Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[S:8][C:7]([NH:9][C:10](=[O:27])[CH2:11][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[S:15][CH:16]=2)=[N:6][CH:5]=1)([CH3:3])[CH3:2].C=O.O.[C:31](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl>[CH:1]([C:4]1[S:8][C:7]([NH:9][C:10](=[O:27])[CH2:11][C:12]2[N:13]=[C:14]([N:17]([CH3:31])[CH2:18][CH2:19][N:20]3[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]3)[S:15][CH:16]=2)=[N:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cnc(NC(=O)Cc2csc(NCCN3CCN(C)CC3)n2)s1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)c1cnc(NC(=O)Cc2csc(N(C)CCN3CCN(C)CC3)n2)s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
N-(5-isopropyl-1,3-thiazol-2-yl)-2-(2-{[2-(4-methyl-1piperazinyl)ethyl]amino}-1,3-thiazol-4-yl)acetamide (1 g, 2.45 mmol) and 40% formaldehyde in water (0.17 ml, 2.45 mmol) were mixed in CHCl3 (10 ml) and then treated with sodium triacetoxyborohydride (0.727 g, 3.43 mmol). The mixture was stirred at room temperature under a nitrogen atmosphere for 5 hours. The reaction mixture was quenched by adding aqueous saturated sodium bicarbonate and the product was extracted with CHCl3. The organic layer was washed with brine, dried and evaporated. The title compound was obtained after chromatographic purification in 75% yield.
Reaction SMILES: [C:1]1(=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.Cl.[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[NH:19]N>CO.C(O)(C)=O.Cl>[Cl:18][C:16]1[CH:15]=[C:14]2[C:13](=[C:12]([Cl:11])[CH:17]=1)[NH:19][C:2]1[C:1](=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2=1
Reactant: O=C1CCCCCC1=O
Reactant: NNc1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: O=C1CCCCc2c1[nH]c1c(Cl)cc(Cl)cc21
Temperature: 60 °C
Yield: 9.4 %

Procedure:
Cycloheptane-1,2-dione (1 g, 7.9 mmol) was dissolved in MeOH (25 mL) and (2,4-dichlorophenyl)hydrazine hydrochloride (1.86 g, 8.7 mmol) in AcOH—HCl (3.5:1, 45 mL) was added and heated to 60° C. for 18 h. MeOH was removed in vacuo, the reaction mixture was basified with aqueous NaHCO3 (pH-8) and then extracted with EtOAc (3×25 mL), The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to give the crude product which was purified by silica gel chromatograph [EtOAc-hexane (9:1) as eluant] to give the title compound (0.2 g, 9.4%). 1H NMR (200 MHz, CDCl3, δ in ppm) 9.0 (br s, 1H), 7.54 (d, J=1.6 Hz, 1H), 7.33 (d, J=1.8 Hz, 1H), 3.11 (t, J=12.0 Hz, 2H), 2.90 (t, J=11.8 Hz, 2H), 2.13-2.20 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:17][OH:18])=[C:10]([C:13]([F:16])([F:15])[F:14])[S:11][CH:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:18][CH2:17][C:9]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:12][S:11][C:10]=1[C:13]([F:14])([F:15])[F:16])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1c(-c2ccc(Cl)cc2)csc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1c(-c2ccc(Cl)cc2)csc1C(F)(F)F
Temperature: 0 °C

Procedure:
Into a 100-mL round-bottom flask, was placed [4-(4-chlorophenyl)-2-(trifluoromethyl)thiophen-3-yl]methanol (500 mg, 1.71 mmol, 1.00 equiv), triethylamine (521 mg, 5.15 mmol, 3.01 equiv), dichloromethane (10.0 mL). This was followed by the addition of MsCl (390 mg, 3.42 mmol, 2.00 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for 0.5 h at 25° C. The reaction progress was monitored by TLC(ethyl acetate/petroleum ether=1:6). The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×15 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 2×20 mL of sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 675 mg of [4-(4-chlorophenyl)-2-(trifluoromethyl)thiophen-3-yl]methyl methanesulfonate as a light yellow solid. The crude could be used for the next step directly. Mass spectrum (ESI, m/z): Calcd. for C13H10C1F3O3S2, 371.0 (M+H). found 371.0.
Reaction SMILES: [CH:1]1([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[I:15]([O-])(=O)(=O)=O.[Na+].II.S(=O)(=O)(O)O>C(O)(=O)C>[CH:1]1([C:5]2[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:13][C:14]=2[I:15])[CH2:2][CH2:3][CH2:4]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COC(=O)c1ccc(C2CCC2)cc1
Agent: II
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C2CCC2)c(I)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 101.4 %

