Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[C:4]([NH:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCOC3)c2n1
Reactant: NCc1ccccc1
Solvent: CCCCO
Product: Clc1nc(NCc2ccccc2)c2ncn(C3CCOC3)c2n1
Temperature: 95 °C

Procedure:
139 mg of the product obtained in Stage 1 above, 2 ml of butanol and 0.06 ml of benzylamine are mixed together and the reaction medium is heated to a temperature of approximately 95° C. for 5 hours 30. The reaction medium is then left to return to ambient temperature and to crystallize, followed by separating, washing with 10 ml of isopropanol and drying under vacuum at approximately 50° C. In this way 157 mg of expected product is obtained in the form of white crystals.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[CH2:29]([NH2:34])[CH2:30][CH:31]([CH3:33])[CH3:32].ClCCl>O.C([O-])(O)=O.[Na+]>[C:18]([O:17][C:15]([N:22]1[CH2:27][CH2:26][CH:25]([NH:34][CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:24][CH2:23]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(C)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)CCNC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
Sodium triacetoxyborohydride (24.9 g, 117.48 mmol) is added to a stirred solution of 1-Boc-4-piperidone (15.6 g, 78.3 mmol), iso-amyl amine (10.0 ml, 86.15 mmol), and dichloromethane (400 ml). The reaction is stirred overnight at room temperature under nitrogen. The reaction is diluted with water and aqueous saturated NaHCO3, and extracted with dichloromethane (150 ml×3). The dichloromethane is concentrated under vacuum, diluted with ethyl acetate and washed with aqueous saturated NaHCO3, dried over Na2SO4, filtered, and concentrated to yield (19.99 g) of 4-(3-methyl-butylamino)-piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z=271 (M+1); 1H NMR (CDCl3): δ=4.05 (2H, brs), 2.84-2.73 (2H, brm), 2.67-2.55 (2H, m), 1.84 (2H, brd), 1.67-1.58 (1H, m), 1.51-1.44 (10H, m), 1.41-1.33 (2H, m), 1.30-1.18 (2H, m), 0.90 (6H, d).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1[CH:34]=[CH:33][C:9]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)=[CH:17][CH:18]=3)[CH:13]=[C:12]2[CH2:31][OH:32])=[CH:8][CH:7]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([O:32][CH2:31][C:12]1[N:11]([CH2:10][C:9]2[CH:8]=[CH:7][C:6]([CH3:5])=[CH:34][CH:33]=2)[C:19]2[C:14]([CH:13]=1)=[CH:15][C:16]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:29])([F:30])[F:28])=[CH:22][CH:21]=1)=[CH:17][CH:18]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(Cn2c(CO)cc3cc(-c4ccc(OC(F)(F)F)cc4)ccc32)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCc1cc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2n1Cc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
Acetyl chloride (0.222 mL, 3.08 mmol) was added to a stirring solution of {1-(4-methylbenzyl)-5-[4-(trifluoromethoxy)phenyl]-1H-indol-2-yl}methanol (0.507 g, 1.23 mmol) and N,N-diisopropylethylamine (0.547 mL, 3.08 mmol) in methylene chloride (8 mL) at 0° C. under a nitrogen atmosphere over a period of 5 minutes. After the reaction mixture was stirred at room temperature overnight, the reaction was quenched carefully with water. The aqueous mixture was extracted with ethyl acetate. The organic extract was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated to afford the title compound as a solid (0.557 g, 99.6%), mp: 125–126° C. Mass spectrum (ESI, [M+H]+) m/z 454. 1HNMR (400 MHz, DMSO-d6): δ 7.86 (s, 1H), 8.77 (d, 2H, J=8.96 Hz), 7.48–7.40 (m, 4H), 7.09 (d, 2H, J=7.94 Hz), 6.90 (d, 2H, J=7.94 Hz), 6.70 (s, 1H), 5.44 (s, 2H), 5.23 (s, 2H), 2.23 (s, 3H), and 1.85 ppm (s, 3H).
Reaction SMILES: [NH3:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]1[CH:15]=[CH:14][C:13](OC)=[CH:12][CH:11]=1>CO>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:15]=[CH:14][C:13](=[NH:1])[CH:12]=[CH:11]1
Reactant: N
Reactant: COc1cc[n+](-c2ccccc2OC)cc1
Solvent: CO
Product: COc1ccccc1-n1ccc(=N)cc1
Temperature: 0 °C
Reaction time: 72 h
Yield: 96 %

