Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)=[N:10][C:11]([NH2:19])=[N:12][C:13]=2[C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:4][N:3]=1.[CH3:25][NH:26][CH3:27]>COCCOC>[CH3:25][N:26]([CH3:27])[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)=[N:10][C:11]([NH2:19])=[N:12][C:13]=2[C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nc(-c2ccco2)c(-c2ccnc(F)c2)c(-c2ccco2)n1
Reactant: CNC
Solvent: COCCOC
Product: CN(C)c1cc(-c2c(-c3ccco3)nc(N)nc2-c2ccco2)ccn1
Temperature: 70 °C
Reaction time: 11 h
Yield: 43 %

Procedure:
In an autoclave, 5-(2-fluoro-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine (200 mg, 0.621 mmol) was suspended in 1,2-dimethoxyethane (10 ml) and then a 50% dimethylamine aqueous solution (5 ml) was added thereto, followed by stirring at 70° C. After 11 hours, the reaction mixture was extracted with ethyl acetate, and the extract was washed with water and brine, dried over anhydrous sodium sulfate and then the filtrate was concentrated. The resulting solid was suspended in ethanol, collected by filtration and washed with ethanol, to give the title compound (92 mg, 43%) as a pale yellow solid.
Reaction SMILES: [Cl-].[CH2:2]([O:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=1)[CH3:3].CN(C)C=O.O[NH:23][C:24](=[NH:35])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>C1C=CC=CC=1>[CH2:2]([O:4][C:5](=[O:16])[C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C:13]2[O:15][N:23]=[C:24]([CH2:25][O:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:35]=2)=[CH:10][CH:11]=1)[CH3:3]
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1
Reactant: COc1ccc(OCC(=N)NO)cc1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCOC(=O)c1ccc(Cc2nc(COc3ccc(OC)cc3)no2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.2 %

Procedure:
Add oxaxyl chloride (1.25 mL, 14 mmol) to 4-carboxymethyl-benzoic acid ethyl ester (365 mg, 1.75 mmol) in benzene (11 mL) and a drop of dimethylformamide at room temperature under argon gas over a 5 minute period. Stir the reaction mixture for 2 hours at room temperature. Concentrate the reaction mixture to an oil. Redissolve the oil in dimethylformamide (10 mL) and N-hydroxy-2-(4-methoxy-phenoxy)-acetamidine (380 mg, 1.9 mmol) is added. Stir the reaction mixture at room temperature for 3 hours. Heat the reaction mixture to 120° C. and stir for 7 hours. After cooling to room temperature, quench the reaction mixture with water and extract with ethyl acetate (3×). Combine the organic layers, wash with brine, dry over sodium sulfate, and concentrate. Purify the residue by flash column chromatography using 20% ethyl acetate/hexane to give the title compound (201 mg, 31%). LC-MS (m/e): 369 (M+1).
Reaction SMILES: COC[C@@H]1[C@H](/C=C/C(/C)=C/C(O)=O)[C@@]1(C)C1C=C(C(C)C)C=C(C(C)C)C=1.[CH2:28]([O:30][CH2:31][C@@H:32]1[C@@H:34](/[CH:35]=[CH:36]/[C:37](/[CH3:44])=[CH:38]/[C:39]([O:41]CC)=[O:40])[C@:33]1([CH3:57])[C:45]1[CH:50]=[C:49]([CH:51]([CH3:53])[CH3:52])[CH:48]=[C:47]([CH:54]([CH3:56])[CH3:55])[CH:46]=1)[CH3:29]>>[CH2:28]([O:30][CH2:31][C@@H:32]1[C@@H:34](/[CH:35]=[CH:36]/[C:37](/[CH3:44])=[CH:38]/[C:39]([OH:41])=[O:40])[C@:33]1([CH3:57])[C:45]1[CH:46]=[C:47]([CH:54]([CH3:55])[CH3:56])[CH:48]=[C:49]([CH:51]([CH3:53])[CH3:52])[CH:50]=1)[CH3:29]
Reactant: CCOC[C@@H]1[C@@H](/C=C/C(C)=C/C(=O)OCC)[C@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Agent: COC[C@@H]1[C@H](/C=C/C(C)=C/C(=O)O)[C@@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Product: CCOC[C@@H]1[C@@H](/C=C/C(C)=C/C(=O)O)[C@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Yield: 85 %

