Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:15][C:16](=[O:18])[NH2:17])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.Cl.Cl.[CH3:21][N:22]([CH2:24][CH:25]([OH:35])[CH2:26][O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)[CH3:23].N>CN1C(=O)CCC1>[CH3:23][N:22]([CH2:24][CH:25]([OH:35])[CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([NH:32][C:2]2[N:7]=[C:6]([N:8]([CH2:15][C:16](=[O:18])[NH2:17])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:33][CH:34]=1)[CH3:21]
Reactant: CN(C)CC(O)COc1ccc(N)cc1
Reactant: NC(=O)CN(c1ccccc1)c1ccnc(Cl)n1
Agent: Cl
Agent: N
Solvent: CN1CCCC1=O
Product: CN(C)CC(O)COc1ccc(Nc2nccc(N(CC(N)=O)c3ccccc3)n2)cc1
Temperature: 120 °C

Procedure:
2-Chloro-4-(N-(carbamoylmethyl)anilino)pyrimidine (prepared by analogy to Method A and the corresponding Reference Examples A-1–A-10) (390 mg, 1.49 mmol) was dissolved in NMP (3 ml) and 4-[3-(N,N-dimethyl)amino-2-hydroxypropoxy]aniline dihydrochloride (Reference Example D-1; 378 mg, 1.34 mmol) was added. The resulting suspension was heated at 120° C. which caused the solid to dissolve. The reaction mixture was heated at 120° C. for 12 hours and allowed to cool to ambient temperature. The reaction mixture was then basified to pH 9–10 using methanolic ammonia and then evaporated onto silica (5 ml). The residue was purified by column chromatography eluting with methanol (15%):DCM:aqueous ammonia (1%). The resulting gum was re-evaporated from EtOAc three times to give the title product as a foam (184 mg). NMR: (300 MHz) 2.31 (s, 6H), 2.49 (m, 2H), 3.8 (m, 1H), 3.92 (m, 2H), 4.42 (s, 2H), 5.68 (d, 1H), 6.79 (d, 2H), 7.4) (m, 5H), 7.58 (d, 2H), 7.82 (d, 1H), 8.93 (s, 1H); m/z: (ES+) 437.5 (MH+).
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH:14]=O)=[CH:10][C:9]([CH2:16][CH2:17][CH3:18])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:19]1([N:25]2[CH2:30][CH2:29][N:28]([CH2:14][CH2:13][CH2:12][C:11]3[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=[C:9]([CH2:16][CH2:17][CH3:18])[CH:10]=3)[CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CCCc1cc(CCC=O)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccccc3)CC2)n(-c2ccccc2)n1

Procedure:
153 mg (87%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-3-propyl-1H-pyrazol-5-yl)propanal (100 mg, 0.413 mmol), 1-phenylpiperazine (0.062 mL, 0.413 mmol), DIPEA (0.110 mL, 0.620 mmol) and NaBH(OAc)3 (263 mg, 1.239 mmol).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=1.Br[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:16]=1
Reactant: Nc1c(C(=O)c2cccc(O)c2)cnn1-c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COc1cccc(C(=O)c2cnn(-c3ccc(F)cc3)c2N)c1
Temperature: 70 °C
Yield: 88.4 %