Procedure:
Ammonia gas was passed into an ice-cooled solution of 3.27 g (10 millimoles) of 1-(2-methoxyphenyl)-4-methoxypyridinium methosulfate in 15 ml of methanol units 2 g of ammonia had been adsorbed. After standing at 25° for 72 hours, the reaction mixture was concentrated, the residue was triturated with cold ethanol and the product was filtered off: 3.01 g (96% yield) of 1-(2-methoxyphenyl)-4(1H)-pyridineimine methosulfate (M.P.=121°-124°) were obtained.
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].[CH:11]([C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19]([NH:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[N:18][CH:17]=[CH:16]2)=[O:12].Cl>O.CS(C)=O>[C:24]([NH:23][C:19]1[C:20]2[C:15](=[CH:14][C:13]([C:11]([OH:6])=[O:12])=[CH:22][CH:21]=2)[CH:16]=[CH:17][N:18]=1)(=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=P([O-])(O)O
Reactant: O=Cc1ccc2c(NC(=O)c3ccccc3)nccc2c1
Agent: Cl
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1ccc2c(NC(=O)c3ccccc3)nccc2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 230.9 %

Procedure:
To a stirred solution of 400 mg sodium chlorite and 80 mg sodium dihydrogen phosphate in 2.5 mL of water and 2.5 mL of dimethylsulfoxide in a cooling bath at room temperature was added dropwise a solution of 510 mg N-(6-formyl-1-isoquinolinyl)benzamide (1f) in 2.5 mL of dimethylsulfoxide. After 16 hours at room temperature a solution of 170 mg sodium chlorite in 0.5 mL of water and 1.0 mL of dimethylsulfoxide was added and stirred at room temperature for an additional 6 hours. Then 100 mL water was added, the pH adjusted to three using 2N hydrochloric acid and the resulting suspension was kept at 5° C. for 16 hours. The precipitate was collected to afford 450 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH:18]3[CH2:20][CH2:19]3)[C:16]3[C:21](Br)=[C:22]([F:25])[CH:23]=[CH:24][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH:18]3[CH2:20][CH2:19]3)[C:16]3[C:21]([C:29]4[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=4)=[C:22]([F:25])[CH:23]=[CH:24][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: OB(O)c1cccnc1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(Br)c2n1C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(-c3cccnc3)c2n1C1CC1
Temperature: 140 °C
Yield: 43.7 %

