Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][N:14]([CH3:31])[C:15]([C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH3:26])[C:18]=1[CH2:27][CH2:28][CH2:29][CH3:30])=[O:16])=[CH:7]2.Br[CH2:33][C:34]#[N:35].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:11]([O:12][CH2:33][C:34]#[N:35])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][N:14]([CH3:31])[C:15]([C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH3:26])[C:18]=1[CH2:27][CH2:28][CH2:29][CH3:30])=[O:16])=[CH:7]2
Reactant: CCCCc1c(C(=O)N(C)Cc2ccc3c(Br)c(O)ccc3c2)c2ccccc2n1C
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1c(C(=O)N(C)Cc2ccc3c(Br)c(OCC#N)ccc3c2)c2ccccc2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
A mixture of 2-butyl-1-methyl-1H-indole-3-carboxylic acid (5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (2.09 g, 4.36 mmol), prepared in the previous step, bromoacetonitrile (364 μL, 5.23 mmol) and potassium carbonate (3.01 g, 21.8 mmol) in 50 mL of DMF was stirred under nitrogen at room temperature for 16 h (overnight). The reaction was partitioned between ethyl acetate and water. The organic layer was separated, extracted multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 2-butyl-1-methyl-1H-indole-3-carboxylic acid (5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide (2.00 g, 88%) as a brown solid foam, MS m/z: 518 [M+H]+.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].CO>C(OCC)(=O)C>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:26]3[CH2:27][CH2:28][CH:23]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[O:16][CH3:15])[CH2:24][CH2:25]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: COc1ccccc1C1CCNCC1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccccc1C1CCN(C[C@H](O)COc2cccc3[nH]ccc23)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(2-methoxyphenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 37% overall yield. FDMS m/e=380 (M+ of free base). α[D]589 =-14.83 (c=0.81, methanol).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH:18]C(=O)OC(C)(C)C)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[NH4+].[OH-]>Cl.CCO.O>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH2:18])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1NC(=O)OC(C)(C)C
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOCc1nc2cnc3ccccc3c2n1N
Yield: 57 %

Procedure:
tert-Butyl N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)carbamate (14.3 g, 41.8 mmol) was dissolved in 150 mL of 2 M HCl in EtOH, and the reaction mixture was heated to reflux for 3 h. The reaction mixture was cooled and concentrated under reduced pressure to give a brown solid. The brown solid was dissolved in 100 mL of H2O and treated with 100 mL of concentrated NH4OH solution. The basic, aqueous solution was then extracted with CH2Cl2 (4×). The combined organic layers were then washed with brine and dried over Na2SO4. The solution was filtered and concentrated under reduced pressure to give a brown foam. The foam was triturated with Et2O (150 mL) and filtered. The filtrate was concentrated to give 2-ethoxymethy-1H-imidazo[4,5-c]quinolin-1-amine (5.77 g) as a tan solid.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=3)[C:10]3([C:21]4=[CH:22][C:23]5[O:27][CH2:26][O:25][C:24]=5[CH:28]=[C:20]4[O:19][CH2:18]3)[C:9]2=[O:29])C=CC=CC=1>[OH-].[Pd+2].[OH-].C(O)(=O)C>[CH3:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][C:9](=[O:29])[C:10]12[C:21]2=[CH:22][C:23]3[O:27][CH2:26][O:25][C:24]=3[CH:28]=[C:20]2[O:19][CH2:18]1
Reactant: Cc1ccc2c(c1)C1(COc3cc4c(cc31)OCO4)C(=O)N2C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)C1(COc3cc4c(cc31)OCO4)C(=O)N2
Temperature: 60 °C
Reaction time: 96 h
Yield: 43.4 %

