Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C([NH:9][C:10]1[CH:15]=[C:14]([NH2:16])[C:13]([F:17])=[CH:12][N:11]=1)C1C=CC=CC=1>[Pd].CO>[ClH:1].[NH2:9][C:10]1[CH:15]=[C:14]([NH2:16])[C:13]([F:17])=[CH:12][N:11]=1
Reactant: Nc1cc(NCc2ccccc2)ncc1F
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1cc(N)c(F)cn1
Reaction time: 48 h
Yield: 98.7 %

Procedure:
To 4 ml of methanol having added 400 mg of concentrated hydrochloric acid added thereto was added 350 mg of 2-benzylamino-4-amino-5-fluoropyridine together with 50 mg of 10% palladium on carbon, and the mixture was hydrogenated at 40° C. for 2 days. The catalyst was separated by filtration, and the solvent and the like were distilled off under reduced pressure. Procedure of adding 10 ml of distilled water to the residue and concentrating under reduced pressure was repeated 4 times, and the procedure of adding 10 ml of ethanol and concentrating under reduced pressure was repeated twice. 260 mg of the title compound was obtained as a residue in the form of a yellowish orange paste.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:9]([NH:11][CH2:12]/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[NH:7][CH:8]=1)(=[O:3])[CH3:2]>C(#N)C>[C:1]([C:4]1[CH:5]=[C:6]2[C:9](=[O:10])[NH:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:7]2[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)/C=C/CNC(=O)c1cc(C(C)=O)c[nH]1
Solvent: CC#N
Product: CCOC(=O)CC1CNC(=O)c2cc(C(C)=O)cn21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
Diaza(1,3)bicyclo[5.4.0]undecane (DBU) (0.04 mL, 0.3 mmol) was added to a solution of ethyl (2E)-4-{[(4-acetyl-1H-pyrrol-2-yl)carbonyl]amino}but-2-enoate (0.343 g, 1.3 mmol) in acetonitrile (8 mL) and the reaction mixture was stirred at room temperature for 30 min. The solvent was evaporated under vacuum and the residue purified by flash chromatography (SiO2, hexane-EtOAc 1:1) to obtain the title compound as an off-white solid (0.24 g, 70% yield).
Reaction SMILES: [ClH:1].Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[C:9]([C:12]1[CH:17]=[CH:16][C:15](OB(O)O)=[CH:14][CH:13]=1)([OH:11])=[O:10].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[ClH:1].[N:6]1[CH:7]=[CH:8][C:3]([C:15]2[CH:16]=[CH:17][C:12]([C:9]([OH:11])=[O:10])=[CH:13][CH:14]=2)=[CH:4][CH:5]=1
Reactant: Brc1ccncc1
Reactant: O=C(O)c1ccc(OB(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(-c2ccncc2)cc1
Temperature: 120 °C
Yield: 64.6 %

Procedure:
4-Bromopyridine hydrochloride (11.7 g) and 4-carboxyphenylboric acid (10.0 g) were dissolved in a mixed solvent of toluene (250 ml) and water (250 ml), tetrakis(triphenylphosphine)palladium(0) (5.0 g) and anhydrous sodium carbonate (25.4 g) were successively added, and the mixture was heated under reflux at 120° C. for 19 hours. After the reaction mixture was cooled to room temperature, ethyl acetate was added to the reaction mixture to extract it with water. Concentrated hydrochloric acid was added to the water layer to acidify it. The water layer was washed with ethyl acetate and then concentrated, and solids deposited were collected to obtain the title compound (8.37 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:4]([O:14][C:15]2[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.CCN(CC)CC.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:13][O:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4]([O:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:17][CH:16]=1)=[C:3]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:2]([CH3:1])=[CH:11]2
Reactant: COc1ccc2c(Oc3ccc(N)cc3)c(-c3ccccc3)c(C)cc2c1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(Oc3ccc(NS(C)(=O)=O)cc3)c(-c3ccccc3)c(C)cc2c1
Reaction time: 8 h
Yield: 46 %

Procedure:
