Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:43])[C:5]([CH3:42])([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([C:25]2[N:26]([CH3:40])[N:27]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)[CH:29]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[CH:10][C:9]=1[CH3:41])[CH3:6])C.[OH-].[Na+]>CCO>[CH3:42][C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([C:25]2[N:26]([CH3:40])[N:27]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:38])([F:37])[F:39])=[CH:32][CH:31]=3)[CH:29]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[CH:10][C:9]=1[CH3:41])([CH3:6])[C:4]([OH:43])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN(Cc2ccccc2OC)c2cc(-c3ccc(C(F)(F)F)cc3)nn2C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccccc1CN(Cc1ccc(OC(C)(C)C(=O)O)c(C)c1)c1cc(-c2ccc(C(F)(F)F)cc2)nn1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 21.6 %

Procedure:
To a solution of example 106 (280 mg, 0.49 mmol) in EtOH (20 mL) was added excess of a 1N NaOH solution and the mixture was stirred at 50° C. for 2 h. The reaction was cooled, evaporated to dryness, the residue taken up with water, neutralized with 1N HCl to pH 7 and then extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and the solvent removed under vacuum. The residue was then chromatographed eluting with CH2Cl2 (100%), CH2Cl2/MeOH (99/1), CH2Cl2/MeOH (98/2) and finally CH2Cl2/MeOH (96/4) to afford the title compound as an oil (60 mg, 22%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.[NH2:18][CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[Cl:17][C:13]1[CH:12]=[C:11]([C:8]2[N:6]3[N:7]=[C:2]([NH:18][CH:19]4[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: NC1CCC(=O)CC1
Reactant: Clc1cccc(-c2cnc3ccc(Cl)nn23)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C1CCC(Nc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1
Temperature: 180 °C
Reaction time: 1 h
Yield: 15.5 %

Procedure:
To a solution of 6-chloro-3-(3-chlorophenyl)imidazo[1,2-b]pyridazine (200 mg, 0.757 mmol) and 4-aminocyclohexanone (290 mg, 2.56 mmol) in NMP (1.0 mL) was added NaHCO3 (118 mg, 1.52 mmol), the mixture was stirred at 180° C. for 60 mins under microwave irridation. The mixture was purified by flash chromatograph to give 4-((3-(3-chlorophenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexanone (40 mg, 0.117 mmol, 16%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:5]2[CH:6]=[C:7]([CH3:8])[C:2]([NH2:1])=[N:3][CH:4]=2)=[CH:13][CH:12]=1
Reactant: Cc1cc(Br)cnc1N
Reactant: OB(O)c1ccc(Cl)cc1
Product: Cc1cc(-c2ccc(Cl)cc2)cnc1N
Yield: 82.5 %

Procedure:
Prepared as described in example C.32 (step 4) from commercially available 2-amino-5-bromo-3-methyl-pyridine (4 g, 21.4 mmol) and commercially available 4-chlorophenylboronic acid (3.68 g, 23.5 mmol). Obtained as an off-white solid (3.86 g, 83%). MS (EI) 218.1 [(M)+]; mp 156° C.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].N1C=CC=CC=1.[CH2:27]([S:30](Cl)(=[O:32])=[O:31])[CH2:28][CH3:29]>ClCCl>[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([NH:20][S:30]([CH2:27][CH2:28][CH3:29])(=[O:32])=[O:31])[CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCS(=O)(=O)Cl
Reactant: CCCCCCN1CC2C(C1)C2(C)c1cccc(N)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCN1CC2C(C1)C2(C)c1cccc(NS(=O)(=O)CCC)c1
Reaction time: 48 h
Yield: 14.4 %

Procedure:
To a solution of 3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation 12, 200 mg, 0.735 mmol), in dichloromethane (5 ml) at room temperature was added pyridine (0.15 ml, 1.84 mmol) then dropwise over 5 minutes propane-sulfonylchloride (0.16 ml, 202 mg, 1.42 mmol). The mixture was stirred for 48 hours, concentrated in vacuo and the residue was purified by silica (10 g) column chromatography eluting with ethyl acetate then 90:10:1 ethyl acetate:methanol:ammonia solution (0.880). Product-containing fractions were combined and concentrated in vacuo to give the title compound as a pale yellow oil (40 mg, 14%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[N:10]=[C:11]([CH:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:28])[F:27])[CH2:15][CH2:16][C:17](O)=[O:18])[NH:12][N:13]=2)[CH:6]=[CH:5][C:4]=1[N:30]1[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]1.C(N(C(C)C)CC)(C)C.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>O1CCCC1>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[N:10]=[C:11]3[CH:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:28])([F:29])[F:27])[CH2:15][CH2:16][C:17](=[O:18])[N:12]3[N:13]=2)[CH:6]=[CH:5][C:4]=1[N:30]1[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]1
Reactant: COc1nc(-c2n[nH]c(C(CCC(=O)O)c3ccccc3C(F)(F)F)n2)ccc1-n1cnc(C)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1nc(-c2nc3n(n2)C(=O)CCC3c2ccccc2C(F)(F)F)ccc1-n1cnc(C)c1
Reaction time: 19 h
Yield: 63.9 %

