Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[NH:23]1[CH2:28][CH:27]=[C:26]([C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[NH:31][CH:30]=2)[CH2:25][CH2:24]1.C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[O:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:21][CH2:22][CH:13]1[CH2:12][N:23]1[CH2:24][CH:25]=[C:26]([C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[NH:31][CH:30]=2)[CH2:27][CH2:28]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccccc3O2)cc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C1=C(c2c[nH]c3ccccc23)CCN(CC2CCc3ccccc3O2)C1
Temperature: 80 °C
Yield: 53.3 %

Procedure:
To a solution of 3,4-dihydro-2H-chromen-2-ylmethyl 4-methylbenzenesulfonate (0.311 g, 0.98 mmol) in methyl sulfoxide (20 mL) was added 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.500 g, 2.52 mmol) and triethylamine (0.318 g, 3.14 mmol) and the reaction mixture was heated to 80° C. for 3 h. The reaction mixture was allowed to cool to room temperature and was diluted with ethyl acetate (200 mL), washed with water (3×100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, methanol:dichloromethane 1:19) provided 0.180 g (58%) of 3-[1-(3,4-dihydro-2H-chromen-2-ylmethyl)-1,2,3,6-tetrahydro-4-pyridinyl]-1H-indole as a pale yellow solid. mp 171-173° C.; Anal. Calcd. for C23H24N2O: C, 80.20; H, 7.02; N, 8.13. Found: C, 79.97; H, 7.02; N, 8.14.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@:4]1([C:17]([N:19]2[CH2:28][CH2:27][C:26]3[N:25]=[CH:24][C:23]([C:29]([F:32])([F:31])[F:30])=[CH:22][C:21]=3[CH2:20]2)=[O:18])[CH2:8][C@H:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:5]1.[C:33]1([Se:39]N2C(=O)C3=CC=CC=C3C2=O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.B(F)(F)F.[OH-].[Na+]>C(Cl)Cl.O>[C:33]1([Se:39][C@@H:6]2[C@H:5]3[O:1][CH2:2][CH2:3][C@@:4]3([C:17]([N:19]3[CH2:28][CH2:27][C:26]4[N:25]=[CH:24][C:23]([C:29]([F:32])([F:31])[F:30])=[CH:22][C:21]=4[CH2:20]3)=[O:18])[CH2:8][C@@H:7]2[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C1c2ccccc2C(=O)N1[Se]c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@](CCO)(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@]2(C(=O)N3CCc4ncc(C(F)(F)F)cc4C3)CCO[C@@H]2[C@H]1[Se]c1ccccc1
Reaction time: 2 h

Procedure:
To a solution of the product of Step D (1.51 g, 3.32 mmol, 1 eq) in DCM (40 mL) at rt under Ar was added N-(phenylseleno)phthalimide (1.60 g, 4.97 mmol, 1.5 eq) and BF3-etherate (0.042 mL, 0.33 mmol, 0.1 eq). After 2 hrs, 1 N NaOH was added and stirred 5 min., water was added, the solution extracted with DCM, the organics combined, dried over MgSO4, and concentrated. Purification by chromatography (80 g column) eluting with 50 to 100% EtOAc/heptane afforded the title compound of Step E. 1H NMR (CHLOROFORM-d) δ: 8.72 (s, 1H), 7.69 (s, 1H), 7.50-7.62 (m, 2H), 7.22-7.27 (m, 3H), 5.35 (s, 1H), 5.06 (d, J=8.1 Hz, 1H), 4.79-5.01 (m, 1H), 4.66-4.78 (m, 1H), 4.53 (br. s., 1H), 3.78-4.06 (m, 4H), 3.68-3.78 (m, 1H), 3.05-3.19 (m, 2H), 2.32 (dd, J=11.6, 5.8 Hz, 2H), 2.16 (d, J=10.9 Hz, 2H), 1.36 (s, 9H). Calculated for C28H32F3N3O4Se: 634.2 (M+23). found: 634.1.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[C:5]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:4]=1.C(N(CC)CC)C.[O:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1S>C(O)CCC>[O:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[N:20]1[CH2:21][CH2:22][N:17]([C:5]2[N:4]=[C:3]([NH2:2])[C:12]3[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=2)[CH2:18][CH2:19]1
Reactant: Sc1nc2ccccc2o1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: COc1cc2nc(N3CCN(c4nc5ccccc5o4)CC3)nc(N)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 6.2 %

