Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[N:10][OH:11])[CH2:2]1.[H-].[Na+].S(OC)(O[CH3:18])(=O)=O>O>[CH3:18][O:11][N:10]=[C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][CH2:2]1
Reactant: COS(=O)(=O)OC
Reactant: ON=C1COc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CON=C1COc2ccccc21
Yield: 42 %

Procedure:
3.7 g of benzofuran-3-one oxime are dissolved in 15 ml of dimethylfornamide. At 20° C., 1 g of sodium hydride (60%) is added and the mixture is stirred until the evolution of gas ceases. 3.15 g of dimethyl sulphate are then added dropwise and the mixture is stirred at 20° C. for 24 hours. The reaction mixture is poured into water, extracted with ethyl acetate, the organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. The residue is chromatographed over silica gel using n-hexane/acetone (4:1). 1.7 g (42% of theory) of benzofuran-3-one O-methyl-oxime are obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([O:12][CH3:13])[N:3]=1.[Cl:14][C:15]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH2:25][C:26]2[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=2[F:34])=[CH:18][C:16]=1[NH2:17].C(N(CC)C(C)C)(C)C.O>C(#N)C>[Cl:14][C:15]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH2:25][C:26]2[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=2[F:34])=[CH:18][C:16]=1[NH:17][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([O:12][CH3:13])[N:3]=[C:2]([Cl:1])[N:7]=1
Reactant: COc1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: COc1cc(Cl)c(N)cc1OCc1c(F)cccc1OC
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(Cl)c(Nc2nc(Cl)nc(OC)c2[N+](=O)[O-])cc1OCc1c(F)cccc1OC
Temperature: 40 °C
Reaction time: 72 h
Yield: 90.2 %

Procedure:
To a solution of 2,4-dichloro-6-methoxy-5-nitropyrimidine (1.79 g) in acetonitrile (21 mL) were added 2-chloro-5-(2-fluoro-6-methoxybenzyloxy)-4-methoxyaniline (2.18 g) and N,N-diisopropylethylamine (1.28 mL), and the mixture was stirred at 40° C. for 3 days. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residual solids were suspended in a mixed solvent (n-hexane/ethyl acetate=3/1), and collected by filtration. The collected solids were dried under reduced pressure to give 2-chloro-N-(2-chloro-6-methoxy-5-nitropyrimidin-4-yl)-5-(2-fluoro-6-methoxybenzyloxy)-4-methoxyaniline (3.15 g). The title compound was prepared in a similar manner to that described in Example 397 using this material instead of 2-chloro-N-(2-chloro-6-methoxy-5-nitropyrimidin-4-yl)-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyaniline.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[O:18]1[CH2:20][CH:19]1[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[CH:23][CH:22]=1>CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:20][CH:19]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=[CH:23][CH:22]=3)[OH:18])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: c1ccc2c(C3CO3)ccnc2c1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2ccnc3ccccc23)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 25.1 %

Procedure:
To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (300 mg, 1.5 mmol) in DMF (5 mL) was added sodium hydride (180 mg, 4.5 mmol) under nitrogen. After stirring at RT for 10 min, 4-(oxiran-2-yl)quinoline (384 mg, 2.25 mmol) was added dropwise under nitrogen into the reaction mixture, which was stirred at RT for 18 h. The progress of reaction was monitored by TLC, LCMS and NMR. The reaction mixture was poured in ice-cold water and extracted with EtOAc (2×50 mL). The combined organic layer was washed with water (3×50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. Re-crystallization with diethyl ether yielded 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(quinolin-4-yl)ethanol (140 mg). 1H NMR (CDCl3, freebase) δ (ppm): 8.86 (d, 1H), 8.19 (d, 1H), 7.97 (d, 1H), 7.78 (t, 1H), 7.41 (d, 1H), 7.56 (t, 1H), 7.2 (d, 1H), 6.93-7.01 (m, 2H), 5.57 (t, 1H), 4.2 (dd, 1H), 4.1 (dd, 1H), 3.37 (dd, 2H), 2.83 (m, 1H), 2.71 (bs, 3H), 2.4 (s, 3H), 2.38 (s, 3H). Separation by chiral HPLC provides enantiomers II-90a-b.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH:8]2[CH2:10][CH2:11][CH2:12][CH:7]2[CH2:6]1.C([O-])([O-])=O.[K+].[K+].[Cl:19][C:20]1[CH:21]=[C:22]([NH:27][C:28]2[C:37]3[C:32](=[CH:33][C:34]([O:39][CH3:40])=[C:35]([OH:38])[CH:36]=3)[N:31]=[CH:30][N:29]=2)[CH:23]=[CH:24][C:25]=1[F:26].C(Cl)Cl>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:19][C:20]1[CH:21]=[C:22]([NH:27][C:28]2[C:37]3[C:32](=[CH:33][C:34]([O:39][CH3:40])=[C:35]([O:38][CH2:2][CH2:3][CH2:4][N:5]4[CH2:9][CH:8]5[CH2:10][CH2:11][CH2:12][CH:7]5[CH2:6]4)[CH:36]=3)[N:31]=[CH:30][N:29]=2)[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: ClCCCN1CC2CCCC2C1
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CC2CCCC2C1
Temperature: 90 °C
Reaction time: 12 h
Yield: 53.3 %