Procedure:
To a solution of methyl 4-cyclobutylbenzoate (168.1, 2.00 g, 10.5 mmol, 1.00 equiv) in acetic acid (30 mL) were carefully added sodium periodate (1.00 g, 4.68 mmol, 0.50 equiv), iodine (3.00 g, 11.8 mmol, 1.10 equiv) and sulfuric acid (0.15 g, 0.15 equiv). The resulting mixture was stirred overnight at 100° C. After cooling to room temperature, the reaction was then quenched by carefully adding 30 mL of Na2S2O3 (aq., sat.) and the resulting mixture was extracted with 3×20 mL of ethyl acetate. The combined organic layers were washed with 3×20 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 1.50 g (45%) of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([CH3:25])([CH3:24])[CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:26](N1C=CN=C1)(N1C=CN=C1)=[S:27]>C(Cl)Cl>[CH3:24][C:14]([CH3:25])([CH2:13][N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[NH:1][C:26]1=[S:27])[CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21]
Reactant: CC(C)(CNC(=O)OC(C)(C)C)CNc1c(N)cnc2ccccc12
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(C)(CNC(=O)OC(C)(C)C)Cn1c(=S)[nH]c2cnc3ccccc3c21
Yield: 96.8 %

Procedure:
tert-Butyl 3-[(3-aminoquinolin-4-yl)amino]-2,2-dimethylpropylcarbamate (7.16 g, 20.8 mmol) was suspended in 200 mL of CH2Cl2 and treated with 1,1′-thiocarbonyldiimidazole (4.07 g, 22.9 mmol) under an atmosphere of N2. After about 2 hours a precipitate had formed. It was isolated by filtration and dried under vacuum to afford tert-butyl 2,2-dimethyl-3-(2-thioxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate (7.78 g) as a white solid.
Reaction SMILES: [CH2:1]([Sn](CCCC)(CCCC)C=C)[CH2:2]CC.Br[C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[N:21][CH:22]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]([C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[N:21][CH:22]=1)=[CH2:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)C(=O)Nc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(NC(=O)C(C)(C)C)nc1
Yield: 80.4 %

Procedure:
Tributyl(vinyl)stannane (50 g, 0.16 mol), Pd(Ph3P)4 (3.3 g, 2.9 mmol) and a catalytic amount of 2,6-t-butyl-4-methylphenol was added to a solution of N-(5-bromopyridin-2-yl)pivalamide (36 g, 0.14 mol) in toluene. The reaction mixture was heated at reflux for 48 h. The solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel (5% EtOAc in petroleum ether) to afford N-(5-vinylpyridin-2-yl)pivalamide (23 g, 80% yield). 1H NMR (CDCl3, 300 MHz) δ 8.24-8.20 (m, 2H), 8.02 (br s, 1H), 7.77 (dd, J=8.7 and 2.4, 1H), 6.65 (dd, J=17.7 and 10.8, 1H), 5.73 (d, J=17.7, 1H), 5.29 (d, J=10.8, 1H), 1.32 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[N:20]1[CH2:21][CH2:22][N:23]([C:6]([C:5]2[CH:4]=[N:3][C:2]([F:1])=[CH:10][C:9]=2[CH3:11])=[O:8])[CH2:24][CH2:25]1
Reactant: Cc1cc(F)ncc1C(=O)O
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3cnc(F)cc3C)CC2)c(C)c1
Yield: 83.3 %

Procedure:
Using 6-fluoro-4-methylnicotinic acid (500 mg) and 1-(2,4-dimethylphenyl)piperazine (607 mg) and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (870 mg) was obtained.
Reaction SMILES: C(O[C:4](=[O:29])[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)[N:11]=[CH:10]2)C.[NH2:30][CH2:31][CH:32]([OH:44])[CH2:33][N:34]1[CH2:43][CH2:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35]1>CCO>[CH2:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:42][CH2:43][N:34]1[CH2:33][CH:32]([OH:44])[CH2:31][NH:30][C:4](=[O:29])[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH:16]1[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]1)[N:11]=[CH:10]2
Reactant: CCOC(=O)COc1ccc2c(cnn2C2CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: NCC(O)CN1CCc2ccccc2C1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3cc(OCC(=O)NCC(O)CN4CCc5ccccc5C4)ccc32)CC1
Temperature: 120 °C
Reaction time: 2 h
Yield: 50.1 %

