Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:63][O:64][C:65](=[O:78])[C:66]1[CH:71]=[CH:70][C:69]([NH2:72])=[C:68]([O:73][CH2:74][CH2:75][CH2:76][CH3:77])[CH:67]=1>>[CH3:63][O:64][C:65](=[O:78])[C:66]1[CH:71]=[CH:70][C:69]([NH:72][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:37])([CH3:35])[CH3:36])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[C:68]([O:73][CH2:74][CH2:75][CH2:76][CH3:77])[CH:67]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CCCCOc1cc(C(=O)OC)ccc1N
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1cc(C(=O)OC)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.4 g, 0.69 mmol), was reacted with diisopropylethylamine (0.46 g, 3.6 mmol), diphenylphosphinic chloride (0.34 g, 1.4 mmol), then reacted with 4-amino-3-butoxy-benzoic acid methyl ester (0.24 g, 1.1 mmol) prepared in Example 149 to give rac-3-butoxy-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-benzoic acid methyl ester as a light brown solid (Yield, 0.14 g, 30%).
Reaction SMILES: N[C:2]1[C:3]([CH3:13])=[CH:4][C:5]([Br:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[ClH:14].N([O-])=O.[Na+]>O1CCOCC1.O.[Cu]Cl>[Br:12][C:5]1[CH:4]=[C:3]([CH3:13])[C:2]([Cl:14])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: Cl
Reactant: COC(=O)c1cc(N)c(C)cc1Br
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(Cl)c(C)cc1Br
Temperature: 5 °C
Reaction time: 2 h

Procedure:
To a cooled solution (15° C.) of methyl 5-amino-2-bromo-4-methylbenzoate (122 g, 0.5 mol) in 1,4-dioxane (633 mL), was added conc. hydrochloric acid (550 mL). After the mixture was cooled to 5° C., a solution of sodium nitrite (35.53 g, 0.515 mol) in 83 mL of H2O was added dropwise at such a rate that the reaction temperature was kept below 0° C. After being stirred at 0° C. for 2 hours, the reaction mixture was added slowly to a flask containing copper (I) chloride (59.4 g, 0.6 mol) and conc. hydrochloric acid (275 mL). It was stirred for 40 min, at which time TLC demonstrated that the reaction was complete. The reaction mixture was poured over ice water (2 L) and then filtered. The filter cake was dissolved in ethyl acetate (1.5 L). The organic layer was washed with brine (3×500 mL), dried over anhydrous Na2SO4. Concentration under reduced pressure provided the title compound as light yellow crystals. Yield: 120 g (92.6%). 1H NMR (CDCl3, 300 MHz): δ 7.82 (s, 1H), 7.54 (s, 1H), 3.92 (s, 3H), 2.38 (s, 3H); MS ESI (m/z) 262 (M)+, calc. 262.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH:14]1([C:17]2[CH:21]=[C:20]([NH:22][C:23]3[C:24]4[CH2:41][CH2:40][CH2:39][C:25]=4[N:26]=[C:27]([N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]4[C:35](OC)=[O:36])[N:28]=3)[NH:19][N:18]=2)[CH2:16][CH2:15]1>C1COCC1>[CH:14]1([C:17]2[CH:21]=[C:20]([NH:22][C:23]3[C:24]4[CH2:41][CH2:40][CH2:39][C:25]=4[N:26]=[C:27]([N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]4[C:35]([NH:8][C:5]4[CH:6]=[N:7][C:2]([F:1])=[CH:3][CH:4]=4)=[O:36])[N:28]=3)[NH:19][N:18]=2)[CH2:15][CH2:16]1
Reactant: Nc1ccc(F)nc1
Reactant: COC(=O)C1CCCCN1c1nc2c(c(Nc3cc(C4CC4)n[nH]3)n1)CCC2
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)nc1)C1CCCCN1c1nc2c(c(Nc3cc(C4CC4)n[nH]3)n1)CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 2 %

Procedure:
To a solution of 6-fluoropyridin-3-amine (586 mg, 5.2 mmol) in dry THF (20 mL) was added 2M solution of isopropylmagnesium chloride in THF (2.6 mL, 5.2 mmol) dropwise under nitrogen at 0° C. The resultant mixture was stirred at 0° C. for 20 min. To this solution was added a solution of methyl 1-(4-(3-cyclopropyl-1H-pyrazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)piperidine-2-carboxylate (500 mg, 1.31 mmol) in THF (4 mL) dropwise at 0° C. and the reaction mixture was allowed to stir at RT for 3 h. The reaction was quenched with saturated ammonium chloride solution (40 mL). The product was extracted with EtOAc (2×75 mL) and the organic layer was dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure afforded an oily residue that was purified by reverse phase HPLC to afford 1-(4-(3-cyclopropyl-1H-pyrazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)piperidine-2-carboxamide (12 mg). 