To a flask containing a solution of 29, Et3N (0.26 g, 2.55 mmol) and DMAP (0.032, 0.26 mmol) in CH2Cl2 (5 mL) was added methanesulfonyl chloride (0.24 g, 2.13 mmol), dropwise at RT and the reaction allowed to stir overnight. After 18 h the reaction was diluted with CH2Cl2 (15 mL) and the reaction rinsed with 10% aqueous HCl (25 mL). The CH2Cl2 layer was dried (MgSO4) and concentrated to a dark amber oil. The crude product was purified by silica gel column chromatography to afford 170 mg (46%) of the title compound (269) as a colorless oil. An additional 90 mg of a mixture of 269 and N,N-bissulfonylated product was also isolated. 1H NMR (400 MHz, DMSO-d6): δ 2.15 (s, 3H), 2.82 (s, 3H), 3.85 (s, 3H), 6.54 (d, J=8.9 Hz, 2H), 6.94 (d, J=8.8 Hz, 2H), 6.97 (dd, J1=2.4 Hz, J2=9.1 Hz, 1H), 6.96 (d, J=6.6 Hz, 1H), 7.15-7.32 (m, 5H), 7.58 (d, J=9.1 Hz, 1H), 7.67 (s, 1H), 9.32 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]([OH:8])[CH2:6][N:5]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([F:21])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:22])[CH2:4]1.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>CO.CCOCC.C(Cl)Cl>[F:21][C:18]1[CH:19]=[C:20]2[C:15]([CH:14]=[CH:13][C:12](=[O:22])[N:11]2[CH2:10][CH2:9][N:5]2[CH2:6][C@@H:7]([OH:8])[C@@H:3]([CH2:2][NH:1][CH2:34][C:32]3[CH:31]=[CH:30][C:27]4[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=4[N:33]=3)[CH2:4]2)=[CH:16][CH:17]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: NC[C@H]1CN(CCn2c(=O)ccc3ccc(F)cc32)C[C@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1COc2ccc(CNC[C@H]3CN(CCn4c(=O)ccc5ccc(F)cc54)C[C@H]3O)nc2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-{2-[(3S,4S)-3-(aminomethyl)-4-hydroxy-1-pyrrolidinyl]ethyl}-7-fluoro-2(1H)-quinolinone (100 mg; 0.33 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde (for a synthesis see WO2003087098, Example 31(e)) (60 mg, 0.33 mmol) in methanol (2 mL), DCM (4 mL) was stirred at room temperature overnight. Sodium triacetoxyborohydride (0.13 g; 0.6 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction was evaporated and chromatographed on silica gel, eluting with 0-20% methanol-DCM-2% NH4OH to give an oil. The oil was treated with 1M HCl in Et2O to give the title compound (73 mg) as the dihydrochloride salt.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH2:10][OH:11])=[CH:4][CH:3]=1.[CH3:17][C:18]1([CH3:26])[C:20]([CH3:22])([CH3:21])[CH:19]1[C:23](Cl)=[O:24].N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH2:10][O:11][C:23]([CH:19]2[C:20]([CH3:22])([CH3:21])[C:18]2([CH3:26])[CH3:17])=[O:24])=[CH:4][CH:3]=1
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Reactant: OCc1cccc(Oc2ccc(F)cc2)c1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC1(C)C(C(=O)OCc2cccc(Oc3ccc(F)cc3)c2)C1(C)C
Yield: 81.8 %

Procedure:
5.05 g (0.0232 mol) of 3-(4-fluoro-phenoxy)-benzyl alcohol and 3.72 g (0.0232 mol) of 2,2,3,3-tetramethylcyclopropanecarboxylic acid chloride were dissolved in 100 ml of anhydrous toluene, and 2.3 g of pyridine, dissolved in 50 ml of anhydrous toluene, were added dropwise at 20°-25° C., while stirring. The reaction mixture was then stirred for a further 3 hours at 25° C. It was poured into 150 ml of water, to which 10 ml of concentrated hydrochloric acid had been added, and the organic phase was separated off and washed again with 100 ml of water. The toluene phase was then dried over sodium sulphate and the solvent was distilled off under a waterpump vacuum. Last residues of solvent were removed by brief incipient distillation at a bath temperature of 60° C./1 mm Hg. 6.5 g (81.9% of theory) of 2,2,3,3-tetramethyl-cyclopropanecarboxylic acid 3-(4-fluorophenoxy)-benzyl ester were obtained as a yellow oil with a refractive index nD20 of 1.5348.
