Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[C:3]([Si:7]([CH3:19])([CH3:18])[O:8][CH:9]([C:11]1[O:12][C:13]([CH2:16]Cl)=[CH:14][N:15]=1)[CH3:10])([CH3:6])([CH3:5])[CH3:4].[N+:20]([C:23]1[CH:27]=[N:26][NH:25][N:24]=1)([O-:22])=[O:21].CCN(C(C)C)C(C)C>CN(C=O)C.CC(C)=O.CC(=O)OCC.O>[C:3]([Si:7]([CH3:19])([CH3:18])[O:8][CH:9]([C:11]1[O:12][C:13]([CH2:16][N:25]2[N:24]=[C:23]([N+:20]([O-:22])=[O:21])[CH:27]=[N:26]2)=[CH:14][N:15]=1)[CH3:10])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1ncc(CCl)o1
Reactant: O=[N+]([O-])c1cn[nH]n1
Agent: N#N
Solvent: CN(C)C=O
Solvent: CC(C)=O
Solvent: O
Product: CC(O[Si](C)(C)C(C)(C)C)c1ncc(Cn2ncc([N+](=O)[O-])n2)o1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-chloromethyl-oxazole (247 mg, 0.89 mmol) in DMF (1.0 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (850 mg of a 10% solution in acetone, 0.75 mmol) in DMF (1.0 mL) pre-treated for 30 min with DIPEA (0.26 mL, 1.49 mmol) and the reaction mixture was stirred for 48 h at 50° C. Water (10 mL), followed by EA (20 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over NaSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (2:1 hept-EA) gave the title compound as a yellow oil. TLC:rf (2:1 hept-EA)=0.36. LC-MS-conditions 02: tR=1.11 min; [M+H]+=354.34.
Reaction SMILES: CN1CC[C:5]2([CH2:8][NH:7][CH2:6]2)CC1.C(OC([N:18]1[CH2:23][CH2:22][C:21](=O)[CH:20]([F:25])[CH2:19]1)=O)(C)(C)C.N1CCC1>>[N:7]1([C@H:21]2[CH2:22][CH2:23][NH:18][CH2:19][C@H:20]2[F:25])[CH2:8][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Reactant: CN1CCC2(CC1)CNC2
Agent: C1CNC1
Product: F[C@@H]1CNCC[C@@H]1N1CCC1

Procedure:
Prepared according to the method used in the preparation of 7-methyl-2,7-diaza-spiro[3.5]nonane using 3-fluoro-4-oxo-piperidine-1-carboxylic acid tert-butyl ester in place of formaldehyde and azetidine in place of 2,7-diaza-spiro[3.5]nonane-2-carboxylic acid tert-butyl ester hydrochloride. The title compound was obtained as a colourless oil (205 mg, 56%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.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.[Cu]I>[F:8][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19]
Reactant: C#C[Si](C)(C)C
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-bromo-4-fluoronitrobenzene (2 g, 9.1 mmol) in tetrahydrofuran (30 ml) was added triethylamine (1.9 ml, 13.6 mmol), trimethylsilylacetylene (1.9 ml, 13.6 mmol), triphenylphosphine (60 mg, 0.23 mmol) and dichlorobis(triphenylphosphine)palladium(II) (319 mg, 0.46 mmol). After stirring at room temperature for 20 minutes copper(I) iodide (17 mg, 0.09 mmol) was added and the mixture left to stir for 18 h at room temperature. The reaction mixture was quenched into isohexane (150 ml) and filtered through a plug of silica using isohexane as eluent. The solvent was removed in vacuo to leave (2-fluoro-5-nitrophenylethynyl)trimethylsilane as a brown solid: 1H NMR (360 MHz, CDCl3) δ 0.10 (9H, s), 7.02 (1H, dd, J 8, 1 Hz), 7.97-8.02 (1H, m), 8.17 (1H, dd, J 6, 3 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([CH:25]=[C:26]([S:28]([CH3:30])=[O:29])[N:27]=2)[C:21](OC)=[O:22])[CH2:14][CH2:13]1)=[O:10].[OH-].[Li+].Cl.Cl.[CH3:35][O:36][NH2:37]>C1COCC1>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[CH:19]=[C:20]([CH:25]=[C:26]([S:28]([CH3:30])=[O:29])[N:27]=2)[C:21]([NH:37][O:36][CH3:35])=[O:22])[CH2:16][CH2:17]1)=[O:10]
Reactant: CON
Reactant: COC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(S(C)=O)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(S(C)=O)c1
Reaction time: 0.75 h

