Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[N:8]=[CH:9][N:10]2[C:16]3[CH:17]=[CH:18][S:19][C:15]=3[C:14](=[O:20])[N:13]([CH3:21])[CH2:12][C:11]=12)=[O:6])[C:2]#[CH:3].IN1C(=O)CCC1=O.[CH2:30]([NH:33][CH2:34][CH2:35][CH3:36])[CH2:31][CH3:32]>C(O)(=O)C>[CH2:30]([N:33]([CH2:3][C:2]1[O:6][C:5]([C:7]2[N:8]=[CH:9][N:10]3[C:16]4[CH:17]=[CH:18][S:19][C:15]=4[C:14](=[O:20])[N:13]([CH3:21])[CH2:12][C:11]=23)=[N:4][CH:1]=1)[CH2:34][CH2:35][CH3:36])[CH2:31][CH3:32]
Reactant: C#CCNC(=O)c1ncn2c1CN(C)C(=O)c1sccc1-2
Reactant: CCCNCCC
Agent: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1cnc(-c2ncn3c2CN(C)C(=O)c2sccc2-3)o1
Temperature: 25 °C
Reaction time: 45 h
Yield: 28.5 %

Procedure:
A solution of 3.0 g (0.010 mol) of 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine-3-carboxylic acid prop-2-ynylamide in 180 ml of acetic acid was treated with 3.36 g (0.015 mol) of N-iodosuccinimide while gassing with argon. After stirring at room temperature for 45 hrs. the dark suspension obtained was completely freed from the solvents and dried azeotropically several times with toluene. The black-brown solid residue was suspended in 200 ml of THF, treated with 13.7 ml (0.10 mol) of dipropylamine and stirred at room temperature for 17 hrs. The suspension obtained was completely freed from the solvents, the residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid and extracted. The aqueous-acidic phase was made basic and extracted with ethyl acetate. The organic phase was concentrated, the orange-brownish product was chromatographed over basic Alox (grade III) with dichloromethane/ethyl acetate 4:1 as the eluent and recrystallized from hot isopropyl ether. There were obtained 1.14 g (29%) of 3-(5-dipropylaminomethyl-oxazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-6-one as yellowish crystals; m.p. 142-144°.
Reaction SMILES: CS[C:3]1[CH2:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[C:6]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:5]=2[N:4]=1.[CH2:22]([O:24][CH:25]([O:30][CH2:31][CH3:32])[C:26]([NH:28][NH2:29])=O)[CH3:23]>CN(C)P(=O)(N(C)C)N(C)C>[CH2:22]([O:24][CH:25]([O:30][CH2:31][CH3:32])[C:26]1[N:4]2[C:5]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:6]=3[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])=[N:8][CH2:9][C:3]2=[N:29][N:28]=1)[CH3:23]
Reactant: CSC1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1
Reactant: CCOC(OCC)C(=O)NN
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(OCC)c1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1F)=NC2