Procedure:
To a solution of tert-butyl 4-(5-(2-ethoxy-2-oxoethoxy)-1H-indazol-1-yl)piperidine-1-carboxylate (100 mg, 0.248 mmol) in EtOH (2 mL) was added 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (102.2 mg, 0.496 mmol) and the mixture was stirred at 120° C. for 2 h in microwave under N2. The mixture was allowed to cool, concentrated under reduced pressure, purified by TLC (Pet.Ether:EtOAc=1:1) to give tert-butyl 4-(5-(2-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)amino)-2-oxoethoxy)-1H-indazol-1-yl)piperidine-1-carboxylate (70 mg, yield 50%) as a colorless oil. LCMS (m/z): 564.3 [M+H]+
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][C:11]2[CH:17]=[C:18]([C:21]3[N:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:19]=[CH:20][C:10]1=2)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:16][N:13]1[CH2:14][CH2:15][CH:9]([OH:8])[C:10]2[CH:20]=[CH:19][C:18]([C:21]3[N:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][C:11]=2[CH2:12]1
Reactant: CN1CCC(O[Si](C)(C)C(C)(C)C)c2ccc(-c3cccnn3)cc2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN1CCC(O)c2ccc(-c3cccnn3)cc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.2 %

Procedure:
To the solution of the (+)-5-(tert-butyldimethylsilyloxy)-2-methyl-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine (2.2 g, 5.8 mmol) from Step G in Example 1, THF (30 mL) was added TBAF (1.0 M in THF, 10 mL, 10 mmol). The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed. The residue was purified by flash chromatography (97:2.7:0.3 to 93:6.3:0.7 ethyl acetate/methanol/concentrated ammonium hydroxide) to give 2-methyl-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-ol (1.01 g, 66%) as a white solid [[α]25D, +37.1°, (C, 0.21 Methanol)]: ESI MS m/z 256 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH2:11]([C:13]1[CH:14]=[C:15]([CH3:25])[C:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:17][CH:18]=1)[CH3:12]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:22]2[CH2:23][CH2:24][N:19]([C:16]3[C:15]([CH3:25])=[CH:14][C:13]([CH2:11][CH3:12])=[CH:18][N:17]=3)[CH2:20][CH2:21]2)=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: CCc1cnc(N2CCNCC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cn3)CC2)c(C)c1
Yield: 42.8 %

Procedure:
Using 5-bromo-2-picolinic acid (206 mg) and 1-(5-ethyl-3-methylpyridin-2-yl)piperazine (220 mg) described in Preparation Example 81 and by the reaction and treatment in the same manner as in Preparation Example 109, the title compound (170 mg) was obtained.
Reaction SMILES: [N:1]1([C:6]2[CH:18]=[CH:17][C:9]([O:10][CH:11]3[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.CO.[CH3:21][O:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH:33]=O)=[CH:25][CH:24]=1>C(Cl)Cl>[N:1]1([C:6]2[CH:18]=[CH:17][C:9]([O:10][CH:11]3[CH2:16][CH2:15][CH2:14][N:13]([CH2:33][C:26]4[C:27]5[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:23]([O:22][CH3:21])=[CH:24][CH:25]=4)[CH2:12]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1cn(-c2ccc(OC3CCCNC3)cc2)cn1
Reactant: COc1ccc(C=O)c2ccccc12
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(CN2CCCC(Oc3ccc(-n4ccnc4)cc3)C2)c2ccccc12
Reaction time: 8 h
Yield: 10.4 %