Procedure:
To a solution of 2-(3-chloropropyl)octahydrocyclopenta[c]pyrrole (2.00 g, 1.2 eq) in DMF (15 mL) was added K2CO3 (2.46 g, 2.0 eq), 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (2.84 g, 1.0 eq) and tetrabutylammonium iodide (0.1 eq). The reaction mixture was stirred at 90° C. for 12 h under N2, and 100 mL of CH2Cl2 was added. The mixture was washed with water followed by brine. The mixture was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to afford the title compound (2.23 g, 75.59%), HPLC: 94.23%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 472.0 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.40-1.43 (m, 2H), 1.58-1.65 (m, 4H), 2.01 (t, J=8.92 Hz, 2H), 2.10 (t, J=13.48 Hz, 2H), 2.57-2.60 (m, 4H), 2.90 (t, J=16.32 Hz, 2H), 3.49 (s, 2H), 4.00 (s, 3H), 4.21 (t, J=12.00 Hz, 2H), 7.13-7.20 (m, 2H), 7.57 (d, J=1.28 Hz, 2H), 7.59-7.60 (m, 1H), 7.91 (m, 1H), 7.93 (m, 1H), 8.65 (s, 1H) ppm.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:31]2[C:32]([C:37](O)=[O:38])=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:28]=[CH:29][CH:30]=1>>[CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][N:6]([C:37]([C:32]3[C:31]([C:27]4[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=4)=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:38])[C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CC(C)C[C@@H]21
Reactant: COc1cccc(-c2ccccc2C(=O)O)c1
Product: COc1cccc(-c2ccccc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with commercially available 3′-methoxy-biphenyl-2-carboxylic acid.
Reaction SMILES: [CH:1]([CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=O.[C:15]([CH:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:17][CH2:18][CH3:19])=[O:16]>C1COCC1>[CH2:18]([O:17][C:15](=[O:16])[CH:20]=[CH:1][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCCC1C=O
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C=CC1CCCN1C(=O)OC(C)(C)C
Yield: 74.3 %

Procedure:
A solution of tert-butyl 2-formylpyrrolidine-1-carboxylate (4 g, 20 mmol) and (carbethoxymethylene)triphenylphosphorane (7 g, 20 mmol) in THF was stirred at room temperature for 2 hr. Then the mixture was concentrated and purified by column chromatography to give 4 g of desired product. MS (ESI): 270 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[O:18][C:19]([F:22])([F:21])[F:20])[NH2:14]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:14][C:13]2[CH:15]=[CH:16][C:17]([O:18][C:19]([F:20])([F:21])[F:22])=[C:11]([Cl:10])[CH:12]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc(OC(F)(F)F)c(Cl)c1
Product: Fc1cnc(Cl)nc1Nc1ccc(OC(F)(F)F)c(Cl)c1

