Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C@@H:10]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24][C@@H:11]3[N:12](C(OC(C)(C)C)=O)[C:13]=2[CH:14]=[CH:15][CH:16]=1.[ClH:36]>O1CCOCC1>[ClH:36].[ClH:36].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C@@H:10]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24][C@@H:11]3[NH:12][C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2c3c(-c4ccccc4F)cccc3N(C(=O)OC(C)(C)C)[C@H]2CC1
Agent: Cl
Solvent: C1COCCO1
Product: Fc1ccccc1-c1cccc2c1[C@@H]1CCNCC[C@@H]1N2
Temperature: 25 °C
Reaction time: 26.5 h
Yield: 72 %

Procedure:
(5aS*,10bS*)-Di(tert-butyl) 10-(2-fluorophenyl)-1,2,4,5,5a,10b-hexahydroazepino[4,5-b]indole-3,6-dicarboxylate (0.094 g, 0.19 mmol) was dissolved in a 4.0 N solution of HCl in dioxane (4 mL) and stirred at room temperature for 26.5 hours. After the reaction mixture was concentrated in vacuo CH3OH was added and the solution was concentrated in vacuo and recrystallized from CH3OH/EtOAc to give 0.054 g (72%) of a white solid as the title compound: mp 248.0-256.7° C. 1H NMR (400 MHz, DMSO-d6) δ 9.19 (m, 1 H), 9.05 (m, 1 H), 7.51-7.43 (m, 2 H), 7.36-7.29 (m, 3 H), 7.03-6.98 (m, 2 H) 4.34-4.33 (m, 1 H), 3.85 (m, 1 H), 3.29 (m, 1 H), 3.06 (m, 1 H), 2.90 (m, 1 H), 2.69-2.67 (m, 1 H), 2.27 (m, 2 H), 1.67 (m, 1 H), 1.36-1.34 (m, 1 H); 13C NMR (100 MHz, DMSO-d6) δ 159.8, 157.3, 132.7, 130.8, 130.7, 130.2, 130.1, 128.6, 126.4, 126.2, 124.8, 124.7, 115.9, 115.7, 59.7, 44.8, 43.9, 41.7, 26.5, 25.7: IR (diffuse reflectance) 2954 (s), 2847 (s), 2817 (s,b), 2755 (s), 2726 (s,b), 2668 (s,b), 2651 (s,b), 2572 (s,b), 2538 (s), 2469 (s), 2350, 2342, 1738, 1474, 771 cm−1; HRMS (FAB) calcd for C18H19FN2+H1: 283.1610 found 283.1612.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([F:22])[C:19]([F:21])=[CH:20][C:15]=3[N:14]=[C:13]2[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[OH:30])[CH2:7][CH2:6]1)=[O:4].Br[CH2:32][CH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([F:22])[C:19]([F:21])=[CH:20][C:15]=3[N:14]=[C:13]2[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[O:30][CH2:32][CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: BrCC1CCCC1
Reactant: COC(=O)C1CCC(Cn2c(-c3ccc(Cl)cc3O)nc3cc(F)c(F)cc32)CC1
Product: COC(=O)C1CCC(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)CC1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 4-[2-(4-chloro-2-hydroxy-phenyl)-5,6-difluoro-benzoimidazol-1-ylmethyl]-cyclohexane carboxylic acid methyl ester and bromomethyl-cyclopentane (CAS Reg. No. 3814-30-0). Brown solid (56%). MS (Turbo Spray): m/z=517.4 (M+H).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH3:17][O:18][C:19]1[C:28]([O:29][CH3:30])=[C:27]([O:31][CH3:32])[CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][C:23]([CH:33]=O)=[CH:24]2>C1COCC1.C(OCC)(=O)C>[CH3:17][O:18][C:19]1[C:28]([O:29][CH3:30])=[C:27]([O:31][CH3:32])[CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][C:23]([CH:33]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:24]2
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1cc2cc(C=O)ccc2c(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C=Cc1ccc2c(OC)c(OC)c(OC)cc2c1
Reaction time: 0.5 h

