)(F)F)O2
Yield: 94.8 %

Procedure:
To a suspension of ethyl 6-chloro-5,7-dimethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate (4.00 g, 11.9 mmol) in 40 mL of EtOH was added a solution of NaOH (1.2 g, 30 mmol) in 18 mL of H2O. The reaction was heated at reflux for 1.5 h. Once cooled, the reaction was neutralized with 2 N HCl. The product that precipitated from solution was filtered and washed with H2O. After drying in the vacuum oven at 50° C., a pale yellow solid, 6-chloro-5,7-dimethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (3.46 g, 95%) was isolated.
Reaction SMILES: [F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:18]=2)=[C:13]([F:30])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].[OH-].[Na+].O>C1COCC1>[F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:18]=2)=[C:13]([F:30])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)COc1ccc(F)c(NCc2cccc(-c3cccc(F)c3)c2)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COc1ccc(F)c(NCc2cccc(-c3cccc(F)c3)c2)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
To a stirred solution of intermediate ethyl 2-[2,4-difluoro-3-[[3-(3-fluorophenyl)phenyl]methylamino]phenoxy]acetate (270 mg, 0.65 mmol, 1.0 eq) in THF (4 mL) was added NaOH (2 M aqueous solution, 2.5 mL, 5 mmol, 7.7 eq). The reaction was stirred at room temperature for 1 h. Water was added and the THF removed in vacuo. The aqueous layer was extracted with EtOAc and the combined organic extracts washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The crude material obtained was crystallised from CH2Cl2/petroleum ether, collected by filtration and dried in vacuo to give the title compound (I(e)) as a white solid (190 mg, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([OH:22])=O)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([Si](C)(C)[O:35][CH2:36][CH2:37][CH2:38][N:39]([CH3:41])[NH2:40])(C)(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([NH:40][N:39]([CH2:38][CH2:37][CH2:36][OH:35])[CH3:41])=[O:22])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:17])[F:18])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: CN(N)CCCO[Si](C)(C)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CN(CCCO)NC(=O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN 1018782-82-5) and N-[3-(t-butyl-dimethyl-silanyloxy)-propyl]-N-methyl-hydrazine trifluoroacetate (1:1) as starting materials; the silyl protecting group was lost during reaction and work-up; LC-MS (UV peak area/ESI) 91.5%, 418.1139 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([N:14]3[CH2:17][CH2:16][CH2:15]3)[N:11]=[C:10]([S:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25]C(=O)OC(C)(C)C)=[CH:21][CH:20]=3)[N:9]=2)[CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([S:18][C:10]2[N:9]=[C:8]([NH:7][C:4]3[NH:5][N:6]=[C:2]([CH3:1])[CH:3]=3)[CH:13]=[C:12]([N:14]3[CH2:15][CH2:16][CH2:17]3)[N:11]=2)=[CH:20][CH:21]=1
Reactant: Cc1cc(Nc2cc(N3CCC3)nc(Sc3ccc(NC(=O)OC(C)(C)C)cc3)n2)n[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2cc(N3CCC3)nc(Sc3ccc(N)cc3)n2)[nH]n1
Reaction time: 8 h

Procedure:
tert-butyl 4-(4-(5-methyl-1H-pyrazol-3-ylamino)-6-(azetidin-1-yl)pyrimidin-2-ylthio)phenylcarbamate (prepared using method similar to that described for example 6) (2.53 g, 5.6 mmol) was dissolved in 1:1 TFA-DCM (20 mL) and the resulting solution allowed to stand overnight at room temperature. The solution was concentrated in vacuo. The residue was taken up in EtOAc and washed with saturated aqueous sodium bicarbonate solution (×2) then brine and dried over sodium sulfate. The resulting tan solid (1.8 g, 91%) [MS (ES+) 354] was used without further purification or characterization in the next step.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([C:14]#[N:15])=[C:11]([NH2:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([C:14]#[N:15])=[C:11]([NH:13][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)N1CCc2c(sc(N)c2C#N)C1
Product: CC(=O)N1CCc2c(sc(NC(=O)c3ccccc3)c2C#N)C1