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 3-chloro-4-trifluoromethoxyaniline gave 2-chloro-N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.15 (d, 1H, J=3.0 Hz), 7.86 (d, 1H, J=2.1 Hz), 7.61 (dd, 1H, J=2.1 and 8.7 Hz); 7.35 (dd, 1H, J=1.2 and 8.7 Hz), 6.98 (bs, 1H); LCMS: purity: 97%; MS (m/e): 342 (M+2H).
Reaction SMILES: Br[C:2]1[NH:19][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]3[CH:12]=[CH:13][C:14]([CH3:18])=[C:15]([OH:17])[CH:16]=3)[C:4]=2[CH:3]=1.[NH2:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:20][C:21]1[CH:26]=[C:25]([C:2]2[NH:19][C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]4[CH:12]=[CH:13][C:14]([CH3:18])=[C:15]([OH:17])[CH:16]=4)[C:4]=3[CH:3]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: Cc1ccc(Nc2ncnc3[nH]c(Br)cc23)cc1O
Reactant: Nc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccc(Nc2ncnc3[nH]c(-c4cccc(N)c4)cc23)cc1O
Temperature: 80 °C
Yield: 57.9 %

Procedure:
5-(6-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2-methyl-phenol (14 mg, 0.0448 mmol) is mixed with 3-aminophenylboronic acid (13 mg, 0.0896 mmol), Pd(dppf)Cl2∩CH2Cl2 (7.5 mg, 0.009 mmol), and K3PO4 (19 mg, 0.0896 mmol) in anhydrous dioxane (0.8 mL) under an argon atmosphere. The mixture is heated to 80° C. for 18 hours, with stirring. The reaction is then cooled to ambient temperature and filtered through a pad of silica with 10% MeOH in DCM. The filtrate is concentrated and the resulting crude product is purified by reverse phase HPLC using a C18 column and 0-95% acetonitrile/water gradient to give 5-[6-(3-amino-phenyl)-7H-pyrrolo[2,3-d]primidin-4-ylamino]-2-methyl-phenol (8.6 mg, 59%); 1H NMR (500 MHz, DMSO): δ 8.16 (s, 1H), 7.27 (s, 1H), 7.17 (t, J=8.1 Hz, 1H), 7.09-7.10 (m, 2H), 7.04 (d, J=8.1 Hz, 1H), 6.92 (d, J=8.1 Hz, 1H), 6.81 (s, 1H), 6.70 (d, J=7.4 Hz, 1H), 2.19 (s, 3H); LC-ESMS observed [M+H]+ 332.1.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[C:15]([O:17][CH3:18])=[O:16].CCN(C(C)C)C(C)C.[O:28](S(C(F)(F)F)(=O)=O)[S:29]([C:32]([F:35])([F:34])[F:33])(=O)=[O:30]>C(Cl)Cl>[F:33][C:32]([F:35])([F:34])[S:29]([O:1][C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C:3]=1[C:15]([O:17][CH3:18])=[O:16])(=[O:30])=[O:28]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-tert-butyl 3-methyl 4-oxopiperidine-1,3-dicarboxylate (2.50 g, 9.72 mmol) in DCM (50 mL) was added DIPEA (2.03 mL, 11.66 mmol) and Tf2O (1.80 mL, 10.69 mmol) at −78° C., and then it was warmed up to room temperature and stirred further for 2 h, the solution was diluted with DCM and the organic layer was washed with Sat. NaHCO3, dried and concentrated to give 1-tert-butyl 3-methyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1,3(2H)-dicarboxylate as crude product (4.4 g).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=[O:4].[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH:24]=O)[CH:22]=2)[CH:17]=[N:16]1>>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21](/[CH:24]=[C:8]3/[C:9](=[O:14])[NH:10][C:11]4[C:7]/3=[CH:6][C:5]([C:3]([NH:2][CH3:1])=[O:4])=[CH:13][CH:12]=4)[CH:22]=2)[CH:17]=[N:16]1
Reactant: O=Cc1ccc2cn[nH]c2c1
Reactant: CNC(=O)c1ccc2c(c1)CC(=O)N2
Product: CNC(=O)c1ccc2c(c1)/C(=C\c1ccc3cn[nH]c3c1)C(=O)N2