Procedure:
A mixture of 5-amino-1-(4-fluorophenyl)-4-[3-hydroxybenzoyl]pyrazole (1.0 g, 3.3 mmol), tert-butyl bromoacetate (1.4 g, 7.2 mmol) and potassium carbonate (1 g, 7.2 mmol) in acetonitrile was heated at 70° C. overnight. The reaction mixture was cooled, diluted with ethyl acetate and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (elution gradient: 10% acetone/hexane) to give 5-amino-4-[3-(tert-butoxycarbonylmethyloxy)benzoyl]-1-(4-fluorophenyl)pyrazole (1.2 g) as a solid.
Reaction SMILES: [N:1]1([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[C:23]4=[N:24][CH:25]=[CH:26][CH:27]=[C:22]4[NH:21][C:20]3=[O:28])=[CH:15][CH:14]=2)[C:5]2=[N:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]2[CH2:3][CH2:2]1.[CH3:29]I.[H-].[Na+].O>CN(C=O)C>[N:1]1([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[C:23]4=[N:24][CH:25]=[CH:26][CH:27]=[C:22]4[N:21]([CH3:29])[C:20]3=[O:28])=[CH:15][CH:14]=2)[C:5]2=[N:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]2[CH2:3][CH2:2]1
Reactant: O=c1[nH]c2cccnc2n1-c1ccc(N2CCn3c2nc2ccccc23)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)n(-c2ccc(N3CCn4c3nc3ccccc34)cc2)c2ncccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-[4-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (57 mg) and methyl iodide (0.012 mL) in DMF (2.0 mL) was added sodium hydride (62 mg) (60% in mineral oil) at 0° C. The mixture was stirred at 0° C. for 1 h, and then added H2O. The precipitate was collected and washed with MeOH to give 3-[4-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)phenyl]-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (43 mg) as white powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:23])[C:9]2[CH:22]=[CH:21][C:12]3[N:13]([CH3:20])[C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:26]=[CH:27][C:28]([Cl:35])=[C:29]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:30]=1>>[Cl:35][C:28]1[CH:27]=[CH:26][C:25]([NH:24][C:2]2[N:7]=[C:6]([N:8]([C:9]3[CH:22]=[CH:21][C:12]4[N:13]([CH3:20])[C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[N:15][C:11]=4[CH:10]=3)[CH3:23])[CH:5]=[CH:4][N:3]=2)=[CH:30][C:29]=1[S:31]([NH2:34])(=[O:33])=[O:32]
Reactant: CC(C)Nc1nc2cc(N(C)c3ccnc(Cl)n3)ccc2n1C
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1
Product: CC(C)Nc1nc2cc(N(C)c3ccnc(Nc4ccc(Cl)c(S(N)(=O)=O)c4)n3)ccc2n1C

Procedure:
The title compound was prepared following the procedure of example 1 with N5-(2-chloropyrimidin-4-yl)-N2-isopropyl-N5,1-dimethyl-1H-benzimidazole-2,5-diamine (83 mg, 0.25 mmol) and 5-amino-2-chloro-benzenesulfonamide (52 mg, 0.25 mmol) as a white solid (74 mg, 59%). 1H NMR (300 MHz, d6-DMSO) δ 9.58 (s, 1H), 8.78 (s, 1H), 7.83 (dd, J=8.7 and 2.1 Hz, 1H), 7.78 (d, J=5.7 Hz, 1H), 7.55 (br s, 1H), 7.40 (d, J=8.7 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.08 (s, 12H), 6.80 (d, J=8.1 Hz, 1H), 6.61 (d, J=7.5 Hz, 1H), 5.64 (d, J=6.0 Hz, 1H), 4.04 (m, 1H), 3.52 (s, 3H), 3.45 (s, 3H), 1.23 (d, J=6.3 Hz, 6H) ppm. MS (ESI) m/z=501 [M+H]+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[SH:30]>>[CH:20]1([C:18]([C:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=2[NH:10][C:8]([NH:7][C:5]2[S:6][C:2]([S:30][C:26]3[NH:25][CH:29]=[CH:28][N:27]=3)=[CH:3][N:4]=2)=[O:9])=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Sc1ncc[nH]1
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Product: Cc1ccc(NC(=O)Nc2ncc(Sc3ncc[nH]3)s2)c(C(=O)C2CCCC2)c1
Yield: 34.9 %

Procedure:
1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-[5-(1H-imidazol-2-ylsulfanyl)-thiazol-2-yl]-urea (149 mg, 35%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 1H-imidazole-2-thiol (200 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)[CH3:9])(=O)=O.[C-:23]#[N:24].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([N:13]2[CH2:14][CH2:15][N:10]([CH:8]([CH3:9])[CH2:7][CH2:6][C:23]#[N:24])[CH2:11][CH2:12]2)=[CH:17][CH:18]=1
Reactant: CC(CCOS(C)(=O)=O)N1CCN(c2ccc(F)cc2)CC1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(CCC#N)N1CCN(c2ccc(F)cc2)CC1
Temperature: 50 °C
Reaction time: 15 h
Yield: 73 %