Procedure:
To a suspension of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline hydrochloride (3.26 g ) in 250 ml of butanol, 1.01 g of triethylamine was added. The mixture was stirred at room temperature for 2 hr and 1.51 g of benzoxazole-2-thiol was added. The mixture was refluxed for 72 hr and evaporated. The solids were triturated with water and filtered to give 2.7 g of crude product. This was chromatographed over silica gel using 7% methanol-methylene chloride as eluent. Appropriate fractions were mixed together to give 0.25 g of the title compound, which was crystallized from hexane-methylene chloride; mp>250° C.; ir (nujol mull) 3420, 3320 and 3200 cm-1 ; uv max (MeOH) 341 (ε=6,650), 282 (ε=28,900), 278 (ε=29,300) and 252 nm (ε=73,000); and Anal. Calcd for C21H22N6O3 : C, 62.06% H, 5.45% N, 20.68% and Found: C, 61.38% H, 5.59% N, 20.78%.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([S:7]([NH:10][NH2:11])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:13]([O:17][C:18]([N:20]1[C:25]2([CH3:29])[CH2:26][CH2:27][CH2:28][C:21]1([CH3:31])[CH2:22][C:23](=O)[CH2:24]2)=[O:19])([CH3:16])([CH3:15])[CH3:14].O.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[C:13]([O:17][C:18]([N:20]1[C:21]2([CH3:31])[CH2:28][CH2:27][CH2:26][C:25]1([CH3:29])[CH2:24][C:23](=[N:11][NH:10][S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:12])=[CH:6][CH:5]=1)(=[O:8])=[O:9])[CH2:22]2)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: CC(C)(C)OC(=O)N1C2(C)CCCC1(C)CC(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)NN=C2CC3(C)CCCC(C)(C2)N3C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Yield: 61.8 %

Procedure:
p-Toluenesulfonyl hydrazine (6.37 g, 34.2 mmol) was added to a benzene solution (115 ml) of N-tert-butoxycarbonyl-1,5-dimethyl-9-azabicyclo[3.3.1]nonan-3-one (3.04 g, 11.4 mmol), and the mixture was heated under reflux for 6 h with a Dean-Stark device. After adding saturated sodium bicarbonate water under ice-cooled condition, the ice-cooled reaction liquid was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to give N-tert-butoxycarbonyl-1,5-dimethyl-3-(tosylhydrazono)-9-azabicyclo[3.3.1]nonane (3.07 g, 62%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:37]1[CH2:41]OC[CH2:38]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH2:38][CH2:37][CH3:41])[C:23]([O:25][CH3:26])=[O:24]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Yield: 75.6 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.120 g; 0.328 mmol), LHMDS 1N in THF (0.362 mL; 0.362 mmol), 1-iodopropane (0.054 mL; 0.554 mmol) in DMF (5 mL) for 3.5 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-15%) in heptane furnished 0.101 g (75%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].CON(C)[C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[S:29][C:30]([CH3:33])=[N:31][N:32]=2)=[CH:24][CH:23]=1>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]3[CH:23]=[CH:24][C:25]([C:28]4[S:29][C:30]([CH3:33])=[N:31][N:32]=4)=[CH:26][CH:27]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COC(C(=O)N(C)OC)c1ccc(-c2nnc(C)s2)cc1
Reactant: COc1cc(-c2ccco2)cc(OC)c1Cl
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-c4nnc(C)s4)cc3)o2)cc(OC)c1Cl