Procedure:
A solution of 15.9 g of 2-(methylthio)-5-(o-fluorophenyl)-7-chloro-3H-1,4-benzodiazepine and 9.7 g of diethoxyacetic acid hydrazide in 100 ml of hexamethylphosphoric acid triamide is heated for 10 hours at 140°; processing is then carried out analogously to the procedure described in Example 1, and the residue recrystallised from ethyl acetate/petroleum ether to obtain 6-(o-fluorophenyl)-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxaldehyde-diethylacetal, M.P. 120°-121°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:11]=[CH:12][N:13]=[C:14]2[C:19]=1[N:18]=[CH:17][C:16]([O:20][CH3:21])=[CH:15]2.CN(C=O)C>CCOC(C)=O>[CH3:21][O:20][C:16]1[CH:15]=[C:14]2[C:19]([C:10]([S:8][C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=3)=[CH:11][CH:12]=[N:13]2)=[N:18][CH:17]=1
Reactant: Nc1ccc(S)cc1
Reactant: COc1cnc2c(Cl)ccnc2c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cnc2c(Sc3ccc(N)cc3)ccnc2c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A RBF was charged with 4-aminothiophenol (161 mg, 1.285 mmol), 8-chloro-3-methoxy-1,5-naphthyridine (250 mg, 1.285 mmol) and 5.2 mL of DMF, and the mixture was stirred at RT for 45 min. The orange, heterogeneous mixture was diluted with EtOAc and washed with 1N NaHCO3. The aqueous portion was extracted two additional times with EtOAc and the combined organics were dried with MgSO4, filtered and concentrated. The crude oil was concentrated twice from toluene to remove DMF and the resulting solids were dried under high vacuum to provide 4-(7-methoxy-1,5-naphthyridin-4-ylthio)benzenamine as a tan solid. MS m/z=284 [M+H]+. Calc'd for C15H13N3OS: 283.35.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]=[CH:9][N:10]([CH2:11][CH2:12][CH2:13][CH2:14][NH:15]C(=O)C)[C:6]=2[C:5]([CH3:19])=[C:4]([CH3:20])[N:3]=1>Cl>[NH2:15][CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[C:6]2[C:5]([CH3:19])=[C:4]([CH3:20])[N:3]=[C:2]([NH2:1])[C:7]=2[N:8]=[CH:9]1
Reactant: CC(=O)NCCCCn1cnc2c(N)nc(C)c(C)c21
Agent: Cl
Product: Cc1nc(N)c2ncn(CCCCN)c2c1C
Temperature: 100 °C
Yield: 80.9 %

Procedure:
A solution of N-[4-(4-amino-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]acetamide (˜2.1 g) in 6 N hydrochloric acid (30 mL) was sealed in a flask and then heated at 100° C. for about 30 hours. The reaction mixture was allowed to cool to ambient temperature and then filtered to remove any particulates. The filtrate was made basic (pH 14) with 25% sodium hydroxide and then extracted with chloroform (×2). The aqueous layer was combined with sodium chloride (20 g) and then extracted with chloroform (×3). The organics were combined, washed with brine, dried over sodium sulfate and then concentrated under reduced pressure to provide 1.44 g of 1-(4-aminobutyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine.
Reaction SMILES: N1(CCC[O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]#[N:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)CCCC1.Cl[CH2:25][CH2:26][CH2:27][N:28]1[C@@H:32]([CH3:33])[CH2:31][CH2:30][C@@H:29]1[CH3:34].CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C>[CH3:34][CH:29]1[CH2:30][CH2:31][CH:32]([CH3:33])[N:28]1[CH2:27][CH2:26][CH2:25][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:22]#[N:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1
Reactant: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: C[C@H]1CC[C@H](C)N1CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1CCC(C)N1CCCOc1ccc(C2(C#N)CCOCC2)cc1
Yield: 41.1 %

Procedure:
4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile (318 mg, 1.56 mmol), 1-(3-chloro-propyl)-2,5-trans-dimethyl-pyrrolidine (250 mg, 1.42 mmol), DMF (5 ml) and K2CO3 (785 mg, 5.70 mmol) were reacted together according to general procedure E. The crude was dissolved in ethyl acetate (20 ml), washed with brine (2×10 ml), dried over MgSO4, filtered and concentrated in vacuo to give the title compound (200 mg, 56%) as a light brown solid. 1H NMR (400 MHz, CDCl3), δ 7.37 (d, 2H), 6.93 (d, 2H), 4.13-3.97 (m, 4H), 3.89 (td, 2H), 3.14-2.98 (m, 2H), 2.76 (m, 1H), 2.55 (m, 1H), 2.16-1.88 (m, 8H), 1.46-1.30 (m, 2H), 0.97 (d, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[N:27]1([CH2:33][CH2:34][C:35](O)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1>ClCCl.CN(C)C=O>[N:27]1([CH2:33][CH2:34][C:35]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:9]=[C:10]4[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][N:11]4[CH:17]=3)=[CH:6][CH:7]=2)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O=C(O)CCN1CCCCC1
Reactant: Cc1cccn2cc(-c3ccc(N)cc3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccn2cc(-c3ccc(NC(=O)CCN4CCCCC4)cc3)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.9 %