Procedure:
To a stirred solution of 3-(4-(4-fluorophenyl) piperazin-1-yl)butyl methanesulfonate (4.5 g, 13.62 mmol) in N,N-dimethylformamide (30 ml) was added potassium cyanide (2.66 g, 40.9 mmol) at 25° C. under nitrogen atmosphere. The reaction mixture was stirred at 50° C. for 15 h. Progress of reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate (150 ml) and washed with water (4×50 ml). The organic layer was dried over sodium sulphate and concentrated under reduced pressure to get oily compound. The resulting crude compound was purified over silica gel (100-200 mesh) by flash chromatography using 30% ethyl acetate in hexane as an eluent to obtain title compound (2.6 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([CH2:12][CH3:13])[C:4]=1[CH:5]=[O:6])[CH3:2].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:12]([C:7]1[CH:8]=[C:9]([O:11][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[C:3]([CH2:1][CH3:2])[C:4]=1[CH:5]=[O:6])[CH3:13]
Reactant: OB(O)c1ccccc1
Reactant: CCc1cc(O)cc(CC)c1C=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1cc(Oc2ccccc2)cc(CC)c1C=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.6 %

Procedure:
To a solution of 1.50 g (8.42 mmol) 2,6-diethyl-4-hydroxy-benzaldehyde in 60 ml dichloromethane were added 1.64 g (13.5 mmol) phenylboronic acid, 2.29 g (12.6 mmol) copper(II) acetate, 30 g 4 Å molecular sieves and 4.06 ml (50.5 mmol) pyridine. The reaction mixture was stirred at room temperature for 72 h and then filtered through celite. The filtrate was extracted with 1 N aqueous hydrochloric acid, the phases were separated, and the organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, ethyl acetate/heptane gradient) to afford 1.64 g (77%) of the title compound as a yellow oil. 1H-NMR (CDCl3): 1.22 (6H, t, CH3), 2.95 (4H, q, CH2), 6.69 (2H, s, ArH), 7.08 (2H, d, ArH), 7.20 (1H, t, ArH), 7.39 (2H, dd, ArH), 10.5 (1H, s, CHO).
Reaction SMILES: [N:1]1([CH2:8][CH2:9][NH2:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS([C:15]1[N:20]=[C:19]([C:21]2[C:22]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=3)=[N:23][N:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=23)[CH:18]=[CH:17][N:16]=1)(=O)=O>O>[N:1]1([CH2:8][CH2:9][NH:10][C:15]2[N:20]=[C:19]([C:21]3[C:22]([C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=4)=[N:23][N:24]4[CH:29]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:27]=[CH:26][C:25]=34)[CH:18]=[CH:17][N:16]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCN1CCCCCC1
Reactant: CS(=O)(=O)c1nccc(-c2c(-c3cccc(Cl)c3)nn3cc(C(F)(F)F)ccc23)n1
Solvent: O
Product: FC(F)(F)c1ccc2c(-c3ccnc(NCCN4CCCCCC4)n3)c(-c3cccc(Cl)c3)nn2c1

Procedure:
2-Azepan-1-ylethylamine (0.04 mL) and 4-[2-(3-chlorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl methyl sulfone (0.02 g) were mixed at room temperature and heated with an airgun until a homogenous melt was obtained (2 min). Upon cooling, water was added. The precipitated solid was filtered and dried to give the title compound as a beige solid (0.014 g); 1H NMR (d6-DMSO) δ 9.51(1H, s), 8.49(1H, bs), 8.16(1H, d), 7.70–7.65(2H, m), 7.60–7.50(3H, m), 7.00(1H, bs), 6.36(1H, bs), 2.6(6H, bs), 1.6(8H, bs); m/z 515(M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[H-].[Na+].[CH:14]1(I)[CH2:18][CH2:17][CH2:16][CH2:15]1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1ncc(Cl)cc1O
Reactant: IC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ncc(Cl)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 60 %