Reaction SMILES: C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O.[CH2:22]([O:29][C@@H:30]1[C@@H:35]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:34]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@@H:33]([CH2:52][O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[O:32][C@H:31]1[O:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][OH:72])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(Cl)Cl.S(=O)(=O)(O)O>C(O)C>[CH2:22]([O:29][C@@H:30]1[C@@H:35]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:34]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C@@H:33]([CH2:52][O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[O:32][C@H:31]1[O:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH:71]=[O:72])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OCCCCCCCCCCO[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: ClCCl
Product: O=CCCCCCCCCCO[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
PDC oxidation of 10-(2,3.4,6-tetra-O-benzyl-β-D-glucopyranosyloxy)-n-decanol. Under an atmosphere of nitrogen, pyridinium dichromate (220 mg, 0.585 mmol) was added to a dry methylene chloride solution (6 mL) of 10-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyloxy)-n-decanol (275 mg, 0.395 mmol). The resulting brown slurry was stirred at room temperature under nitrogen. TLC analysis (visualization by UV and char with 10% sulfuric acid in ethanol) of the reaction mixture indicated complete consumption of the starting material and the formation of a new compound after 16 h. The reaction mixture was treated with ether (10 mL), filtered through silica gel and Celite with an ether wash (25 mL) and concentrated to an off-white oil. Chromatographic purification (silica gel, 20% ethyl acetate in hexanes) afforded 204 mg (0.294 mmol, 74%) of 10-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyloxy)-n-decanal as a clear oil. Rf =0.40 (silica gel, 30% ethyl acetate in hexanes); 1H NMR (CDCl3, 300 MHz) δ: 9.75 (t, J=1.8 Hz, 1H), 7.32 (m, 20H), 4.98 (dd, J=10.8, 9.6 Hz, 2H), 4.84 (t, J=10.5 Hz, 2H), 4.75 (d, J=10.8 Hz, 1H), 4.61 (d, J=8.4 Hz, 1H), 4.56 (dd, J=10.8, 6.0 Hz, 1H), 4.43 (d, J=7.8, 1H), 4.00 (m, 1H), 3.8-3.4 (m, 8H), 2.40 (dt, J=7.2, 1.5 Hz, 2H), 1.70 (m, 6H), 1.31, (m, 10H); MS (FAB+): 701.0 ((M+Li)+, 100), 609.0 (4), 455.0 (5), 423.1 (7), 181.1 (35), 160.0 (10), 107.0 (4), 105.0 (5).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:13]3[CH:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:15][CH2:16][CH2:17][C:12]=3[NH:11][C:10]=2[CH:26]=1)=O)C.CC(C[AlH]CC(C)C)C>C(Cl)Cl.C1(C)C=CC=CC=1>[CH2:18]([CH:14]1[C:13]2[C:9]3[CH:8]=[CH:7][C:6]([CH2:4][OH:3])=[CH:26][C:10]=3[NH:11][C:12]=2[CH2:17][CH2:16][CH2:15]1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCC1CCCc2[nH]c3cc(C(=O)OCC)ccc3c21
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCCCCCC1CCCc2[nH]c3cc(CO)ccc3c21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 96.2 %

Procedure:
A solution of 30.4 g of 5,6,7,8-tetrahydro-9-octyl-9H-dibenzo[b,d]pyrrole-3-carboxylic acid ethyl ester from Example 9, in 300 ml of methylene chloride was treated with 124 ml of a 1.5M DIBAH solution in toluene at 0°-5° C. (ice-water bath) in approximately 20 minutes. After an additional 20 minutes stirring at the same temperature, the reaction mixture was cautiously poured into cold 2N-HCl ice and extracted with methylene chloride. The organic extracts were washed with water and brine, then dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 28.3 g of a crude yellow oil. Purification of this material on a small silica gel pad (eluting system:hexane-ethyl acetate 1:1) produced 25.8 g (96.2%) of 5,6,7,8-tetrahydro-9-octyl-9H-dibenzo[b,d]pyrrole-3-methanol as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=O)[CH:3]=1.