Procedure:
To a mixture of the product of Step B (330 mg) and N, N-diisopropylethylamine (0.28 mL) in dichloromethane (3 mL) and N, N-dimethylformamide(1 mL), was added 1-piperidinepropionic acid (256 mg), WSC.HCl (1-Ethyl-3-(3′dimethylaminopropyl)-carbodiimide.HCl) (312 mg), and 1-hydroxybenzotriazole hydrate (220 mg). The solution was stirred at ambient temperature for approximately 18 hours. The mixture was poured into a separatory funnel and washed sequentially with an equal volume of 1 N sodium hydroxide and water. The organic phase was dried over sodium sulfate, decanted and evaporated. The residue was purified via silica gel chromatography (methanol/dichloromethane) to yield the title compound (128 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([O:14]CC)=O)[C:6]3[CH2:17][CH2:18][N:19]([CH3:21])[CH2:20][C:5]=3[C:4]=2[CH:3]=1.[CH3:22][NH:23][CH3:24]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([N:23]([CH3:24])[CH3:22])=[O:14])[C:6]3[CH2:17][CH2:18][N:19]([CH3:21])[CH2:20][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Reactant: CNC
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)N(C)C)C1
Temperature: 120 °C

Procedure:
A mixture of ethyl 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetate (100 mg) and dimethylamine (1 ml) was heated at 120° C. for 15 h to obtain 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-N,N-dimethylacetamide after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv) in anhydrous THF.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].[O:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.[NH4+].[OH-].O>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH:10][CH:15]1[CH2:16][CH2:17][O:12][CH2:13][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [NH4+]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CC(C)(C)OC(=O)NCCNC1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of (2-amino-ethyl)-carbamic acid tert-butyl ester (5 g, 31.2 mmol) in DCE (150 mL) was added tetrahydro-pyran-4-one (2.7 mg, 27.1 mmol). The mixture was stirred at RT for 1 h, then sodium triacetoxyborohydride (8.63 g, 40.7 mmol) was added and stirring was continued for 18 h. The reaction mixture was diluted with NH4OH 10% in water and extracted with DCM. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo to give the title compound as colourless oil (6.60 g, 99%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:14]([N:15]2[C:24](=[O:25])[C:23]3[C:18](=[C:19]4[CH:38]=[CH:37][CH:36]=[CH:35][C:20]4=[C:21]([CH2:26][C:27]4[CH:28]=[N:29][C:30]([CH2:33]O)=[CH:31][CH:32]=4)[CH:22]=3)[N:17]=[CH:16]2)[CH2:13][CH2:12][O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].COCCN(S(F)(F)[F:49])CCOC>ClCCl>[Si:1]([O:8][C@@H:9]1[C@@H:14]([N:15]2[C:24](=[O:25])[C:23]3[C:18](=[C:19]4[CH:38]=[CH:37][CH:36]=[CH:35][C:20]4=[C:21]([CH2:26][C:27]4[CH:28]=[N:29][C:30]([CH2:33][F:49])=[CH:31][CH:32]=4)[CH:22]=3)[N:17]=[CH:16]2)[CH2:13][CH2:12][O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1COCC[C@@H]1n1cnc2c(cc(Cc3ccc(CO)nc3)c3ccccc32)c1=O
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1COCC[C@@H]1n1cnc2c(cc(Cc3ccc(CF)nc3)c3ccccc32)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-((3R,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}tetrahydro-2H-pyran-4-yl)-6-{[6-(hydroxymethyl)pyridine-3-yl]methyl}benzo[h]quinazolin-4(3H)-one (Example 21, 0.035 g, 0.066 mmol) in 1 mL of dichloromethane at −78° C. was added [bis(2-methoxyethyl)amino]sulfur trifluoride (0.015 mL, 0.079 mmol). The reaction was warmed to rt, and after 3 h, the solution was purified via silica gel chromatography, eluting with 0-3% methanol in dichloromethane to provide 3-((3R,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}tetrahydro-2H-pyran-4-yl)-6-{[6-(fluoromethyl)pyridine-3-yl]methyl}benzo[h]quinazolin-4(3H)-one that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 534.0 for [M+H]+.
Reaction SMILES: CO[C:3]([CH:5]1[CH2:9][C:8](=[CH2:10])[CH2:7][CH:6]1[C:11]([OH:13])=[O:12])=O.C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+].Cl.[Na+].[Cl-]>C1COCC1>[CH2:10]=[C:8]1[CH2:7][C@H:6]2[C:11](=[O:12])[O:13][CH2:3][C@H:5]2[CH2:9]1
Reactant: C=C1CC(C(=O)O)C(C(=O)OC)C1
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C1C[C@@H]2COC(=O)[C@@H]2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At −15° C., a solution of 2-methoxycarbonyl-4-methylidenecyclopentanecarboxylic acid (189.2 g; 1.027 mol) in THF (1 L) was admixed with triethylamine (156.6 ml; 1.130 mol) and ethyl chloroformate (18.2 ml; 1.027 mol), and the reaction mixture was stirred at room temperature for 1 h. The precipitate was filtered off with suction and the filtrate was concentrated, taken up in methanol (1 L), NaBH4 (97.146 g; 2.568 mol) was added a little at a time at −15° C. and the mixture was stirred at room temperature for 1 h. For work-up, the mixture was admixed with 1 N HCl, saturated with NaCl and extracted with ethyl acetate. The combined organic phases were dried (Na2SO4) and concentrated, and the crude product was purified by chromatography.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[F:20][C:21]([F:28])([F:27])[CH2:22][CH2:23][C:24](O)=[O:25]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:24](=[O:25])[CH2:23][CH2:22][C:21]([F:28])([F:27])[F:20])[N:11]=2)=[CH:13][CH:14]=1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Reactant: O=C(O)CCC(F)(F)F
Product: O=C(CCC(F)(F)F)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product from Example 86A and 4,4,4-trifluorobutanoic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.40-8.43 (m, 1H), 7.89-8.05 (m, 2H), 7.73-7.75 (m, 1H), 7.60-7.70 (m, 4H), 2.58-2.71 (m, 4H); MS (ESI−) M/Z 394 (M−H)−.
Reaction SMILES: COC1C=CC(N2C=CN=C2C=[N:15][S@@:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[O:17])=CC=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:30][C:31]([CH:34]=O)=[CH:32][N:33]=2)=[CH:25][CH:24]=1.CC([S@@](N)=O)(C)C>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:30][C:31](/[CH:34]=[N:15]\[S:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[O:17])=[CH:32][N:33]=2)=[CH:25][CH:24]=1
Reactant: O=Cc1cnc(-c2ccc(Cl)cc2)o1
Reactant: COc1ccc(-n2ccnc2C=N[S@](=O)C(C)(C)C)cc1
Agent: CC(C)(C)[S@@](N)=O
Product: CC(C)(C)S(=O)/N=C\c1cnc(-c2ccc(Cl)cc2)o1