Procedure:
Methyl 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-6-(methylsulfinyl)isonicotinate (Example 334; 200 mg, 0.422 mmol) was dissolved in anhydrous THF (5 ml) and treated with 2 N lithium hydroxide (10 ml) with stirring for 45 minutes. The mixture was cooled in an ice bath and acidified with 1 N HCl. The aqueous solution was extracted with EtOAc. The organic phase was washed with water, dried over sodium sulfate and concentrated in vacuo to give the acid derivative as a brown solid (LCMS showed a peak of 459). This acid (95 mg, 0.207 mmol) was treated with methoxyamine hydrochloride (17.3 mg, 0.207 mmol) in a manner analogous to Example 8 to afford the title compound. (30 mg).
Reaction SMILES: [C:1]1([CH:7]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:8][N:9]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[C:30]=2[Cl:39])[CH2:10][CH2:11][CH2:12][O:13][C:14]2[C:15]([CH3:27])([CH3:26])[CH:16]([CH:20]([CH3:25])[C:21]([O:23]C)=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO.O>[C:1]1([CH:7]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:8][N:9]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:37])[F:38])[C:30]=2[Cl:39])[CH2:10][CH2:11][CH2:12][O:13][C:14]2[C:15]([CH3:26])([CH3:27])[CH:16]([CH:20]([CH3:25])[C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(C)C1C=CC=C(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)C1(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C(=O)O)C1C=CC=C(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)C1(C)C
Yield: 91.6 %

Procedure:
A solution of methyl N-(2,2-diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-2,2-dimethyl-3-(3-aminopropoxy)phenylpropionate (195 mg, 0.3 mmol) in MeOH (10 mL), H2O (1 mL), and 2.5N NaOH (2 mL) was refluxed for 5 h. The reaction was cooled, diluted with H2O, and acidified with 3N HCl to pH=5.1. The mixture was extracted with EtOAc, the extracts were washed with H2O, dried, and concentrated to yield the titled compound (172 mg, 92%). MS (ESI) 625 (M+H+).
Reaction SMILES: [ClH:1].[CH2:2]([C:7]1[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=1)[CH2:3][CH2:4][C:5]#[CH:6].[N:13]([CH2:16][CH2:17][C:18]1[CH:22]=[CH:21][S:20][CH:19]=1)=[N+:14]=[N-:15]>>[ClH:1].[S:20]1[CH:21]=[CH:22][C:18]([CH2:17][CH2:16][N:13]2[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][C:7]3[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=3)[N:15]=[N:14]2)=[CH:19]1
Reactant: [N-]=[N+]=NCCc1ccsc1
Reactant: C#CCCCc1c[nH]c(N)n1
Agent: Cl
Product: Nc1nc(CCCc2cn(CCc3ccsc3)nn2)c[nH]1
Yield: 40.8 %

Procedure:
4-Pent-4-ynyl-1H-imidazol-2-ylamine hydrochloride (0.090 g, 0.485 mmol) was reacted with 3-(2-Azido-ethyl)-thiophene (0.089 g, 0.581 mmol) following the general procedure for click reactions outlined above to produce 4-{3-[1-(2-Thiophen-3-yl-ethyl)-1H-[1,2,3]triazol-4-yl]-propyl}-1H-imidazol-2-ylamine hydrochloride (0.067 g, 41%) as a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 7.42 (s, 1H), δ 7.12 (d, 1H), δ 6.83 (s, 1H), δ 6.70 (d, 1H), δ 6.29 (s, 1H), δ 4.41 (t, 2H), δ 3.04 (t, 2H), δ 2.50 (t, 2H), δ 2.29 (t, 2H), δ 1.72 (m, 2H) ppm; 13C NMR (75 MHz, CD3OD) δ 146.8, 146.8, 137.7, 127.8, 127.6, 125.7, 122.6, 121.9, 109.0, 50.7, 30.7, 27.9, 23.7 ppm; HRMS (ESI) calcd for C14H18N6S (M+) 302.1313. found 302.1317.
Reaction SMILES: FC1C=CC(C[N:7]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)=CC=1.[CH3:24][C:25]1[N:26]=[C:27]([N:33]2[CH2:37][CH2:36][N:35]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=3)[C:34]2=[O:49])[S:28][C:29]=1[C:30](O)=[O:31]>>[CH3:24][C:25]1[N:26]=[C:27]([N:33]2[CH2:37][CH2:36][N:35]([CH2:38][C:39]3[CH:40]=[CH:41][C:42]([C:45]([F:47])([F:46])[F:48])=[CH:43][CH:44]=3)[C:34]2=[O:49])[S:28][C:29]=1[C:30]([NH2:7])=[O:31]
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(N)=O
Yield: 23 %

