Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]([CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)[CH2:3][C:4](=[O:6])[CH3:5]>C1(C)C=CC=CC=1>[F:18][C:16]([F:17])([F:19])[C:13]1[CH:14]=[CH:15][C:10]([S:9][CH2:8][CH2:7][CH:2]=[CH:3][C:4](=[O:6])[CH3:5])=[CH:11][CH:12]=1
Reactant: CC(=O)CC(O)CCSc1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: CC(=O)C=CCCSc1ccc(C(F)(F)F)cc1

Procedure:
0.5 Gram of 4-hydroxy-6-(4-trifluoromethylphenylthio)-2-hexanone was dissolved in 10 ml of toluene, and 0.38 g of silica gel was added thereto. The resulting mixture was refluxed for 8 hours with stirring, allowed to cool and then treated in the same manner as in Production example 34. Thus, 6-(4-trifluoromethylphenylthio)-3-hexen-2-one was obtained (purity: 77.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH:13][C:14](=[O:27])[CH2:15][S:16][C:17]2[S:18][CH:19]=[C:20]([C:22](OCC)=[O:23])[N:21]=2)[CH2:7]1.[BH4-].[Na+].[Cl-].[Li+].O>C(O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH:13][C:14](=[O:27])[CH2:15][S:16][C:17]2[S:18][CH:19]=[C:20]([CH2:22][OH:23])[N:21]=2)[CH2:7]1
Reactant: CCOC(=O)c1csc(SCC(=O)NC[C@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)n1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: O=C(CSc1nc(CO)cs1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
The resultant product (2.09 g) of (1-4) was dissolved in ethanol (40 mL) and tetrahydrofuran (40 mL), sodium borohydride (454 mg) was added, lithium chloride (509 mg) was further added, and the mixture was stirred at room temperature for 4.5 hrs. Water was poured into the reaction mixture, the organic solvent alone was evaporated under reduced pressure, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (1.53 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:7][CH:6]([N:8]2[C:12](=[O:13])[C:11]3=[CH:14][C:15]([C:18]([OH:20])=[O:19])=[CH:16][CH:17]=[C:10]3[C:9]2=[O:21])[CH2:5][C:4]([CH3:23])([CH3:22])[NH:3]1.[CH2:25]1[O:33][CH:26]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CN(C)C=O>C(Cl)Cl>[CH3:22][C:4]1([CH3:23])[CH2:5][CH:6]([N:8]2[C:12](=[O:13])[C:11]3=[CH:14][C:15]([C:18]([O:20][CH2:25][CH:26]([OH:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:19])=[CH:16][CH:17]=[C:10]3[C:9]2=[O:21])[CH2:7][C:2]([CH3:24])([CH3:1])[NH:3]1
Reactant: c1ccc(C2CO2)cc1
Reactant: CC1(C)CC(N2C(=O)c3ccc(C(=O)O)cc3C2=O)CC(C)(C)N1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)CC(N2C(=O)c3ccc(C(=O)OCC(O)c4ccccc4)cc3C2=O)CC(C)(C)N1

Procedure:
Into a 125 ml reaction flask equipped with a magnetic stirrer, thermometer, condenser and nitrogen atmosphere were placed the HALS of Example 1 (5.0 g, 0.015 mol), styrene oxide (1.6 g, 0.013 mol), ADOGEN® (Ashland Chemical Co.) (0.15 g) and 60 ml of dimethylformamide. The reaction was refluxed for 5 hours then cooled. The mixture was transferred to a separatory funnel with 100 ml methylene chloride and washed with 200 ml of 2.5% sodium hydroxide. Additional methylene chloride, 100 ml, was added and the solution extracted with two 100 ml portions of 5% sodium hydroxide and then 100 ml water. The organic solution was then dried with anhydrous magnesium sulfate and the solvent stripped using aspirator and high vacuum systems. The solid residue (2.9 g) was recrystallized from aqueous ethanol, then recrystallized again from methyl t-butyl ether/hexanes. After high vacuum removal of residual solvent, the product weighed 0.6 g and melted at 144°-146° C. The infrared spectrum (in chloroform) showed a broad carbonyl absorption at 1710 cm-1 (imide and ester). The structure of this material was further confirmed using proton NMR spectroscopy.