Procedure:
55% Sodium hydride (241 mg) was suspended in THF (2.5 mL) at −10° C. under an argon atmosphere, a solution of ethyl diethylphosphonoacetate (1.23 g) in THF (5 mL) was added dropwise to the suspension, and the mixture was stirred for 30 minutes. A solution of 5,6,7-trimethoxynaphthalene-2-carboaldehyde (1.23 g) in THF (10 mL) was then added dropwise, and the mixture was stirred for 30 minutes at −10° C. and 1 hour at room temperature. The reaction mixture was diluted with ethyl acetate, washed with 2 M hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:2) to obtain the title compound.
Reaction SMILES: Cl[CH:2]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)[C:3]([CH3:8])([N+:5]([O-:7])=[O:6])[CH3:4].C(OCC)(=O)C>CO.[C].[Pd]>[CH3:8][C:3]([N+:5]([O-:7])=[O:6])([CH3:4])[CH2:2][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1
Reactant: CC(C)(C(Cl)c1ccc2ccccc2c1)[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(Cc1ccc2ccccc2c1)[N+](=O)[O-]
Reaction time: 2 h
Yield: 79.9 %

Procedure:
2-(1-Chloro-2-methyl-2-nitropropyl)naphthalene (200 mg) obtained in Step 4 was dissolved in methanol (5 ml) and ethyl acetate (5 ml) and to the solution was added 10% palladium carbon (20 mg). A hydrogenation reaction was performed at pressure of 3 atm for 2 hr. After filtration of the reaction mixture using Celite, the title compound (139 mg) was obtained by purification using silica gel column chromatography (n-hexane:ethyl acetate=95:5).
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[F:16][C:17]([F:32])([CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31])[CH2:18]O.N1C=CC=CC=1>ClCCl>[F:15][C:12]([F:13])([F:14])[S:9]([O:8][CH2:18][C:17]([F:32])([F:16])[CH2:20][N:21]1[C:22](=[O:31])[C:23]2=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]2[C:25]1=[O:26])(=[O:10])=[O:11]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C1c2ccccc2C(=O)N1CC(F)(F)CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1c2ccccc2C(=O)N1CC(F)(F)COS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Triflic anhydride (1.1 ml, 6.6 mmol) was added to a cold (0° C.) solution of 2,2-difluoro-3-phthalimido-1-propanol (1.4 g, 6 mmol), pyridine (0.5 ml, 6.6 mmol) in anhydrous dichloromethane (30 ml). The mixture was stirred 1 h at 0° C. and, after usual work-up, the product was purified by flash chromatography on silica gel (ethyl acetate:hexane; 20:80) (1.7 g, 75%).
Reaction SMILES: C[Si](Br)(C)C.C(OC([NH:13][C@H:14]([CH:18]=[C:19]([CH3:27])[CH2:20][P:21]([O:25]C)([O:23]C)=[O:22])[C:15]([OH:17])=[O:16])=O)(C)(C)C.O>ClCCl>[NH2:13][C@H:14]([CH:18]=[C:19]([CH3:27])[CH2:20][P:21]([OH:25])([OH:23])=[O:22])[C:15]([OH:17])=[O:16]
Reactant: COP(=O)(CC(C)=C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)OC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: O
Product: CC(=C[C@@H](N)C(=O)O)CP(=O)(O)O
Reaction time: 4 h
Yield: 81.3 %

Procedure:
0.71 ml of trimethylsilyl bromide is added at 0° to a solution of 123 mg of 9 in 3 ml of dichloromethane. After stirring at 0° for 4 hours, 20 ml of water are added. After 30 minutes, the dichloromethane phase is separated off and washed three times with 15 ml of water each time. The aqueous phases are extracted three times with 20 ml of dichloromethane each time and concentrated by evaporation in vacuo. The residue is dissolved in 10 ml of 5N hydrochloric acid and is then stirred for 48 hours, diluted with 20 ml of water and extracted three times with 20 ml of dichloromethane each time. The aqueous phase is concentrated by evaporation in vacuo, and the residue is dried under a high vacuum and dissolved in 3 ml of etharol, and then approximately 1 ml of propylene oxide is added dropwise thereto. The suspension is filtered. Washing of the filtration residue with ethanol and drying under a high vacuum at roomtemperature yields 62 mg of 10, m.p. 165° C. (decomposition).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].N[N:13]1[CH:17]=[N:16][N:15]=[CH:14]1.O>C(O)(C)C>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:15]2[CH:14]=[N:13][CH:17]=[N:16]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: Nn1cnnc1
Solvent: CC(C)O
Solvent: O
Product: O=[N+]([O-])c1ccc(Cn2cncn2)cc1
Temperature: -2 °C
Reaction time: 0.67 h
Yield: 37.4 %