Procedure:
A stainless steel hydrogenating vessel was successively charged with 1′-(diphenylmethyl)-5′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.90 g, 1.95 mmol), glacial acetic acid (50.0 mL) and palladium hydroxide (0.10 g, 1.35 mmol, 20 wt % on carbon). The vessel was flushed with nitrogen, sealed then heated to 60° C. and placed under 120 Psi of H2. After 4 days of stirring, the reaction mixture was diluted with ethyl acetate and passed through a bed of celite. The filtrate was washed with water (6×100 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography eluting with ethyl acetate/hexane (40-50%) to afford the title compound (0.25 g, 43%): mp 269-271° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.45 (s, 1H), 7.00 (d, 1H), 6.87 (s, 1H), 6.76 (d, 1H), 6.63 (s, 1H), 6.21 (s, 1H), 5.87 (d, 2H), 4.64 (ABq, 2H), 2.17 (s, 3H); MS (ES+) m/z 296.28 (M+1).
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=O)=[CH:11][CH:10]=2)[CH2:3]1.[NH2:19][C:20]1[N:24](C(OC(C)(C)C)=O)[N:23]=[C:22]([CH2:32][CH2:33][C:34]2[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[C:36]([O:42][CH3:43])[CH:35]=2)[CH:21]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH3:41][O:40][C:38]1[CH:39]=[C:34]([CH2:33][CH2:32][C:22]2[CH:21]=[C:20]([NH:19][C:13](=[O:15])[C:12]3[CH:11]=[CH:10][C:9]([N:4]4[CH2:5][CH:6]([CH3:8])[NH:7][CH:2]([CH3:1])[CH2:3]4)=[CH:18][CH:17]=3)[NH:24][N:23]=2)[CH:35]=[C:36]([O:42][CH3:43])[CH:37]=1
Reactant: COC(=O)c1ccc(N2CC(C)NC(C)C2)cc1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CC(C)NC(C)C4)cc3)[nH]n2)cc(OC)c1
Yield: 10.5 %

Procedure:
N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(3,5-dimethylpiperazin-1-yl)benzamide was prepared as for Example 94, but starting from methyl 4-(3,5-dimethylpiperazin-1-yl)benzoate (221 mg, 0.84 mmol), tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (244 mg, 0.7 mmol) and 1M NaHMDS (1.13 ml, 1.13 mmol) in THF (5 ml). The crude product was purified by reverse phase prep. HPLC (basic) using a 34-54% gradient of acetonitrile in water containing 1% 0.880 ammonia. The clean fractions were taken and evaporated to afford the title compound as a white solid (34 mg, 10%); 1H NMR (399.9 MHz, DMSO-d6) δ 1.04 (6H, d), 2.22 (2H, t), 2.53 (2H, d), 2.82 (2H, t), 2.87 (4H, s), 3.71 (1H, s), 3.73 (7H, s), 6.33 (1H, t), 6.42 (2H, d), 6.44 (1H, s), 6.94 (2H, d), 7.89 (2H, d), 10.27 (1H, s), 12.07 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2O.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccc(Cl)cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnc2ccc(Cl)cc2c1Cl
Temperature: 0 °C

Procedure:
11 g (48.97 mmol) of 6-chloro-3-nitro-quinolin-4-ol (step b) in 80 ml of POCl3 are heated under reflux for 5 h (tlc-control). The cool reaction mixture is poured slowly into 1.5 l of ice water. The title compound separates as a solid. The mixture is stirred for 15 min, the temperature not exceeding 0-5° C. The solid is filtered off, washed with water and dissolved in 200 ml ethylacetate. The organic phase is washed with a mixture of 200 ml of water and 38 ml of a 2 N sodium hydroxide solution, then again with water. After drying over MgSO4, the solvent is evaporated almost to dryness; hexane is added to the residue and the title compound is isolated by filtration as a dark-grey powder. This material is used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[S:3]([C:6]1[CH:7]=[C:8]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]1[CH:13]=[N:12][C:11]([C:19]3[O:23][N:22]=[C:21]([CH2:24][CH3:25])[N:20]=3)=[CH:10][C:9]2=1)(=[O:5])=[O:4].[H-].[Na+].Br[CH2:30][CH2:31][CH2:32][Cl:33]>CN(C=O)C>[Cl:33][CH2:32][CH2:31][CH2:30][N:15]1[C:14]2[CH:13]=[N:12][C:11]([C:19]3[O:23][N:22]=[C:21]([CH2:24][CH3:25])[N:20]=3)=[CH:10][C:9]=2[C:8]2[C:16]1=[CH:17][CH:18]=[C:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:26])[CH3:1])[CH:7]=2
Reactant: CCc1noc(-c2cc3c(cn2)[nH]c2ccc(S(=O)(=O)N(C)C)cc23)n1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1noc(-c2cc3c4cc(S(=O)(=O)N(C)C)ccc4n(CCCCl)c3cn2)n1
Yield: 7 %