Procedure:
5-Chloro-2-nitro-pyridine-3-ol (3.4 mmol) is dissolved in DMF (2 ml) and NaH (1.4 eq., 60% suspension in liquid paraffin) is added and the suspension is stirred 45 min at room temperature. Cyclopentyliodide (1 eq.) is added and the reaction suspension is heated to 100° C. for 24 hours. The reaction solution is pored into water and extracted with dichloromethane. The combined organic layers are washed with brine, dried over MgSO4 and the solvent is removed in vacuo. 5-Chloro-3-cyclopentyloxy-2-nitro-pyridine is obtained after column chromatography as yellow oil in a yield of 60%; HPLC (method C): 2.11 min; LC-MS (method A): 2.07 min, 243.10 (M+H+).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1.C([O:17][C:18]([C:20]1[CH:21]=[N:22][C:23]([S:26][CH3:27])=[N:24][CH:25]=1)=O)C>C1COCC1>[F:7][C:8]1[CH:14]=[CH:13][C:11]([NH:12][C:18]([C:20]2[CH:21]=[N:22][C:23]([S:26][CH3:27])=[N:24][CH:25]=2)=[O:17])=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1cnc(SC)nc1
Reactant: Nc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CSc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reaction time: 0.02 h
Yield: 80 %

Procedure:
To a solution of potassium tert-butoxide (1 M in THF, 66 mL, 66 mmol) in THF (66 mL) in an ice bath was added 4-fluoroaniline over 1.5 min. The solution was stirred for 1 min, then a solution of 2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (3.745 g, 18.9 mmol) in THF (30 mL) was added via syringe over 4 min. The syringe was washed with 4 mL THF, and the reaction allowed to proceed for 5 min. The reaction was quenched with 1% HCl (450 mL) resulting in a solid precipitate. The solution was filtered, and the solids washed with water. After drying, the solids were triturated with 10% ethyl acetate/hexane to afford 4.0 g (80% yield) of the titled product as a pale yellow solid, which was used in the following preparations.
Reaction SMILES: [C:1]([OH:14])(=[S:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:15]1[O:17][CH2:16]1>C(O)C>[C:1]([S:13][CH:16]([OH:17])[CH3:15])(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C1CO1
Reactant: CCCCCCCCCCCC(O)=S
Solvent: CCO
Product: CCCCCCCCCCCC(=O)SC(C)O
Reaction time: 8 h

Procedure:
Thiolauric acid (15 g) is dissolved in dry ethanol (50 ml) and thereto is added a solution of ethylene oxide (15 ml) in cold dry ethanol (20 ml) and the mixture is allowed to stand at room temperature overnight. The solvent is distilled off under reduced pressure and the resulting residue is recrystallized from petroleum ether to give colorless scales of S-lauroylmercaptoethanol (8 g), m.p. 45° - 46° C (SH test with DTNB: negative).
Reaction SMILES: I.[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14](=[NH:17])SC)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.[NH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:39]=[CH:38][C:26]([O:27][CH2:28][C:29]([N:31]([CH2:35][CH2:36][OH:37])[CH2:32][CH2:33][OH:34])=[O:30])=[CH:25][CH:24]=1.C(N(CC)CC)C>C(O)C>[NH2:2][C:3]1[C:4]([C:11]([N:13]=[C:14]([NH2:17])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:39]=[CH:38][C:26]([O:27][CH2:28][C:29]([N:31]([CH2:35][CH2:36][OH:37])[CH2:32][CH2:33][OH:34])=[O:30])=[CH:25][CH:24]=2)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: NCCCCc1ccc(OCC(=O)N(CCO)CCO)cc1
Agent: I
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(=NC(=O)c1nc(Cl)c(N)nc1N)NCCCCc1ccc(OCC(=O)N(CCO)CCO)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 63.7 %