Procedure:
Following a procedure similar to that for the preparation of Compound 28 but using Compound 27b as the starting material afforded the title compound (28 mg, 85% yield) as a white solid:
Reaction SMILES: [C:1](O)(=O)[C:2]1C=CC=N[CH:3]=1.C([O:12][C:13](=[O:22])[C:14]1[CH:19]=[C:18]([CH3:20])[C:17](Cl)=[N:16][CH:15]=1)C>>[CH3:20][C:18]1[C:17]([CH2:1][CH2:2][CH3:3])=[N:16][CH:15]=[C:14]([CH:19]=1)[C:13]([OH:12])=[O:22]
Reactant: O=C(O)c1cccnc1
Reactant: CCOC(=O)c1cnc(Cl)c(C)c1
Product: CCCc1ncc(C(=O)O)cc1C

Procedure:
5-Methyl-6-propyl-nicotinic acid (1.85 g as hydrochloride) is prepared in analogy to Nicotinic acid 6 from 6-chloro-5-methyl-nicotinic acid ethyl ester (2.0 g) and commercially available trans-1-propen-1-yl broronic acid (1.3 g); 1H NMR (d6-DMSO) δ 0.96 (t, J=7.3 Hz, 3H), 1.72 (m, 2H), 3.05 (t, J=7.5 Hz, 2H), 8.66 (m, 1H), 8.86 (d, J=1.5 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:25]3[CH2:30][CH2:29][CH2:28][CH:27]=[CH:26]3)[C:17]=2[O:31][C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=2[CH3:39])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:17]=2[O:31][C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=2[CH3:39])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(F)cc1Oc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2n1C1C=CCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(F)cc1Oc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2n1C1CCCCC1
Reaction time: 8 h
Yield: 97.9 %

Procedure:
The compound of example 22, step 4 (66.0 mg, 124 μmol) was dissolved in ethanol (5 ml), and palladium on activated carbon (20 mg, 10%) was added. The mixture was hydrogenated overnight at room temperature and a hydrogen pressure of 4.5 bar. The mixture was filtered over celite and evaporated under reduced pressure to give 65.0 mg of the crude title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20]C=CC=2)[N:3]=1.[H-].[Na+].[CH3:24]OS(OC)(=O)=O.[CH2:31]1[CH2:35]OC[CH2:32]1>>[CH3:9][C:6]1[C:7]([O:8][CH3:24])=[C:2]([CH3:1])[N:3]=[C:4]([NH:10][CH2:11][CH:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:21][CH:20]=2)[CH2:32][CH2:31][CH3:35])[N:5]=1
Reactant: COS(=O)(=O)OC
Reactant: C1CCOC1
Reactant: Cc1nc(NCCCCCc2ccccc2)nc(C)c1O
Agent: [H-]
Agent: [Na+]
Product: CCCC(CNc1nc(C)c(OC)c(C)n1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
4,6-Dimethyl-5-hydroxy-2-phenpentylaminopyrimidine (0.5 g, 1.8 mmol) prepared by the method of example 1 was dissovled in dry THF (20 ml) under nitrogen and treated with sodium hydride (0.07 g, 1.8 mmol, 60% oil dispersion). The reaction mixture was stirred at 0° C. for 2 hours. Dimethylsulfate (0.11 ml, 1.8 mmol) was added with a syringe and the reaction was stirred for an additional hour. After quenching with saturated NH4Cl (aqueous, 20 ml), the reaction mixture was extracted with ethylacetate (75 ml). The extracts were washed with 50 ml water and 50 ml brine, dried over MgSO4 and concentrated. Chromatography on silica gel with ethylacetate/hexane (1:1) eluent yielded 0.15 g of the title compound as a yellow oil, m.p.: 31° to 33° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([NH:14][CH3:15])=[O:13])=[N:10][CH:11]=1.[H-].[Na+].Cl[C:19]1[C:20]2[C:27]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[CH:26][S:25][C:21]=2[N:22]=[CH:23][N:24]=1.C(O)(=O)C>CN(C)C(=O)C>[CH3:15][NH:14][C:12]([C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:1][C:19]2[C:20]3[C:27]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)=[CH:26][S:25][C:21]=3[N:22]=[CH:23][N:24]=2)=[CH:11][N:10]=1)=[O:13]
Reactant: Clc1ncnc2scc(-c3ccncc3)c12
Reactant: CNC(=O)c1ccc(OCCCO)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: CNC(=O)c1ccc(OCCCOc2ncnc3scc(-c4ccncc4)c23)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 683.3 %