Procedure:
Prepared according to general procedure A starting from 6-acetyl-2-amino-3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine (compound A3) and benzoyl chloride.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:6][C:7]=1[CH3:8].C[Li].C([Li])(C)(C)C.N1([CH:34]=[O:35])CCCCC1>O1CCCC1>[CH3:8][C:7]1[C:2]([CH:34]=[O:35])=[CH:3][CH:4]=[C:5]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:6]=1
Reactant: Cc1nc(NCc2ccc(C(F)(F)F)cc2)ccc1Br
Reactant: O=CN1CCCCC1
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1nc(NCc2ccc(C(F)(F)F)cc2)ccc1C=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
(5-Bromo-6-methyl-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-amine (34, 1.7 g, 4.93 mmol) was dissolved in tetrahydrofuran (40 mL) and cooled at −78° C. under a nitrogen atmosphere. To this mixture was added methyllithium (1.6 M in diethyl ether, 5.91 mmol) dropwise over 20 minutes. After the addition of methyllithium was completed, the reaction mixture was stirred at −78° C. for 2 hours. To this mixture was added tert-butyllithium (1.7 M in pentane, 10.85 mmol) and the mixture was stirred for 4 hours. The reaction mixture was maintained at −78° C., and 1-piperidinecarboxaldehyde (0.60 mL, 5.42 mmol) was added dropwise. The reaction was allowed to stir at −78° C. for an additional 2 hours and warming to 25° C. was achieved from the slow evaporation of the dry ice/acetone cooling bath. The reaction was quenched with ice cold saturated sodium chloride and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. Concentration under reduced pressure afforded an orange oil (35, 1.4 g, 4.93 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([S:15]([NH2:18])(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)[CH:6]=[C:5]([NH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[N:4]=1.[H-].[Na+].Cl[C:33]([O:35][CH3:36])=[O:34].O>C1COCC1>[CH3:36][O:35][C:33]([NH:18][S:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:7]2[CH:6]=[C:5]([NH:19][CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[N:4]=[C:3]([O:2][CH3:1])[N:8]=2)[CH:10]=1)(=[O:16])=[O:17])=[O:34]
Reactant: COc1ccc(CCNc2cc(-c3cccc(S(N)(=O)=O)c3)nc(OC)n2)cc1
Reactant: COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)NS(=O)(=O)c1cccc(-c2cc(NCCc3ccc(OC)cc3)nc(OC)n2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzenesulfonamide [100 mg, Example 3] in THF (10 mL) is treated with sodium hydride (20 mg). The mixture is stirred at 0° C. for 60 minutes, treated with methyl chloroformate (1 mL) and stirring is continued 0° C. for a further 60 minutes. The reaction mixture is poured into water and extracted twice with EtOAc (50 mL). The combined extracts are washed with water, dried over sodium sulfate, filtered, and evaporated. The residue is subjected to chromatography on silica gel eluting with EtOAc in heptanes (1:1, v/v) to give N-methoxycarbonyl-3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzenesulfonamide [41 mg, Example 4(c)] as a solid. MS: 473 (M+H), 1H NMR [(CD3)2SO]: δ 12.2 (1H, s); 8.4 (1H, s); 8.15 (1H, m); 8 (1H, d, J=3 Hz); 7.65-7.8 (1H, m); 7.2 (2H, d, J=7 Hz); 6.9 (2H, d, J=7 Hz); 6.7 (1H, s); 3.9 (3H, s); 3.7 (3H, s); 3.5-3.6 (2H, m); 3.6 (3H, s); 2.8 (2H, t).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Cl)=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18].[K].[CH2:21]([OH:27])[C:22]1[O:26][CH:25]=[CH:24][CH:23]=1.C1OCCOCCOCCOCCOCCOC1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:27][CH2:21][C:22]2[O:26][CH:25]=[CH:24][CH:23]=2)=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: OCc1ccco1
Reactant: COC(=O)c1ccc(CCl)cc1-c1ccccc1C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(COCc2ccco2)cc1-c1ccccc1C
Temperature: 90 °C
Yield: 32.8 %