Procedure:
Following the procedure as described in Example 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-(4-(trifluoromethyl)benzyl)-imidazolidin-1-yl)thiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 23% yield: mp 216-217° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 7.74 (d, J=8.2 Hz, 2H), 7.55 (d, J=8.2 Hz, 2H), 7.32 (s, 2H), 4.54 (s, 2H), 4.02 (dd, J=9.0, 7.3 Hz, 2H), 3.49 (dd, J=9.0, 7.3 Hz, 2H), 2.46 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 163.5, 157.4, 155.2, 150.7, 141.5 (d, JC-F=1.2 Hz), 128.5, 128.1 (q, 2JC-F=31.6 Hz), 125.5 (q, 3JC-F=3.8 Hz), 124.3 (q, 1JC-F=272.2 Hz), 118.5, 46.5, 42.0, 41.8, 17.0; MS (ES+) m/z 384.9 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][CH2:10][CH2:11]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:9][CH2:10][CH2:11][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: ClCCBr
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccc(OCCCl)cc1
Temperature: 25 °C
Yield: 31 %

Procedure:
4-Fluorophenol (8.92 mmol) and 1-chloro-2-bromoethane (13.4 mmol) were dissolved in acetone (18 mL). The solution was added with potassium carbonate (12.5 mmol) and heated under reflux for 10 hours. The mixture was allowed to cool to room temperature and then filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (yield: 31%).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11](=[CH2:13])[CH2:12][CH:7]2[CH2:6]1)=[O:4].C[Si]([C:19]#[N:20])(C)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.Cl([O-])(=O)(=O)=O.[Ag+]>[CH3:1][N:2]([CH3:14])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([N+:20]#[C-:19])([CH3:13])[CH2:12][CH:7]2[CH2:6]1)=[O:4]
Reactant: C[Si](C)(C)C#N
Reactant: C=C1CC2CN(C(=O)N(C)C)CC2C1
Agent: [Ag+]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: [C-]#[N+]C1(C)CC2CN(C(=O)N(C)C)CC2C1
Reaction time: 0.17 h
Yield: 18.1 %

Procedure:
5-Methylene-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 11a (1.6 g, 8.23 mmol) was dissolved in 30 mL of dichloromethane with stirring followed by addition of trimethylsilyl cyanide (4.08 g, 41.2 mmol) and silver perchlorate (5.12 g, 24.7 mmol) under nitrogen atmosphere. The reaction mixture was stirred overnight at room temperature and then some of the reaction mixture was treated with saturated aqueous sodium carbonate. The reaction was monitored by TLC, which showed that there remained most of the starting materials. Then the mixture was treated with 20 mL of saturated aqueous sodium carbonate upon cooling by an ice-water bath, and the reaction released heat. After 10 minutes, the mixture was filtered to remove the residue. The separated aqueous phase was extracted with ethyl acetate (50 mL×4). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 5-isocyano-5-methyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 11b (0.33 g, yield 18.1%) as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[C:11]3[CH:12]=[C:13]([O:16]C)[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[C:11]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: COc1ccn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2c1
Temperature: 25 °C