Procedure:
5-(3-Hydroxypropoxy)-N-methylpyridine-2-carboxamide (52 mg, 0.25 mmol) in N,N-dimethylacetamide (2.0 mL, 22 mmol) was treated with sodium hydride (11 mg, 60%, 0.27 mmol) at ambient temperature. After 1.5 hours, the mixture was added to a solution of 4-chloro-5-pyridin-4-ylthieno[2,3-d]pyrimidine (62 mg, 0.025 mmol) in N,N-dimethylacetamide (1.0 mL) and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was then quenched by the addition of acetic acid (0.12 mL, 2.0 mmol) and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), washed with 5% aqueous sodium bicarbonate (2×30 mL) and the organic layer was concentrated. The product was purified by silica gel chromatography using 3 to 5% methanol in ethyl acetate to give 72 mg (68%) of N-methyl-5-{3-[(5-pyridin-4-ylthieno[2,3-d]pyrimidin-4-yl)oxy]propoxy}pyridine-2-carboxamide as a white solid. MS [M+H] 422.0, 1H NMR (CDCl3) δ (ppm) 8.74 (s, 1H), 8.66 (s, 1H), 8.54 (d, J=3.9 Hz, 1H), 8.11 (d, J=8.4 Hz, 1H), 8.05 (d, J=2.7 Hz, 1H), 7.90-7.73 (m, 2H), 7.33 (s, 1H), 7.28 (dd, J=7.8, 4.8 Hz, 1H), 7.11 (dd, J=8.7, 2.7 Hz, 1H), 4.62 (t, J=6.0 Hz, 2H), 3.76 (t, J=6.0 Hz, 2H), 3.01 (d, J=4.8 Hz, 3H), 2.13 (t, J=6.0 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[N:24]=[C:23](Cl)[CH:22]=[CH:21][N:20]=3)[S:18][C:14]=2[C:13]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>O1CCOCC1>[C:1]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[N:24]=[C:23]([N:40]4[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]4)[CH:22]=[CH:21][N:20]=3)[S:18][C:14]=2[C:13]=1[C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3nccc(Cl)n3)sc2c1-c1ccc(Cl)cc1
Reactant: CN1CCNCC1
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3nccc(N4CCN(C)CC4)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(4-chloropyrimidin-2-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (30 mg, 0.06 mmol) in dioxane (1 mL) was added 1-methylpiperazine (56.7 mg, 0.063 mL, 0.566 mmol). The RM was stirred at room temperature for 20 minutes, concentrated, and used without further purification. LCMS-ESI+ calc'd for C31H37ClN5O3S (M+H+): 594.2; Found: 593.7 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18](=[O:28])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N+:25]([O-])=O)[N:10]=[N:9]2)=[CH:5][CH:4]=1>C(O)C.[Pd]>[NH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]([C:11]1[N:10]=[N:9][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:30][CH:29]=2)[C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:28]
Reactant: CCOC(=O)c1c(C(=O)c2ccccc2[N+](=O)[O-])nnn1Cc1ccc(OC)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1c(C(=O)c2ccccc2N)nnn1Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.2 %

Procedure:
Ethyl 1-(4-methoxybenzyl)-4-(2-nitrobenzoyl)-1,2, 3-triazole-5-carboxylate (629 mg, 1.53 mmole) was dissolved in ethanol (6.0 ml), and 10% palladium on carbon (58 mg) was added. After the mixture was stirred under a hydrogen atmosphere at room temperature for 16 hours, 10% palladium on carbon (60 mg) was added, and the mixture was further stirred for 2 hours. The reaction mixture was filtered through celite, and the solvent was removed under reduced pressure. Precipitate was collected by filtration to give ethyl 4-(2-aminobenzoyl)-1-(4-methoxybenzyl)-1,2,3-triazole-5-carboxylate (548 mg, 94.2%) as a yellow crystalline powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1([CH:14]=O)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1([CH2:14][NH:22][C:21]2[CH:23]=[CH:24][C:18]([Br:17])=[CH:19][CH:20]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)NC1(C=O)CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1(CNc2ccc(Br)cc2)CCOCC1
Temperature: 25 °C