Procedure:
1-(5-(4-Chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)ethanone was prepared from 2-(4-chloro-3,5-dimethoxyphenyl)furan and N,2-dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (80% EtOAc-hexanes) gave the product as a pale yellow solid (0.106 g, 26% yield). MS: m/z 485.4 [M+H]+.
Reaction SMILES: S(=O)(=O)(O)O.C1C([OH:12])=CC=C(O)C=1.[CH2:14]([O:18][C:19](=[O:23])[C:20]([CH3:22])=[CH2:21])[CH:15]1[O:17][CH2:16]1>O>[OH:12][CH2:16][CH:15]([CH2:14][OH:18])[OH:17].[C:19]([O-:23])(=[O:18])[C:20]([CH3:22])=[CH2:21]
Reactant: Oc1ccc(O)cc1
Reactant: C=C(C)C(=O)OCC1CO1
Agent: O=S(=O)(O)O
Solvent: O
Product: C=C(C)C(=O)[O-]
Product: OCC(O)CO
Temperature: 90 °C

Procedure:
0.035 g sulfuric acid and 0.025 g hydrochinone are dissolved in 64 g water and heated up to 90° C. Within 3 h a total of 50 g glycidylmethacrylate are slowly added to the stirred hot solution. After an additional hour at 90° C. the solution is cooled down to 40° C. The water is removed at about 40 mbar. A clear viscous solution of the monomer glycerol-methacrylate is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:9][C:6]([CH:7]=O)=[C:5]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[CH:4]=1.[C:27]([C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=1)(=[O:29])[CH3:28]>>[CH3:1][O:2][C:3]1[C:10]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:9][C:6](/[CH:7]=[CH:28]/[C:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=2)=[O:29])=[C:5]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[CH:4]=1
Reactant: COCCOCCOCCOc1cc(OC)c(-c2cccs2)cc1C=O
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: COCCOCCOCCOc1cc(OC)c(-c2cccs2)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1
Yield: 82 %

Procedure:
The title compound was prepared by condensing 4-methoxy-2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-5-thiophen-2-yl-benzaldehyde (Ex-68B) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 137–138° C., 82% yield. 1H-NMR (300 MHz, DMSO-d6) δ 8.20–8.23 (m, 3H), 8.09 (d, 2H, J=8.3 Hz), 8.01 (m, 2H), 7.66 (d, 1H, J=3.6 Hz), 7.52 (d, 1H, J=5.1 Hz), 7.13 (dd, 1H, J=5.1, 3.6 Hz), 6.88 (s, 1H), 4.37 (t, 2H, J=3.6 Hz), 4.01 (s, 3H), 3.89 (t, 2H, J=3.6 Hz), 3.64–3.67 (m, 2H), 3.53–3.56 (m, 2H), 3.47–3.50 (m, 2H), 3.36–3.95 (m, 2H), 3.19 (s, 3H). MS (ESI) m/z=527 ([M+H]+, 100%). Anal. Calcd. for C28H30O8S: C, 63.86; H, 5.74; S, 6.09. Found: C, 64.08; H, 5.77; S, 6.09.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][N:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](O)=[O:25]>>[CH3:18][N:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:25]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: Cn1cccc1C(=O)O
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cccn4C)cc23)CC1
Yield: 107 %

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 19.0 mg (0.15 mMol) N-methylpyrrole-2-carboxylic acid, 18.0 mg (100%) of the title compound were recovered.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[S:22][CH:23]=[C:24]([CH:26]=O)[N:25]=2)=[CH:17][CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[S:22][CH:23]=[C:24]([CH2:26][N:4]3[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]3)[N:25]=2)=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1csc(-c2ccc(F)cc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2csc(-c3ccc(F)cc3)n2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.8 %