Procedure:
The compound was synthesized by mixing (Compound 12) (3.0 g, 8.8 mM), NaH (0.46 g, 11.0 mmol) and 1-bromo-3-chloropropane (1.5 g, 9.7 mmol) in DMF, in the same manner as illustrated in example 3 to give the title compound (0.25 g, 7%). M.p. 223°-224° C.
Reaction SMILES: [C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:11][CH:10]([NH:25]C(OC(C)(C)C)=O)[C:9]1=[O:33])=[O:6])([CH3:4])([CH3:3])[CH3:2]>C(O)C.Cl.O1CCOCC1>[C:1]([C:5]([CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:11][CH:10]([NH2:25])[C:9]1=[O:33])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CN(C2CCCCC2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CC(C)(C)C(=O)CN1C(=O)C(N)CN(C2CCCCC2)c2ccccc21
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of (±)-1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahy dro-2H-1,5-benzodiazepine (2.2 g) in ethanol (10 mL), 4 N hydrochloric acid-dioxane solution (10 mL) was added. The resulting mixture was stirred at 50° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the residue for neutralization. The resultant mixture was extracted with methylene chloride. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and diisopropyl ether was added to the residue for crystallization. Crystals so precipitated were collected by filtration, whereby the title compound (1.1 g) was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[C:4]([CH3:22])[CH:3]=1.[CH3:23][C:24]1[CH:29]=[C:28](B(O)O)[CH:27]=[C:26]([CH3:33])[N:25]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[CH3:23][C:24]1[CH:29]=[C:28]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][N:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)=[C:4]([CH3:22])[CH:3]=2)[CH:27]=[C:26]([CH3:33])[N:25]=1
Reactant: Cc1cc(B(O)O)cc(C)n1
Reactant: Cc1cc(Br)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(C)c2)cc(C)n1
Temperature: 75 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
A 25 mL round-bottom flask maintained with an inert atmosphere of nitrogen was charged with tert-butyl 4[(4-bromo-2-methylphenyl)methyl]piperazine-1-carboxylate (368 mg, 1.00 mmol, 1.00 equiv), (2,6-dimethylpyridin-4-yl)boronic acid (300 mg, 1.99 mmol, 1.99 equiv), Pd(PPh3)4 (116 mg, 0.100 mmol, 0.10 equiv), potassium carbonate (414 mg, 3.00 mmol, 3.01 equiv), dioxane (6 mL) and water (1 mL). The resulting solution was stirred overnight at 75° C. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of water (10 mL). The resulting solution was extracted with ethyl acetate (3×10 mL) and the organic layers were combined, washed with brine (2×10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/1) to yield 350 mg (89% yield) of tert-butyl 4-[[4-(2,6-dimethylpyridin-4-yl)-2-methylphenyl]methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 396 [M+H]+.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:9]2[C:12](=[O:18])[C:13]([C:15]([OH:17])=[O:16])=[CH:14][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:19].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.C(#N)C>C(O)C>[N:20]1([C:2]2[CH:11]=[CH:10][C:9]3[C:12](=[O:18])[C:13]([C:15]([OH:17])=[O:16])=[CH:14][N:7]4[C:8]=3[C:3]=2[CH2:4][CH2:5][N:6]4[CH3:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CN1CCc2c(F)ccc3c(=O)c(C(=O)O)cn1c23
Reactant: C1CCNC1
Solvent: CCO
Solvent: CC#N
Product: CN1CCc2c(N3CCCC3)ccc3c(=O)c(C(=O)O)cn1c23
Yield: 84 %

Procedure:
15 mg (0.06 mmol) of the compound (191) obtained in Example 64 and 0.1 ml of pyrrolidine were added to 5 ml of acetonitrile, and the solution was heated at reflux for 2 hours. After the solvent was removed by distillation, obtained crystals were dispersed in ethanol and filtered off and washed with ethanol and ether in this order to obtain 15 mg of the subject compound (192) in a 84% yield.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH2:7][C:8]1[CH:28]=[CH:27][C:11]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[NH:20][CH2:21][C:22]([O:24]CC)=[O:23])=[C:10]([Cl:29])[CH:9]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:19][C:17]1[CH:16]=[CH:15][C:14]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[C:13]([O:12][C:11]2[CH:27]=[CH:28][C:8]([NH:7][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:9][C:10]=2[Cl:29])[CH:18]=1
Reactant: CCS(=O)(=O)Cl
Reactant: CCOC(=O)CNc1ccc(Cl)cc1Oc1ccc(N)cc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1ccc(Oc2cc(Cl)ccc2NCC(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethanesulphonyl chloride (0.1 ml) was added to a mixture of the product from step (iii) (0.11 g) and pyridine (0.5 ml) in DCM (4 ml). After stirring at room temperature for 4 h the mixture was partitioned between diethylether/2 M HCl. The organics separated, dried and evaporated under reduced pressure. The residue was dissolved in methanol (5 ml) then 2M NaOH added and stirred at room temperature for 20 h. The solvent was removed under reduced pressure and the residue partitioned between ethylacetate/1M HCl. The organics were separated, washed with water, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 80% ethylacetate/isohexane, yield 0.025 g.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[C:15]([O:34][CH3:35])=[CH:16][CH:17]=[C:18]2[C:23]=1[O:22][C:21](=[O:24])[CH:20]=[C:19]2[NH:25][C:26]1[C:31]([Cl:32])=[CH:30][N:29]=[CH:28][C:27]=1[Cl:33]>>[Cl:33][C:27]1[CH:28]=[N:29][CH:30]=[C:31]([Cl:32])[C:26]=1[NH:25][C:19]1[C:18]2[C:23](=[C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[C:15]([O:34][CH3:35])=[CH:16][CH:17]=2)[O:22][C:21](=[O:24])[CH:20]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCBr
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCN1CCN(C)CC1