Procedure:
A solution of (4-formyl-tetrahydro-pyran-4-yl)-carbamic acid tert-butyl ester (4.48 g, 19.5 mmol), 4-bromoaniline (3.38 g, 19.7 mmol), and acetic acid (1.2 mL, 21.2 mmol) in ethyl acetate (50 mL) contained in a 250 mL round bottom flask fitted with a reflux condenser and a Dean and Stark trap was heated at reflux under N2 blanket for 2 h then cooled to ambient temperature. Sodium cyanoborohydride (1.29 g, 19.5 mmol) was added and the mixture stirred over night. The reaction mixture was then washed with water (50 mL), saturated aqueous sodium chloride (50 mL), dried (MgSO4), preabsorbed on silica gel and flash chromatographed (elution solvent: 10% (v/v) ethyl acetate/hexane) to isolate the desired product as 3.1 g of white solid foam. LRMS (ESI) m/z 385.0, 387.0 [(M+H)+, calcd for C17H26N2O3Br 386.3].
Reaction SMILES: [CH:1]1[C:6]2=[CH:7][C:8]3[C:17]([CH:18]=[C:5]2[CH:4]=[CH:3][CH:2]=1)=[CH:16][C:15]1[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH:9]=3.C1(=O)[O:23][CH:22]=[CH:21][O:20]1>>[CH:14]1[C:15]2[CH:16]3[CH:21]([OH:20])[CH:22]([OH:23])[CH:9]([C:10]=2[CH:11]=[CH:12][CH:13]=1)[C:8]1[C:17]3=[CH:18][C:5]2[C:6]([CH:7]=1)=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: c1ccc2cc3cc4ccccc4cc3cc2c1
Reactant: O=c1occo1
Product: OC1C2c3ccccc3C(c3cc4ccccc4cc32)C1O

Procedure:
A mixture of 7.0 g. of benz[b]anthracene and 26 g. of vinylene carbonate is heated at reflux under nitrogen for 20 hours. The excess vinylene carbonate is removed by vacuum distillation (57° C./9 mm.) and the residue is taken up in 25 ml. of methylene chloride and filtered. The filtrate is treated with twice its volume of methanol and then cooled, producing a tan solid and a mother liquor which is saved. This solid is recrystallized from 60 ml. of 1,2-dichloromethane, collected by filtration, washed with methanol and saved. The mother liquor (saved above) is concentrated giving a gummy solid which is recrystallized from a mixture of methylene chloride and methanol giving a gray solid which is combined with the above solid and recrystallized from ethyl acetate with charcoal treatment giving 5,12-dihydro-5,12-ethanobenz[b]anthracene-13,14-diol, cyclic carbonate as colorless rods. A mixture of 1.3 g. of the cyclic carbonate, 1.05 g. of potassium hydroxide, one ml. of water and 15 ml. of ethanol is stirred at 60°-65° C. for 2 hours. The mixture is diluted with 1-2 volumes of water, filtered and the solid is washed with water and dried giving cis-5,12-dihydro-5,12-ethanobenz[b]anthracene-13,14-diol as a colorless solid. To a solution of 2.6 g. of cis-5,12-dihydro-5,12-ethanobenz[b]anthracene-13,14-diol in 400 ml. of glacial acetic acid at 20° C. is added portionwise 4.4 g. of lead tetraacetate. The reaction is stirred for 45 minutes. The weakly purple colored solid is filtered off, washed with glacial acetic acid and finally water and dried leaving 1.0 g. (m.p. 170°-172° C.) of 5,12-dihydro-5,12-benz[b]anthracene dicarboxaldehyde.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[CH2:4][O:3]1.Cl>CO.O>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C@H:5]([OH:6])[CH2:4][OH:3])=[CH:10][CH:11]=1)#[N:16]
Reactant: CC1(C)OC[C@H](COc2ccc(C#N)cc2)O1
Agent: Cl
Solvent: CO
Solvent: O
Product: N#Cc1ccc(OC[C@H](O)CO)cc1
Reaction time: 8 h
Yield: 72.1 %