Procedure:
tert-Butyl piperazine-1-carboxylate (62 mg, 0.33 mmol) was added to a solution of 2-(4-fluorophenyl)thiazole-4-carbaldehyde (70 mg, 0.34 mmol) in 1,2-dichloroethane (3 mL) at 0° C., followed by sodium triacetoxyborohydride (85 mg, 0.4 mmol). The reaction mixture was allowed to warm up to room temperature, stirred for 16 h and further heated to 50° C. for another 4 h. The reaction mixture was quenched with 10% aqueous NaHCO3 and extracted with EtOAc. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 35% EtOAc in petroleum ether) to afford tert-butyl 4-((2-(4-fluorophenyl)thiazol-4-yl)methyl)piperazine-1-carboxylate (82 mg, yield 64%). 1H NMR (300 MHz, CDCl3) δ 7.96-7.91 (dd, J=9.0 Hz, 5.3 Hz, 2H), 7.15-7.09 (m, 3H), 3.75 (s, 2H), 3.50-3.46 (m, 4H), 2.55-2.52 (m, 4H), 1.46 (s, 9H). MS (ESI) m/z: Calculated for C19H24FN3O2S: 377.16. found: 378.3 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](OCC)=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1.CC(C[AlH]CC(C)C)C.O.[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Agent: CC(C)C[AlH]CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=Cc1cnc(Cl)cc1Cl
Temperature: -78 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
To a solution of ethyl 4,6-dichloronicotinate (500 mg, 2.43 mmol) in DCM at −78° C., DIBAL-H (2.67 mL, 2.67 mmol) was added dropwise and stirred for 3 h at −78° C. The mixture was allowed to warm up to 0° C. then water (0.12 mL) was added dropwise to the mixture followed by aq. NaOH (15%, 0.12 mL). H2O (0.3 mL) was added then the mixture was warmed up to room temperature and stirred for 15 min and the organic layer collected, dried over MgSO4 and filtered with the filtrate concentrated to give the desired product with was used without further purification (280 mg, Yield 65%). LCMS (m/z): 176.1 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14](=O)[CH:15]=[CH:16][N:17](C)C)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10].[F:21][C:22]([F:32])([F:31])[C:23]1[C:28]([NH:29]N)=[CH:27][CH:26]=[CH:25][N:24]=1>C(O)C.Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]2[N:29]([C:28]3[C:23]([C:22]([F:32])([F:21])[F:31])=[N:24][CH:25]=[CH:26][CH:27]=3)[N:17]=[CH:16][CH:15]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10]
Reactant: NNc1cccnc1C(F)(F)F
Reactant: COc1cc(C(=O)C=CN(C)C)cc([N+](=O)[O-])c1OC
Agent: Cl
Solvent: CCO
Product: COc1cc(-c2ccnn2-c2cccnc2C(F)(F)F)cc([N+](=O)[O-])c1OC
Temperature: 25 °C

Procedure:
To a stirred solution of 1-(3,4-dimethoxy-5-nitro-phenyl)-3-dimethylamino-prop-2-en-1-one (0.5 g, 1.79 mmol) and (2-trifluoromethyl-pyridin-3-yl)-hydrazine (0.33 g, 1.87 mmol) in ethanol (10 mL) was added 10 drops of concentrated hydrochloric acid and the mixture was heated at reflux for two hours. The mixture was allowed to cool to room temperature and the resulting precipitate was filtered off, washed with ethanol and dried to give 3-[5-(3,4-dimethoxy-5-nitro-phenyl)-pyrazol-1-yl]-2-trifluoromethyl-pyridine, 0.58 g (82%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][N:9]=[C:10]([C:13]#[N:14])[C:11]#[N:12])[CH:5]=[CH:6][CH:7]=1.FC1C=C(C=CC=1)N.C(#N)CC#N.O.[NH2:29][NH2:30]>>[NH2:14][C:13]1[C:10](=[N:9][NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[C:11]([NH2:12])=[N:30][N:29]=1
Reactant: NN
Reactant: N#CC(C#N)=NNc1cccc(F)c1
Agent: Nc1cccc(F)c1
Solvent: N#CCC#N
Solvent: O
Product: NC1=NN=C(N)C1=NNc1cccc(F)c1
Yield: 37 %

Procedure:
This compound was prepared using 94 mg (0.5 mmol) of 2-[(3-fluorophenyl)-hydrazono]malononitrile, which was derived from 3-fluoroaniline (96 μL, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. Precipitate formed in the reaction tube approximately 5 min after the addition of hydrazine hydrate. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 41 mg (37%) of the title compound as a yellow solid. 1H NMR (ppm, DMSO-d6): 6.2 (br s, 4H), 7.0 (t, 1H), 7.35-7.62 (m, 3H), 10.80 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=O)[CH:3]=1.C(N(CC)C(C)C)(C)C.Cl.[NH2:29][OH:30]>CO>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8]/[C:9](/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:29]/[OH:30])[CH:3]=1
Reactant: NO
Reactant: COc1ccc(C(=O)Cc2cc(Br)ccn2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COc1ccc(/C(Cc2cc(Br)ccn2)=N\O)cc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 67.8 %