1H NMR (400 MHz, CD3OD, freebase) δ (ppm): 0.58-0.68 (m, 2H), 0.82-0.97 (m, 2H), 1.60-1.90 (m, 6H), 2.10-2.24 (m, 3H), 2.30-2.41 (m, 1H), 2.77-2.81 (m, 2H), 2.81-2.91 (m, 2H), 4.46 (d, 1H), 5.39 (s, 1H), 6.06 (s, 1H), 7.00 (dd, 1H), 8.02-8.12 (m, 1H), 8.27 (s, 1H). Separation by chiral HPLC provided enantiomers 9a and 9b.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[C@H:11]([CH2:27][OH:28])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>[Pd].CO>[Si:1]([O:8][C@H:9]1[CH2:13][NH:12][C@H:11]([CH2:27][OH:28])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@H]1CN[C@H](CO)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of (2S,4R)-4-t-butyldimethylsilyloxy-2-hydroxymethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (10.0 g), methanol (100 ml) and 10% palladium on carbon (1.0 g), was stirred in a nitrogen stream at ambient temperature for 3 hours. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give (2S,4R)-4-t-butyldimethylsilyloxy-2-hydroxymethylpyrrolidine. To a solution of the compound obtained above in tetrahydrofuran (100 ml) was added di-t-butyl dicarbonate (5.60 g) and the mixture was refluxed for 30 minutes. The reaction mixture was concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (160 g) and eluted with chloroform to give (2S,4R)-1-t-butoxycarbonyl-4-t- butyldimethylsilyloxy-2-hydroxymethylpyrrolidine (7.97 g).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:22]([O:31][CH3:32])=[N:23][N:24]([CH3:30])[C:25]=2[C:26]([F:29])([F:28])[F:27])[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[CH3:32][O:31][C:22]1[C:21]([CH:18]2[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]2)=[C:25]([C:26]([F:28])([F:27])[F:29])[N:24]([CH3:30])[N:23]=1
Reactant: COc1nn(C)c(C(F)(F)F)c1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1nn(C)c(C(F)(F)F)c1C1CCNCC1
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (3.0 mL) was added to a solution of 1-(tert-butoxycarbonyl-4-(3-methoxy-1-methyl-5-(trifluoromethyl)-(1H)-pyrazol-4-yl)piperidine (150 mg, 0.41 mmol, from Step D) in CH2Cl2 (3.0 mL). After 2 h, the reaction was concentrated and the residue was dissolved in EtOAc (15 mL) and washed with saturated aq. NaHCO3 (6 mL) followed by saturated aq. NaCl (5 mL). The organic layer was dried (Na2SO4), decanted, and evaporated to give the title compound as a white solid. For the title compound: 1H NMR (500 MHz, CD3OD) δ 3.89 (s, 3H), 3.80 (s, 3H), 3.32 (d, J=13, 2H), 2.95 (tt, J=13, 4, 1H), 2.93 (td, J=13, 3, 2H), 2.18 (qd, J=13, 4, 2H), 1.76 (d, J=13, 2H); ESI-MS 264.1 (M+H); HPLC A: 1.3 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=O)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:16]#[N:17])[CH3:2].COC1C=CC(/C=[C:33]2/[C:34]([NH:36][C:37]([S:39]/2)=[NH:38])=[O:35])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:38][C:37]1[S:39]/[C:33](=[CH:14]\[C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]=[CH:6][C:5]([C:16]#[N:17])=[C:4]3[O:3][CH2:1][CH3:2])/[C:34](=[O:35])[N:36]=1
Reactant: CCOc1c(C#N)cnc2ccc(C=O)cc12
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOc1c(C#N)cnc2ccc(/C=C3\SC(N)=NC3=O)cc12
Temperature: 110 °C
Yield: 46.2 %

Procedure:
To the suspension of 4-ethoxy-6-formyl-quinoline-3-carbonitrile (example 14e) (45 mg, 0.2 mmol) and pseudothiohydantoin (35 mg, 0.3 mmol) in acetic acid (1 mL) was added sodium acetate (66 mg, 0.8 mol). The mixture was heated to 110° C. for 4 h. After cooling to room temperature, the ice water was added. The solid was collected by filtration, washed with water and dried. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 0%-5% methanol in methylene chloride in 30 min) afforded 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-ethoxy-quinoline-3-carbonitrile (30 mg, 47%) as a light yellow solid: LC-MS m/e 445 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:11]([OH:12])=[C:10]([F:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:14](N1C=CN=C1)(N1C=CN=C1)=[S:15]>C1COCC1>[F:13][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]2[C:11]=1[O:12][C:14](=[S:15])[NH:1]2
Reactant: COC(=O)c1ccc(F)c(O)c1N
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(F)c2oc(=S)[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
A mixture of methyl 2-amino-4-fluoro-3-hydroxybenzoate (1.5 g, 8.11 mmol) and 1,1′-thiocarbonyldiimidazole (1.46 g, 8.2 mmol) in THF (30 mL) was stirred at ambient temperature overnight, and at 50° C. for 6 h. The reaction mixture was cooled to ambient temperature and the solvent was removed under reduced pressure. The residue was washed with ether (3×50 mL) and dried to afford methyl 7-fluoro-2-thioxo-2,3-dihydrobenzoxazole-4-carboxylate (1.3 g, 70%) as a yellow solid. 1H NMR (500 MHz, CDCl3) δ 7.82-7.78 (m, 1H), 6.40 (t, J=9.0 Hz, 1H), 4.00 (s, 3H); (ESI+) m/z 228 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH:3]1[CH2:9][OH:10].[H-].[Na+].F[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18]>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH:3]1[CH2:9][O:10][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18]
Reactant: N#Cc1cccc(F)c1
Reactant: CN1CCN(C)C(CO)C1
Agent: [H-]
Agent: [Na+]
Product: CN1CCN(C)C(COc2cccc(C#N)c2)C1

Procedure:
The title compound was synthesized according to Example 13a from (1,4-dimethylpiperazin-2-yl)methanol (0.500 g, 3.47 mmol), NaH (0.208 g, 5.20 mmol, 55% in oil) and 3-fluorobenzonitrile (0.441 g, 3.64 mmol) to give the title compound as an oil. Yield: 0.682 g (76%). 1H NMR (400 MHz, CDCl3) δ 7.32-7.38 (m, 1H), 7.20-7.25 (m, 1H), 7.10-7.15 (m, 2H), 3.95-4.06 (m, 2H), 2.77-2.86 (m, 2H), 2.65-2.72 (m, 1H), 2.51-2.58 (m, 1H), 2.37-2.44 (m, 1H), 2.36 (s, 3H), 2.28 (s, 3H), 2.19-2.27 (m, 1H), 2.09-2.17 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:10][NH:11][C:12]([NH2:14])=[S:13])=[CH:4][CH:3]=1.Br[CH:24]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=1)[C:25](OCC)=[O:26]>C(O)C.C(N(C(C)C)CC)(C)C>[C:18]([O:17][C:16](=[O:22])[NH:15][C@@H:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:10][NH:11][C:12]1[S:13][C:24]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=2)=[C:25]([OH:26])[N:14]=1)([CH3:19])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N[C@H](CNC(N)=S)Cc1ccc(Cl)cc1
Reactant: CCOC(=O)C(Br)c1ccc(F)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H](CNc1nc(O)c(-c2ccc(F)c(F)c2)s1)Cc1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
A mixture of (S)-tert-butyl 3-(4-chlorophenyl)-1-thioureidopropan-2-ylcarbamate (0.585 g, 1.70 mmol) and ethyl 2-bromo-2-(3,4-difluorophenyl)acetate (0.500 g, 1.79 mmol) in ethyl alcohol (2 mL) and diisopropylethylamine (0.3 mL) in a sealed vial (Biotage microwave vial, 5 mL) with a magnetic stirring bar was heated in a microwave oven (Initiator, Biotage) at 120° C. for 15 minutes. After cooling to ambient temperature, the volatiles were removed in vacuum. The residue was partitioned between EtOAc and water. The combined organic portions were washed with brine. The crude product was purified by flash column chromatography (20% of EtOAc in hexanes for 5 minutes, 20% to 100% of EtOAc in hexanes over 23 minutes). The product was obtained as a white solid, 0.201 g, 24%. 1H NMR (300 MHz, CD3OD) δ 1.22-1.39 (m, 9H), 2.52-2.97 (m, 2H), 3.35-3.60 (m, 1H), 3.64-3.85 (m, 1H), 3.92-4.24 (m, 1H), 7.11-7.46 (m, 7H). LCMS (API-ES): 496.1/498.1 (M++H), chloro pattern.
