Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13](F)[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[CH2:24][OH:25])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[C-:26]#[N:27].[Na+]>CS(C)=O>[C:1]([C:5]1[CH:14]=[C:13]([C:26]#[N:27])[C:12]2[C:11](=[O:16])[N:10]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[CH2:24][OH:25])[N:9]=[CH:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(Cl)c3CO)ncc2c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(C#N)c2c(=O)n(-c3cccc(Cl)c3CO)ncc2c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 57 %

Procedure:
To a 100 mL round-bottomed flask were added 6-tert-butyl-2-[3-chloro-2-(hydroxymethyl)phenyl]-8-fluorophthalazin-1(2H)-one (671 mg, 1.86 mmol, prepared according to US2010/0222325), sodium cyanide (365 mg, 7.44 mmol) and DMSO (10 mL) to give a light yellow suspension. The mixture was stirred at 80° C. for 16 hrs. Additional sodium cyanide (182 mg, 3.72 mmol) was added and the mixture was further stirred at 80° C. for 60 hrs. The mixture was cooled to room temperature and extracted with ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate and filtered. Solvents were evaporated and the residue was purified through flash column chromatography (220 g silica gel, 0% to 40% acetone in heptane) to give 7-tert-butyl-3-[3-chloro-2-(hydroxymethyl)phenyl]-4-oxo-3,4-dihydrophthalazine-5-carbonitrile as a yellow solid (390 mg, 57% yield).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12.CCN(CC)CC.[H][H]>CO.[Pd]>[NH:8]1[C:7]2=[CH:2][N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9]1
Reactant: Clc1nccc2cc[nH]c12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: c1cc2cc[nH]c2cn1
Yield: 96.8 %

Procedure:
A mixture of Example 695H (3.6 g, 23.6 mmol), Pd/C (0.5 g, 5%), and Et3N (2.3 g, 23.6 mmol) in MeOH (100 mL) was stirred under a balloon of hydrogen at room temperature overnight. The reaction mixture was filtered through diatomaceous earth (Celite®), and the solid was washed with additional MeOH. The solvent was removed to near dryness, and the semi-solid was treated with 300 mL of EtOAc. The precipitate was removed right away by filtration, and the filtrate was concentrated. The residue was re-dissolved in CH2Cl2, and loaded onto a silica gel column eluted with 100/5:0/5 (EtOAc/MeOH/NH4OH) to give 2.7 g (100%) of the desired product. MS (DCI) m/e 119 (M+H)+, 1H NMR (300 MHz, DMSO-d6): □ 11.6 (br s, 1H), 8.76 (dd, J=1.0, 1.0 Hz, 1H), 8.08 (d, J=5.4 Hz, 1H), 7.60 (d, J=3.0 Hz, 1H), 7.53 (dd, J=5.4, 1.0 Hz, 1H), 6.50 (dd, J=3.0, 1.0 Hz, 1H).
Reaction SMILES: C([NH:8][CH2:9][CH2:10][NH:11][C:12]1[C:20]2[C:15](=[N:16][CH:17]=[N:18][C:19]=2[NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[NH:14][N:13]=1)(OC(C)(C)C)=O>Cl>[ClH:28].[ClH:28].[NH2:8][CH2:9][CH2:10][NH:11][C:12]1[C:20]2[C:15](=[N:16][CH:17]=[N:18][C:19]=2[NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[NH:14][N:13]=1
Reactant: CC(C)(C)OC(=O)NCCNc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Agent: Cl
Product: NCCNc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Temperature: 20 °C
Reaction time: 18 h