Procedure:
A mixture of 4-amino-6-[(S)-1-(7-bromo-1-cyclopropyl-6-fluoro-1H-benzoimidazol-2-yl)ethylamino]pyrimidine-5-carbonitrile (68 mg, 0.16 mmol), pyridine-3-boronic acid (26 mg, 0.21 mmol), tetrakis(triphenylphosphine)palladium (19 mg, 10 mol %) and caesium carbonate (106 mg, 0.33 mol) in dioxane (3 mL) and H2O (1.5 mL) was purged with argon gas then heated at 140° C., for 30 min, by microwave irradiation. After cooling to RT, the reaction mixture was diluted with MeOH and loaded into an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a gradient 10-90%, 0.1% NH4OH in acetonitrile/water) to afford 414 as a white solid (29 mg, 43%). LCMS (Method K): RT 2.80 min [M+H]+ 415.06. 1H NMR (CDCl3 400 MHz): δ 8.74 (1H, s), 8.66 (1H, dd, J=4.86, 1.69 Hz), 8.17 (1H, s), 7.86 (1H, s), 7.70 (1H, dd, J=8.79, 4.66 Hz), 7.43 (1H, dd, J=7.83, 4.85 Hz), 7.13 (1H, dd, J=10.24, 8.78 Hz), 6.45-6.14 (1H, br m), 5.97 (1H, m), 5.36 (2H, s), 2.95 (1H, m), 1.70 (3H, d, J=6.73 Hz), 1.02-0.09 (4H, m)
Reaction SMILES: [CH:1]1([C@@H:4]([OH:21])[C@H:5](OS(C2C=CC(C)=CC=2)(=O)=O)[C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:2]1.O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:1]1([C@H:4]2[O:21][C@H:5]2[C:6]([O:8][CH3:9])=[O:7])[CH2:2][CH2:3]1
Reactant: COC(=O)[C@@H](OS(=O)(=O)c1ccc(C)cc1)[C@H](O)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)[C@@H]1O[C@@H]1C1CC1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
To a solution of 2.97 g of methyl (2S,3R)-3-cyclopropyl-3-hydroxy-2-(p-toluenesulfonyloxy)propionate in 50 ml of acetonitrile are added 10.86 ml of water and 3.96 g of potassium carbonate successively at room temperature. Then, the reaction mixture is stirred at 50° C. for 2 days. The reaction mixture is cooled to room temperature, and insoluble materials are removed by filtration. The filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; diethylether) to give methyl (2R,3R)-3-cyclopropyl-2,3-epoxypropionate quantitatively. MS(m/z): 142(M+) IR(neat,cm-1): 1750
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][C@H:19]([C:21]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=2)[CH3:20])=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37]([NH2:40])(=[O:39])=[O:38]>>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)=[C:4]([CH:3]=1)[C:16]([NH:18][C@H:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:40][S:37]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[Cl:30])(=[O:39])=[O:38])=[O:27])=[CH:23][CH:22]=1)[CH3:20])=[O:17]
Reactant: NS(=O)(=O)c1ccccc1Cl
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(F)cc1)c1ccc(C(=O)O)cc1
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(F)cc1)c1ccc(C(=O)NS(=O)(=O)c2ccccc2Cl)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 103 from 4-[(1S)-1-({[5-chloro-2-(4-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid (step 5 of Example 44) and 2-chlorobenzenesulfonamide: 1H-NMR (CDCl3) δ 8.54 (1H, d, J=2.6 Hz), 8.23–8.12 (2H, m), 8.04 (1H, d, J=2.6 Hz), 7.87 (1H, d, J=7.3 Hz), 7.47–7.16 (5H, m), 7.15–7.01 (5H, m), 5.45–5.25 (1H, m), 1.48 (3H, d, J=6.4 Hz); MS (ESI) m/z 588 (M+H)+, 586 (M−H)−.
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=[O:12])[CH2:3]1)[CH2:9]2.CN(C1C=CC=CN=1)C.[C:22](OC(=O)C)(=[O:24])[CH3:23]>ClCCl>[O:12]=[C:5]1[CH:6]2[CH2:7][CH:8]3[CH2:9][C:2]([O:1][C:22](=[O:24])[CH3:23])([CH2:3][CH:4]1[CH2:10]3)[CH2:11]2
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CC(=O)OC12CC3CC(C1)C(=O)C(C3)C2
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of 5-hydroxy-2-adamantanone (2.6 g, 15.66 mmoles) in dichloromethane (DCM) (50 mL) was treated with dimethylaminopyridine (DMAP) (2.1 g, 17 mmoles) and acetic anhydride (2.3 mL, 23 mmoles) and stirred overnight at 50° C. The solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. Combined organic extracts were washed with water, dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to provide the title compound as an off-white solid.
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].[Na].Br[CH2:22][CH2:23][CH:24]=[CH2:25].[OH-].[Na+]>C(O)C.C(Cl)(Cl)Cl>[CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[N:12]([CH2:25][CH2:24][CH:23]=[CH2:22])[CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCCBr
Reactant: CCCCn1c(=O)c2[nH]cnc2n(CCCC)c1=O
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: C=CCCn1cnc2c1c(=O)n(CCCC)c(=O)n2CCCC
Temperature: 70 °C
Reaction time: 46 h