[CH3:12][O:13][C:14]([C:16]1[N:20]([CH:21]2C3C(=CC=CC=3)C=[CH:23][C:22]2([CH3:32])[CH3:31])[CH:19]=[N:18][CH:17]=1)=[O:15]>C(Cl)Cl>[CH3:12][O:13][C:14]([C:16]1[N:20]([CH:21]2[C:3]3[C:4](=[CH:5][CH:6]=[CH:7][CH:2]=3)[CH:8]3[O:10][CH:23]3[C:22]2([CH3:32])[CH3:31])[CH:19]=[N:18][CH:17]=1)=[O:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1cncn1C1c2ccccc2C=CC1(C)C
Solvent: ClCCl
Product: COC(=O)c1cncn1C1c2ccccc2C2OC2C1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.9 %

Procedure:
9.4 g of 55% 3-chloroperbenzoic acid are added to a solution of 8.5 g of 1-(1,2-dihydro-2,2-dimethylnaphthalen-1-yl)-5-imidazolecarboxylic acid methyl ester in 150 ml of methylene chloride and the mixture is stirred at room temperature for 2 hours. The precipitate is separated off and the filtrate is washed twice using 50 ml of sodium hydrogen carbonate solution (5%) each time, dried over magnesium sulfate and concentrated by evaporation. Chromatography of the residue on silica gel [eluant: ether/hexane (3:1)] yields 1.7 g of a mixture of 1,4-cis-1-(3,4-epoxy-2,2-dimethyltetralin-1-yl)-5-imidazolecarboxylic acid methyl ester and 1,4-trans-1-(3,4-epoxy-2,2-dimethyltetralin-1-yl)-5-imidazolecarboxylic acid methyl ester in a ratio of 1:1 (m.p. 60°-68° C.).
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[S:4][C:3]=1[CH3:17].C([Li])CCC.CN(C)[CH:25]=[O:26].Cl>O1CCCC1>[CH3:17][C:3]1[S:4][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)=[CH:6][C:2]=1[CH:25]=[O:26]
Reactant: CN(C)C=O
Reactant: Cc1sc(-c2cccc(C(F)(F)F)c2)cc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1sc(-c2cccc(C(F)(F)F)c2)cc1C=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
The compound (0.83 g) obtained in Example 129a was dissolved in tetrahydrofuran (15 mL), cooled to −78° C., and n-butyllithium (2.5M hexane solution, 1.24 mL) was added. The mixture was stirred at the same temperature for 1 hr, N,N-dimethylformamide (1.0 mL) was added, the reaction mixture was warmed to room temperature and stirred for 1 hr. 1N Hydrochloric acid (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane/ethyl acetate) to give the title compound (0.45 g) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[N:8]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([NH:21][CH:22]([CH2:27][C:28]3[CH:29]=[C:30]4[C:34](=[C:35]([CH3:37])[CH:36]=3)[NH:33][N:32]=[CH:31]4)[C:23]([O:25]C)=[O:24])=[O:20])[CH2:15][CH2:14]1)[CH2:7]2.O1CCCC1.CO.[OH-].[Li+]>O>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[N:8]([CH:13]1[CH2:14][CH2:15][N:16]([C:19]([NH:21][CH:22]([CH2:27][C:28]3[CH:29]=[C:30]4[C:34](=[C:35]([CH3:37])[CH:36]=3)[NH:33][N:32]=[CH:31]4)[C:23]([OH:25])=[O:24])=[O:20])[CH2:17][CH2:18]1)[CH2:7]2