Reaction SMILES: Cl[C:2]1([C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:7])[C:5]([CH3:8])=[CH:4][S:3]1.[CH3:13][OH:14]>>[OH:7][C:6]1[C:5]([CH3:8])=[C:4]([O:14][CH3:13])[S:3][C:2]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C1(Cl)SC=C(C)C1=O
Reactant: CO
Product: COC(=O)c1sc(OC)c(C)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product of (d) above (3 g) was dissolved in 15 ml of methanol and stirred 8 hours at room temperature. The precipitate was filtered and recrystallised from methanol, m.p. 63°-65° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[C:20]4[S:27][C:26]([C:28]5[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=5)=[CH:25][C:21]=4[N:22]=[CH:23][N:24]=3)=[CH:15][CH:16]=2)[CH:11]=[CH:10]1>>[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[C:20]4[S:27][C:26]([C:28]5[CH:35]=[CH:34][C:31]([CH2:32][N:5]6[CH2:6][CH2:7][CH2:8][CH:4]6[CH2:3][O:2][CH3:1])=[CH:30][CH:29]=5)=[CH:25][C:21]=4[N:22]=[CH:23][N:24]=3)=[CH:15][CH:16]=2)[CH:11]=[CH:10]1
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Reactant: COCC1CCCN1
Product: COCC1CCCN1Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from 2-methoxymethyl-pyrrolidine and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. M.P. 161-177° C.; LC-MS: 470 (MH+); HPLC RT: 4.55 minutes.
Reaction SMILES: [H-].[Na+].[C:3]1([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]#[N:18])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:19][N:20]([CH2:24][CH2:25]Cl)[CH2:21][CH2:22][Cl:23].Cl.Cl>CN(C)C=O.CCOCC>[ClH:23].[C:17]([C:16]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:25][CH2:24][N:20]([CH3:19])[CH2:21][CH2:22]1)#[N:18]
Reactant: N#CCc1ccccc1Sc1ccccc1
Reactant: CN(CCCl)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN1CCC(C#N)(c2ccccc2Sc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.6 g of 99% sodium hydride are added portionwise to a solution of 4.4 g of 2-(phenylthio)phenylacetonitrile in 50 ml of dimethylformamide. The resulting reddish brown mixture is stirred for 30 minutes before adding dropwise a solution of 4.0 g of mechlorethamine hydrochloride in 50 ml of dimethylformamide, maintaining gas evolution at a slow rate. After total addition, the mixture is stirred at 80°-85° C. for 15 hours. Thereafter, 100 g of ice are added before the mixture is extracted thrice with ether. The combined ether extracts are dried over potassium carbonate and then the solvent is removed under vacuum leaving a brownish oil. The oil is dissolved in a small amount of ether and passed through, with additional ether, an alumina column which is packed in ether. The effluent is concentrated leaving an oil which is converted to its hydrochloride which is recrystallized from an acetone-ether mixture, leaving 4-cyano-1-methyl-4-(2-phenylthiophenyl)piperidine hydrochloride.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:3]=1[CH2:4][CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]12.C([Sn](CCCC)(CCCC)[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)CCC>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:10]=[C:8]1[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]2[C:18]3[C:3]([CH2:4][CH:5]2[CH2:9]1)=[C:2]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[CH:21]=[CH:20][CH:19]=3
Reactant: CC(C)(C)OC(=O)N1C(=O)CC2Cc3c(Br)cccc3C21
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C(=O)CC2Cc3c(-c4cccnc4)cccc3C21
Reaction time: 0.08 h

Procedure:
Tert-butyl 5-bromo-2-oxo-3,3a,4,8b-tetrahydroindeno[1,2-b]pyrrole-1-carboxylate (Example 1. Step 3, 0.500 g, 1.42 mmol), tributyl(3-pyridyl)stannane (0.784 g, 2.12 mmol) and tetrakis(triphenylphosphine) palladium (0.164 g, 0.142 mmol) were dissolved in toluene. The mixture was irradiated in the microwave at 160° C. and normal absorption level for 5 minutes. The toluene was removed and the mixture was taken up in acetonitrile and n-hexan. The hexane layer was extracted again with acetonitrile and the combined acetonitrile layers were dried over sodium sulphate and evaporated. The crude was purified by flash chromatography to give tert-butyl 2-oxo-5-(3-pyridyl)-3,3a,4,8b-tetrahydroindeno[1,2-b]pyrrole-1-carboxylate E11 (0.409 g, 82%); LCMS (method A) RT 1.45 min; ES+351 (M+H+). The compounds E9-E13 were prepared according to this procedure.