Procedure:
To a mixture of 3-[4-(imidazol-1-yl)phenoxy]piperidine (308 mg, 1.26 mmol), methanol (6.0 mL) was added 4-methoxy-1-naphthaldehyde (1.25 eq, 298 mg), followed by borane pyridine complex (0.196 mL, 1.25 eq.). The resulting mixture was stirred overnight. The methanol was evaporated, and the residue diluted with ethyl acetate, washed with water and brine. Evaporation of the solvent in vacuo gave a crude product. Flash column chromatography on silical gel with 1–2% methanol in methylene chloride afforded 3-[4-(imidazol-1-yl)phenoxy]-1-[(4-methoxynaphth-1-yl)methyl]piperidine (54 mg), 1H NMR(CDCl3) 8.30 (m, 2), 7.70 (s, 1), 7.50 (m, 2), 7.30 (s, 1), 7.20 (m, 4), 6.90 (m, 2), 6.70 (d, 2), 4.30 (m, 1), 4.00 (s, 3), 3.90 (AB q , 2), 3.10 (m, 1), 2.80 (m, 1), 2.10–2.30 (m, 3), 1.80 (m, 1), 1.40–1.70 (m, 2) ppm.
Reaction SMILES: [OH:1][C@H:2]([CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1([CH3:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[H-].[Na+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C=O)C>[CH2:25]([O:1][C@H:2]([CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1([CH3:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: C[C@@H](O)CCCCOC1(C)CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](CCCCOC1(C)CCN(C(=O)OC(C)(C)C)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
To a solution of (R)-tert-butyl 4-((5-hydroxyhexyl)oxy)-4-methylpiperidine-1-carboxylate (4.5 g, 14.27 mmol) in DMF (50 mL) at 0° C. was added 60% NaH (0.685 g, 17.12 mmol) and the resulting mixture was stirred at room temp for 1 h. Benzyl bromide (2.55 mL, 21.40 mmol) was then added and the mixture was stirred for 16 h. Water (20 mL) was then added and the mixture was extracted with ether (100 mL), washed with brine (25 ml), dried (Na2SO4), filtered and concentrated. The residue was then purified by Biotage (0-20% EtOAc/hexane) to afford (R)-tert-butyl 4-((5-(benzyloxy)hexyl)oxy)-4-methylpiperidine-1-carboxylate (3.5 g, 8.63 mmol, 60.5% yield) as light yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.38-7.35 (m, 4H), 7.31-7.25 (m, 1H), 4.60 (d, J=11.8 Hz, 1H), 4.48 (d, J=11.8 Hz, 1H), 3.86-3.62 (m, 3H), 3.58-3.50 (m, 1H), 3.31 (t, J=6.3 Hz, 2H), 3.14 (br. s., 2H), 1.74 (d, J=12.9 Hz, 2H), 1.59-1.51 (m, 3H), 1.47 (s, 9H), 1.46-1.37 (m, 4H), 1.22 (d, J=6.1 Hz, 3H), 1.17 (s, 3H). LCMS (M+H)=406.3.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([NH:14]C(OC(C)(C)C)=O)[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22]O>>[CH3:22][O:13][C:11](=[O:12])[C@H:10]([NH2:14])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)O
Product: COC(=O)[C@H](N)COCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 100 %

Procedure:
A solution of (2R)-3-benzyloxy-2-(N-(t-butoxycarbonyl)amino)propanoic acid (23 g, 78 mmol, [α]D −4.4° (c=2, H2O )) in methanol (250 mL) was cooled to 0° C. and HCl (g) bubbled into the solution until saturated. The resulting mixture was stirred at ambient temperature for 17 hours and then concentrated in vacuo to afford 17 g (100% yield) of (2R)-3-benzyloxy-2-aminopropanoic acid methyl ester, a compound of formula (M), as a white solid; NMR (DMSO-d6) 8.7 (br s, 3), 7.4-7.3 (m, 5), 4.5 (q, 2), 4.4 (br s, 1), 3.8 (s, 2), 3.7 (s, 3) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1>>[C:24]1([C:22]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:31][CH:32]4[CH2:37][CH2:36][CH2:35][CH2:34][O:33]4)[CH:3]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]([F:21])([F:19])[F:20])=[O:23])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: BrCC1CCCCO1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCC2CCCCO2)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 2-Bromomethyl-tetrahydropyran following the procedure of Example 478: MS (ESI) m/z 492.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[CH3:20][C:21]1[S:25][C:24]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)=[N:23][CH:22]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([C:24]3[S:25][C:21]([CH3:20])=[CH:22][N:23]=3)[CH:27]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: Cc1cnc(-c2cccc(C=O)c2)s1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2ncc(C)s2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 3-(5-methylthiazol-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.87 min.; [M+H]+: 423.11 g/mol.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][C:7](=[O:9])[CH2:8][CH:4]2[CH2:3][NH:2]1.[C:10](OC(=O)C)(=[O:12])[CH3:11].C(N(CC)CC)C>C(#N)C>[C:10]([N:2]1[CH2:3][CH:4]2[CH2:8][C:7](=[O:9])[CH2:6][CH:5]2[CH2:1]1)(=[O:12])[CH3:11]
Reactant: O=C1CC2CNCC2C1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)N1CC2CC(=O)CC2C1
Reaction time: 8 h
Yield: 71.8 %