Procedure:
15 g (36.25 mmol) of 3-[2-(Boc-amino)-ethylamino]-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine (water content: 2.39%; see Example 105) are dissolved in 250 ml of 3N methanolic hydrochloric acid and the reaction mixture is stirred at 20° C. for 18 hours. Subsequent filtration and washing the filter residue with methanol and diethyl ether yield 3-(2-aminoethylamino)-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine dihydrochloride having a water content of 3.31%; m.p.>260° C.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[C:14]1[N:23]=[C:22]([NH:24][C@H:25]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1>ClCCl>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([OH:6])=[C:8]([C:14]2[N:23]=[C:22]([NH:24][C@H:25]3[CH2:29][CH2:28][NH:27][CH2:26]3)[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH:9]=1
Reactant: COc1ccc(C)cc1-c1nc(N[C@H]2CCN(C(=O)OC(C)(C)C)C2)c2ccccc2n1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccc(O)c(-c2nc(N[C@H]3CCNC3)c3ccccc3n2)c1
Reaction time: 16 h
Yield: 33.9 %

Procedure:
Boron tribromide (0.454 mL of a 1 M solution in dichloromethane, 0.45 mmol) was added to a solution of (S)-tert-butyl 3-(2-(2-methoxy-5-methylphenyl)quinazolin-4-ylamino)pyrrolidine-1-carboxylate (0.079 g, 0.23 mmol) in dichloromethane (2.3 mL). After 16 hours, the reaction was quenched by the addition of methanol (2 mL). Hydrochloric acid (1.5 mL of a 4 M solution in dioxane) was added and the mixture was heated at reflux for 6 hours. The solution was cooled, concentrated, and purified by SCX-2 Isolute column (2 g), eluting first with methanol and finally 1 M ammonia in methanol. Silica column chromatography (5% methanol in DCM) gave the title compound as a yellow solid (0.025 g, 35%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH:6]=[CH:7][C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:9].Br[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][CH:23]=1>>[C:25]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:26]=[CH:27][C:22](/[C:6](/[C:5]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:7]/[C:8]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[O:9])=[CH:23][CH:24]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: COc1ccc(C=CC(=O)N2CCOCC2)cc1OC
Product: COc1ccc(/C(=C\C(=O)N2CCOCC2)c2ccc(-c3ccccc3)cc2)cc1OC

Procedure:
Analogous to Example 21, the title compound was prepared starting from 3,4-dimethoxycinnamic acid morpholide and 4-bromo-biphenyl.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([SH:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[H-].[Na+].[Br:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26]Br)=[CH:22][CH:21]=1.O>CN(C=O)C>[Br:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][S:13][C:7]2[C:6]3[C:11](=[CH:12][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][CH:5]=3)[N:10]=[CH:9][CH:8]=2)=[CH:22][CH:21]=1
Reactant: FC(F)(F)c1ccc2c(S)ccnc2c1
Reactant: BrCc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2c(SCc3ccc(CBr)cc3)ccnc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15 %