Reaction SMILES: [F:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]([CH2:10][C:11]([O-:13])=O)=[N:4][C:3]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[Na+].[CH3:21][C@H:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23]1>>[F:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]([CH2:10][C:11]([N:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:30][C@@H:22]2[CH3:21])=[O:13])=[N:4][C:3]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C[C@H]1Cc2ccccc2N1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)c(F)c1=O
Agent: [Na+]
Product: C[C@H]1Cc2ccccc2N1C(=O)Cc1nc(N2CCOCC2)c(F)c(=O)n1C
Yield: 51.7 %

Procedure:
The product is prepared by following the procedure described in example 1a (step 5a) using 88 mg of sodium (5-fluoro-1-methyl-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate described in step 2a and 40 mg of (S)-2-methyl-2,3-dihydro-1H-indole (which can be prepared according to Krasnov, V. P. et al. (Mendeleev Commun. (2002), 12(1), 27-28). After silica column purification: eluent 98/02 dichloromethane/methanol, 60 mg of 5-fluoro-3-methyl-2-[2-((S)-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a solid, the characteristics of which are the following:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:32])[NH:22][C:23]3[S:24][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[N:26][N:27]=3)=[CH:17][C:16]=2[NH:33][C:34]2[C:35]3[CH:43]=[CH:42][C:41]([CH:44]([CH3:46])[CH3:45])=[N:40][C:36]=3[N:37]=[CH:38][N:39]=2)=[CH:10][CH:9]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:22][C:23]3[S:24][C:25]([C:28]([CH3:30])([CH3:31])[CH3:29])=[N:26][N:27]=3)=[O:32])=[CH:17][C:16]=2[NH:33][C:34]2[C:35]3[CH:43]=[CH:42][C:41]([CH:44]([CH3:45])[CH3:46])=[N:40][C:36]=3[N:37]=[CH:38][N:39]=2)=[CH:12][CH:13]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4nnc(C(C)(C)C)s4)ccc3Oc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4nnc(C(C)(C)C)s4)ccc3Oc3ccc(N)cc3)ncnc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product from Example 225d (212 mg, 0.323 mmol) was dissolved in a 1:1 mixture of TFA in CH2Cl2 and stirred at room temperature for 2 hrs. The solvent was removed under vacuum and the crude oil was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (9 mg, 5%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.34 (d, J=6.99 Hz, 6 H), 1.42 (s, 9 H), 3.21-3.36 (m, 1 H), 6.79-6.87 (m, 2 H), 6.94 (d, J=8.82 Hz, 3 H), 7.86 (d, J=8.46 Hz, 1 H), 8.15 (dd, J=8.82, 2.21 Hz, 1 H), 8.28 (d, J=2.21 Hz, 1 H), 8.88 (s, 1 H), 8.99 (d, J=8.46 Hz, 1 H); MS (ESI+) m/z 555 (M+TFA+H)+; (ESI−) m/z 553 (M+TFA−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][C:10]=1[N+:21]([O-])=O>CO.[Ni]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][C:10]=1[NH2:21]
Reactant: COc1ccc2ncc([N+](=O)[O-])c(Nc3ccccc3Cl)c2c1
Agent: [Ni]
Solvent: CO
Product: COc1ccc2ncc(N)c(Nc3ccccc3Cl)c2c1

Procedure:
The title compound is prepared in analogy to Example 19e, starting from 0.8 g (2.4 mmol) of (2-chloro-phenyl)-(6-methoxy-3-nitro-quinolin-4-yl)-amine (Example 44h) and 0.4 g Raney-Ni in 30 ml methanol. Time of hydrogenation: 1 h at rt. Crystallization of the product from ethyl acetate-hexane. mp: 120-123° C.; MS: 300 (M++1); HPLC: tret=8.41 min (Grad 1).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]2[CH3:21])[C:5]2[CH2:10][N:9]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[CH2:8][C:6]=2[N:7]=1.[CH2:22]([NH:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1)=[O:27])[CH2:23][CH3:24]>>[CH:12]1([CH2:11][N:9]2[CH2:10][C:5]3[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]4[CH3:21])=[N:3][C:2]([C:32]4[CH:31]=[CH:30][C:29]([NH:28][C:26]([NH:25][CH2:22][CH2:23][CH3:24])=[O:27])=[CH:34][CH:33]=4)=[N:7][C:6]=3[CH2:8]2)[CH2:14][CH2:13]1
Reactant: CCCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(CC1CC1)C2
Product: CCCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(CC2CC2)C3)cc1

Procedure:
Method as described for example 47 using intermediate 8 and 1-propyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea as starting materials. Purified by prep. LCMS (low pH).