Reaction SMILES: [BH4-].[Na+].[CH:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][C:4]=1[C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(O)(=O)C.O>C(O)C>[OH:19][CH:13]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:3]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(=O)c1ccc2c(c1)CCCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(O)c1ccc2c(c1)CCCC2
Temperature: 0 °C
Yield: 99.1 %

Procedure:
A solution of sodium borohydride (2.0 g) in ethanol (100 ml) was added dropwise to an ice-cooled solution of ethyl 5,6,7,8-tetrahydro-2-naphthylglyoxylate (34.5 g) in ethanol (200 ml). After completion of dropwise addition, acetic acid (6 ml) was added and the reaction mixture was poured into water and extracted with chloroform. The chloroform layer was washed with water, dried (MgSO4) and the solvent was distilled off to give ethyl 2-hydroxy-(5,6,7,8-tetrahydro-2-naphthyl)acetate (34.5 g, yield 9%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[O:16][C@@H:15]([CH3:18])[CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C:11]=3[S:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1>C(OCC)(=O)C.Cl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[O:16][C@@H:15]([CH3:18])[CH2:14][NH:13][CH2:12][C:11]=3[S:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)Cc2scc(-c3cccc(F)c3)c2O1
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@H]1CNCc2scc(-c3cccc(F)c3)c2O1
Yield: 104.5 %

Procedure:
tert-Butyl (2S)-8-(3-fluorophenyl)-2-methyl-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (416 mg) was stirred in 4N hydrogen chloride-ethyl acetate solution (5 mL) for 20 min. The reaction solution was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give (2S)-8-(3-fluorophenyl)-2-methyl-2,3,4,5-tetrahydrothieno[2,3-f][1,4]oxazepine 1 hydrochloride (315 mg, 92%) as colorless crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]([OH:12])=O)=[CH:5][CH:4]=1)#[N:2].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[C:35]1([CH3:53])[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[C:46]([CH2:47][NH2:48])=[CH:45][CH:44]=[C:43]([C:49]([F:52])([F:51])[F:50])[N:42]=2)[CH:36]=1.C(N(CC)CC)C>C(#N)C.C(OC(=O)C)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH3:13])[C:10]([NH:48][CH2:47][C:46]2[C:41]([C:37]3[CH:36]=[C:35]([CH3:53])[CH:40]=[CH:39][CH:38]=3)=[N:42][C:43]([C:49]([F:52])([F:50])[F:51])=[CH:44][CH:45]=2)=[O:12])=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(C(=O)O)c1ccc(C#N)cc1
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CN)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(C#N)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
To a stirred solution of 2-(4-cyanophenyl)propanoic acid (148 mg, 0.85 mmol) in acetonitrile were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (243 mg, 1.27 mmol), 1-hydroxybenzotriazole (171 mg, 1.27 mmol), (2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methanamine (247 mg, 0.93 mmol) and triethylamine (0.29 mL, 2.11 mmol). The reaction mixture was stirred for overnight at room temperature. The mixture was diluted with ethylacetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. 2-(4-Cyanophenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (311 mg) was obtained as 87% yield.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([N:33]3[C:37](=[O:38])[CH:36]([CH3:39])[NH:35][C:34]3=[O:40])[CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([N:33]3[C:37](=[O:38])[CH:36]([CH3:39])[NH:35][C:34]3=[O:40])[CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2ccc(N3C(=O)NC(C)C3=O)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc2ccc(N3C(=O)NC(C)C3=O)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-propyl-6-(5-methyl-imidazolidin-2,4-dion-3-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[CH:22][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[CH:24][CH:25]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2C(=O)O)cc1
Yield: 89.9 %

Procedure:
To a mixture of ethyl 1-benzyl-3-[(4{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylate (2.0 g), tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N aqueous sodium hydroxide solution (16 mL), and the mixture was heated under reflux for 7 hrs. 1N Hydrochloric acid (16 mL) and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 1-benzyl-3-[(4{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylic acid as crystals (1.70 g, yield 90%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 170-171° C.