Procedure:
A solution of 2-(4-fluorophenyl)-3-(4-pyridyl)-5-methoxypyrazolo[1,5-a]pyridine (Example 5. 0.05 g, 0.16 mmol) in dry CH2Cl2 was cooled to about −78° C. under nitrogen. Boron tribromide (0.8 mL of a 1M solution in CH2Cl2, 0.8 mmol) was added dropwise and the mixture was stirred and warmed to room temperature over about 24 h. Ice was added to the reaction mixture and the resulting slurry was stirred for about 15 min. The CH2Cl2 was evaporated under vacuum and the resulting aqueous slurry was treated with conc hydrochloric acid (1 mL) and stirred. The aqueous solution was basified by the addition of a saturated solution of NaHCO3, and the resulting solid was collected by filtration and was dried under vacuum to give the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:20]=[CH:19][C:12]([O:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=1)C1C=CC=CC=1.Cl>C(O)C>[CH3:17][N:16]([CH3:18])[CH2:15][CH2:14][O:13][C:12]1[CH:19]=[CH:20][C:9]([OH:8])=[CH:10][CH:11]=1
Reactant: CN(C)CCOc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CCO
Product: CN(C)CCOc1ccc(O)cc1

Procedure:
A stirred solution of [2-(4-benzyloxyphenoxy)ethyl]dimethylamine (3.36 g, 0.01238 mol) in the mixture of 6 M HCl (67 ml) and ethanol (33.5 ml) was refluxed for 6.5 h. Then ethanol was evaporated and pH was adjusted to 8 with 2.5 M NaOH. The product was extracted into ethyl acetate. The extracts were washed with water and dried over Na2SO4. Removal of solvent under reduced pressure gave a raw product which was purified by flash chromatography on silica gel using heptane/ethyl acetate (9:1-6:4) as a gradient eluent. 1H NMR (300 MHz, DMSO-d6): 2.20 (6H, s), 2.57 (2H, t, 3J=5.9 Hz), 3.92 (2H, t, 3J=5.9 Hz), 6.65 (2H, d, 3J=9.1 Hz), 6.74 (2H, d, 3J=9.0 Hz), 8.85 (1H, s, —OH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[C:14]=2[OH:23])=[O:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.IC.[C:26]([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[C:14]=2[O:23][CH3:26])=[O:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(OC)cc(C(=O)c2ccc(OC)c(OC)c2O)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(OC)cc(C(=O)c2ccc(OC)c(OC)c2OC)c1
Temperature: 35 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
To a mixture of (3,5-dimethoxyphenyl)-(2-hydroxy-3,4-dimethoxyphenyl)methanone (1.59 g, 5.00 mmol) in DMF (25 ml) was added iodomethane (0.62 ml, 10.00 mmol), and powdered Na2CO3 (1.06 g, 10.00 mmol) at rt. The suspension was stirred at ˜35° C. overnight. DMF was evaporated in vacuo and to the residue was added CH2Cl2 (100 ml) and washed with H2O (3×80 ml). The white salt was filtered and the solution was washed with 5 N KOH (4×80 ml), H2O (1×80 ml), dried over MgSO4 and concentrated to a brown oil, which was purified via flash column chromatography (20% EtOAc in hexane) to give (3,5-dimethoxy-phenyl)-(2,3,4-trimethoxy-phenyl)methanone as a clear oil (1.49 g, 90%): 1HNMR (CDCl3) δ 7.12 (d, J=8 Hz, 1H, Ar), 6.94 (d, J=2 Hz, 2H, Ar), 6.71 (d, J=8 Hz, 1H, Ar), 6.65 (t, J=2 Hz, 1H, Ar), 3.93 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 3.81 (s, 6H, 2OCH3), 3.79 (s, 3H, OCH3); 13C NMR (CDCl3) δ 195.2, 160.7, 156.3, 152.9, 142.2, 140.5, 126.6, 125.1, 107.7, 106.8, 105.4, 62.0, 61.1, 56.3, 55.7; Anal. Calcd. For C18H20O6: C, 65.05; H, 6.07. Found: C, 64.93; H, 6.09. The product was carried over to the next step.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]3[CH2:18][CH2:19][N:20]([C:22](OCC4C=CC=CC=4)=O)[CH2:21][C:5]=3[C:4]=2[CH:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[O:43]C(O)[CH2:41][CH2:40]2)=[CH:35][CH:34]=1>C(OCC)(=O)C.[Pd]>[F:17][C:14]1[CH:15]=[CH:16][C:11]2[N:7]([C:8]3[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[C:6]3[CH2:5][CH2:21][N:20]([CH2:22][CH2:41][CH2:40][CH:39]([C:36]4[CH:35]=[CH:34][C:33]([F:32])=[CH:38][CH:37]=4)[OH:43])[CH2:19][C:18]=3[C:12]=2[CH:13]=1
Reactant: OC1CCC(c2ccc(F)cc2)O1
Reactant: O=C(OCc1ccccc1)N1CCc2c(c3cc(F)ccc3n2-c2ccc(F)cc2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: OC(CCCN1CCc2c(c3cc(F)ccc3n2-c2ccc(F)cc2)C1)c1ccc(F)cc1
Reaction time: 20 h