Procedure:
In 25 mL round-bottomed flask 25 mL 7-trifluoromethyl-quinoline-4-thiol (1.0 g, 4.37 mmol) was dissolved in 8 mL DMF anhydrous and NaH (60% dispersion in oil, 184 mg) was added slowly. The reaction was stirred at RT for 10 min. In a 50 mL round-bottomed flask 1,4-bis-bromomethyl-benzene (1.27 g, 4.80 mmol) was dissolved in DMF anhydrous (10 mL) and the solution was stirred at 0° C. for 10 min. The first solution was added via syringe to this solution and the reaction was stirred at 0° C. for 15 min. The solution orange became pale yellow and the mixture stirred 2 h at RT. Water (50 mL) was added and the product extracted with diethyl ether (5×100 mL). The organic layer was washed with water (3×50 mL), brine (3×50 mL), dried with MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent cyclohexane:diethyl ether=7:3. 4-(4-(Bromomethyl)benzylthio)-7-(trifluoromethyl)quinoline 29 was obtained (265 mg, 15% yield) as white solid.
Reaction SMILES: [CH3:1][NH:2][CH:3]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11]C(=O)C(C)(C)C.[ClH:24]>>[ClH:24].[ClH:24].[CH3:1][NH:2][CH:3]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11]
Reactant: CNC(Cc1ccccc1NC(=O)C(C)(C)C)c1ccccc1
Agent: Cl
Product: CNC(Cc1ccccc1N)c1ccccc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
N-[2-(2-methylamino-2-phenylethyl)phenyl]-2,2-dimethylpropanamide (62 g, 0.2 mol) was dissolved in 6N HCl (124 g) and stirred under a nitrogen atmosphere at 100° C. for 24 hours. The warm reaction mixture (about 35°-40° C.) was extracted with toluene (2×100 ml) to effect recovery of trimethylacetic acid. The aqueous phase was dried by azeotropic distillation with toluene (200 ml) using a Dean-Stark phase separator. The product was collected by filtration, slurried in hot 2-propanol (200 ml), refiltered and dried in vacuo (30 mm) at 45° C. for 12 hours to give N-methyl-2-amino-α-phenylphenethylamine dihydrochloride (58.7 g, 0.196 mol) in 98% yield. The product had a melting point of 251°-253° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@@H:11]([OH:14])[C@H:10]([CH2:15][O:16][C:17]2[N:18]=[N:19][C:20]([CH2:36][CH2:37][CH2:38][CH3:39])=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:25][CH:24]=3)[CH:22]=2)[CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[CH2:36]([C:20]1[N:19]=[N:18][C:17]([O:16][CH2:15][C@H:10]2[C@H:11]([OH:14])[CH2:12][CH2:13][NH:8][CH2:9]2)=[CH:22][C:21]=1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:25][CH:24]=1)[CH2:37][CH2:38][CH3:39]
Reactant: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@H]2O)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCCc1nnc(OC[C@@H]2CNCC[C@H]2O)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (±)-trans-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.157 mmol, 0.85 g; Example 46) in DCM (1 mL) was added 4 N HCl in dioxane (4 mL) and continued stirring for 30 min at room temperature. The volatiles were removed under reduced pressure. The residue was washed with anhydrous ether and the solid was dried under high vacuum to provide (±)-trans-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-piperidin-4-ol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH2:14][OH:15])=[C:12]([CH:16]([CH3:18])[CH3:17])[N:11]=[C:10]3[NH:19][CH:20]=[CH:21][C:9]=23)=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14]=[O:15])=[C:12]([CH:16]([CH3:18])[CH3:17])[N:11]=[C:10]3[NH:19][CH:20]=[CH:21][C:9]=23)=[CH:4][CH:3]=1
Reactant: CC(C)c1nc2[nH]ccc2c(-c2ccc(F)cc2)c1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)c1nc2[nH]ccc2c(-c2ccc(F)cc2)c1C=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
23.9 g (84 mmol) of the compound from Example VII are suspended in 1.6 1 of dichloromethane, 17.1 g of neutral alumina and 36.1 g (168 mmol) of pyridinium chlorochromate are added and the mixture is stirred at room temperature for 1 h. The suspension is filtered through 1.2 kg of silica gel (230-400 mesh) in a glass suction filter and washed without sucking dry using petroleum ether/ethyl acetate 3:2. The eluate is concentrated to dryness in vacuo and the residue which remains is stirred thoroughly in ether.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:11]1([CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)([CH3:22])[CH3:21])[CH:15]=[CH:14][N:13]=[CH:12]1.C(N(CC)CC)C>ClCCl>[C:1]1([S:7]([O:29][C:26]2[CH:27]=[CH:28][C:23]([C:20]([NH:19][CH2:18][CH2:17][CH2:16][N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)([CH3:22])[CH3:21])=[CH:24][CH:25]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(NCCCn1ccnc1)c1ccc(O)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(NCCCn1ccnc1)c1ccc(OS(=O)(=O)c2ccccc2)cc1