Procedure:
The title compound was prepared according to the method presented for the synthesis of compound 5B of Example 5 utilizing 19B and (S)-2-methylpropane-2-sulfinamide. MS (m/z) 311.1 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:16]2=[C:17]3[C:12](=[CH:13][CH:14]=[CH:15]2)[CH2:11][CH2:10][CH:9]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:8]3[CH:7]=1)=[O:5])C.[OH-].[Na+].Cl>O.C(O)C>[CH:18]1([CH:9]2[CH2:10][CH2:11][C:12]3[C:17]4=[C:16]([C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]24)[CH:15]=[CH:14][CH:13]=3)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CCOC(=O)c1cn2c3c(cccc13)CCC2C1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cn2c3c(cccc13)CCC2C1CCCC1
Yield: 85.7 %

Procedure:
To a solution of 4-cyclopentyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxylic acid ethyl ester (1.45 g, 4.9 mmol) in water (10 ml) and ethanol (15 ml) was added sodium hydroxide (1.96 g, 49 mmol) and the reaction mixture heated at reflux overnight (˜14 h). The reaction was cooled and acidifed with 5 M HCl. The resulting white precipitate was filtered and dried in vacuo to give 4-cyclopentyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxylic acid (1.13 g, 4.2 mmol) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)[CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.B(Br)(Br)Br>>[F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=2)[CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2
Reactant: COc1ccc(-c2cc(F)c3cc(O)ccc3c2)cc1
Agent: BrB(Br)Br
Product: Oc1ccc(-c2cc(F)c3cc(O)ccc3c2)cc1