Procedure:
To a stirred solution of the 4-chloromethyl-2-(2-methylphenyl)benzoic acid methyl ester (1.12 g , 4.08 mmol) in toluene (20 mL) under N2 was added the furfuryl alcohol potassium salt prepared in Example 299A (0.84 g, 6.1 mmol) followed by 18-crown-6 (1.6 g, 6.1 mmol). The solution was heated at 90° C. for 30 minutes. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate and washed with H2O (2×), saturated NaHCO3 solution (2×), dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (10% ethyl acetate-hexane) to give the title compound (0.45 g, 33%) as an orange oilwhich was contaminated with ˜10% of the 2-furanmethyl ester.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:12]([Cl:20])=[N:13][C:14]([S:18][CH3:19])=[N:15][C:16]=1Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([CH2:40][CH2:41][OH:42])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>C1COCC1>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([CH2:40][CH2:41][O:42][C:16]2[C:11]([C:9](=[O:10])[NH:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:12]([Cl:20])[N:13]=[C:14]([S:18][CH3:19])[N:15]=2)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CSc1nc(Cl)c(C(=O)NCc2ccccc2)c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CSc1nc(Cl)c(C(=O)NCc2ccccc2)c(OCCC2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4,6-dichloro-2-methylsulfanylpyrimidine-5-carboxylic acid benzylamide (3 mmol) in THF (20 mL) is added KOtBu (3.6 mmol) at 0° C. under N2. After stirred at 0° C. for 20 min, the above mixture is added dropwise to a solution of 4-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester (3.3 mmol) in THF (20 mL) at −78° C. The resulting mixture is gradually warm up to −30° C. over 2.5 h. The reaction is quenched by the addition of H2O. The mixture is extracted twice with AcOEt. The organic layer is dried over Na2SO4, filtered, and concentrated to give 4-[2-(5-benzylcarbamoyl-6-chloro-2-methylsulfanylpyrimidin-4-yloxy)ethyl]piperidine-1-carboxylic acid tert-butyl ester as a white solid; 1H-NMR (CDCl3), δ 1.07-1.17 (2H, m), 1.48 (9H, s), 1.62-1.70 (2H, m), 2.54 (3H, s), 2.64 (2H, br t), 4.06 (2H, m), 4.45 (2H, t), 4.64 (2H, d), 6.06 (1H, t), 7.30-7.34 (2H, m), 7.35-7.36 (3H, m).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[Cl:26].C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:23]4[CH:22]=[CH:21][C:20]([Cl:19])=[C:25]([Cl:26])[CH:24]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(Cl)c(Cl)c4)cc3CC[C@@H]12
Yield: 64.1 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 3,4-dichlorophenylboronic acid (149 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 16 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 156 mg (64%) of the title compound as a foam. mp 129°-135°. FDMS: m/e=374. α[D]589 =+68.66 (c=1.03, chloroform).
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:11]([OH:15])(=[O:14])[CH:12]=O>O1CCOCC1>[O:10]=[C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]/[C:2]/1=[CH:12]\[C:11]([OH:15])=[O:14]
Reactant: O=CC(=O)O
Reactant: O=C1CCc2ccccc21
Solvent: C1COCCO1
Product: O=C(O)/C=C1\Cc2ccccc2C1=O
Yield: 91.7 %

Procedure:
A mixture of 1-indanone (145) (25 g, 190 mmol), glyoxylic acid (50% aqueous solution, 70 g, 470 mmol), and CH2SO4 (6.25 mL) in dioxane (25 mL) were stirred at reflux temperature for 4 h. The mixture was cooled, the product filtered off, washed with water and dried to give acid 146 (32.8 g, 92%) as a white solid: mp 201-203° C. [lit. (Nagasawa et al., Japanese Patent 04338358, 1992) 205-206° C.]; 1H NMR [(CD3)2SO] δ 12.00 (br s, 1H, OH), 7.73-7.80 (m, 2H, H-5, H-7), 7.68 (br d, J=7.7 Hz, 1H, H-4), 7.49 (t, J=7.9 Hz, 1H, H-6), 6.55 (t, J=2.4 Hz, 1H, CHCO2), 4.08 (d, J=1.8 Hz, 2H, H-3).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11](=O)[C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)[CH:15]=[C:14]([CH3:26])[C:13]=1[CH3:27]>C1COCC1>[F:25][C:20]1[CH:19]=[C:18]([C:16]2[CH:15]=[C:14]([CH3:26])[C:13]([CH3:27])=[C:12]([CH2:11][NH:10][C:3]3[C:2]([F:1])=[C:7]([OH:8])[CH:6]=[CH:5][C:4]=3[F:9])[CH:17]=2)[CH:23]=[CH:22][C:21]=1[F:24]
Reactant: Cc1cc(-c2ccc(F)c(F)c2)cc(C(=O)Nc2c(F)ccc(O)c2F)c1C
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(F)c(F)c2)cc(CNc2c(F)ccc(O)c2F)c1C
Temperature: 60 °C
Yield: 81.1 %

Procedure:
To a solution of N-(2,6-difluoro-3-hydroxy-phenyl)-5-(3,4-difluorophenyl)-2,3-dimethyl-benzamide (90 mg, 0.23 mmol, 1.0 eq) in THF (1.5 mL) under N2 was added dropwise a solution of BH3 (1M in THF, 1.03 mL, 1.03 mmol, 4.6 eq) at 0° C. The reaction mixture was heated at 60° C. overnight then cooled and the reaction quenched with water. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 30:1 to 15:1) to give the title compound as a colorless oil (70 mg, 81%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH:3]=1.C(OCC)(=O)C>[OH-].[Pd+2].[OH-].CO>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:4]2[CH:3]=[CH:2][N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(Oc2ccncn2)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 31.4 %