Procedure:
4-[5-[6-Methoxy-5-(4-methyl-imidazol-1-yl)-pyridin-2-yl]-2H-[1,2,4]-triazol-3-yl]-4-(2-trifluoromethylphenyl)-butyric acid (208 mg) was dissolved in tetrahydrofuran (4.3 ml). Diisopropylethylamine (220 ul), 1-hydroxybenzotriazole (86.8 mg) and benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (334 mg) were added at room temperature and the reaction was initiated. After 19 hours, the reaction was terminated with water, followed by dilution with ethyl acetate. The organic layer was washed with saturated ammonium chloride and brine and dried over magnesium sulfate. Concentration under reduced pressure gave an oil. The oil was purified by silica gel column chromatography (mobile phase:ethyl acetate/heptane=0 to 100%) to obtain the title compound (128 mg) as an orange solid.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[SH:11][CH2:12][C:13]([NH2:15])=[O:14].C[O-].[Na+]>CN(C=O)C.CO>[NH2:6][C:5]1[C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([Br:1])[C:3]=2[S:11][C:12]=1[C:13]([NH2:15])=[O:14]
Reactant: N#Cc1cccc(Br)c1F
Reactant: NC(=O)CS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: NC(=O)c1sc2c(Br)cccc2c1N
Temperature: 70 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To a stirred solution of 3-bromo-2-fluoro-benzonitrile (2 g, 10 mmol) in DMF (50 mL) was added 2-mercaptoacetamide (1.2 eq., 12 mL, 100 mg/mL in MeOH-ammonia solution) followed by sodium methoxide (1.2 eq., 24 mL, 0.5 M in MeOH) at room temperature under nitrogen. After 2 h, the resulting homogenous yellow solution was warmed to 70° C. for 17 h. Upon cooling to room temperature, the resulting dark green reaction mixture was concentrated to give a green solid. This solid was diluted with MeOH and collected via filtration to give 2.0 g (74%) of 3-amino-7-bromo-benzo[b]thiophene-2-carboxylic acid amide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[CH2:31][NH:30][CH2:29]2>CN(C=O)C>[F:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[CH2:31][N:30]([C:15]1[C:16]([F:18])=[C:17]3[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:13][C:14]=1[F:20])[CH2:29]2
Reactant: Fc1ccc2c(c1)CNC2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CN(C)C=O
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(N3Cc4ccc(F)cc4C3)c(F)cc2c1=O
Yield: 77.3 %

Procedure:
170 mg of 1-(4-fluorophenyl]-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 210 mg of 5-fluoroisoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 177 mg of the target compound.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[CH3:7][C:8]1[CH:13]=[C:12]([B:14]2[O:18]C(C)(C)C(C)(C)[O:15]2)[CH:11]=[CH:10][C:9]=1[OH:23].C([O-])(=O)C.[NH4+]>CC(C)=O.O>[OH:23][C:9]1[CH:10]=[CH:11][C:12]([B:14]([OH:18])[OH:15])=[CH:13][C:8]=1[CH3:7]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(B(O)O)ccc1O
Yield: 36.4 %

Procedure:
Sodium periodate (4.22 g, 19.74 mmol) was added to 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.54 g, 6.58 mmol) and ammonium acetate (1.52 g, 19.74 mmol) in acetone and water (2:1, 66 mL) at room temperature. The mixture was stirred for nineteen hours, then filtered, and concentrated. Sodium chloride was added to the filtrate, and it was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with 1:1 ethyl acetate:hexanes to ethyl acetate to give 364.4 mg (36%) of (4-hydroxy-3-methylphenyl)boronic acid as a solid. 1H NMR (400 MHz, d6-DMSO): δ 9.31 (s, 1H), 7.55 (s, 1H), 7.52 (d, J=8 Hz, 1H), 6.76 (d, J=8 Hz, 1H), 2.14 (s, 3H). ESI-LCMS m/z 151 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N1C=CC=CC=1.[Cl:19][CH2:20][C:21](Cl)=[O:22]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[CH2:4][N:5]([C:21](=[O:22])[CH2:20][Cl:19])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: COC(=O)CNc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CN(C(=O)CCl)c1ccccc1
Yield: 69.1 %