Procedure:
38.9 g of 1,3-di-n-butyl-xanthine are added at 25° C. to a solution of 3.4 g of sodium in 200 ml of absolute ethanol. 20.5 g of 4-bromobut-1-ene are then added at 50° C. After stirring for 46 hours under a nitrogen atmosphere at 70° C. the reaction mixture is cooled to 20° C., precipitated sodium bromide is filtered off and the filtrate is then evaporated under reduced pressure. The residue obtained is treated with chloroform and 1 N sodium hydroxide solution to remove 1,3-di-n-butyl-xanthine. From the chloroform phase there is obtained a yellow oily residue which after column chromatography on silica gel with methylene chloride/acetone (8:2) as eluent and after distillation under reduced pressure yields 29.7 g (78.8% of theory relative to reacted 1,3-di-n-butyl-xanthine) of the title compound with a melting point of 41° to 42° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][O:6][CH:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][S:17][C:18]3[NH:22][C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[N:19]=3)[C:11]=2[CH3:27])[O:4][CH2:3]1.ClC1C=CC=C(C(OO)=[O:37])C=1.C(=O)([O-])O.[Na+]>CO.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:28])[CH2:7][O:6][CH:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][S:17]([C:18]3[NH:19][C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)=[O:37])[C:11]=2[CH3:27])[O:4][CH2:3]1
Reactant: Cc1c(OCC2OCC(C)(C)CO2)ccnc1CSc1nc2ccccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1c(OCC2OCC(C)(C)CO2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Temperature: -50 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
The 2-(((4-((5,5-dimethyl-1,3-dioxan-2-yl)methoxy)-3-methylpyridin-2-yl)methyl)thio)-1H-benzimidazole (599 mg, 1.5 mmol) obtained by the step (1e) was mixed with methanol (5 ml) and toluene (15 ml), and the mixture was cooled to −50° C. 3-chloroperbenzoic acid (358 mg, 1.35 mmol, as the content was regarded as 65%) dissolved in a solvent mixture of methanol and toluene was slowly added dropwise to the mixture, and stirred at −47° C. to −70° C. for 3 hours. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over potassium carbonate, and the solvent was distilled off. The residue was purified with silica gel column chromatography (NH silica gel: 40 g, elution solvent: dichloromethane/heptane=7/3→methanol/dichloromethan=3/97 to 1/9). To the obtained product, heptane (20 ml) and diethyl ether (2 ml) were added, the precipitate was obtained by filtration. In this manner, the title compound (475 mg, yield: 76.2%) was obtained as a light orange solid.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrCC1CCCCC1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(CC3CCCCC3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.72 g) and (bromomethyl)cyclohexane (0.25 mL) as starting materials, 5-benzyloxy-N-{[1-(cyclohexylmethyl)pyrazol-4-yl]methyl}-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.86 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 139, N-{[1-(cyclohexylmethyl)pyrazol-4-yl]methyl}-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.63 g) was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14](Cl)=[O:15])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][NH:21][S:22]([C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1)(=[O:24])=[O:23]>>[CH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:33]=[CH:34][C:25]=1[S:22]([NH:21][CH2:20][CH2:19][CH2:18][NH:17][C:14](=[O:15])[CH2:13][N:10]1[CH2:11][CH2:12][N:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:8][CH2:9]1)(=[O:24])=[O:23]
Reactant: NCCCNS(=O)(=O)c1ccc2ccccc2c1
Reactant: O=C(Cl)CN1CCN(c2ccncc2)CC1
Product: O=C(CN1CCN(c2ccncc2)CC1)NCCCNS(=O)(=O)c1ccc2ccccc2c1
Yield: 34 %

Procedure:
Using an analogous procedure to that described in Example 1, 2-[4-(4-pyridyl)piperazin-1-yl]acetyl chloride was reacted with N-(3-aminopropyl)naphthalene-2-sulphonamide to give N-[3-(2-naphthalene-sulphonamido)propyl]-2-[4-(4-pyridyl)piperazin-1-yl]acetamide in 34% yield;
Reaction SMILES: [OH:1][CH:2]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Cl.[CH3:40][N:41]([CH3:47])[CH2:42][CH2:43][C:44](O)=[O:45].CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>ClCCl.CN(C1C=CN=CC=1)C>[CH3:40][N:41]([CH3:47])[CH2:42][CH2:43][C:44]([O:21][CH:3]([C:2](=[O:1])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:45]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)C(O)CCCCCCC/C=C\C/C=C\CCCCC
Reactant: CN(C)CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)C(CCCCCCC/C=C\C/C=C\CCCCC)OC(=O)CCN(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.6 %

Procedure:
To a solution of (6Z,9Z,27Z,30Z)-19-hydroxyhexatriaconta-6,9,27,30-tetraen-18-one (1.0 g, 1.9 mmol), 3-(dimethylamino)propanoic acid hydrogen chloride (876 mg, 5.7 mmol) and EDCI (1.2 g, 6.3 mmol), in dichloromethane (20 mL) was added DIPEA (1.0 mL, 5.7 mmol) and DMAP (20 mg). The solution was stirred at room temperature for 16 hours under nitrogen. Upon completion, the reaction was diluted with dichloromethane (50 mL) and washed with sodium bicarbonate solution (50 mL). The dichloromethane layer was dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography (100% ethyl acetate) to afford the title compound as a colorless oil (675 mg, 57%). 1H NMR (400 MHz, CDCl3): δ 5.43-5.28 (m, 8H), 5.03-4.98 (m, 1H), 2.80-2.75 (m, 4H), 2.74-2.56 (m, 4H), 2.54-2.36 (m, 2H), 2.28 (s, 6H), 2.09-2.01 (m, 8H), 1.82-1.64 (m, 2H), 1.63-1.52 (m, 2H), 1.42-1.23 (m, 30H), 0.93-0.86 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:15][CH2:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([CH3:9])=[N:6][C:7]=1[NH2:8].O.[CH:23]([CH:25]=O)=O>C1(C)C=CC=CC=1>[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17][CH2:16][NH:15][C:3]1[C:2]2[C:7](=[N:8][CH:23]=[CH:25][N:1]=2)[N:6]=[C:5]([CH3:9])[C:4]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1c(C)nc(N)c(N)c1NCCCN(C)C
Reactant: O=CC=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1c(C)nc2nccnc2c1NCCCN(C)C