Procedure:
1-(3,5-Diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (0.13 g, 0.33 mmol) was added to a solution of 2-[4-(4-aminobutyl)phenoxy]-N,N-bis-(2-hydroxyethyl)acetamide 26 (0.09 g, 0.3 mmol), triethylamine (0.12 mL), and ethanol (1.7 mL). The reaction mixture was stirred at 60° C. for 3 h. The solvent was evaporated in vacuo. The residue was triturated with water and then purified by flash chromatography (silica gel, 20–10:1:0–0.2 CH2Cl2/methanol/concentrated ammonium hydroxide, v/v) to provide 2-(4-{4-[N′-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]butyl}-phenoxy)-N,N-bis-(2-hydroxyethyl)acetamide 27 (0.1 g, 64%) as a yellow solid. mp 114–116° C. 1H NMR (300 MHz, CD3OD) δ 1.70 (m, 4H), 2.60 (m, 2H), 3.32 (m, 2H), 3.50 (m, 4H), 3.70 (m, 4H), 4.81 (s, 2H), 6.85 (d, 2H), 7.10 (d, 2H). m/z (ESI): 523 [C22H31ClN8O5+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[Br-].[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:12]=1[CH2:13][Zn+]>C1COCC1.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>[Cl:1][C:2]1[N:3]=[N:4][C:5]([CH2:13][C:12]2[C:11]([F:10])=[CH:18][CH:17]=[CH:16][C:15]=2[F:19])=[CH:6][CH:7]=1
Reactant: Fc1cccc(F)c1C[Zn+]
Reactant: Clc1ccc(Cl)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Fc1cccc(F)c1Cc1ccc(Cl)nn1
Temperature: 80 °C
Yield: 47.4 %

Procedure:
To a solution of 3,6-dichloro pyridazine (7.39 g, 50 mmol) and tetrakis(triphenylphosphine)palladium (2.89 g, 2.5 mmol) in THF (500 mL) was added 2,6 difluoro benzyl zinc bromide (120 mL, 60 mmol). The reaction mixture was heated to 80° C. for 1.5 hours until the reaction was complete by TLC. The reaction was cooled to room temperature, filtered through celite, and concentrated in vacuo. The crude residue was recrystalized from ether to yield 5.7 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH2:16]1[O:21][C@H:20]([CH2:22]O)[C@@H:18]([OH:19])[CH2:17]1.N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][CH2:22][C@H:20]1[O:21][CH2:16][CH2:17][C@@H:18]1[OH:19])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: OC[C@H]1OCC[C@@H]1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(OC[C@H]1OCC[C@@H]1O)C(F)(F)F

Procedure:
To a -20° C. solution, under argon, of 8.4 ml of trifluoromethanesulfonic anhydride in 75 ml of methylene chloride is added, dropwise, a solution of 5.9 g of product from Example 268 and 4.05 ml of pyridine in 25 ml of methylene chloride. The temperature is maintained below -10° C. during the addition. The progress of the reaction is monitored by tlc. The reaction is filtered and the filtrate concentrated in vacuo to an oily residue. The residue is purified by chromatography (silica gel: 50% ethyl acetate/hexane) to give 7.03 g of the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29]2)[CH2:25][CH2:24]1)=[O:22].[CH3:37][S:38]([NH2:41])(=[O:40])=[O:39]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:41][S:38]([CH3:37])(=[O:40])=[O:39])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29]2)[CH2:25][CH2:24]1)=[O:22]
Reactant: CS(N)(=O)=O
Reactant: Cc1ccccc1Nc1c(C(=O)N2CCC3(C=Cc4ccccc43)CC2)cnc2c(C(=O)O)cnn12
Product: Cc1ccccc1Nc1c(C(=O)N2CCC3(C=Cc4ccccc43)CC2)cnc2c(C(=O)NS(C)(=O)=O)cnn12
Yield: 7.5 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-methylphenyl)amino-6-(spiro[inden-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.080 g, 0.167 mmol) obtained in step 2 and methanesulfonamide (0.080 g, 0.834 mmol), the title compound (0.007 g, 7.5%) was obtained.
Reaction SMILES: [NH2:1][N:2]1[C:6]([CH3:7])=[N:5][NH:4][C:3]1=[O:8].[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=O)[CH:10]=1>Cl>[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[N:1][N:2]2[C:6]([CH3:7])=[N:5][NH:4][C:3]2=[O:8])[CH:10]=1
Reactant: Cc1n[nH]c(=O)n1N
Reactant: O=Cc1cccnc1
Agent: Cl
Product: Cc1n[nH]c(=O)n1N=Cc1cccnc1