Procedure:
4-Nitrobenzyl bromide (64.22 g), 4-amino-1,2,4-triazole (26 g) and isopropyl alcohol (586 ml) were stirred together at reflux for 71/2 hours. The isopropanol solvent was replaced with water by using an azeotropic distillation procedure, in vacuo, on a Buchi rotary evaporator. The volume of the final aqueous slurry was 750 ml. 675 ml of this slurry was cooled to -2° C. and hydrochloric acid (50.8 ml, 12 M) added over a few minutes. A solution of sodium nitrite (21.7 g) in water (86 ml) was then added dropwise, and subsurface over a 40 minute period. The temperature of the batch was kept between -2° and -1° C. during the addition and then allowed to warm to 18° C. over 30 minutes. The temperature was then increased to 28° C. and held for 1 hour and the solution treated with charcoal (4.5 g, Fisons) for 15 minutes. The charcoal was removed and the filtrate (750 ml) divided equally in two. One half of the solution was made basic with ammonia solution (22 ml) and the precipitated base collected, washed with water (2×30 ml) and dried (16 hours at 35° C. in vacuo). This gave an 83.3% yield (22.73 g) of 1-(4-nitrobenzyl)-1,2,4-triazole.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH3:19])[C@H:8]1[C@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[CH3:30][S:31]([N:34]1[CH2:39][CH2:38][N:37]([C:40](Cl)=[O:41])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:20])[N:7]([C@H:8]1[C@H:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:11][N:10]([C:40]([N:37]2[CH2:36][CH2:35][N:34]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:39][CH2:38]2)=[O:41])[CH2:9]1)[CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)N1CCN(C(=O)Cl)CC1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CNC[C@H]1c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)C[C@H]1c1ccccc1
Yield: 65.3 %

Procedure:
To a solution of rac-methyl-((3S,4R)-4-phenyl-pyrrolidin-3-yl)-carbamic acid tert-butyl ester (0.57 g, 2.1 mmol) in CH2Cl2 (15 ml) was added ethyl-diisopropyl-amine (0.53 ml, 3.11 mmol) and 4-methanesulfonyl-piperazine-1-carbonyl chloride (0.56 g, 2.5 mmol). Stirring was continued over night at RT, concentrated under vacuo and purification by flash chromatography (SiO2, EtOAc/Hx 1:1) afforded 0.64 g (66%) of rac-[(3S,4R)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-4-phenyl-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester as a white solid. ES-MS m/e: 467.3 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([C:12]([OH:14])=[O:13])=[C:7]([Cl:15])[CH:6]=[CH:5][C:4]=2[N:3]=1.[NH:16]1[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]1>>[Cl:15][C:7]1[CH:6]=[CH:5][C:4]2[N:3]=[C:2]([N:16]3[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH:11]=[CH:10][C:9]=2[C:8]=1[C:12]([OH:14])=[O:13]
Reactant: O=C(O)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: CCOC(=O)C1CCNCC1
Product: CCOC(=O)C1CCN(c2ccc3c(C(=O)O)c(Cl)ccc3n2)CC1
Yield: 75.1 %