Reaction SMILES: Br[C:2]1[C:3]([O:9][C@H:10]2[CH2:14][CH2:13][O:12][CH2:11]2)=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.C[C:16]([N:18](C)C)=O>[C-]#N.[Zn+2].[C-]#N.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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.[Fe+2]>[NH2:8][C:5]1[N:4]=[C:3]([O:9][C@H:10]2[CH2:14][CH2:13][O:12][CH2:11]2)[C:2]([C:16]#[N:18])=[CH:7][N:6]=1
Reactant: CC(=O)N(C)C
Reactant: Nc1ncc(Br)c(O[C@H]2CCOC2)n1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: N#Cc1cnc(N)nc1O[C@H]1CCOC1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
(S)-5-bromo-4-((tetrahydrofuran-3-yl)oxy)pyrimidin-2-amine (intermediate 64, 38 mg, 0.146 mmol), zinc cyanide (18.0 mg, 0.153 mmol), zinc (1.9 mg, 0.029 mmol), Pd2(dba)3 (13.4 mg, 0.015 mmol) and dppf (16.2 mg, 0.029 mmol) were treated with DMA (2 ml) under argon and stirred at 100° C. for 16 h. The reaction mixture was cooled to room temperature, quenched with sat. aq. NaHCO3 and diluted with EtOAc. The organic layer was separated, washed with water (2×) and brine (2×), dried over Na2SO4, filtered and concentrated. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) to give the title compound as a brown solid. (UPLC-MS 3) tR 0.54 min; ESI-MS 207.2 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[C:12]([Cl:23])=[N:13][C:14]([CH2:17][C:18]([O:20]CC)=[O:19])=[CH:15][CH:16]=1.[OH-].[Na+]>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[C:12]([Cl:23])=[N:13][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:15][CH:16]=1
Reactant: CCOC(=O)Cc1ccc(Nc2nc3ccccc3o2)c(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(Nc2nc3ccccc3o2)c(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
In THF (8 ml) was dissolved ethyl (3-(2-benzoxazolyl)amino-2-chloro-6-pyridyl)acetate (460 mg, 1.39 mmol). To the resulting solution was added 0.5N NaOH (8.0 ml, 4.00 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was poured in ice-1N HCl to acidify the mixture. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give (3-(2-benzoxazolyl)amino-2-chloro-6-pyridyl)acetic acid (332 mg, 79%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([N+:10]([O-])=O)[N:3]=1.[OH-].[NH4+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>CCCCCC.C(OCC)(=O)C.O.C(O)C>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([NH2:10])[N:3]=1
Reactant: COc1ccc([N+](=O)[O-])nc1Br
Agent: O=S([O-])S(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(N)nc1Br
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
2-Bromo-3-methoxy-6-nitropyridine (470 mg, 2.0 mmol) was added to 8 mL (3:1 water: ethanol) and 2 mL of 30% ammonium hydroxide. Added 350 mg (2 mmol) of sodium hydrosulfite (Na2SsO4) and heated to 60° C. After 30 min, no starting material was seen. Added 50 mL of water and extracted the product with methylene chloride (2×25 mL). Dried over MgSO4, filtered and reduced the volume. Flash chromatography (75/25 hexane/ethyl acetate) recovered 200 mg of product (50% yield). 1H NMR (CDCl3, 200 MHz) δ 7.06 (d, 1H, 10 Hz), 6.41 (d, 1H, J=10 Hz), 3.8 (s, 3H) ppm
Reaction SMILES: [C:1]1([CH:7]2[C:16]3[C:11]4=[C:12]([CH:21]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:22][CH2:23][N:10]4[CH2:9][CH2:8]2)[CH:13]=[C:14]([CH2:17][C:18]([OH:20])=O)[CH:15]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:30]([NH2:32])[CH3:31].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>ClCCl>[CH2:30]([NH:32][C:18](=[O:20])[CH2:17][C:14]1[CH:13]=[C:12]2[C:11]3=[C:16]([CH:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:8][CH2:9][N:10]3[CH2:23][CH2:22][CH:21]2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:15]=1)[CH3:31]
Reactant: CCN