Procedure:
A solution of benzenesulphonyl chloride (0.51 g) in dichloromethane (5 ml) was added in portions over 5 minutes to a solution of 4-{1-[3-(imidazol-1-yl)propylamino]-1-methylethyl}phenol (0.75 g) and triethylamine (0.29 g) in dichloromethane (5 ml) at 0° C. with stirring. The mixture was stirred at ambient temperature for 3 hours then diluted with dichloromethane and washed with water. The organic layer was separated, dried and evaporated. The residue was purified by flash column chromatography on silica using methanol as the mobile phase to give 4-{1-[3-(imidazol-1-yl)propylamino]-1-methylethyl}phenyl benzenesulphonate as an oil.
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=1.[CH3:8][S:9]([C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1)(=[O:11])=[O:10].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O.C(OCC)(=O)C>[CH3:8][S:9]([C:12]1[CH:19]=[CH:18][C:15]([CH2:16][S:1][C:2]2[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=2)=[CH:14][CH:13]=1)(=[O:10])=[O:11]
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Reactant: Cn1ccnc1S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1ccnc1SCc1ccc(S(C)(=O)=O)cc1
Reaction time: 18 h

Procedure:
To a solution of 2-mercapto-N-methylimidazole (570 mg, 4.9 mmol) and 4-methanesulfonylbenzyl chloride (1 g, 4,9 mmol) in DMF (10 mL) at 21° C. was added cesium carbonate (0.8 g, 2.5 mmol). After 18 h, the reaction mixture was diluted with water and ethyl acetate. The organic extracts were washed (H2O), (brine), dried (MgSO4), filtered and concentrated to provide the 2-(4-methanesulfonyl-benzylsulfanyl)-1-methyl-1H-imidazole compound as a white solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:11][C:10](=[O:12])[C:9]([C:13]#[N:14])=[CH:8][CH:7]=1.Cl[CH2:16][C:17]([NH2:19])=[O:18].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C.O>[C:13]([C:9]1[C:10]([O:12][CH2:16][C:17]([NH2:19])=[O:18])=[N:11][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:7][CH:8]=1)#[N:14]
Reactant: NC(=O)CCl
Reactant: N#Cc1ccc(-c2ccco2)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(-c2ccco2)nc1OCC(N)=O
Temperature: 60 °C
Reaction time: 6 h
Yield: 53.5 %

Procedure:
A suspension of 6-(2-furyl)-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (6.0 g, 32.3 mmol), 2-chloroacetamide (3.0 g, 37.7 mmol), sodium iodide (5.7 g, 38.0 mmol) and potassium carbonate (9.0 g, 56.2 mmol) in acetone (100 ml) was stirred at 60° C. for 6 hours. After cooling as it was, the reaction solution was diluted with ethyl acetate and water. The organic layer was washed with an aqueous saturated solution of sodium bicarbonate (×2) and an aqueous saturated solution of ammonium chloride, dried over anhydrous sodium sulfate, and concentrated. Diethyl ether was added to the residue, and the resulting precipitates were collected by filtration and washed with diethyl ether, to give the title compound (4.2 g, 54%) as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.[CH3:24][CH:25]([NH2:30])[C:26]([F:29])([F:28])[F:27]>>[F:27][C:26]([F:29])([F:28])[C@@H:25]([NH:30][C:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:20][N:19]=1)=[O:23])[CH3:24]
Reactant: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)O)nc1
Reactant: CC(N)C(F)(F)F
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)N[C@@H](C)C(F)(F)F)nc1
Yield: 70 %