Procedure:
To methylene chloride (20 ml) was added N-phenylglycine methyl ester (2.02 g, 10 mmol) and pyridine (1.58 g, 20 mmol) and the mixture was stirred. To the mixture was added dropwise a solution of chloroacetyl chloride (1.13 g, 10 mmol) in methylene chloride (3 ml) at room temperature and the resulting mixture was stirred for 15 hours, washed with water, dried and evaporated. The resultant residue was crystallized from isopropyl ether to give N-chloroacetyl-N-phenylglycine methyl ester (1.67 g, 70%) as a colorless powder.
Reaction SMILES: C([O:8][C:9](=[O:18])[CH2:10][CH2:11][CH2:12][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)C1C=CC=CC=1>[C].[Pd].C(O)C>[N:13]1([CH2:12][CH2:11][CH2:10][C:9]([OH:18])=[O:8])[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: O=C(CCCn1ccnc1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CCCn1ccnc1
Yield: 72.8 %

Procedure:
A mixture of 4-(1-imidazolyl)butyric acid benzyl ester (7.4 g), 5% palladium-carbon (1.0 g) and ethanol (400 ml) was catalytically reduced at room temperature under 1 atm. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the residual crystal was recrystallized from ethanol, to yield 4-(1-imidazolyl)butyric acid (3.4 g, 75%) as a colorless prismatic crystal having a melting point of 125 to 126° C.
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][N:29]=1)[C:7]([NH:9][C:10]1[S:11][C:12]2[C:18]([CH:19]3[CH2:24][O:23][CH2:22][CH2:21][O:20]3)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=2[N:14]=1)=[O:8].C(Cl)(Cl)Cl.CN([CH:37]=[O:38])C>O1CCOCC1>[O:20]1[CH2:21][CH2:22][O:23][CH2:24][CH:19]1[C:18]1[C:12]2[S:11][C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:27]=[CH:28][N:29]=[C:4]([O:20][CH:19]4[CH2:24][CH2:37][O:38][CH2:17][CH2:18]4)[CH:5]=3)=[N:14][C:13]=2[C:15]([O:25][CH3:26])=[CH:16][CH:17]=1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(OC4CCOCC4)c3)nc12

Procedure:
From (+)-2-bromo-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide sodium hydride and tetrahydro-2H-pyranol-4-ol in dioxane and DMF. [α]D20=+12.4° (c=0.11, CHCl3), ES-MS m/e (%): 472 (M+H+, 100).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:17])[C:5](=[O:16])[N:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N1C2C(=CC=CC=2)C(=O)C1=O)CCCC.O1C2C=CC(O)=CC=2OC1.[Cl:44][C:45]1[CH:46]=[C:47]([OH:52])[CH:48]=[CH:49][C:50]=1[Cl:51]>>[Cl:44][C:45]1[C:50]([Cl:51])=[CH:49][C:48]([C:4]2([OH:17])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][CH:2]=3)[N:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:5]2=[O:16])=[C:47]([OH:52])[CH:46]=1
Reactant: CCCCCN1C(=O)C(=O)c2c(Br)cccc21
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: CCCCCN1C(=O)C(=O)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CCCCCN1C(=O)C(O)(c2cc(Cl)c(Cl)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1C, and making non-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dione with 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with 3,4-dichlorophenol, the title compound was obtained (26%): 1H NMR (300 MHz, CDCl3) δ 9.60 (s, 1H), 7.50-7.40 (m, 2H), 7.22 (td, 1H), 7.11 (s, 1H), 6.95 (d, 1H), 6.86 (s, 1H), 4.31-4.12 (br, 1H), 3.79-3.59 (m, 2H), 1.76-1.62 (m, 2H), 1.40-1.27 (m, 4H), 0.88 (t, 3H); MS (ES+) m/z 363 (M−17), 403 (M+23).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][CH2:12][C:13]([C:26]#[N:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(=O)([O-])[O-:30].[Na+].[Na+]>S(=O)(=O)(O)O>[CH2:1]([N:8]([CH2:10][CH2:11][CH2:12][C:13]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:26]([NH2:27])=[O:30])[CH3:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CN(CCCC(C#N)(c1ccccc1)c1ccccc1)Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CN(CCCC(C(N)=O)(c1ccccc1)c1ccccc1)Cc1ccccc1
Temperature: 25 °C