Procedure:
Prepared according to the method of example 30, using 2,6-dichloro-5-quinolinecarboxylic acid (Example 76(b)) (800 mg) and 4-piperidinecarboxylic acid, ethyl ester (2.7 g). Purification (Varian NH2 cartridge using methanol (100 mL) and then 2% acetic acid in methanol (100 mL) as eluant) afforded the title compound as a solid (900 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[N:5]=[CH:4][N:3]=1.[CH3:16][C:17]([CH3:23])([CH3:22])[C:18]#[C:19][CH2:20][OH:21].[H-].[Na+].O>CN(C)C=O>[CH3:16][C:17]([CH3:23])([CH3:22])[C:18]#[C:19][CH2:20][O:21][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[N:5]=[CH:4][N:3]=1
Reactant: Fc1cccc(-c2cc(Cl)ncn2)c1F
Reactant: CC(C)(C)C#CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C#CCOc1cc(-c2cccc(F)c2F)ncn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.6 %

Procedure:
In 6 ml of N,N-dimethylformamide were dissolved 199 mg of 4-chloro-6-(2,3-difluorophenyl)pyrimidine and 118 mg of 4,4-dimethyl-2-pentyn-1-ol, to which 43 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 3 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 190 mg of 4-(4,4-dimethyl-2-pentynyloxy)-6-(2,3-difluorophenyl)pyrimidine (the present compound (119)).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[CH3:19][C:20]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:21]=1[C:22](O)=[O:23]>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:22](=[O:23])[C:21]3[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:20]=3[CH3:19])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18]
Reactant: Cc1ccc(C)c(C(=O)O)c1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(C)ccc3C)CC2)ccc1Cl
Yield: 10 %

Procedure:
The title compound (4 mg, 10%) was prepared analogously to example 8 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with 2,5-dimethylbenzoic acid. MS: 401.4 (MH+).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][Cl:19]>CN(C=O)C.CCOC(C)=O>[Cl:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: ClCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: ClCCCCCCn1ccc2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
To a mixture of NaH (0.249 g, 10.0 mmol) in DMF (5.00 mL) was added a solution of 1-H-indole (0.585 g, 5.00 mmol) in DMF (2.00 mL) at 0° C. The reaction mixture was stirred for 30 minutes at 0° C. and warmed up to room temperature. To the reaction mixture 1-bromo-6-chlorohexane (0.998 g, 5.00 mmol) was added dropwise via syringe and the reaction mixture was stirred overnight. The reaction mixture was diluted with EtOAc (30 mL), washed with water (3×10 mL), brine (10 mL), dried over MgSO4, concentrated in vacuo and purified by chromatography using hexane:EtOAc (97.5:2.5) to give the desired product (0.900 g, 76.0%): 1H NMR (400 MHz, CDCl3) δ 7.76-7.54 (m, 1H), 7.47-6.96 (m, 4H), 6.60-6.34 (m, 1H), 4.13 (t, 2H, J=6.8 Hz), 3.50 (t, 2H, J=5.6 Hz), 1.98-1.79 (m, 2H), 1.79-1.64 (m, 2H) 1.54-1.17 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH:18]([NH:29][OH:30])[C:19]#[C:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:31](OC(=O)C)=[O:32]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH:18]([N:29]([OH:30])[CH:31]=[O:32])[C:19]#[C:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)OC=O
Reactant: COc1cccc(C#CC(CS(=O)(=O)N2CCN(c3ccc(F)cc3)CC2)NO)c1
Solvent: C1CCOC1
Product: COc1cccc(C#CC(CS(=O)(=O)N2CCN(c3ccc(F)cc3)CC2)N(O)C=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
A solution of 1-(4-fluorophenyl)-4-{[2-(hydroxyamino)-4-(3-methoxyphenyl)but-3-yn-1-yl]sulfonyl}piperazine (349 mg; 0.81 mmol) and acetyl formate (prepared as described by Koller et al., 1983, above 8; 0.58 mL of a 1.39 M solution in THF; 0.81 mmol) was stirred at rt for 1 h. THF was removed under reduced pressure and replaced by MeOH. The solution was heated at 60° C. for 1 h and concentrated under reduced pressure. Purification of the crude by flash chromatography on silica (EtOAc:c-Hex 60:40 to 100:0) gave the title compound as an orange oil (90 mg, 24% yield). HPLC, Rt: 3.69 min (purity: 99.3%). LC/MS, M+(ESI): 462.3. 1H NMR (DMSO-d6) δ: 8.45 (brs, 0.4H), 8.13 (brs, 0.6H), 7.19 (m, 1H), 6.97-7.04 (m, 7H), 5.80 (brs, 0.4H), 5.25 (brs, 0.6H), 3.77 (s, 3H), 3.68 (brs, 1H), 3.44 (m, 6H), 3.14 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]([CH2:16][CH2:17][O:18]COC)[CH:13]=[CH:12][C:4]=1[O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])#[N:2].Cl.O>C(O)C>[C:1]([C:3]1[CH:15]=[C:14]([CH2:16][CH2:17][OH:18])[CH:13]=[CH:12][C:4]=1[O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])#[N:2]
Reactant: CCOC(=O)COc1ccc(CCOCOC)cc1C#N
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)COc1ccc(CCO)cc1C#N
Temperature: 70 °C
Reaction time: 2 h
Yield: 101.2 %