Procedure:
As described for example 7, 5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid (100 mg, 0.32 mmol) was converted, using L-2,2,2-trifluoro-1-(methyl)ethylamine instead of isopropylamine, to the title compound (92 mg, 70%), which was obtained as a white solid. MS: m/e=407.2 [M+H]+.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:31]1[CH2:30][CH2:29][CH:28]([NH:27][C:25]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:8]4[CH:9]=[C:10]([CH2:13][CH3:14])[CH:11]=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:16]=3[NH:23][C:22]=2[CH3:24])=[O:26])[CH2:33][CH2:32]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Agent: Cl
Product: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(C)=O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f48) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [N+](C1C(O)=C(N=NC2C=CC=CC=2)C=C(C)C=1)([O-])=O.[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[N:30]=[N:31][C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:33]=1[OH:43])([O-])=O>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]2=[N:20][N:31]([C:32]3[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:33]=3[OH:43])[N:30]=[C:24]2[CH:25]=1
Reactant: Cc1cc(N=Nc2cc(Cl)ccc2[N+](=O)[O-])c(O)c(C(C)(C)C)c1
Agent: Cc1cc(N=Nc2ccccc2)c(O)c([N+](=O)[O-])c1
Product: Cc1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1

Procedure:
When in Example 1, the 2 nitro-2'-hydroxy-5'-methyl-azobenzene is replaced by an equivalent amount of 2-nitro-5-chloro-2'-hydroxy-3'-tert-butyl-5'-methylazobenzene, the above noted product is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1Br)([O-:3])=[O:2].[CH2:11]([N:15]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][NH2:19])[CH2:12][CH2:13][CH3:14].C([O-])(=O)C.[Na+].Cl>>[CH2:11]([N:15]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][NH:19][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCN(CCCC)CCCN
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: CCCCN(CCCC)CCCNc1ccccc1[N+](=O)[O-]

Procedure:
15 g. of o-nitrobromobenzene and 13 g. of 3-dibutylaminopropylamine are agitated with 15 g. of anhydrous sodium acetate for 7 hours at 135° C. The reaction mixture is taken up in 70 ml. of 6N hydrochloric acid and 80 ml. of water, the unreacted o-nitrobromobenzene is subjected to steam distillation, the distillation residue is rendered alkaline with potassium hydroxide solution, and extracted with ether. After distilling the residue of the ether extract, 12 g. of 2-(3-dibutylaminopropylamino)-nitrobenzene is obtained, b.p. 140°-160° C. at 0.1 mm Hg.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:35]=[CH:34][CH:33]=[CH:32][C:26]=2[C:27]([NH:29][CH2:30][CH3:31])=[O:28])[C:21]([Cl:36])=[CH:20][N:19]=1>>[Cl:36][C:21]1[C:22]([NH:24][C:25]2[CH:35]=[CH:34][CH:33]=[CH:32][C:26]=2[C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[N:23][C:18]([NH:14][C:11]2[CH:12]=[CH:13][C:8]3[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:9]=3[CH:10]=2)=[N:19][CH:20]=1
Reactant: CCN1CCN(CC)c2cc(N)ccc2C1
Reactant: CCNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CCNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)N(CC)CCN(CC)C3)ncc1Cl

Procedure:
The title compound was prepared from 1,4-Diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-ethyl-benzamide in an analogous manner to example 712. Product was isolated as a tan solid (0.060 g, 53%); Mp 181-186° C.; LCMS (m/e) 494 (M); 1H-NMR (DMSO, 400 MHz) δ 11.56 (s, 1H), 9.30 (s, 1H), 8.81-8.74 (m, 2H), 8.21 (s, 1H), 7.75-7.77 (d, 1H, J=8.09 Hz), 7.44-7.48 (t, 1H, J=7.83 Hz), 7.23-7.25 (d, 1H, J=8.08 Hz), 7.14-7.16 (t, 2H, J=8.09 Hz), 6.99-7.01 (d, 1H, J=8.08 Hz), 3.60 (s, 2H), 3.05-3.07 (q, 2H, J=7.07 Hz), 2.92 (m, 2H), 2.77 (m, 2H), 2.39-2.41 (q, 2H, J=7.33 Hz), 1.18-1.09 (m, 6H), 1.06-1.00 (t, 3H, J=7.08 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@H:13]2[O:25][CH3:26])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.C(OCC)(=O)C>CO>[ClH:1].[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[O:25][CH3:26])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)nc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1[nH]c(C(=O)N[C@H]2CCNC[C@H]2OC)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 201 %