Reactant: O=C(O)Cc1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCNC(=O)Cc1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.7 %

Procedure:
To a solution of 2-(1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-yl)acetic acid (16), (85 mg, 0.229 mmol) in dicloromethane (10 mL) were added Ethyl amine (0.015 mL, 0.229 mmol), EDCI (103 mg, 0.538 mmol), followed by HOBt (72 mg, 0.538 mmol) under argon at 0° C. The reaction mixture was then stirred at room temperature for overnight. The reaction was quenched with water (30 mL). The residue was isolated in a typical aqueous workup and purified by MPLC (medium pressure liquid chromatography) using silica gel column with 5% MeOH:CH2Cl2 to give N-ethyl-2-(1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-yl)acetamide (371), (27 mg, 29%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.C([O:21][C:22]([C:24]1[N:29]2[C:30]([C:33](=[O:38])C(Cl)(Cl)Cl)=[CH:31][N:32]=[C:28]2[CH:27]=[CH:26][CH:25]=1)=O)C>C(#N)C>[NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:7]2[C:22](=[O:21])[C:24]3[N:29]4[C:30](=[CH:31][N:32]=[C:28]4[CH:27]=[CH:26][CH:25]=3)[C:33]2=[O:38])=[CH:4][CH:3]=1
Reactant: NCc1ccc(N)cc1
Reactant: CCOC(=O)c1cccc2ncc(C(=O)C(Cl)(Cl)Cl)n12
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(Cn2c(=O)c3cccc4ncc(c2=O)n43)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 88.5 %

Procedure:
To a solution of 1.47 g (12.0 mmol) of 4-aminobenzylamine and 1.68 g (13.0 mmol) of N,N-diisopropylethylamine was added a solution of 3.50 g (10.0 mmol) of 5-ethoxycarbonyl-3-trichloroacetylimidazo[1,2-a]pyridine in 10 ml of acetonitrile. The mixture was stirred for 7 hours at room temperature. The resulting precipitate was collected by filtration, washed with acetonitrile and dried to afford 2.586 g of the desired compound (86.7%, a yellow crystals).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:13](=[N:15][OH:16])[NH2:14])(=[O:3])[CH3:2].[C:17](Cl)(=O)[CH2:18][CH2:19][CH3:20]>N1C=CC=CC=1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:13]1[N:14]=[C:17]([CH2:18][CH2:19][CH3:20])[O:16][N:15]=1)(=[O:3])[CH3:2]
Reactant: CCCC(=O)Cl
Reactant: CC(=O)N1c2ccccc2CC1C(N)=NO
Solvent: c1ccncc1
Product: CCCc1nc(C2Cc3ccccc3N2C(C)=O)no1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A mixture of intermediate (14) (0.00898 mole) and butanoyl chloride (0.0094 mole) in pyridine (140 ml) was stirred at room temperature for 40 hours and then heated to reflux. After 21 hours the reaction was cooled and concentrated in vacuo. The residue was extracted between DCM and saturated aqueous NaHCO3 and the organic fraction was dried over Na2SO4, filtered, and concentrated.The residue was subjected to silica gel flash column chromatography (eluent 100% CH2Cl2 to 95/5 CH2Cl2/ether), yielding 1-acetyl-2,3-dihydro-2-(5-propyl-1,2,4-oxadiazol-3-yl)-1H-indole (compound 89, mp. 93–94° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:27]([O:29]C)=O)[C:13]3[NH:14][C:15]4[CH:16]=[C:17]([C:23]([O:25][CH3:26])=[O:24])[CH:18]=[CH:19][C:20]=4[C:21]=3[N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[OH-].[Na+].Cl.[Cl-].[NH4+].Cl.C[N:38](C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>O1CCCC1.CCOC(C)=O.CN(C)C=O.CO>[C:27]([C:12]1[C:13]2[NH:14][C:15]3[CH:16]=[C:17]([C:23]([O:25][CH3:26])=[O:24])[CH:18]=[CH:19][C:20]=3[C:21]=2[N:22]=[C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[CH:11]=1)(=[O:29])[NH2:38]
Reactant: CCN=C=NCCCN(C)C
Reactant: COC(=O)c1ccc2c(c1)[nH]c1c(C(=O)OC)cc(-c3ccc(OC)c(F)c3)nc12
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(-c3ccc(OC)c(F)c3)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