Procedure:
A mixture of 5.7 g of 4-amino-5-methyl-1,2,4-triazol-3-one and 100 ml of alcohol is heated to the reflux temperature and 5.4 g of pyridine-3-carbaldehyde and 2 drops of 6N hydrochloric acid are added thereto. After 14 hours under reflux the reaction mixture is cooled to 20°. The product that has precipitated is then filtered off with suction and dried under a high vacuum. 3.4 g of the title compound having a melting point of 208-210° are obtained.
Reaction SMILES: [C:1]1([CH2:11][CH2:12][S:13](Cl)(=[O:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]2[C:26]3[N:35]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:34]([CH2:40][CH2:41][CH3:42])=[N:33][C:27]=3[C:28]([NH2:32])=[N:29][C:30]=2[CH:31]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[NH2:32][C:28]1[C:27]2[N:33]=[C:34]([CH2:40][CH2:41][CH3:42])[N:35]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:26]=2[C:25]2[CH:24]=[CH:23][C:22]([O:21][CH2:20][CH2:19][CH2:18][NH:17][S:13]([CH2:12][CH2:11][C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)(=[O:15])=[O:14])=[CH:31][C:30]=2[N:29]=1
Reactant: CCCc1nc2c(N)nc3cc(OCCCN)ccc3c2n1CC(C)C
Reactant: O=S(=O)(Cl)CCc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCc1nc2c(N)nc3cc(OCCCNS(=O)(=O)CCc4cccc5ccccc45)ccc3c2n1CC(C)C
Reaction time: 0.5 h
Yield: 42.5 %

Procedure:
2-(1-Naphthyl)ethanesulfonyl chloride (0.358 g, 1.40 mmol) was added in one portion to a suspension of 7-(3-aminopropoxy)-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (0.500 g, 1.41 mmol) in chloroform, and the reaction was stirred for 30 minutes. Triethylamine (0.250 mL, 1.79 mmol) was then added. The reaction mixture was poured into saturated aqueous sodium carbonate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting pale yellow oil was purified by column chromatography on silica gel (eluting with dichloromethane:methanol ranging in ratios from 99:1 to 94:6) and subsequent recrystallization from acetonitrile to yield 0.341 g of N-(3-{[4-amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propyl)-2-(1-naphthyl)ethanesulfonamide as white crystals, mp 164-168° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:19][O:20][C:21]1[C:22]([CH3:51])=[C:23]([C:42]([O:49][CH3:50])=[C:43]([O:47][CH3:48])[C:44]=1[O:45][CH3:46])[CH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[C:27]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:26]=1>C(Cl)Cl>[CH3:19][O:20][C:21]1[C:22]([CH3:51])=[C:23]([C:42]([O:49][CH3:50])=[C:43]([O:47][CH3:48])[C:44]=1[O:45][CH3:46])[CH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:30])=[C:27]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:26]=1
Reactant: C1CCNCC1
Reactant: COc1c(C)c(Cc2ccc(C(=O)O)c(OCc3ccccc3)c2)c(OC)c(OC)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1c(C)c(Cc2ccc(C(=O)N3CCCCC3)c(OCc3ccccc3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
Piperidine (56 mg, 0.6576 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (169 mg, 0.8815 mmol) were added to a methylene chloride solution (20 ml) of 4-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-benzyloxybenzoic acid (173 mg, 0.3827 mmol) and the resulting solution was stirred at room temperature for 8 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by flash column chromatography (hexand:ethyl acetate=2:1) to obtain the titled compound (129 mg, 0.2485 mmol, 65%).