Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:33])=[C:6]([CH:32]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=2[O:30][CH3:31])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:33])=[C:6]([CH:32]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([O:29][S:42]([CH3:41])(=[O:44])=[O:43])=[CH:25][C:24]=2[O:30][CH3:31])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(OS(C)(=O)=O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
8-(5-Fluoro-2-methylphenoxymethyl)-7-(4-hydroxy-2-methoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 14-1, 61.1 mg, 0.136 mmol) was dissolved in anhydrous dichloromethane (1 mL), and triethylamine (44 μL, 0.319 mmol) and methanesulfonyl chloride (13 μL, 0.168 mmol) were added thereto successively. The reaction mixture was stirred at room temperature for 3 hours and 15 minutes. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (68.3 mg) as a colorless amorphous product. (Yield 98%)
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=2[CH:20]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:21]([CH3:23])[CH3:22])=[N:6][CH:7]=1.CC(C)([O-])C.[K+].[F:36][C:37]([F:51])([F:50])[C:38]1[CH:39]=[C:40]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[CH2:41]Br>C1COCC1>[F:36][C:37]([F:50])([F:51])[C:38]1[CH:39]=[C:40]([CH:43]=[C:44]([C:46]([F:49])([F:47])[F:48])[CH:45]=1)[CH2:41][N:8]([C:5]1[CH:4]=[N:3][C:2]([Br:1])=[CH:7][N:6]=1)[CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[CH:12][C:11]=1[CH:20]([N:24]1[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1)[CH:21]([CH3:23])[CH3:22]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CC(C)C(c1ccc(C(F)(F)F)cc1CNc1cnc(Br)cn1)N1CCOCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)C(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Br)cn1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.07 h
Yield: 80.3 %

Procedure:
To a flask charged with (5-Bromo-pyrazin-2-yl)-[2-(2-methyl-1-morpholin-4-yl-propyl)-5-trifluoromethyl-benzyl]-amine (94 mg, 0.198 mmol) was added THF (2 mL) followed by potassium t-butoxide (28 mg, 0.249 mmol). After 4 minutes, 3,5-bis(trifluoromethyl)benzyl bromide (0.05 mL; 0.272 mol) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water and diluted with ethyl acetate. The mixture was washed with 2N HCl. The aqueous layer was basified with 1N NaOH and extracted with ethyl acetate (2×). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel) (eluting with 10-40% ethyl acetate in hexanes) to afford the title compound (111 mg, 0.159 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10](N(OC)C)=[O:11])=[CH:4][CH:3]=1.[CH3:24][Mg+].[Br-]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C:10](=[O:11])[CH3:24])=[CH:6][CH:7]=1
Reactant: C[Mg+]
Reactant: COc1ccc(C(Cc2ccc(Br)cc2)C(=O)N(C)OC)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1ccc(C(Cc2ccc(Br)cc2)C(C)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
3-(4-bromophenyl)-2-(4-methoxyphenyl)propanoic acid (3.0 g, 8.95 mmol), Weinreb amine (1.05 g, 10.7 mmol) were dissolved in DMF (90 ml) and diisopropylethylamine (1.88 ml, 10.7 mmol) was added in one portion. EDC (2.06 g, 10.7 mmol) and HOAt (0.122 g, 0.895 mmol) were added to the resulting solution portionwise. The resulting solution was allowed to stir at 25° C. for 1 hour. After one hour the reaction was diluted with EtOAc, washed with 10% KHSO4, saturated NaHCO3, and LiCl (×3). The organic layer was dried over sodium sulfate and concentrated in vacuo, which afforded 3.2 g of 3-(4-bromophenyl)-N-methoxy-2-(4-methoxyphenyl)-N-methylpropanamide as a colorless oil. 3-(4-bromophenyl)-N-methoxy-2-(4-methoxyphenyl)-N-methylpropanamide (1.0 g, 2.64 mmol) was dissolved in anhydrous THF (26.4 ml) and the resulting solution was cooled to 0° C. MeMgBr (1.32 ml, 3.97 mmol) was added dropwise to the cooled solution, and the resulting solution was allowed to stir for 30 min. at 0° C. The solution was then warmed to 25° C. for one hour, at which point the solution was filtered over a pad of celite and concentrated in vacuo. The resulting crude oil was purified using silica gel chromatography (0-40% EtOAc in hexanes gradient to afford 627 mg of 4-(4-bromophenyl)-3-(4-methoxyphenyl)butan-2-one as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:21]=[C:22]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)[CH:23]=[CH:24][CH:25]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH:36]1([C:42]2[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:42]1([C:36]2[CH:37]=[CH:38][C:39]([C:2]3[CH:3]=[CH:4][C:5]([CH2:6][C:7]4[N:8]([C:20]5[CH:21]=[C:22]([N:26]6[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]6)[CH:23]=[CH:24][CH:25]=5)[CH:9]=[C:10]([C:12]5[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=5[Cl:19])[N:11]=4)=[CH:34][CH:35]=3)=[CH:40][CH:41]=2)[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]1
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)c2)S(=O)(=O)N1
Reactant: OB(O)c1ccc(C2CCCCC2)cc1
Product: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(C5CCCCC5)cc4)cc3)c2)S(=O)(=O)N1