Procedure:
The title compound was synthesized from N-methyl-2-oxoindoline-5-carboxamide (11 mg, 0.0578 mmol) and 1H-indazole-6-carbaldehyde (10 mg, 0.0636 mmol) according to the method described for Example A1 to obtain 3.0 mg, 17%. 1H NMR (400 MHz, d6-DMSO) δ 13.33 (s, 1H), 10.88 (s, 1H), 8.24-8.22 (m, 1H), 8.18 (s, 2H), 7.93-7.88 (m, 2H), 7.84 (s, 1H), 7.72 (d, J=7.9 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 6.91 (d, J=8.0 Hz, 1H), 2.68 (d, J=4.0 Hz, 3H); MS ESI 319.1 [M+H]+, calcd for [C18H14N4O2+H]+ 319.12.
Reaction SMILES: [CH:1]([C:4]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)([C:30](=[O:32])[NH2:31])[N:5]1[C:11](=[O:12])[CH:10]([NH:13][C:14]([C:16]2[NH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[C:9](=[O:25])[NH:8][C:7]2[CH:26]=[CH:27][CH:28]=[CH:29][C:6]1=2)([CH3:3])[CH3:2].Br[C:42]1[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=1.[K+].C([O-])(=O)C>CN(C=O)C.[Cu]>[CH:1]([C:4]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)([C:30](=[O:32])[NH2:31])[N:5]1[C:11](=[O:12])[CH:10]([NH:13][C:14]([C:16]2[NH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[C:9](=[O:25])[N:8]([C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)[C:7]2[CH:26]=[CH:27][CH:28]=[CH:29][C:6]1=2)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(C(N)=O)(C(C)C)N2C(=O)C(NC(=O)c3cc4ccccc4[nH]3)C(=O)Nc3ccccc32)cc1
Reactant: Brc1cccnc1
Agent: [Cu]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C(C(N)=O)(C(C)C)N2C(=O)C(NC(=O)c3cc4ccccc4[nH]3)C(=O)N(c3cccnc3)c3ccccc32)cc1
Temperature: 100 °C
Reaction time: 15 h
Yield: 11.9 %

Procedure:
To a solution of 1H-Indole-2-carboxylic acid {1[isopropyl-(4-methoxy-phenyl)-carbamoylmethyl]-2,4-dioxo-2,3,4,5-tetrhydro-1H-benzo[b][1,4]diazepine-3-yl}amide (0.14 g, 0.26 mmol) and 3-bromopyridine (40 μL, 0.42 mmol)in DMF (1 mL) was added copper powder (46 mg, 0.73 mmol) and acetic acid potassium salt (38 mg, 0.73 mmol). The heterogenous solution was stirred at 100° C. for 15 h and subsequently hot filtered through celite and washed with methanol. The resulting precipitate was filtered and purified by RPHPLC (40-60% C. over 30 min) to yield the title compound (19 mg) as a white lyophile: Tr=8.7 min (40-60% C. over 30 min); 1HNMR (d6 -Acetone, 300 MHz) δ 10.98 (s, 1H), 9.02 (s, 1H), 8.76 (s, 1H), 7.85 (d, 1H, J=8.8), 7.5 (m, 15H), 5.68 (d, 1H, J=7.6), 5.02 (m, 1H), 4.65 (ABq, 2H, J=16.8, 135), 4.02 (s, 3H), 2.19 (d, 3H, J=2.0), 2.18 (d, 3H, J=2.0); low resolution MS(FAB) m/e 617 (MH+).
Reaction SMILES: [CH3:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH:5]=[CH:4][CH2:3]1.OS(O)(=O)=O>C(Cl)(Cl)Cl>[CH3:1][C:2]12[C:8](=[O:10])[O:9][CH:4]([CH2:5][CH2:6][CH2:7]1)[CH2:3]2
Reactant: CC1(C(=O)O)CC=CCC1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CC12CCCC(C1)OC2=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 59.6 %