Procedure:
To a solution of 2-hydroxy-5-(2-methoxymethoxyethyl)benzonitrile (496 mg) in N,N-dimethylformamide (5 ml) were added potassium carbonate (435 mg) and ethyl bromoacetate (292 μl), and the mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, and removal of the solvent under reduced pressure gave ethyl 2-[2-cyano-4-(2-methoxymethoxyethyl)phenoxy]acetate (619 mg). To a solution of the obtained ethyl 2-[2-cyano-4-(2-methoxymethoxyethyl)phenoxy]acetate (522 mg) in ethanol (5 ml) was added concentrated hydrochloric acid (20 μl), and the mixture was stirred for 2 hours at 70° C. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, and removal of the solvent under reduced pressure gave ethyl 2-[2-cyano-4-(2-hydroxyethyl)phenoxy]acetate (449 mg).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]([C:7]1[N:15]=[CH:14][C:13]2[NH:12][C:11]3[N:16]=[CH:17][CH:18]=[CH:19][C:10]=3[C:9]=2[CH:8]=1)=[O:6].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:3][O:4][C:5]([C:7]1[N:15]=[CH:14][C:13]2[NH:12][C:11]3[N:16]=[CH:17][C:18]([Br:1])=[CH:19][C:10]=3[C:9]=2[CH:8]=1)=[O:6]
Reactant: COC(=O)c1cc2c(cn1)[nH]c1ncccc12
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1cc2c(cn1)[nH]c1ncc(Br)cc12
Temperature: 100 °C
Yield: 103.9 %

Procedure:
Bromine (6.76 ml, 132.0 mmol) was added to a mixture of 9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid methyl ester (10.0 g, 44.0 mmol) and sodium acetate (11.2 g, 136.4 mmol) in acetic acid (360 mL) and then the reaction mixture was heated at 100° C. for 90 minutes. The reaction mixture was then cooled to ambient temperature and the solvent removed under reduced pressure then the residue was treated with saturated sodium thiosulfate solution (40 mL) followed by water (100 mL) and then the pH of the aqueous solution was adjusted to 7 by the addition of saturated sodium hydrogen carbonate solution. The resultant precipitate was collected by filtration and the solid was washed with water (20 mL) then dried at 60° C. until constant weight was achieved, to afford the desired material as an off-white solid (14.0 g, quantitative yield). 1H NMR (DMSO-D6, 300 MHz): 9.13 (d, J=2.3 Hz, 1H), 9.00 (d, J=2.0 Hz, 2H), 8.70 (d, J=2.3 Hz, 1H), 3.92 (s, 3H). LCMS (Method B): RT=2.92 min, M+H+=306/308.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.B(F)(F)F.[CH3:18][CH2:19][O:20]CC>C(OC(=O)C)(=O)C>[C:19]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)(=[O:20])[CH3:18]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: CCOCC
Agent: FB(F)F
Solvent: CC(=O)OC(C)=O
Product: CC(=O)n1c2ccccc2c2ccccc21
Temperature: 0 °C