Procedure:
The title compound was prepared from 1-methylpiperazine and 8-(4-bromobutoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (Example 25) following the procedure outlined in Example 52. 1H NMR (400 MHz, DMSO-d6; bis HCl salt): δ 11.74 (br, 2H), 9.66 (s, 1H), 8.82 (s, 2H), 8.02 (d, 1H), 7.22 (d, 1H), 4.63 (s, 1H), 4.01 (t, 2H), 3.94 (s, 3H), 3.84-3.18 (br m, 10H), 2.81 (s, 3H), 1.97 (m, 2H), 1.75 (m, 2H); MS (ESI): 507.0.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[H-].[Na+].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[CH2:14]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=[O:6])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1cc(O)cc(Cl)c1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cc(Cl)cc(OCc2ccccc2)c1

Procedure:
To a solution of 173 mg. (1 m mole) of 3-hydroxy-5-chlorobenzoic acid in 2 ml. of dimethylformamide is added 85 mg. (2 m moles) of 56.6% sodium hydride in an oil suspension. After ten minutes, the resulting suspension is treated with 130 mg. (1 m mole) of benzyl chloride and the mixture heated to 100° C. for one hour. The reaction mixture is then cooled, diluted with 5 ml. of water, and extracted with ether. The aqueous phase is separated, acidified with 6N hydrochloric acid and the product extracted with ether. The ether solvent is removed in vacuo and the residual product triturated with water and filtered. The dried product is sublimed at 125° C. and 0.02 mm of pressure to provide 50 mg. of the desired produce, m.p. 127-129° C.
Reaction SMILES: [C:1]1([S:7]([C:9]2[C:10]([CH2:15][O:16]C(=O)C)=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+]>CO.C(Cl)Cl>[C:1]1([S:7]([C:9]2[C:10]([CH2:15][OH:16])=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OCc1ncccc1S(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: O=S(c1ccccc1)c1cccnc1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.4 %

Procedure:
To a solution of the crude Acetic acid 3-benzenesulfinyl-pyridin-2-ylmethyl ester (268 mg) in anhydrous MeOH (4 mL) was added powdered K2CO3 (254 mg, 1.84 mmol) and the mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with CH2Cl2 (30 mL), filtered by vacuum filtration, and the filtrate was concentrated. Purification by flash chromatography on silica gel (Hexanes/EtOAc, 20:80 then 0:100) provided (3-Benzenesulfinyl-pyridin-2-yl)-methanol (128 mg, 42% over 2 steps) as a colorless oil. 1H NMR (CDCl3) δ 4.18 (t, 1H, J=5.7 Hz), 4.58 (dd, 1H, J=14.8, 4.3 Hz), 4.88 (dd, 1H, J=14.9, 5.3 Hz), 7.45-7.53 (m, 4H), 7.59-7.66 (m, 2H), 8.33 (dd, 1H, J=7.9, 1.4 Hz), 8.66 (dd, 1H, J=5.3, 1.8 Hz).
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)=[O:13])[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].[ClH:22].[CH3:23][NH:24][CH3:25]>>[ClH:22].[ClH:22].[CH3:23][N:24]([CH2:18][C:17]1[CH:20]=[CH:21][C:14]([C:12]([N:9]2[CH2:10][CH2:11][N:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH2:7][CH2:8]2)=[O:13])=[CH:15][CH:16]=1)[CH3:25]
Reactant: CCC(CC)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Reactant: CNC
Agent: Cl
Product: CCC(CC)N1CCN(C(=O)c2ccc(CN(C)C)cc2)CC1