Procedure:
4-(N-Benzyl-N-methylamino)-1-cyano-1,1-diphenylbutane (2%--see Preparation 2) was dissolved in 90% sulphuric acid (11 l) and the solution heated at 100° for 3 hours. The solution was allowed to cool to room temperature then poured slowly into water (100 ml). The mixture was made basic (pH 10) by the addition of 10% aqueous sodium carbonate and extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to leave the title compound as a colourless foam, yield 1.9 g.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8](=[O:20])[NH:9][CH2:10][CH2:11][CH2:12][CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16].[H-].[Na+]>CN(C)C=O.O.[Cl-].[Na+]>[CH2:15]([O:14][CH:13]([O:17][CH2:18][CH3:19])[CH2:12][CH2:11][CH2:10][N:9]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1=[O:20])[CH3:16]
Reactant: CCOC(CCCNC(=O)OCCCCCCl)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(CCCN1CCCCCOC1=O)OCC
Temperature: 25 °C
Reaction time: 15 h
Yield: 16.9 %

Procedure:
To a solution of (4,4-diethoxybutyl)carbamic acid 5-chloro-pentyl ester (11.4 g, 44 mmole) dissolved in N,N-dimethylformamide (100 mL) was added de-oiled sodium hydride (1.01 g, 42.3 mmole). The reaction mixture was stirred for 15 hours at room temperature, and then at 70° C. for 3 hours. The mixture was diluted with water, saturated aqueous sodium chloride was added, and extracted with ethyl ether. The organic phase was washed with water, dried (magnesium sulfate), and concentrated. Purification by silica gel chromatography, gave 3-(4,4-diethoxybutyl)-[1,3]oxazocan-2-one (2.03 g) as a viscous oil.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:18][CH2:19][CH2:20][CH3:21])=[N:5][C:6]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:7][CH:8]=1)#[N:2].[Cl-].[NH4+].[N-:24]=[N+:25]=[N-:26].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)(Cl)Cl.CN(C=O)C>[CH2:19]([NH:18][C:4]1[C:3]([C:1]2[NH:26][N:25]=[N:24][N:2]=2)=[CH:8][N:7]=[C:6]([NH:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)[N:5]=1)[CH2:20][CH3:21]
Reactant: CCCNc1nc(NCCc2ccncc2)ncc1C#N
Reactant: [N-]=[N+]=[N-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCCNc1nc(NCCc2ccncc2)ncc1-c1nnn[nH]1
Temperature: 100 °C
Reaction time: 24 h
Yield: 22 %

Procedure:
To 20 mL of DMF, the total amount of 5-cyano-4-n-propylamino-2-[2-(4-pyridyl)ethylamino]pyrimidine obtained in Step 2 was dissolved, then DMF (16 mL) solution of ammonium chloride (856 mg) and sodium azide (1.04 g) was added thereto, followed by stirring at 100° C. for 24 hours. After completion of the reaction was confirmed by thin-layer chromatography, the reaction mixture was added with chloroform and 5% an aqueous citric acid solution, and then the mixture was separated. The pH of an aqueous layer was adjusted to about 6 and the crystals were precipitated. The crystals were collected by filtration, washed with water, then dried fully under reduced pressure to give 4-n-propylamino-2-[2-(4-pyridyl)ethylamino]-5-tetrazolylpyrimidine [Compound (Z) in which R1 is n-propylamino and R2 is 2-(4-pyridyl)ethylamino] (700 mg, overall yield from 4-chloro-5-cyano-2-methylthiopyrimidine: 22%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][C@H:12]1[O:14][CH2:13]1)([O-:3])=[O:2].[Cl:15][C:16]1[CH:17]=[C:18]([CH2:23][CH2:24][NH2:25])[CH:19]=[CH:20][C:21]=1[Cl:22]>C(O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][C@@H:12]([OH:14])[CH2:13][NH:25][CH2:24][CH2:23][C:18]1[CH:19]=[CH:20][C:21]([Cl:22])=[C:16]([Cl:15])[CH:17]=1)([O-:3])=[O:2]
Reactant: NCCc1ccc(Cl)c(Cl)c1
Reactant: O=[N+]([O-])c1ccccc1OC[C@@H]1CO1
Solvent: CCO
Product: O=[N+]([O-])c1ccccc1OC[C@@H](O)CNCCc1ccc(Cl)c(Cl)c1
Yield: 49 %