Procedure:
77 g of (4S)-2,2-dimethyl-4-(4-cyanophenoxy)methyl-1,3-dioxolane, was dissolved in methanol (200 ml) and water (75 ml). Concentrated hydrochloric acid (0.5 ml) was added and the mixture was kept at 50° C. overnight. It was evaporated at reduced pressure and recrystallized from water to yield 46 g of the title compound as white leaves, m.p. 63°-65° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:6][C@@H:5]3[CH2:30][C@H:31]([N:33]([CH2:37][CH2:38][CH3:39])[CH2:34][CH2:35][CH3:36])[CH2:32][C:3]=1[C:4]=23.C([Li])CCC.CN(C)[CH:47]=[O:48]>O1CCCC1.CCCCCC>[CH:47]([C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:6][C@@H:5]3[CH2:30][C@H:31]([N:33]([CH2:37][CH2:38][CH3:39])[CH2:34][CH2:35][CH3:36])[CH2:32][C:3]=1[C:4]=23)=[O:48]
Reactant: CN(C)C=O
Reactant: CCCN(CCC)[C@@H]1Cc2c(Br)ccc3c2[C@@H](C1)CN3C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCN(CCC)[C@@H]1Cc2c(C=O)ccc3c2[C@@H](C1)CN3C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of (-)(2aR,4S)-6-bromo-1-trityl-4-(di-n-propylamino) -1,2,2a, 3,4,5-hexahydrobenz [cd]indole (6.8 g, 12 mmol) in 100 ml of tetrahydrofuran cooled to -78° C. under a nitrogen atmosphere was added dropwise a 1.6M solution of n-butyllithium in hexane. The reaction mixture was stirred at -78° C. for 1 hour. Dimethylformamide (3 ml) was added to the reaction mixture and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with water and then extracted with ethyl acetate. The ethyl acetate solution was washed with a saturated brine solution, dried over magnesium sulfate and concentrated to dryness to provide 5.6 g of the above-titled compound as an oil.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[N:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([OH:15])=[CH:8]2.[C:16]([O:20][C:21]([NH:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31]OS(C)(=O)=O)[CH2:26][CH2:25]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C)C=O>[C:16]([O:20][C:21](=[O:22])[NH:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][O:15][C:9]2[CH:10]=[N:11][C:12]3[C:7]([CH:8]=2)=[N:6][C:5]([O:4][CH3:3])=[CH:14][CH:13]=3)[CH2:26][CH2:25]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Reactant: COc1ccc2ncc(O)cc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2ncc(OCCN3CCC(NC(=O)OC(C)(C)C)CC3)cc2n1
Yield: 30.5 %

Procedure:
Sodium hydride (55% purity, 9 mg, 0.22 mmol, 1.5 eq) is added at room temperature to a stirred solution of 6-methoxy-[1,5]naphthyridin-3-ol (42 mg, 0.22 mmol, 1.0 eq) in N,N-dimethylformamide (5 mL), followed by methanesulfonic acid 2-(4-tert-butoxycarbonylamino-piperidin-1-yl)-ethyl ester (102 mg, 0.22 mmol, 1.0 eq). The reaction mixture is irradiated by microwaves at 110° C. for 10 minutes, then solvent is evaporated, and the residue is extracted with ethyl acetate (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: cyclohexane: ethyl acetate:methanol, 1:1:0 to 0:9:1, v/v/v) to afford {1-[2-(6-methoxy-[1,5]naphthyridin-3-yloxy)-ethyl]-piperidin-4-yl}-carbamic acid tert-butyl ester as an orange solid (27 mg, 29% yield).
Reaction SMILES: BrC1C=CC(OCCCBr)=CC=1.[OH:13][CH:14]([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[CH2:15][CH2:16][CH2:17][C:18]1C=CC=C[CH:19]=1.C1(O)C=CC=CC=1>>[OH:13][CH:14]([C:24]1[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: Oc1ccc(C(O)CCCc2ccccc2)cc1
Agent: BrCCCOc1ccc(Br)cc1
Solvent: Oc1ccccc1
Product: CCCCCC(O)c1ccc(O)cc1

Procedure:
Following the procedure of Step 2 Example 1, but substituting 3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl bromide for 3-(4-bromophenoxy)propyl bromide (from Step 2, Example 7) and substituting 4-(1-hydroxy-4-phenylbutyl)phenol for the phenol of Step 1, the title compound was prepared.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:10][O:11][CH2:12][O:13][CH2:14][C:15](N)=[NH:16]>C(O)C>[NH2:9][C:8]1[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=[C:15]([CH2:14][O:13][CH2:12][O:11][CH3:10])[N:16]=1
Reactant: N#Cc1nccnc1N
Reactant: COCOCC(=N)N
Solvent: CCO
Product: COCOCc1nc(N)c2nccnc2n1