A solution of dimethyl 2-(3-fluoro-4-methoxyphenyl)-5H-pyrido[3,2-b]indole-4,7-dicarboxylate (612 mg, 1.50 mmol) in a mixture of tetrahydrofuran (24 ml), MeOH (8 ml) and 1 N aqueous sodium hydroxide (2.4 ml, 2.4 mmol) was stirred at room temperature for 30 minutes and then neutralized with 1 N aqueous HCl. The organic solvents were removed on the rotary evaporator and the residue was dissolved in water and acidified to about pH 3 with 1 N aqueous HCl. This was chilled in an ice bath and the precipitate was collected by filtration and dried. LC/MS indicated that the major component of this was 2-(3-fluoro-4-methoxyphenyl)-7-(methoxycarbonyl)-5H-pyrido[3,2-b]indole-4-carboxylic acid [MS (ESI) m/z 395.0 (M+H); retention time 2.75 min; Xbridge S10 4.6×50 mm column; flow rate=4 mL/min; gradient from 0% B to 100% B over 3 min; Solvent A=0.1% TFA/95% water/5% methanol, Solvent B=0.1% TFA/5% water 95% methanol]. Dimethylformamide (5 mL) was added to a mixture of a portion of this material (400 mg, about 1.01 mmol), ammonium chloride (0.163 gm, 3.04 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (0.583 g, 3.04 mmol), and 1-hydroxybenzotriazole hydrate (0.411 g, 3.04 mmol). After stirring for a few minutes, triethylamine (0.42 mL, 3.0 mmol) was added and the reaction was left stirring overnight. It was diluted with EtOAc, washed with water and dried with sodium sulfate. The solvent was removed and the residue was suspended in warm (40° C.) methylene chloride for 10 minutes and then filtered to gave methyl 4-carbamoyl-2-(3-fluoro-4-methoxyphenyl)-5H-pyrido[3,2-b]indole-7-carboxylate (0.35 g) as a yellow solid. 1H NMR (DMSO-d6) δ ppm 11.90 (1H, s), 8.64 (1H, br. s.), 8.51 (1H, s), 8.44 (1H, s), 8.39 (1H, d, J=8.24 Hz), 8.09-8.22 (2H, m), 7.97 (1H, br. s.), 7.89 (1H, d, J=8.24 Hz), 7.36 (1H, t, J=8.70 Hz), 3.95 (3H, s), 3.93 (3H, s).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:13]2[C:14]3[NH:21][CH:20]=[C:19]([C:22]([OH:24])=O)[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[C:25]([O:29][C:30](=[O:39])[NH:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([NH2:38])[CH2:34][CH2:33]1)([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30](=[O:39])[NH:31][C@H:32]1[CH2:33][CH2:34][C@H:35]([NH:38][C:22]([C:19]2[C:15]3[N:16]=[CH:17][N:18]=[C:13]([C:7]4[CH:8]=[C:9]([CH3:12])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:14]=3[NH:21][CH:20]=2)=[O:24])[CH2:36][CH2:37]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c[nH]c23)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c[nH]c23)c1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-methyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A83) and trans-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:16]C(=O)C(O)(C)C)[CH:12]=[C:13]([CH3:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C>O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:13]([CH3:15])[CH:14]=1)[NH2:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(NC(=O)C(C)(C)O)cc(OCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(N)cc(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 62.1 %

Procedure:
N-(3-Benzyloxy-5-methylphenyl)-2-hydroxy-2-methylpropanamide (600 mg, 2.0 mmol), as prepared in the preceding step, was mixed with 10N NaOH (25 mL) and ethanol (10 mL), and the mixture was refluxed for 2 days. After cooling to ambient temperature, the mixture was diluted with water (60 mL) and extracted with dichloromethane (3×60 mL). The dichloromethane solution was washed with brine (2×50 mL) and dried over Na2SO4. After evaporating the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane) to give the title compound as a yellow oil (265 mg, 61%). 1H-NMR (300 MHz, CDCl3) δ 7.37 (m, 5 H), 6.24 (s, 1 H), 6.14 (s, 2 H), 5.00 (s, 2 H), 3.59 (br s, 2 H), 2.23 (s, 3 H).