Procedure:
5-{3-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (592 mg, 1 mmol) was treated as described in general procedure G using 4-cyclohexylphenylboronic acid (408 mg, 2 mmol) to give 5-{3-[2-(4′-cyclohexyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]2[C:17]3[C:18]([OH:22])=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][CH:14]=2)=[CH:7][CH:6]=1)(=O)C.Cl.C(=O)([O-])O.[Na+]>C(O)CC>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][C:13]2[C:17]3[C:18]([OH:22])=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][CH:14]=2)=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1ccc(CCc2coc3cccc(O)c23)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCO
Product: Nc1ccc(CCc2coc3cccc(O)c23)cc1
Temperature: 25 °C
Yield: 49.6 %

Procedure:
A mixture of 3-[2-(4-acetylaminophenyl)ethyl]-4-hydroxybenzofuran (1.2 g) and n-propanol (4 mL)-5 mol/L aqueous sodium hydroxide solution (8 mL) was heated for ref lux overnight. The reaction mixture was cooled to room temperature. To the reaction mixture was added 2 mol/L hydrochloric acid (21 mL). The mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethylacetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was treated with ethyl acetate. The precipitated crystals were collected by filtration and dried under reduced pressure to give the title compound (0.51 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>CN(C=O)C>[CH3:12][N:13]([CH3:15])[CH:14]=[CH:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccccc1
Solvent: CN(C)C=O
Product: CN(C)C=CC(=O)c1ccccc1
Yield: 85.3 %

Procedure:
To a stirred solution of 5.0 ml (42.8 mmol) acetophenone in 40 ml DMF was added 11.4 ml (85.6 mmol) N,N-dimethylformamide dimethyl acetal and the mixture heated at reflux for 16 h. The reaction mixture was then concentrated in vacuo. Trituration in hexane/ethyl acetate (4/1) afforded 6.4 g (85%) 3-(dimethylamino)acrylophenone as a crystalline solid. EI-MS m/e (%): 175 (M+, 45), 158 ([M—OH]+, 100), 98 ([M—C6H5)+, 63), 42 (72).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH3:25])=O)C.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35]>>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[C:4](=[O:3])[C:6]2[CH:7]=[N:8][C:9]3[C:10]([O:24][CH3:25])=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]=2[N:16]([CH:17]2[CH2:18][CH2:19][CH:20]([CH3:23])[CH2:21][CH2:22]2)[C:34]1=[O:35]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCC(C)CC1
Reactant: O=C=Nc1ccccc1Cl
Product: COc1cccc2c1ncc1c(=O)n(-c3ccccc3Cl)c(=O)n(C3CCC(C)CC3)c12
Yield: 67.8 %