Reactant: COC(=O)C(Cc1cc(C)c2[nH]ncc2c1)NC(=O)N1CCC(N2Cc3cccc(F)c3NC2=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(CC(NC(=O)N2CCC(N3Cc4cccc(F)c4NC3=O)CC2)C(=O)O)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of (±)-methyl 2-(4-(8-fluoro-1,2-dihydro-2-oxoquinazolin-3(4H)-yl)piperidine-1-carboxamido)-3-(7-methyl-1H-indazol-5-yl)propanoate (0.4 g, 0.79 mmol) in 1:1 tetrahydrofuran/methanol (30 mL) at room temperature was treated with a solution of lithium hydroxide (83 mg, 2.5 equiv) in water (4 mL) and stirred at room temperature overnight. The solvents were evaporated and the pH was adjusted to ca. 1 with 1 N hydrochloric acid. The resulting white suspension was stored at 4° C. overnight and the product was collected by filtration, washed with a small amount of water, and dried in vacuo to afford 0.21 g (74%) as a white powder. Mass spec.: 495.06 (MH)+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH2:7][C@:8]1([C:30](OC)=[O:31])[CH2:12][CH2:11][C@@H:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:15][CH:14]=2)[CH2:9]1.[OH-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>CCOCC.C1COCC1.O>[NH2:7][C@:8]1([CH2:30][OH:31])[CH2:12][CH2:11][C@@H:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21][O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:15][CH:14]=2)[CH2:9]1
Reactant: COC(=O)[C@@]1(N)CC[C@@H](c2ccc(C#CCOCc3ccccc3)cc2)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: N[C@]1(CO)CC[C@@H](c2ccc(C#CCOCc3ccccc3)cc2)C1
Yield: 81.3 %

Procedure:
To a slurry of LAH (7.83 g, 206 mmol) in Et2O (500 mL) at about 0° C. was added a solution of (1R,3R)-methyl 1-amino-3-(4-(3-(benzyloxy)prop-1-ynyl)phenyl)cyclopentanecarboxylate (25 g, 68.8 mmol) in THF (100 mL). After about 2 hours water (7.8 mL) followed by 2N NaOH (7.8 mL) followed by water (15 mL) was added. After stirring for about 15 hours Na2SO4 and Celite® was added to the reaction mixture and the slurry was filtered, rinsing with EtOAc. The filtrate was concentrated in vacuo to provide ((1R,3R)-1-amino-3-(4-(3-(benzyloxy)prop-1-ynyl)phenyl)cyclopentyl)methanol (25 g, 55.9 mmol, 81% yield) as an brown oil.
Reaction SMILES: C([O:4][CH2:5][C:6]([N:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[NH2:19])[C:10]1=[O:20])([CH3:8])[CH3:7])(=O)C.C(Cl)Cl.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27][C:26]=1[C:35]([F:38])([F:37])[F:36].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CO.C(=O)([O-])[O-].[K+].[K+]>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([NH:19][C:15]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:16]=2[CH:17]=[CH:18][N:9]([C:6]([CH3:7])([CH3:8])[CH2:5][OH:4])[C:10]3=[O:20])=[O:33])=[CH:27][C:26]=1[C:35]([F:36])([F:37])[F:38]
Reactant: O=C(O)Cc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(=O)OCC(C)(C)n1ccc2c(N)cccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CO)n1ccc2c(NC(=O)Cc3ccc(Cl)c(C(F)(F)F)c3)cccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(5-amino-1-oxoisoquinolin-2(1H)-yl)-2-methylpropyl acetate (90.0 mg, 0.000328 mol) in methylene chloride (2 mL, 0.03 mol) were added 2-(4-chloro-3-(trifluoromethyl)phenyl)acetic acid (120 mg, 0.00049 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (310 mg, 0.00082 mol) and N,N-diisopropylethylamine (300 μL, 0.002 mol). The reaction mixture was stirred overnight at room temperature. The mixture was then purified by HPLC. The combined pure fractions were concentrated in vacuo and taken up in methanol (2 mL, 0.06 mol). Potassium carbonate (136 mg, 0.000984 mol) was added and the mixture was stirred at room temperature for one hour. This was followed by purification using HPLC thus producing the title compound. 1H-NMR (400 MHz, DMSO-d6) δ 10.06 (s, 1H), 8.06 (d, 1H, J=8.09 Hz), 7.88 (d, 1H, J=1.06 Hz), 7.77 (dd, 1H, J=7.79 Hz), 7.73-7.67 (m, 2H), 7.51 (d, 1H, J=8.16 Hz), 7.40 (t, 1H, J=7.91 Hz), 6.56 (d, 1H, J=8.14 Hz), 4.99 (t, 1H, J=5.64 Hz), 3.91 (s, 2H), 3.88 (d, 2H, J=5.69 Hz), 1.57 (s, 6H).