Procedure:
Compound 17a-S (1.05 g, 5.4 mmol) and 3,4-dichloropenylethylamine (1.02 g, 0.8 ml, 5.4 mmol) were dissolved in 25 ml ethanol and refluxed for 12 hours. Then the solvent was evaporated and the residue recrystallized from ethylacetate-petroleum ether to give the product (1.02 g, 99% yield, m.p. 73-74° C.) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH: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)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30]>ClCCl.O>[C:29]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)=[CH:4][CH:3]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Sc2ccc(N)cc2)CC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(SC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a 10 mL round-bottomed flask was added tert-butyl 4-(4-aminophenylthio)piperidine-1-carboxylate (100 mg, 0.324 mmol) and triethylamine (249 μl, 1.783 mmol) in dichloromethane (3242 μl). The mixture was cooled to −78° C. and acetyl chloride (115 μl, 1.621 mmol) was added. The solution was warmed to room temperature, stirred for 1 h and then diluted with water and additional dichloromethane. The aqueous phase was extracted twice with dichloromethane and the combined organics were dried with sodium sulfate, filtered and concentrated to give the title compound.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[N:15]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:2].Cl[CH:23]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CCN(CC)CC>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[N:15]1[CH2:21][CH2:20][CH2:19][N:18]([CH:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[CH2:17][CH2:16]1)[CH3:2]
Reactant: Clc1ccc(C(Cl)c2ccccc2)cc1
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCCn1c(N2CCCN(C(c3ccccc3)c3ccc(Cl)cc3)CC2)nc2ccccc21

Procedure:
A solution of compound 15 (2 mmols) and 21 (2 mmols) in methylene chloride (10 mL) and Et3N (0.3 mL) is stirred under an inert atmosphere. The solution is warmed and the course of the reaction is followed by TLC. When the reaction is complete, dil. aq. Na2CO3 is added to the solution, shaken, and the layers are separated. The aqueous layer is extracted with additional CH2Cl2, the combined organic extracts are washed with half-saturated brine, dried (Na2SO4), filtered and concentrated under reduced pressure giving the crude product. The desired compound 1-(2-ethoxyethyl)-2-[hexahydro-4-(4-chlorobenzhydryl)-1H-1,4-diazepin-1-yl]-1H-benzimidazole 25 is obtained by purification of the crude product with the use of HPLC.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[CH2:5]([C:8]1[N:9]([CH2:21][CH2:22][CH2:23][CH:24]=O)[C:10]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:20]=1)[CH2:6][CH3:7].[OH-].[Na+]>C(O)C.O>[CH3:3][O:2][N:4]=[CH:24][CH2:23][CH2:22][CH2:21][N:9]1[C:10]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:20]=[C:8]1[CH2:5][CH2:6][CH3:7]
Reactant: CON
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCc1nc2cnc3ccccc3c2n1CCCC=NOC
Temperature: 0 °C
Reaction time: 72 h
Yield: 105.3 %

Procedure:
Methoxylamine hydrochloride (3.37 g, 40.3 mmol) was added to a stirred solution of 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyraldehyde (10.0 g, 35.5 mmol) in ethanol (100 mL) cooled to 0° C., followed by addition of 50% sodium hydroxide solution (12.5 M, 3.2 mL, 40 mmol) in water (7 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 3 days. The reaction mixture was then concentrated under reduce pressure and diluted with dichloromethane (150 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (50 mL). The combined organics were dried over potassium carbonate, filtered and concentrated to afford 11.6 g of 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-butyraldehyde O-methyloxime as a reddish oil.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5](N)=[CH:4][C:3]=1[O:9][CH3:10].Cl.N([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+].[Cu][C:23]#[N:24].[C-]#N.[K+]>O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([C:23]#[N:24])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: N#C[Cu]
Reactant: COc1cc(N)ccc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Product: COc1cc(C#N)ccc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.5 %

Procedure:
To a solution of 4-bromo-3-methoxyaniline (4 g, 19.8 mmol) in water (22 mL) was added concentrated HCl (7 mL). After cooling to 0° C., a solution of sodium nitrite (1.5 g, 22 mmol) in water (5 mL) was added dropwise. The resulting mixture was stirred at 0° C. for 30 min. After neutralizing with solid potassium carbonate, the reaction mixture was added to a mixture of copper (I) cyanide (2.13 g, 23.8 mmol) and potassium cyanide (3.2 g, 50 mmol) in water (22 mL) at 70° C. The reaction mixture was stirred at 70° C. for 1 h. After cooling to room temperature, the reaction was extracted with toluene (100 mL*4). The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 4-bromo-3-methoxybenzonitrile (1.7 g) as a yellow solid. 1HNMR (400 MHz, CDCl3) δ 7.64 (d, J=8.4 Hz, 1H), 7.14 (dd, J=8.0, 1.6 Hz, 1H), 7.09-7.10 (m, 1H), 3.87 (s, 3H).