Procedure:
3-(2-Chloro-phenyl)-7-methoxy-1-(4-methyl-cyclohexyl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (50 mg) was prepared from 8-methoxy-4-(4-methyl-cyclohexylamino)-quinoline-3-carboxylic acid ethyl ester (0.164 mmol) and 1-chloro-2-isocyanato-benzene (0.25 mmol) following general procedure C. LCMS: m/z 450 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 9.58 (s, 1H), 7.62 (m, 1H), 7.54-7.59 (m, 1H), 7.52 (m, 2H), 7.06 (m, 2H), 6.42 (m, 1H), 4.91 (m, 1H), 4.06 (s, 3H), 2.71 (m, 1H), 1.98 (m, 1H), 1.65 (m, 4H), 1.56 (m, 1H), 1.08 (d, 3H) ppm.
Reaction SMILES: Cl.[F:2][C:3]([F:15])([F:14])[C:4]([NH:6][CH2:7][C@@H:8]1[C@H:12]([OH:13])[CH2:11][NH:10][CH2:9]1)=[O:5].[CH:16]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[N:26]=2)[N:21]=[CH:20][C:19]=1[C:30]#[N:31])=[CH2:17]>C(O)C>[C:30]([C:19]1[CH:20]=[N:21][C:22]2[C:27]([C:18]=1[CH2:16][CH2:17][N:10]1[CH2:11][C@@H:12]([OH:13])[C@@H:8]([CH2:7][NH:6][C:4](=[O:5])[C:3]([F:2])([F:14])[F:15])[CH2:9]1)=[N:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)#[N:31]
Reactant: O=C(NC[C@H]1CNC[C@H]1O)C(F)(F)F
Reactant: C=Cc1c(C#N)cnc2ccc(OC)nc12
Agent: Cl
Solvent: CCO
Product: COc1ccc2ncc(C#N)c(CCN3C[C@H](CNC(=O)C(F)(F)F)[C@H](O)C3)c2n1
Temperature: 95 °C
Reaction time: 18 h
Yield: 47.1 %

Procedure:
To 2,2,2-trifluoro-N-{[(3R,4S)-4-hydroxy-3-pyrrolidinyl]methyl}acetamide HCl (0.137 g, 0.552 mmol) was added EtOH (2.0 mL). 4-ethenyl-6-(methyloxy)-1,5-naphthyridine-3-carbonitrile (0.117 g, 0.552 mmol) was added to the mixture along with TEA (0.231 mL, 1.66 mmol) and the reaction was heated and stirred at 95 degrees C. for 18 hours, allowing the ethanol to evaporate. The solution was concentrated under reduced pressure and was chromatographed on silica gel to yield an oil (0.110 g, 47%). LCMS: m/z 424.4 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[Cl:25][C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:32][C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([Cl:25])[CH:27]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: Oc1cccc(Cl)c1
Product: CC(NC(=O)c1coc(Oc2cccc(Cl)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 29.3 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 3-chlorophenol (34 mg, 0.26 mmol) to give the title compound (18 mg, 29%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:14][CH:13]=2)[C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+]>CO>[C:22]([O:21][CH2:20][CH2:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([N:9]2[C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)=[CH:17][CH:16]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CCOC(=O)c1cnn(-c2ccc(OCCOC(C)(C)C)cc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)O)cnn1-c1ccc(OCCOC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
To a solution of 1-(4-tert-butoxyethoxyphenyl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (870 mg) in methanol (30 ml) was added 4 N aqueous solution of sodium hydroxide (10 ml), and stirred at room temperature overnight. After completion of the reaction, the organic solvent was evaporated in vacuo, then water and diethyl ether were added thereto, and the aqueous layer was separated. To the aqueous layer was added concentrated hydrochloric acid under ice-cooling to adjust the layer to pH 5, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo. The obtained residue was purified with silica gel chromatography (chloroform/methanol), isopropylether was added thereto, the precipitated solid was collected by filtration, and heat-dried at 60° C. in vacuo to give the titled compound (363 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:47]([C@@H:49]3[CH2:53][CH2:52][CH2:51][N:50]3C(OC(C)(C)C)=O)=[O:48])=[CH:42][CH:41]=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C@@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[C:24](=[O:38])[C@@H:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:18])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C@@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[C:24](=[O:38])[C@@H:25]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:26]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)=[O:18])=[CH:12][CH:11]=2)[CH2:39][C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:47]([C@@H:49]3[CH2:53][CH2:52][CH2:51][NH:50]3)=[O:48])=[CH:42][CH:41]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)[C@@H](c3ccccc3)N3CCCCC3)cc2)c2ccc(F)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)[C@@H](c3ccccc3)N3CCCCC3)cc2)c2ccc(F)cc2)cc1)[C@@H]1CCCN1
Yield: 93 %