Reaction SMILES: C1(CC2CCCCN2CC[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22](OC)[CH:23]=3)[NH:18][CH:17]=2)CCCCC1.C1(CC2CCCCN2CCCC2C3C(=C(C(F)(F)F)C=CC=3)NC=2)CCCCC1.[CH:56]1([CH2:62][CH:63]2[CH2:68][CH2:67][CH2:66][CH2:65][N:64]2[CH2:69][CH2:70][CH2:71][CH2:72][C:73]2C3C(=C(C(F)(F)F)C=C(Cl)C=3)NC=2)[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1.C1(CC2CCCCN2CCCC2C3C(=CC=C(OC)C=3)NC=2CO)CCCCC1.C1(CC2CCCCN2CCCC2C3C(=C(F)C=C(F)C=3)NC=2CO)CCCCC1.[H-].[Na+].[Na].C(Cl)(=O)C1C=CC=CC=1>CN(C=O)C>[CH:56]1([CH2:62][CH:63]2[CH2:68][CH2:67][CH2:66][CH2:65][N:64]2[CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1
Reactant: FC(F)(F)c1cc(Cl)cc2c(CCCCN3CCCCC3CC3CCCCC3)c[nH]c12
Reactant: COc1ccc2[nH]cc(CCN3CCCCC3CC3CCCCC3)c2c1
Agent: COc1ccc2[nH]c(CO)c(CCCN3CCCCC3CC3CCCCC3)c2c1
Agent: FC(F)(F)c1cccc2c(CCCN3CCCCC3CC3CCCCC3)c[nH]c12
Agent: OCc1[nH]c2c(F)cc(F)cc2c1CCCN1CCCCC1CC1CCCCC1
Solvent: O=C(Cl)c1ccccc1
Solvent: CN(C)C=O
Product: c1ccc2c(CCCCCN3CCCCC3CC3CCCCC3)c[nH]c2c1

Procedure:
3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxyindole (both disclosed in U.S. Pat. No. 3,238,215); 3-[3-(2-cyclohexylmethylpiperidino)propyl]-7-trifluoromethylindole (m.p. 90.5°-91.5° C.); 3-[4-(2-cyclohexylmethylpiperidino)butyl]-5-chloro-7-trifluoromethylindole (m.p. 80°-81° C.) (both prepared according to the procedure described in U.S. Pat. No. 3,238,215); 3-[3-(2-cyclohexylmethylpiperidino)propyl]-5-methoxy-2-hydroxymethylindole; or 3-[3-(2-cyclohexylmethylpiperidino)propyl]-5,7-difluoro-2-hydroxymethylindole (both disclosed in U.S. Pat. No. 3,578,669) with a mineral oil dispersion of sodium hydride in DMF, and reaction of the resulting sodium salt with benzoyl chloride using the procedure described above in Example 1, affords the respective compounds of formula I in Examples 66-71 where, in each instance, A is benzoyl and N=B is 2-cyclohexylmethylpiperidino.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][N:2]1[C:14]1[N:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][N:15]=1.[CH3:24]C(C)([O-])C.[K+].CI>CN(C=O)C.CCOC(C)=O>[CH3:24][N:12]1[C:13]2[CH2:1][N:2]([C:14]3[N:15]=[CH:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:19]=3)[CH2:3][CH2:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1cnc(N2CCc3c([nH]c4ccccc34)C2)nc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(N2CCc3c(n(C)c4ccccc34)C2)nc1
Temperature: 0 °C
Reaction time: 0.21 h
Yield: 76.5 %

Procedure:
To a stirred solution of Example 8 (200 mg, mmol) in DMF (5 mL) was added potassium t-butoxide (145 mg) at 0° C. After stirring the suspension for 10-15 min at 0° C., methyl iodide (0.11 g, mmol) was added. The mixture was stirred at 0° C. for 30 min. and then stirred at room temperature for 3 hours. After completion, the reaction mixture was diluted with EtOAc. The organic layer was separated, washed with saturated sodium bicarbonate, dried over sodium sulfate and concentrated under vacuum. The crude product obtained was purified by column chromatography using EtOAc in hexanes (50%) to obtain methyl 2-(9-methyl-1,3,4,9-tetrahydro-2H-b-carbolin-2-yl)pyrimidine-5-carboxylate (160 mg, 76.5% yield). 1HNMR (DMSO-d6) ppm: 2.8 (t, 2H, CH2); 3.65 (s, 3H, N—CH3); 3.8 (s, 3H, OCH3); 4.2 (t, 2H, CH2); 5.15 (s, 2H, CH2); 7.0-7.2 (m, 2H); 7.4 (d, 2H); 8.8 (s, 2H); m/e=323 (M+1).