Procedure:
Prepared from the product of Example 12 and dimethylamine hydrochloride.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].CI.[C:13](=O)([O-])[O-].[Li+].[Li+]>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:13])[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [Li+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1O
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 82.2 %

Procedure:
3,4-Dihydroxybenzaldehyde (2.76 g, 20 mmol) was dissolved in DMF (15 ml), and methyl iodide (37.4 ml, 60 mmol) and anhydrous lithium carbonate (4.4 g, 60 mmol) were successively added to this solution. After being stirred at an external temperature of 90° C. for 1.5 hours, the reaction mixture was cooled to room temperature and the inorganic salt was filtered off. A saturated aqueous solution of ammonium chloride (200 ml) was added to the filtrate to adjust the aqueous layer to a pH of from 7 to 8, and the solution was extracted with ethyl acetate (300 ml×2). The combined organic layer was washed with a saturated aqueous solution of sodium chloride (300 ml), dried over anhydrous magnesium sulfate, filtered to remove the desiccating agent, and concentrated under reduced pressure to give the title compound (2.5 g, 82.2%) (Table 1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH:6]=[CH:7][C:8]([OH:10])=[O:9])#[N:2].O[N:15]1[C:19](=[O:20])[CH2:18][CH2:17][C:16]1=[O:21].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]([O:10][N:15]2[C:19](=[O:20])[CH2:18][CH2:17][C:16]2=[O:21])=[O:9])[CH:11]=[CH:12][CH:13]=1)#[N:2]
Reactant: O=C1CCC(=O)N1O
Reactant: N#Cc1cccc(C=CC(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: N#Cc1cccc(C=CC(=O)ON2C(=O)CCC2=O)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.6 %

Procedure:
To methylene chloride (300 mL) suspension of 3-cyanocinnamic acid (9.0 g) and N-hydroxysuccinic acid imide (9.0 g) was added WSC.HCl (15.0 g) at 0° C., and the mixture was stirred for 6 hours at room temperature. The reaction mixture was washed with water, and the organic layer was dried over anhydrous sodium sulfate. The crystals obtained by distilling off the solvent under a reduced pressure were filtered with diethyl ether, to give the captioned compound (13.0 g, 93%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[NH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:22])=[N:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2cc(OCc3ccccc3)ccc12
Product: Clc1ncnc2cc(OCc3ccccc3)ccc12
Yield: 90 %

Procedure:
A solution of the product from Step 2 (2.82 g, 11.2 mmol) in phosphorous oxychloride (20 mL) was heated at 100° C. for 16 hours. The reaction was concentrated and azeotroped once with dichlromethane. The residue was dissolved in EtOAc and washed with saturated sodium bicarbonate solution then saturated sodium chloride solution. The organic layer was dried over sodium sulfate and concentrated to provide 7-(benzyloxy)-4-chloroquinazoline (2.72 g, 90%) as a yellow solid. MS 271.2 (ES+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[C:6](O)=[N:7][CH:8]=1)#[N:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[NH2:25][C@H:26]1[CH2:31][CH2:30][C@H:29]([OH:32])[CH2:28][CH2:27]1>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[C:6]([NH:25][C@H:26]2[CH2:31][CH2:30][C@H:29]([OH:32])[CH2:28][CH2:27]2)=[N:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cnc(O)c([N+](=O)[O-])c1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cnc(N[C@H]2CC[C@H](O)CC2)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
To a solution of 5-cyano-2-hydroxy-3-nitropyridine (600 mg) in 6 mL of dichloromethane containing triethylamine(0.557 mL) was added methanesulfonyl chloride (0.295 mL) under stirring at 0° C. The reaction mixture was stirred at the same temperature for 30 minutes, and then trans-4-aminocyclohexanol (1.26 g) was added to the mixture at 0° C. After stirring at room temperature for 2 hours, the mixture was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was subjected to a preparative silica gel column chromatography eluting with 5% methanol in chloroform. The obtained substance was triturated with diisopropyl ether to give 5-cyano-2-(trans-4-hydroxycyclohexylamino)-3-nitropyridine (198.9 mg) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[NH:11][C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1.[Br:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br>>[Br:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][N:11]1[C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=[C:2]1[Cl:1]
Reactant: BrCc1ccccc1Br
Reactant: Cn1c(=O)c2[nH]c(Cl)nc2n(C)c1=O
Product: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2Br)n(C)c1=O

Procedure:
From 8-Chorotheophylline (10 g, 46.6 mol) and 2-bromobenzyl bromide (12.2 g, 48.93 mol).