Reaction SMILES: [CH:1]([C:3]1[C:8]([OH:9])=[CH:7][C:6]([OH:10])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]=1[CH2:17][C:18]([O:20][CH3:21])=[O:19])=O>CO.[C].[Pd]>[OH:10][C:6]1[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:3]([CH3:1])=[C:8]([OH:9])[CH:7]=1
Reactant: COC(=O)Cc1c(C=O)c(O)cc(O)c1-c1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1c(C)c(O)cc(O)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
Compound 55 (44 mg, 0.15 mmol) obtained in Example 55 was dissolved in methanol (10 mL), and 10% palladium-carbon (50% wet., 40 mg) was added thereto and stirred under hydrogen pressure (0.3 MPa) at room temperature for 8 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure, purified through preparative thin-layer chromatography (methanol/chloroform 1/9) and crystallized (ethyl acetate/n-hexane=1/4) to obtain Compound 56 (31 mg, 74%).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:8]=[C:9]([CH:33]=[CH:34][C:35]=1[O:36][CH2:37][CH2:38][CH:39]([CH3:41])[CH3:40])[C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:27][CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])=[C:16]([CH2:18][C:19]([O:21]CCC(C)C)=[O:20])[CH:17]=1)=[O:11])[CH2:2][CH:3]([CH3:5])[CH3:4].[OH-].[Na+].C(Cl)(Cl)Cl.Cl>C(O)C.O>[CH2:1]([O:6][C:7]1[CH:8]=[C:9]([CH:33]=[CH:34][C:35]=1[O:36][CH2:37][CH2:38][CH:39]([CH3:41])[CH3:40])[C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:27][CH2:28][CH2:29][CH:30]([CH3:31])[CH3:32])=[C:16]([CH2:18][C:19]([OH:21])=[O:20])[CH:17]=1)=[O:11])[CH2:2][CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)CCOC(=O)Cc1cc(C(=O)c2ccc(OCCC(C)C)c(OCCC(C)C)c2)ccc1OCCC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCO
Product: CC(C)CCOc1ccc(C(=O)c2ccc(OCCC(C)C)c(OCCC(C)C)c2)cc1CC(=O)O
Temperature: 50 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
In 12 ml of ethanol is dissolved 1.20 g of isopentyl 2-[5-(3,4-diisopentyloxybenzoyl)-2-isopentyloxyphenyl]acetate. After adding 0.6 ml of 5 mol/L aqueous solution of sodium hydroxide, the mixture is stirred at 50° C. for one hour. Chloroform and water are added to the reaction mixture, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively, and the solvent is distilled off from the reaction mixture under reduced pressure. Thus, 0.88 g of 2-[5-(3,4-diisopentyloxybenzoyl)-2-isopentyloxyphenyl]acetic acid is obtained as a white solid product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1.Br[CH2:15][CH2:16][CH2:17][C:18]#[N:19]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]([CH2:15][CH2:16][CH2:17][C:18]#[N:19])[CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1csc(CNCc2cccs2)c1
Reactant: N#CCCCBr
Product: N#CCCCN(Cc1cccs1)Cc1cccs1

Procedure:
In a manner analogous to Example 21 a, 4-[N, N-bis-(2-thienylmethyl )amino]butyronitrile was prepared by alkylation of bis-(2-thienylmethyl)amine using 4-bromobutyronitrile.