Procedure:
A solution of 1-methyl-3-cyclohexenecarboxylic acid (47 g) in chloroform (200 ml) was cooled to -5° C. Then, a mixture of conc. H2SO4 (100 ml) and chloroform (100 ml) was added. After stirring at 0° C. for 15 minutes, the mixture was poured onto ice (500 g) and extracted with chloroform. The chloroform layer was washed in sequence with water, saturated aqueous sodium hydrogen carbonate solution and water, and dried (MgSO4), and the chloroform was distilled off. The residual oily substance was subjected to column chromatography using silica gel (500 g) and eluted with ether-hexane (1:3 v/v). From the first eluate fractions, crystals of 1-methylcyclohexane-1,3-carbolactone (28.0 g, 59.6% yield) were recovered and recrystallized from hexane. m.p. 37°-38° C.
Reaction SMILES: [F:1][C:2]([F:20])([CH:17]([F:19])[F:18])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[N:14][NH:13][C:12]2=[O:16])=[CH:7][CH:6]=1.FC(F)(F)S(O[C@@H:27]([CH3:38])[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])(=O)=O.C(O)(=O)C>CN(C)C=O.[H-].[Na+].O1CCCC1.C(OCC)(=O)C.C(OC(C)C)(C)C>[F:20][C:2]([F:1])([CH:17]([F:19])[F:18])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:12](=[O:16])[N:13]([C@H:27]([CH3:38])[C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])[N:14]=[CH:15]2)=[CH:7][CH:6]=1
Reactant: C[C@H](OS(=O)(=O)C(F)(F)F)C(=O)OCc1ccccc1
Reactant: O=c1[nH]ncn1-c1ccc(OCC(F)(F)C(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@H](C(=O)OCc1ccccc1)n1ncn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 85.6 %

Procedure:
4-[4-(2,2,3,3-Tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone (18 g) was dissolved in 180 ml of dimethylformamide, to which 60% sodium hydride in oil (2.52 g) was added. The mixture was vigorously stirred at room temperature for 40 minutes. The reaction solution was added to a solution of 20 g of benzyl (2S)-2-trifluoromethanesulfonyloxypropionate prepared in Example 3 in 240 ml of tetrahydrofuran under nitrogen atmosphere at -40° to -30° C. over the period of ca. 40 minutes. The mixture was stirred at -40° to -20° C. for 40 minutes, to which 10 ml of acetic acid was added. Then, the reaction solution was diluted with a mixture of 100 ml of ethyl acetate and 500 ml of diisopropyl ether, washed with 250 ml of water, 2N-hydrochloric acid (250 ml×2) and 250 ml of an aqueous solution of sodium chloride successively. After dring over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (silica gel: 250 g, eluent; hexane:ethyl acetate=2:1) to give 24 g of benzyl (2R)-2-[4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]propionate (yield: 82%) as a colorless oil.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:16][C:17]([OH:19])=O.[NH3:20].O>O1CCCC1.C(Cl)(=O)C(Cl)=O.CN(C)C=O>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:16][C:17]([NH2:20])=[O:19]
Reactant: N
Reactant: O=C(O)Cc1ccc2c(c1)CCc1ccccc1O2
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)Cc1ccc2c(c1)CCc1ccccc1O2
Yield: 48 %