Procedure:
Carbazole (100.24 g) was suspended in acetic anhydride (300 mL) with catalytic boron trifluoride etherate (0.65 mL) and the solution refluxed for 25 min. then cooled to 0° C. and the solid was then collected and recrystallized from hexane to give 82.65 g 9-acetyl-carbazole.
Reaction SMILES: Br[C:2]1[O:23][C:5]2[N:6]([CH3:22])[CH:7]=[C:8]([C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[O:12])[C:9](=[O:10])[C:4]=2[CH:3]=1.[CH2:24]([OH:28])[CH2:25][C:26]#[CH:27]>C(N(CC)CC)C.CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][NH:13][C:11]([C:8]2[C:9](=[O:10])[C:4]3[CH:3]=[C:2]([C:27]#[C:26][CH2:25][CH2:24][OH:28])[O:23][C:5]=3[N:6]([CH3:22])[CH:7]=2)=[O:12])=[CH:16][CH:17]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(Br)oc21
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCCO)oc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Bromo-N-(4-chlorobenzyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]-pyridine-5-carboxamide (Example 79, 0.100 g) was suspended in a mixture of triethylamine (2.5 mL) and DMF (0.5 mL). CuI (0.006 g), Pd(PPh3)2Cl2 (0.017 g), and then 3-butyn-1-ol (0.038 mL) were added. The mixture was stirred at room temperature for 30 min and then was partitioned between CH2Cl2 (10 mL) and water (10 mL). The aqueous layer was separated and was extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with a sat. aq. ammonium chloride solution (10 mL), dried (MgSO4), filtered, and concentrated in vacuo. The resulting solid was purified by column chromatography (CH2Cl2/methanol; 99/1, 98/2) followed by recrystallization from ethyl acetate to yield 0.035 g of the title compound as a pale yellow solid. Physical characteristics. M.p. 242-243° C. (dec); 1H NMR (400 MHz, DMSO-d6) δ 10.51, 8.59, 7.41-7.32, 7.21, 5.01, 4.55, 3.92, 3.61, 2.67; MS (ESI+) m/z 385 (,M+H)+.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:32]2[CH2:31][CH2:30][N:29]([CH:28]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:25]3[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=3)[CH2:34][CH2:33]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)cc1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(CCCN3CCN(C(c4ccc(F)cc4)c4ccc(F)cc4)CC3)nn2C(C)(C)C)cc1

Procedure:
111 mg (86%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (60 mg, 0.222 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (64 mg, 0.222 mmol), DIPEA (0.06 mL, 0.333 mmol) and NaBH(OAc)3 (141 mg, 0.666 mmol).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][N:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>Cl.CO.[Pt]=O>[CH:1]1([CH2:7][CH2:8][CH:9]2[CH2:10][CH:11]([C:12]([O:14][CH3:15])=[O:13])[CH2:16][CH2:17][NH:18]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccnc(/C=C/c2ccccc2)c1
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Product: COC(=O)C1CCNC(CCC2CCCCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-[(E)-2-phenylvinyl]isonicotinate in hydrochloric acid and MeOH was added platinum oxide, followed by stirring at room temperature for 8 hours under a hydrogen atmosphere of 3 atm. The reaction mixture was filtered through Celite, and the filtrate was then concentrated under reduced pressure. To the residue were added an aqueous Na2CO3 solution and xylene, and the aqueous layer was extracted with CHCl3. The organic layer was dried over MgSO4 and then concentrated under reduced pressure to obtain methyl 2-(2-cyclohexylethyl)piperidine-4-carboxylate as a colorless oily substance.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=O)[CH2:9][CH2:8][CH2:7][C:6]=2[O:5][C:4](=[O:13])[CH:3]=1.[CH:14]([NH2:17])([CH3:16])[CH3:15]>>[CH:14]([N:17]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:5])[C:11]=2[C:2]([CH3:1])=[CH:3][C:4]1=[O:13])([CH3:16])[CH3:15]
Reactant: CC(C)N
Reactant: Cc1cc(=O)oc2c1C(=O)CCC2
Product: Cc1cc(=O)n(C(C)C)c2c1C(=O)CCC2

Procedure:
Prepared analogously to Example 5(b) from 4-methyl- 5,6,7,8-tetrahydro-cumarin-5-one and isopropylamine.