Procedure:
The product from Example 114B (0.20 g, 0.24 mmol) was dissolved in dichloromethane (3 mL) and treated with trifluoroacetic acid (2 mL) at ambient temperature for 2 hours. The solution was concentrated, taken up in 25% isopropanol in chloroform, washed with sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated to give 0.16 g (91%) of the title compound.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[NH2:3].C(N(CC)CC)C.C[O:21][C:22](=O)[N:23]=[C:24](SC)[C:25](=[N:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[C:39]([F:45])[CH:38]=1)[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=1>CN(C=O)C>[C:43]([C:40]1[CH:41]=[CH:42][C:37]([NH:36][CH:25]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)[C:24]2[NH:23][C:22](=[O:21])[N:2]([C:4]3[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=3[C:6]([OH:8])=[O:7])[N:3]=2)=[CH:38][C:39]=1[F:45])#[N:44]
Reactant: NNc1ccccc1C(=O)O
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(C#N)c(F)c1)c1ccc(OC)c(OC)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C(Nc2ccc(C#N)c(F)c2)c2nn(-c3ccccc3C(=O)O)c(=O)[nH]2)cc1OC
Temperature: 85 °C
Reaction time: 16 h
Yield: 70.7 %

Procedure:
After adding 55 mg of 2-hydrazinobenzoic acid hydrochloride and 101 μl of triethylamine to a solution of 120 mg of [2-(4-cyano-3-fluorophenylimino)-2-(3,4-dimethoxyphenyl)-1-methylsulfanylethylidene]carbamic acid methyl ester in 3 ml of DMF, the mixture was stirred at 85° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of a methanol:THF=1:1 mixed solvent. After adding 58 μl of acetic acid and 91 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 15 hours. Ethyl acetate was then added to the reaction mixture. The organic layer was washed with dilute hydrochloric acid and saturated brine and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (100 mg) as a light yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][C@@H:25]([CH3:34])[C@H:26]([OH:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[OH-].[Na+]>CO>[OH:33][C@H:26]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C@@H:25]([NH:24][CH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:13]=1[C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:35])=[O:2])[CH:6]=1)[CH3:34]
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN[C@@H](C)[C@H](O)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1CN[C@@H](C)[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
{2′-[((1S,2R)-2-Hydroxy-1-methyl-2-phenyl-ethylamino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid methyl ester (0.021 g, 0.04 mmol) in MeOH (0.33 mL) and THY (0.4 mL) was treated with IN aqueous NaOH (0.1 mL) and stirred at room temperature for 4 hours. Analytical LCMS showed that some starting material was still present, so additional 1N aqueous NaOH (0.05 mL) was added, and the reaction was stirred at room temperature overnight. Analytical LCMS showed that starting material still remained, so additional 1N aqueous NaOH (0.1 mL) was added, and the reaction was stirred for 4 hours. After work-up with CH2Cl2 and 1N aqueous HCl, the combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]=[C:9]([C:38]([F:41])([F:40])[F:39])[N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:37])[CH2:17][C@H:18]([NH:29]C(OC(C)(C)C)=O)[CH2:19][C:20]3[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=3[F:28])[CH2:12][C:11]=12)=[O:6])([CH3:3])[CH3:2].[ClH:42]>C(OCC)(=O)C>[ClH:42].[CH:1]([O:4][C:5]([C:7]1[N:8]=[C:9]([C:38]([F:40])([F:39])[F:41])[N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:37])[CH2:17][C@H:18]([NH2:29])[CH2:19][C:20]3[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=3[F:28])[CH2:12][C:11]=12)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@H](N)Cc1cc(F)c(F)cc1F)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid isopropyl ester 35a (0.17 g, 0.29 mmol) and 10 mL of ethyl acetate were added into the reaction flask. A solution of 5.5 N hydrochloric acid in 5 mL of ethyl acetate was then added to the reaction flask in an ice-water bath. Upon completion of the addition, the ice-water bath was removed. The reaction mixture was stirred at room temperature for 2 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure, and washed with n-hexane (10 mL×2). The filtrate was concentrated under reduced pressure to obtain the title compound (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid isopropyl ester hydrochloride 35 (0.15 g, yield 97.8%) as a white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]2[C:14]3([CH2:18][CH2:17][CH2:16][CH2:15]3)[C:13](=[O:19])[O:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([SH:30])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].[OH-].[Na+]>C(O)(C)C>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([S:30][CH:11]([C:14]2([C:13]([OH:12])=[O:19])[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: COc1ccc(S)cc1OC
Reactant: O=C1OC(CCCCc2ccccc2)C12CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: COc1ccc(SC(CCCCc2ccccc2)C2(C(=O)O)CCCC2)cc1OC
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 66.7 %