Procedure:
Palladium hydroxide (20 mg) was added to solution of 6-chloro-4-(4-nitrophenoxy)pyrimidine (300 mg) in an ethyl acetate (10 ml)-methanol (10 ml) mixed solvent, and the mixture was stirred for 13 hours at room temperature under a hydrogen atmosphere at normal pressure. The reaction solution was filtered, the filtrate was concentrated, and the residue was passed through NH silica gel (Fuji Silicia Chemical). Elution was performed with a solvent (ethyl acetate:hexane=1:2) to obtain 70 mg of 4-(4-aminophenoxy)pyrimidine. The title compound (107 mg) was obtained from the obtained 4-(4-aminophenoxy)pyrimidine (70 mg) and 4-methoxyphenyl isocyanate, in the same manner as Example 10.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].Cl.[NH2:8][C:9]1[CH:38]=[CH:37][C:12]2[NH:13][C:14]([C:19]3[C:20](=[O:36])[C@:21]([CH3:35])([CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[C:22]4[C:27]([C:28]=3[OH:29])=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1.N1C=CC=CC=1>CC(C)=O>[OH:29][C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@@:21]([CH3:35])([CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[C:20](=[O:36])[C:19]=1[C:14]1[NH:13][C:12]2[CH:37]=[CH:38][C:9]([NH:8][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:10][C:11]=2[S:16](=[O:18])(=[O:17])[N:15]=1
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)c3ccccc3[C@@](C)(CCC(C)C)C1=O)N2
Reaction time: 4 h
Yield: 94.7 %

Procedure:
Ethane sulfonylchloride (75.6 mg, 0.588 mmol) was added carefully dropwise to a solution of Example 39H (70.0 mg, 0.147 mmol) and pyridine (93.1 mg, 1.18 mmol) in acetone (7 mL). The reaction mixture was stirred for 4 h and then concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with a 0-25% ethyl acetate/hexane gradient to give the title compound (74 mg, 95%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.42 m, 1 H) 0.69 (d, J=6.62 Hz, 3H) 0.72 (d, J=6.62 Hz, 3 H) 0.80 m, 1 H) 1.22 (t, J=7.35 Hz, 3 H) 1.33 (m, 1 H) 1.57 (s, 3 H) 2.07 m, 1 H) 2.22 m, 1 H) 3.19 m, 2 H) 5.76 (s, 1 H) 7.53 (dd, J=7.91, 4.23 Hz, 1H) 7.57 (dd, J=8.82, 2.21 Hz, 1 H) 7.63 (d, J=2.21 Hz, 1 H) 7.71 (d, J=8.82 Hz, 1 H) 7.76 (d, J=3.68 Hz, 2 H) 8.16 (d, J=7.72 Hz, 1 H) 10.31 (s, 1 H) 13.77 (s, 1 H).). MS (ESI+) m/z 532.0 (M+H)+, 549.1 (M+NH4)+ (ESI−) m/z 530.1 (M−H)−.
Reaction SMILES: [Br:1][C:2](Br)(Br)[F:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([C@H:27]1[CH2:32][CH2:31][C@H:30]([C@H:33]2[CH2:38][CH2:37][C@H:36]([CH:39]=O)[CH2:35][CH2:34]2)[CH2:29][CH2:28]1)[CH3:26]>COCCOC.O1CCCC1>[CH2:25]([C@H:27]1[CH2:32][CH2:31][C@H:30]([C@H:33]2[CH2:38][CH2:37][C@H:36]([CH:39]=[C:2]([F:3])[Br:1])[CH2:35][CH2:34]2)[CH2:29][CH2:28]1)[CH3:26]
Reactant: CC[C@H]1CC[C@H]([C@H]2CC[C@H](C=O)CC2)CC1
Reactant: FC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: COCCOC
Product: CC[C@H]1CC[C@H]([C@H]2CC[C@H](C=C(F)Br)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of tribromofluoromethane and triphenyl phosphine in ethylene glycol dimethyl ether was stirred at 70° C. for 1 hour. The reaction solution was cooled with ice, and a solution of trans-4-(trans-4-ethylcyclohexyl)cyclohexane carboaldehyde in tetrahydrofuran was added thereto. After the reaction solution was further stirred for 1 hour, the temperature of the solution was gradually raised up to room temperature, and insoluble substances were removed by filtration. Dilute hydrochloric acid was added to the filtrate, and it was extracted with toluene. After the organic layer was washed with water, it was dried by using anhydrous magnesium sulfate, and concentrated under a reduced pressure to obtain a brown oily product. After this product was purified by using a silica gel column chromatography, it was recrystallized from heptane to obtain trans-4-(trans-4-ethylcyclohexyl)cyclohexyl-2-fluoro-2-bromoethene.