Procedure:
To 100 mg of (10,11-dihydro dibenzo[b,f]oxepin-2-yl)-acetic acid in 5 ml of dry tetrahydrofuran were added 4 drops of oxalyl chloride, and the mixture was stirred with ice-cooling. To the mixture were added 1 drop of dimethylformamide 1.75 hours later, 4 drops of oxalyl chloride 4 hours later and 1% ammonia in 5 ml tetrahydrofuran 6 hours later, and the resulting mixture was stirred for 17 hours at room temperature. To this was added water, and the mixture was extracted with ethyl acetate. The extract was washed with a 1% sodium hydroxide solution and then with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a residue, which was recrystallized from ethyl acetate to yield 48 mg (yield: 48%) of (10,11-dihydro dibenzo[b,f]oxepin-2-yl)-acetamide as colorless crystals having a melting point of 205°-206° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:25])[C@@H:15]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:16][CH3:17].[H-].[Na+].[CH3:28]I>CN(C)C=O>[CH3:28][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:25])[C@@H:15]([NH:18][C:19](=[O:24])[C:20]([F:21])([F:23])[F:22])[CH2:16][CH3:17]
Reactant: CC[C@H](NC(=O)C(F)(F)F)C(=O)NCCCc1cc2ccccc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@H](NC(=O)C(F)(F)F)C(=O)NCCCc1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 20 mL cintillation vial was charged with (S)—N-(3-(1H-indol-2-yl)propyl)-2-(2,2,2-trifluoroacetamido)butanamide (60 mg, 0.169 mmol) and dimethylformamide (0.75 mL). Sodium hydride (6.0 mg, 0.25 mmol) was added and the resulting mixture was stirred at room temperature for 15 minutes. Methyl iodide (0.012 mL, 0.193 mmol) was added and the resulting mixture was stirred at room temperature for 1 h. The resulting mixture was then concentrated in-vacuo and purified via flash silica gel chromatography (Analogix IF-280, SF25-40 g column, gradient 90:10-50:50 Heptane:EtOAc) to yield N-[3-(1-methyl-1H-indol-2-yl)-propyl]-2-(S)-(2,2,2-trifluoro-acetylamino)-butyramide. 1H NMR (300 MHz, CDCl3) δ7.52 (d, J=7.7 Hz, 1H), 7.25-7.28 (m, 1H), 7.14-7.19 (m, 1H), 7.04-7.10 (m, 1H), 6.26 (s, 1H), 4.31-4.36 (m, 1H), 3.64 (s, 3H), 3.33-3.46 (m, 2H), 2.75-2.82 (m, 2H), 1.80-2.09 (m, 3H), 1.59-1.71 (m, 1H), and 0.87-0.92 (m, 3H); MS (ES+) 370 (M+1).
Reaction SMILES: CI.[CH3:3][C:4]1(C)[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]1.[C:15]([O-])([O-])=[O:16].[K+].[K+]>CC(C)=O>[CH3:15][O:16][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([CH3:3])[CH:13]=[CH:12]2
Reactant: CC1(C)C=Cc2ccccc2N1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cccc2ccc(C)nc12

Procedure:
Methyl iodide (10.8 g, 76.3 mmol) was added to a stirred solution of 2-methylquinaldine (1.0 g, 6.3 mmol) and K2CO3 (5.0 g, 36.2 mmol) in 30 ml acetone at RT for 10 h. The reaction mixture was filtered and filtrate removed under a reduced pressure. The residue was purified by flash column chromatography with Hex/EA (3:1) and recrystallized with Hexane/EA to give 8-methoxy-2-methylquinoline as intermediates. LHMDS (2.2 to 2.5 equiv.) was treated with a stirred solution of intermediate (1 equiv.) in THF at 0° C. for 1 h. Corresponding Br(CH2)n−1OH (1.0 to 1.2 equiv.) was added to a reaction mixture and recover to RT for further 12 to 30 h. The solvent was removed under a reduced pressure. The brown oily residue was purified by flash column chromatography with Hex/EA or DCM/EA and recrystallized by Hex/EA to afford series of compounds C.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)=[CH:15][CH:14]=1)[CH2:4][CH:5]([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].Cl[C:27](=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C=O)C>[Cl:25][C:21]1[CH:20]=[C:19]([C:16]2[CH:15]=[CH:14][C:13]([CH2:12][C@@H:3]([NH:2][C:27](=[O:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:4][CH:5]([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:18][CH:17]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: CCOC(=O)C(C)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)N[C@H](Cc1ccc(-c2cccc(Cl)c2)cc1)CC(C)C(=O)OCC
Yield: 82.1 %

Procedure:
To a solution of (4S)-ethyl 4-amino-5-(3′-chlorobiphenyl-4-yl)-2-methylpentanoate hydrochloride salt (600 mg, 1.74 mmol) in DMF (13.1 mL) is added TEA (0.25 mL, 1.82 mmol) and ethyl 2-chloro-2-oxoacetate (0.19 mL, 1.74 mmol) at room temperature. After stirring this reaction for 1 hour at room temperature, the reaction is quenched with H2O, and diluted in EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography (eluent: heptane/EtOAc=70:30 to 50:50) to give (4S)-ethyl 5-(3′-chlorobiphenyl-4-yl)-4-(2-ethoxy-2-oxoacetamido)-2-methylpentanoate (637 mg). HPLC retention time=1.66 minutes (condition A); MS 446.5 (M+1).