Procedure:
In a Parr bottle were combined 5% Pd/C (5 g of 50% water-wet), 8-fluoro-5-(p-fluorophenyl)-2-carbobenzoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (5.0 g, 0.0119 mole) in 100 ml ethyl acetate, and 5.5 grams (0.03 mole) 5-(p-fluorophenyl)-2-hydroxytetrahydrofuran in 100 ml ethyl acetate. The mixture was agitated and hydrogenated at 30-40 psig for 20 hours. The solution was filtered to recover catalyst, with ethyl acetate and CH2Cl2 wash. The filtrate and washes were concentrated in vacuo to a viscous oil. The oil was dissolved in 400 ml ethyl acetate and filtered. The solution was concentrated to an oil, diluted with 150 ml ether, and filtered to yield title product, 3.8 gm, m.p. 145°-149° C.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4([C:25]#[N:26])[CH2:24][CH2:23]4)=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:28][C:29]1[CH:30]=[N:31][C:32]2[N:33]([N:35]=[C:36]([CH:38]=O)[N:37]=2)[CH:34]=1>CO>[Cl:28][C:29]1[CH:30]=[N:31][C:32]2[N:33]([N:35]=[C:36]([CH2:38][CH:9]3[C:8](=[O:13])[O:7][C:6]([CH2:14][CH2:15][C:16]4[CH:21]=[CH:20][C:19]([C:22]5([C:25]#[N:26])[CH2:23][CH2:24]5)=[C:18]([F:27])[CH:17]=4)([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:11][C:10]3=[O:12])[N:37]=2)[CH:34]=1
Reactant: O=Cc1nc2ncc(Cl)cn2n1
Reactant: N#CC1(c2ccc(CCC3(C4CCCC4)CC(=O)CC(=O)O3)cc2F)CC1
Solvent: CO
Product: N#CC1(c2ccc(CCC3(C4CCCC4)CC(=O)C(Cc4nc5ncc(Cl)cn5n4)C(=O)O3)cc2F)CC1
Reaction time: 1 h

Procedure:
A solution of 1-{4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile (568 mg, 1.54 mmol) in anhydrous MeOH (6.0 mL) was treated with 6-chloro-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (365 mg, 2.0 mmol), followed by borane-dimethylamine complex (118 mg, 2.0 mmol) at room temperature. The reaction was stirred for 1 hour and then was concentrated to an oil. The oil was purified by flash chromatography (50 g SiO2, 70% ethyl acetate, 6% methanol, 0.5% acetic acid, 23.5% hexanes). The resultant oil was further purified by flash 509 SiO2, 1:3->1:0 (93.5% ethyl acetate, 6% methanol, 0.5% acetic acid): (81.5% hexanes, 12% ethyl acetate, 6% methanol, 0.5% acetic acid) to give the desired product as an oil. It was further purified by crystallization from ethyl acetate/hexanes to give a white powder (48.6 mg, 6%). 1H NMR (400 MHz, CDCl3) δ: 1.19–1.24 (m, 2 H), 1.39–1.61 (m, 10 H), 1.83–1.87 (m, 2 H), 2.25 (t, J=8.59 Hz, 1 H), 2.38 (d, J=17.94 Hz, 1 H), 2.54 (t, J=7.71 Hz, 2 H), 2.64 (d, J=17.94 Hz, 1 H), 3.98 (d, J=5.56 Hz, 2 H), 6.71–6.77 (m, 2 H), 7.06 (t, J=7.83 Hz, 1 H), 8.66 (s, 1 H), 8.73 (s, 1 H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][CH2:12][CH2:13][N:14]2C(=O)C3C(=CC=CC=3)C2=O)[CH:4]=[CH:3][N:2]=1.O.NN>C(O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][CH2:12][CH2:13][NH2:14])[CH:4]=[CH:3][N:2]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc2ccncc12
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCc1cccc2ccncc12
Yield: 100.5 %