Procedure:
The title compound was prepared by reacting 8-fluoro-6-(4-methoxyphenyl)-2-naphthol (0.10 g, 0.37 mmol) with boron tribromide (0.56 mL of 1N solution, 0.56 mmol) according to method D to yield 0.10 g (quantitative) of a white solid: mp 236-238° C.; 1H NMR (DMSO-d6): δ 6.87 (2H, d, J=8.57 Hz), 7.14-7.18 (2H, m), 7.52 (1H, dd, J=1.18 Hz, J=12.78 Hz), 7.61 (2H, d, J=8.59 Hz, 7.86-7.89 (2H, m), 9.61 (1H, bs), 10.05 (1H, bs); MS (ESI) m/z253 (M−H)−.
Reaction SMILES: C(O[C:4]([C:6]1[C:10]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][S:8][C:7]=1[NH:19][C:20](=[O:24])[CH2:21][C:22]#[N:23])=[O:5])C.C(OC(C1C(C=CC2C=CC=CC=2)=CSC=1NC(=O)CC#N)=O)C>>[OH:5][C:4]1[C:6]2[C:10]([C:11]#[C:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:9][S:8][C:7]=2[NH:19][C:20](=[O:24])[C:21]=1[C:22]#[N:23]
Reactant: CCOC(=O)c1c(C#Cc2ccccc2)csc1NC(=O)CC#N
Agent: CCOC(=O)c1c(C=Cc2ccccc2)csc1NC(=O)CC#N
Product: N#Cc1c(O)c2c(C#Cc3ccccc3)csc2[nH]c1=O
Yield: 5.7 %

Procedure:
Example 241 was prepared using the same procedure as described for Example 240 substituting 2-(2-cyano-acetylamino)-4-phenylethynyl-thiophene-3-carboxylic acid ethyl ester (0.087 g, 0.256 mmol) for 2-(2-Cyano-acetylamino)-4-styryl-thiophene-3-carboxylic acid ethyl ester in Example 240 to give the title compound (0.0043 g, 5.8%). MS m/e (CI) 292.8 (M+H)+314.8 (M+Na); 1H NMR (300 MHz, MeOH-d4) δ ppm 7.09 (s, 1H), 7.33 (m, 3H), 7.58 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:8])=[CH:5][CH:4]=1.[OH:20][C@H:21]1[CH2:27][CH2:26][C@@H:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[O:24][C:22]1=[O:23].C(OCC)C>CN(C)C=O.[Ag]=O>[CH2:10]([O:9][C:7]([C:6]1[CH:18]=[CH:19][C:3]([CH2:2][O:20][C@H:21]2[CH2:27][CH2:26][C@H:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[O:24][C:22]2=[O:23])=[CH:4][CH:5]=1)=[O:8])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCC[C@@H]1CC[C@H](O)C(=O)O1
Reactant: CCCCCCCCOC(=O)c1ccc(CBr)cc1
Agent: O=[Ag]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCCCCCOC(=O)c1ccc(CO[C@H]2CC[C@H](CCCCCC)OC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 2.2 %