Procedure:
3 g. of crude 5,6-diamino-4-[[3-(dimethylamino)propyl]-amino]-2-methylpyridine-3-carboxylic acid, ethyl ester and 1 g. of glyoxal-monohydrate are refluxed in 20 ml. of toluene for 4 hours. After evaporation of the solvent and addition of a small amount of charcoal, the residue is extracted with 50 ml. of boiling gasoline. On cooling 8-[[3-(dimethylamino)propyl]amino]-6-methylpyrido[2,3-b]pyrazine-7-carboxylic acid, ethyl ester precipitates, m.p. 42°-44° (gasoline).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([OH:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=O)=[N:9]2)=[CH:4][CH:3]=1.[C:23]([O:27][C:28]([CH:30]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]3[CH2:30][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(O)N1c1ccc2ccc(Cl)nc2n1
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 90.1 %

Procedure:
A mixture of 46.0 g of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxyisoindolin-1-one, 78 g of t-butyloxycarbonylmethylenetriphenylphosphorane and 800 ml of toluene was refluxed for 5 hours. The mixture was concentrated and the residue was purified by silica gel column chromatography (dichloromethane-ethyl acetate) to give 54.5 g of t-butyl 2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxoisoindoline-1-acetate. Recrystallization from toluene-ether gave colorless crystals melting at 210°-211° C.
Reaction SMILES: C(O)(=O)C.[N+:5]([C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2)([O-])=O>C(O)C.[Fe]>[NH2:5][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1cccc2[nH]ccc12
Yield: 99.9 %

Procedure:
Iron powder (1.20 g, 21.58 mmol) and acetic acid (2.47 mL, 43.19 mmol) are added to a solution of 4-nitroindole (1.0 g, 6.17 mmol) in ethanol (20 mL). The resulting suspension is heated to reflux for 14 hours. The ethanol is removed by rotary evaporation and the residue is partitioned between water and ethyl acetate. The ethyl acetate layer is dried over magnesium sulfate, filtered, and the solvents removed by rotary evaporation. The crude residue is purified via silica gel column chromatography using 1% methanol/methylene chloride as the eluent. The appropriate fractions are combined and the solvents removed by rotary evaporation to yield 0.815 g of 4-aminoindole as an orange solid (82% yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:21]3[CH:22]=[N:23][C:24]([NH2:38])=[C:25]([O:26][C@@H:27]([C:29]4[C:34]([Cl:35])=[CH:33][CH:32]=[C:31]([F:36])[C:30]=4[Cl:37])[CH3:28])[C:20]=3[O:19][CH:18]=2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.CCOCC>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:21]3[CH:22]=[N:23][C:24]([NH2:38])=[C:25]([O:26][C@@H:27]([C:29]4[C:34]([Cl:35])=[CH:33][CH:32]=[C:31]([F:36])[C:30]=4[Cl:37])[CH3:28])[C:20]=3[O:19][CH:18]=2)=[O:16])[CH2:10][CH2:9]1
Reactant: C[C@@H](Oc1c(N)ncc2c(C(=O)NC3CCN(C(=O)OC(C)(C)C)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@@H](Oc1c(N)ncc2c(C(=O)NC3CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-({6-amino-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]furo[3,2-c]pyridine-3-carbonyl}-amino)-piperidine-1-carboxylic acid tert-butyl ester (6.0 mg, 0.01 mmol) in DCM (0.2 mL) was added 1M HCl in Et2O (0.5 mL). The resulting mixture was stirred at rt overnight. LC-MS showed the reaction was complete and gave the desired product. Evaporation under reduced gave the title compound as a white solid. LC-MS (ES+): 467.00/469.04 [MH+].