Procedure:
tert-Butyl cis(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1g) (500 mg, 1.29 mmol) was dissolved in methanol (30 mL). A 4 N hydrochloric acid/ethyl acetate solution (20 mL) was added, and the mixture was stirred at room temperature for one hour. Concentration under reduced pressure gave 419 mg of the title compound as a white solid (100%).
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+].CC(C)=O>O>[CH2:18]([O:1][C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc2ccc3cccc4ccc1c2c34
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: c1ccc(COc2ccc3ccc4cccc5ccc2c3c45)cc1
Yield: 25.1 %

Procedure:
To a RB flask equipped with overhead stirrer, condenser and N2 inlet line with bubbler was added 1-hydroxypyrene (Cambridge Chemical, Inc., 5.0 g, 23 mmol), benzyl bromide (Aldrich, 15.64 g, 92 mmol, 10.94 mL), K2CO3 (Mallinckrodt, 12.72 g, 92 mmol) and acetone (100 mL). The mixture was refluxed overnight, cooled and then poured into H2O (250 mL) and extracted with EtOAc (3×100 mL). The EtOAc layers were combined and washed successively with 1N NaOH (100 mL), H2O (100 mL) and saturated NaCl solution (2×100 mL). The solution was then dried (K2CO3) and the solvent removed by rotary evaporation to give the crude product. This material was purified by passing it through a plug of SiO2 using PhCH3 as the eluting solvent. The solvent was then removed from the appropriate fractions by rotary evaporation and the solid recrystallized from CH2Cl2 /hexane to give 1.78 g (25.9% yield) of 1-benzyloxypyrene, mp 105°-106°, (C,H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:13]=[N:14][N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:25])[CH3:24])[CH2:19][CH2:18]3)[CH:16]=2)=[C:6]2[CH:10]=[C:9](Cl)[O:8][C:7]=12.[CH3:26][N:27]1[C:32](=[O:33])[CH:31]=[C:30]2[S:34][CH:35]=[C:36](B3OC(C)(C)C(C)(C)O3)[C:29]2=[CH:28]1>>[C:23]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]2[CH:16]=[C:12]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[C:7]4[O:8][C:9]([C:36]5[C:29]6=[CH:28][N:27]([CH3:26])[C:32](=[O:33])[CH:31]=[C:30]6[S:34][CH:35]=5)=[CH:10][C:6]=34)[CH:13]=[N:14]2)[CH2:18][CH2:19]1)(=[O:25])[CH3:24]
Reactant: Cn1cc2c(B3OC(C)(C)C(C)(C)O3)csc2cc1=O
Reactant: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(Cl)cc34)cn2)CC1
Product: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(-c5csc6cc(=O)n(C)cc56)cc34)cn2)CC1
Yield: 30 %

Procedure:
The title compound was prepared in 30% yield from 1-{4-[4-(7-amino-2-chlorofuro[2,3-c]pyridin-4-yl)-1H-pyrazol-1-yl]piperidin-1-yl}ethanone and 5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thieno[3,2-c]pyridin-6(5H)-one by a procedure analogous to Example 223, Step D. 1H NMR (400 MHz, CD3OD): δ 9.01 (s, 1 H), 8.29 (s, 1 H), 8.17 (s, 1 H), 8.03 (s, 1 H), 7.83 (s, 1 H), 7.75 (s, 1 H), 7.07 (s, 1 H), 4.69 (m, J=13.1 Hz, 1 H), 4.51-4.62 (m, 1 H), 4.11 (m, J=16.4 Hz, 1 H), 3.87 (s, 3 H), 3.33-3.42 (m, 1 H), 2.80-2.96 (m, 1 H), 2.16-2.30 (m, 5 H), 1.95-2.15 (m, 2 H); MS (ESI): 489.37 [M+H]+; HPLC tR=2.32 min (ZQ3, polar—4 min).