Procedure:
In 1.5 ml of dry dimethylformamide were dissolved 180 mg of octyl p-bromomethylbenzoate and 100 mg of (2S,5R)-2-hydroxy-5-hexyl-δ-valerolactone, and 300 mg of silver oxide was added to the solution and the mixture was stirred overnight at room temperature to effect reaction. After the reaction, diethyl ether was added to the reacted solution to extract the reaction product. The extract was washed with a saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate. Diethyl ether was removed by distillation under a reduced pressure. The obtained crude product was purified by the silica gel column chromatography to obtain 5 mg of (2S,5S)-2-(4'-octyloxycarbonylbenzyloxy)-5-hexyl-δ-valerolactone.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:49]([OH:55])[CH2:50][O:51][CH2:52][CH2:53]O.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:17]=3)[N:12]([CH2:53][CH2:52][O:51][CH2:50][CH2:49][OH:55])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(CN3CCOCC3)cc2c1O
Reactant: OCCOCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CCOCCO)c2ccc(CN3CCOCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A dry flask containing N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (0.20 gm) from Preparation No. 40 in dry THF (5 mL) under an argon atmosphere is added triphenylphosphine (165 mg), diethyleneglycol (0.20 mL) and diethyl azodicarboxylate (0.10 mL). The mixture is stirred at room temperature for 2 hrs. The reaction mixture is concentrated under reduced pressure. The crude product is purified by flash column chromatography eluting with 10% to 40% methanol in ethyl acetate and then by recrystallization from ethyl acetate to afford 68 mg of the title compound as a white solid.
Reaction SMILES: Cl(O)(=O)(=O)=O.[CH3:6][N:7]1[C:16](=[O:17])[C:15]2[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH:22]3[O:24][CH2:23]3)[CH:13]=[N:12][C:11]=2[N:10]([CH3:25])[C:8]1=[O:9].C[O:27]CCOC.C(=O)(O)[O-].[Na+]>O>[CH3:6][N:7]1[C:16](=[O:17])[C:15]2[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([OH:24])[CH2:23][OH:27])[CH:13]=[N:12][C:11]=2[N:10]([CH3:25])[C:8]1=[O:9]
Reactant: COCCOC
Reactant: Cn1c(=O)c2c(ncn2CCCCC2CO2)n(C)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Product: Cn1c(=O)c2c(ncn2CCCCC(O)CO)n(C)c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.24 ml of perchloric acid (70% strength) was added dropwise with stirring in 5 minutes to a solution of 3.6 g of 1,3-dimethyl-7-(5,6-epoxyhexyl)xanthine in 280 ml of a mixture of ethylene glycol dimethyl ether and water (volume ratio 3:2) at room temperature. After stirring at room temperature for 16 hours, the mixture was neutralized with sodium bicarbonate solution and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (mobile phase: chloroform/ethanol, volume ratio 8/2) and recrystallization from ethyl acetate.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([N:15]2[CH:19]=[C:18]([I:20])[CH:17]=[N:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C[O:24][CH2:23]C1.[Li+].CC([N-]C(C)C)C.C1CCCCC1.CN(C=O)C.[NH4+].[Cl-]>>[Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:19]([CH:23]=[O:24])=[C:18]([I:20])[CH:17]=[N:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(n2cc(I)cn2)CC1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCCCC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2ncc(I)c2C=O)CC1
Reaction time: 0.08 h

Procedure:
A solution of 1-[4-(tert-butyl-dimethylsilanyloxy)-cyclohexyl]-4-iodo-1H-pyrazole (100.0 mg, 0.2461 mmol) in THF (6 mL, 70 mmol) was cooled to −78° C. and added 1.5 M of LDA in cyclohexane (0.213 mL, 0.320 mmol). After stirring for 5 min, DMF (0.1 mL, 1 mmol) was added slowly, and the mixture was stirred at −78° C. for 30 min. Sat. NH4Cl was added to quench, and the organic solvent was removed in vacuo. The material was extracted with DCM and water, and the organic layer was dry-loaded onto silica gel for column chromatography, eluting with 1-3% EtOAc/heptane. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a clear oil. MS (ES+): m/z=435.10 (100) [MH+]. HPLC: tR=2.18 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: BrC1C=C[C:5](NCC(OC)=O)=[N:6]C=1.[F:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][CH:21]=[C:20]2[CH:24]=O.CN1C2C(=CC=CC=2)C(C)=C1C=O>>[F:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][CH:21]=[C:20]2[CH2:24][NH:6][CH3:5]
Reactant: O=Cc1c[nH]c2c(F)cccc12
Reactant: COC(=O)CNc1ccc(Br)cn1
Agent: Cc1c(C=O)n(C)c2ccccc12
Product: CNCc1c[nH]c2c(F)cccc12
Yield: 90 %

Procedure:
According to the procedure of Preparation 13 (c), except substituting 7-fluoro-1H-indole-3-carboxaldehyde (0.5 g, 3.1 mmole) for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (0.5 g, 90%) was prepared as a viscous oil: MS (ES) m/e 179 (M+H)+.