Procedure:
Hexahydro-cyclopenta[c]pyrrol-5-one triflutate 1f (717 mg, 3 mmol) was dissolved in 20 mL of acetonitrile, and acetic anhydride (0.42 mL, 4.5 mmol) and triethylamine (0.98 mL, 9 mmol) were then added to the solution in an ice-water bath. Upon completion of the addition, the reaction mixture was then stirred overnight in an ice-water bath. The solvent was evaporated, and water (50 mL) was then added to the residue. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic extracts were washed with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 2-acetyl-hexahydro-cyclopenta[c]pyrrol-5-one 5a (0.36 g, yield 72%) as a colorless oil.
Reaction SMILES: [C:1]([Sn:3]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][CH2:5][CH2:6][CH3:7])#[CH:2].[CH2:16]([N:23]=[N+:24]=[N-:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:23]1[CH:2]=[C:1]([Sn:3]([CH2:8][CH2:9][CH2:10][CH3:11])([CH2:4][CH2:5][CH2:6][CH3:7])[CH2:12][CH2:13][CH2:14][CH3:15])[N:25]=[N:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cn(Cc2ccccc2)nn1

Procedure:
Ethynyltributylstannane (1 mL, 3.4 mmol) and benzyl azide (0.65 mL, 5.2 mmol) were heated to 130° C. for 24 hours. The mixture was adsorbed onto silica gel, and purified by silica gel chromatography eluting with 1:4 ethyl acetate:hexanes to afford the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[C:6]([C:7](O)=[O:8])[C:5]=1[OH:16])([CH3:3])[CH3:2].ClCCl.C(Cl)(=O)C(Cl)=O.C[N:27](C=O)C>>[CH:1]([C:4]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[C:6]([C:7]([NH2:27])=[O:8])[C:5]=1[OH:16])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)c1cc(C(=O)O)c(O)c(C(C)C)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(C)c1cc(C(N)=O)c(O)c(C(C)C)c1
Yield: 40 %

Procedure:
To a solution of 3,5-diisopropylsalicylic acid (Aldrich) (10 mmole, 2.2 g) and dichloromethane (20 mL), oxalyl-chloride (Merck) (11.0 mmole, 1.03 mL) and DMF (Aldrich) (80 μL) were added. The reaction mixture was refluxed for 1 hour, whereupon the solvent and the excess of oxalyl-chloride were removed under reduced pressure. The obtained oily product was dissolved in dichloromethane (50 mL) and ammonia gas was introduced into reaction mixture under cooling. The solution was diluted with water and, after drying with sodium sulfate, the organic layer was evaporated under reduced pressure. A yellow residue was recrysatallized from n-hexane, whereat there were obtained 876 mg (40%) of 3,5-diisopropyl salicylamide in the form of a white crystalline product:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([OH:19])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH:21]1([C:24]2[C:29]([CH2:30][CH2:31]O)=[CH:28][N:27]=[C:26]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=3)[N:25]=2)[CH2:23][CH2:22]1>>[CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([O:19][CH2:31][CH2:30][C:29]2[C:24]([CH:21]3[CH2:23][CH2:22]3)=[N:25][C:26]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:40])[F:41])=[CH:35][CH:34]=3)=[N:27][CH:28]=2)[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: OCCc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Reactant: CCOC(=O)C(C)(C)Oc1cc(O)cc2ccccc12
Product: CCOC(=O)C(C)(C)Oc1cc(OCCc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc2ccccc12

Procedure:
A] In analogy to the procedures described in example 4D] and 4E], 2-(3-hydroxy-naphthalen-1-yloxy)-2-methyl-propionic acid ethyl ester (example 14C]) was reacted with 2-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-ethanol (example 16B]) to give 2-(3-{2-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-ethoxy}-naphthalen-1-yloxy)-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].C(=O)([O-])[O-].[Na+].[Na+].F[C:19]1[CH:20]=[N+:21]([O-:28])[CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26].O>CN(C)C=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:19]1[CH:20]=[N+:21]([O-:28])[CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26]
Reactant: Oc1ccc2ccccc2c1
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc[n+]([O-])cc1Oc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-naphthol (7 g) in 50 ml dimethylformamide was added sodium carbonate (10 g), followed by 3-fluoro-4-nitropyridine-N-oxide. After stirring three hours at ambient temperature the reaction mixture was stirred with water and extracted with ethyl acetate. The organic extract was washed with water and saturated sodium chloride solution, dried (anhy. MgSO4), filtered and concentrated to a solid. This solid was triturated with ether, collected and dried to give a solid, 11.6 g, m.p. 130°-133° C. A three gram portion was recrystallized from ethanol to give crystals, 2.8 g, m.p. 131°-133° C.