Procedure:
To a refluxing solution of 0.174 g of [3-(8-isoquinolinyl)propyl]-1H-isoindole-1,3-(2H)-dione in 8 mL of ethanol was added 0.12 mL of hydrazine hydrate and the reaction was stirred at reflux for 5.5 hours. The solvent was removed under reduced pressure and the residue was triturated with chloroform. The chloroform extract was concentrated to an oil which was passed through a short column of silica gel (chloroform-methanol-triethylamine; 1:4:15) to yield 0.103 g of 8-isoquinolinepropanamine as an oil.
Reaction SMILES: FC1C=CC(C=O)=CC=1.[Cl:10][C:11]1[CH:19]=[CH:18][C:14](/[CH:15]=[N:16]\[OH:17])=[CH:13][CH:12]=1.[Cl:20]N1C(=O)CCC1=O>CN(C=O)C>[OH:17]/[N:16]=[C:15](\[Cl:20])/[C:14]1[CH:18]=[CH:19][C:11]([Cl:10])=[CH:12][CH:13]=1
Reactant: O/N=C\c1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=Cc1ccc(F)cc1
Solvent: CN(C)C=O
Product: O/N=C(\Cl)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a solution of (E)- and/or (Z)-4-chloro-benzaldehyde oxime 4-fluorobenzaldehyde (27.0 g, 173 mmol) in DMF (173 mL) was added N-chlorosuccinimide (22.8 g, 173 mmol) portionwise over 1 h, keeping the temperature below 35° C. The reaction mixture was stirred at room temperature for 1 h. The mixture was then poured onto ice-water, and extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated to afford the title compound (28.4 g, 86%) which was obtained as a light yellow solid. MS: m/e=189.1 [M]+.
Reaction SMILES: [C:1]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl.[F:17][C:18]([F:45])([F:44])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1>COCCOC>[F:17][C:18]([F:44])([F:45])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])=[O:40])=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(C(=O)OC(C)(C)C)C(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1

Procedure:
A solution of 28.0 g. of tert-butyl ethyl malonate in 10 ml. of 1,2-dimethoxyethane is added to a suspension of 4.0 g. of sodium hydride in 1,2-dimethoxyethane under argon. A solution of 17.3 g. of 4-[15-(trifluoromethyl)pentadecylamino]benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then added. The reaction mixture is refluxed for 5 hours, cooled, poured on ice and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to dryness. The residue is then recrystallized from ether to yield the product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13](B3OC(C)(C)C(C)(C)O3)=[CH:12][C:11]=2[F:25])=[N:4][CH:3]=1.Br[C:27]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:28]=1[O:29][C:30]1[N:35]=[CH:34][CH:33]=[CH:32][N:31]=1>>[NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:27]3[CH:39]=[CH:38][C:37]([C:40]([F:42])([F:43])[F:41])=[CH:36][C:28]=3[O:29][C:30]3[N:31]=[CH:32][CH:33]=[CH:34][N:35]=3)=[CH:12][C:11]=2[F:25])=[N:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(Br)c(Oc2ncccn2)c1
Reactant: CC1(C)OB(c2ccc(-c3ncc(N)nc3C#N)c(F)c2)OC1(C)C
Product: N#Cc1nc(N)cnc1-c1ccc(-c2ccc(C(F)(F)F)cc2Oc2ncccn2)cc1F

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 utilizing 6-amino-3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile and 2-(2-bromo-5-(trifluoromethyl)phenoxy)pyrimidine. MS (ESI): mass calcd. for C22H12F4N6O, 452.10; m/z found, 453.1 [M+H]+. 1H NMR (600 MHz, DMSO-δ6) δ 8.56 (d, J=4.8, 2H), 8.20 (s, 1H), 7.89-7.81 (m, 2H), 7.81-7.75 (m, 1H), 7.61-7.54 (m, 1H), 7.48 (dd, J=11.1, 1.7, 1H), 7.43 (dd, J=8.1, 1.7, 1H), 7.37 (s, 2H), 7.22-7.17 (m, 1H).