Procedure:
3-(4-Phenylbutyl)-2-oxaspiro[3,4]octan-1-one (2 g, 7.7 mmol) and 3,4-dimethoxybenzenethiol (2 g, 11.7 mmol) are dissolved in isopropanol (30 mL) and cooled to 0° C. A 1 M solution of NaOH (9.7 mL, 9.7 mmol) is added slowly, and after 5 minutes at 0° C., the reaction is allowed to stir at room temperature overnight. The solvent is removed in vacuo and the residue is dissolved in CH2Cl2 (100 mL). This solution is washed with 1 N HCl (50 mL), brine (30 mL) and dried over MgSO4. The solution is concentrated in vacuo and the crude product is purified by column chromatography (silica, 1% MeOH in CH2Cl2) to yield 1-[1-(3,4-dimethoxyphenylsulfanyl)-5-phenylpentyl]-cyclopentanecarboxylic acid (2.2 g, 65%). 1H NMR (300 MHz, CDCl3) δ 7.28-7.23 (m, 2H), 7.18-7.09 (m, 3H), 7.01-6.91 (m, 2H), 6.76 (d, J=8.1 Hz, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 3.31 (dd, J=10.0, 3.0 Hz, 1H), 2.58-2.51 (m, 2H), 2.18-2.08 (m, 2H), 1.89-1.40 (m, 12H); MS (EI) m/e 428 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27]>C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:26](=[O:28])[CH3:27])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: CC(=O)Cl
Reactant: COc1cc(OC2CCNCC2)ccc1C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(OC2CCN(C(C)=O)CC2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Methoxy-4-(4-piperidyloxy)benzoic acid (0.6 g, 2.09 mmol) was stirred in THF (10 ml) and treated with triethylamine (0.29 ml, 0.21 g, 2.08 mmol), followed by acetyl chloride (0.18 ml, 0.2 g, 2.5 mmol) and an additional 0.35 ml of triethylamine. The mixture was stirred at ambient temperature for 18 hours, then concentrated in vacuo. The residue was partitioned between aqueous sodium bicarbonate and ethyl acetate. The ethyl acetate layer was extracted with sodium bicarbonate solution. The combined sodium bicarbonate layers were acidified with 1N HCl and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and evaporated to dryness in vacuo to give 2-methoxy-4-(1-acetyl-4-piperidyloxy)benzoic acid.