Procedure:
Obtained using the procedure described in section c of Example 2, starting with 12.0 g (0.10 mole) of 3-amino-2-pyrazinecarbonitrile and 18.0 g (0.15 mole) of 2-(methoxymethoxy)acetamidine in 400 ml of absolute ethanol. Refluxing time: 4 hours. Yld: 15.8 g (71%), m.p. 129°-131° C. (ethanol).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]3[C:16]4[CH2:17][NH:18][CH2:19][CH2:20][C:21]=4[O:22][C:12]=3[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:25](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:39]CCCl>>[ClH:39].[CH3:25][N:18]1[CH2:19][CH2:20][C:21]2[O:22][C:12]3[CH:11]=[C:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH:15]=[CH:14][C:13]=3[C:16]=2[CH2:17]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=S(=O)(c1ccccc1)c1ccc2c3c(oc2c1)CCNC3
Reactant: ClCCCl
Agent: C=O
Agent: [Na+]
Product: CN1CCc2oc3cc(S(=O)(=O)c4ccccc4)ccc3c2C1
Product: Cl
Reaction time: 15 h

Procedure:
To a solution of the product of Example 60, step E (15 mg, 0.05 mmol) in 1,2-dichloroethane (0.5 mL) was added formaldehyde (12 μL, 37% in water). The reaction mixture was stirred at ambient temperature for 10 min before sodium triacetoxyborohydride (61 mg, 0.29 mmol) was added. The reaction mixture was stirred for 15 h, quenched with saturated sodium bicarbonate solution and extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was treated with 1.25 M HCl in methanol and the resulting solution concentrated in vacuo to afford 2-methyl-7-(phenylsulfonyl)-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine hydrochloride (9.5 mg, 61%, AUC HPLC 95.7%) as a white solid: mp 242-245° C.; 1H NMR (CD3OD, 300 MHz) δ 8.21-8.13 (m, 1H), 7.98 (d, J=7.2 Hz, 2H), 7.87 (dd, J=8.3 Hz, 1.2 Hz, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.63-7.54 (m, 3H), 4.74-4.30 (br s, 2H), 3.96-3.60 (br s, 2H), 3.30 (br s, 2H), 3.13 (s, 3H); ESI MS m/z 328 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17])=[CH:5]2.[CH:24]12[CH2:29][CH:28]1[CH2:27][N:26]([CH2:30][CH2:31][CH2:32]OC1C=C3C(=CC=1)NC(C(N1CCOCC1)=O)=C3)[CH2:25]2.FC(F)(F)COS(C(F)(F)F)(=O)=O>>[CH:24]12[CH2:29][CH:28]1[CH2:27][N:26]([CH2:30][CH2:31][CH2:32][O:1][C:2]1[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([F:15])([F:13])[F:14])[C:6]([C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17])=[CH:5]3)[CH2:25]2
Reactant: O=C(c1cc2cc(O)ccc2n1CC(F)(F)F)N1CCOCC1
Reactant: O=C(c1cc2cc(OCCCN3CC4CC4C3)ccc2[nH]1)N1CCOCC1
Agent: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Product: O=C(c1cc2cc(OCCCN3CC4CC4C3)ccc2n1CC(F)(F)F)N1CCOCC1

Procedure:
In analogy to the procedure described for the synthesis of intermediate 1, step 1, the title compound was synthesized from {5-[3-(3-aza-bicyclo[3.1.0]hex-3-yl)-propoxy]-1H-indol-2-yl}-morpholin-4-yl-methanone (Example 5, step 4) and 2,2,2-trifluoroethyl-trifluoromethanesulfonate. The title product was obtained in 45% yield as white solid. MS (m/e): 452.5 (MH+, 100%).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:36]=[CH:35][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][N:22]([C:25]5[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=5)[CH2:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([C:37]#[N:38])[CH:3]=1.[CH3:39]/[C:40](/B(O)O)=[CH:41]/[CH3:42]>>[C:37]([C:4]1[CH:3]=[C:2](/[C:40](/[CH3:39])=[CH:41]\[CH3:42])[C:10]2[O:9][C:8]([C:11]3[CH:36]=[CH:35][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:20][CH2:21][N:22]([C:25]5[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][N:26]=5)[CH2:23][CH2:24]4)=[O:16])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=1)#[N:38]
Reactant: N#Cc1cc(Br)c2oc(-c3ccc(C(=O)NCC4CCN(c5ccc(C(F)(F)F)cn5)CC4)cc3)nc2c1
Reactant: C/C=C(/C)B(O)O
Product: C/C=C(/C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCN(c5ccc(C(F)(F)F)cn5)CC4)cc3)oc12

Procedure:
The title compound was prepared from 4-(7-bromo-5-cyano-1,3-benzoxazol-2-yl)-N-({1-[5-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}methyl)benzamide and [(1E)-1-methylprop-1-en-1-yl]boronic acid by a procedure analogous to that described in EXAMPLE 113, Step B. Mass spectrum (ESI) 560.2 (M+1).