Procedure:
To a stirred solution of 2-(4-bromopyridin-2-yl)-1-(4-methoxyphenyl)ethanone (3.8 g, 12.4 mmol) and N,N-diisopropylethylamine (5.4 mL, 31 mmol) in methanol (60 mL) at room temperature was added hydroxylamine hydrochloride (1.7 g, 24.8 mmol). The mixture was stirred at 60° C. for 2 days. After cooling to room temperature, the precipitate formed was filtered and dried under vacuum to afford white needles (2.7 g, 68%). The material was used as is in the next step. LCMS m/z 321.0; 323.0 (M+H)+, ret. time=2.37 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=CC=C[CH:9]=2)[N:5]=[C:4]([O:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH:3]=1.ClC1C=C(Cl)N=C(C2C=CC=CC=2)N=1.ClC1C=C(Cl)N=C(C(C)C)N=1>>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]([CH3:13])[CH3:9])[N:5]=[C:4]([O:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH:3]=1
Reactant: CC(C)CCOc1cc(Cl)nc(-c2ccccc2)n1
Agent: CC(C)c1nc(Cl)cc(Cl)n1
Agent: Clc1cc(Cl)nc(-c2ccccc2)n1
Product: CC(C)CCOc1cc(Cl)nc(C(C)C)n1

Procedure:
The compound of Example 22 is prepared analogously to the compound of Example 3, with 4,6-dichloro-2-phenylpyrimidine being replaced by 4,6-dichloro-2-i-propylpyrimidine
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[F:10])[CH3:2].C([Li])CCC.CN(C)CCN(C)CCN(C)C.[C:28](=[O:30])=[O:29]>C1COCC1.Cl>[CH2:1]([O:3][C:4]1[C:5]([F:10])=[C:6]([CH:7]=[CH:8][CH:9]=1)[C:28]([OH:30])=[O:29])[CH3:2]
Reactant: O=C=O
Reactant: CCOc1ccccc1F
Agent: CN(C)CCN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1cccc(C(=O)O)c1F
Temperature: -78 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
To 1-ethoxy-2-fluoro-benzene (1.0 g, 7.1 mmol) in THF (10 mL) at −78° C. was added dropwise butyllithium (4.5 mL of 1.6 M, 7.2 mmol) followed by N′-(2-dimethylaminoethyl)-N,N,N′-trimethyl-ethane-1,2-diamine (1.2 g, 7.2 mmol). The mixture was stirred for 3 h at −78° C. before it was transferred quickly via large cannula to a mixture of crushed dry ice (freshly crushed under N2) under ether. The mixture was warmed to RT, diluted with 30 mL of 2M HCl (aq.), extracted with ethyl acetate (2×30 mL), washed with 10 mL brine, and dried over MgSO4 to give 3-ethoxy-2-fluorobenzoic acid (65%) as a white solid. ESI-MS m/z calc. 184.1. found 185.1 (M+1)+; Retention time: 1.04 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.42-7.30 (m, 2H), 7.20-7.16 (m, 1H), 4.12 (q, J=7.0 Hz, 2H), 1.35 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([CH2:16][CH2:17][CH:18]4[N:24]=[C:23]([NH2:25])[CH2:22][CH2:21][CH2:20][CH2:19]4)[NH:13][C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([N:28]1[CH2:33][CH2:32][N:31]([S:34](C2C=CC(C3C=C4N=C(CCC5NC(=S)CCCC5)NC4=NC=3)=CC=2)(=[O:36])=[O:35])[CH2:30][CH2:29]1)[CH3:27].N>CO>[CH2:26]([N:28]1[CH2:33][CH2:32][N:31]([S:34]([C:4]2[CH:3]=[CH:2][C:1]([C:7]3[CH:8]=[C:9]4[N:15]=[C:14]([CH2:16][CH2:17][CH:18]5[N:24]=[C:23]([NH2:25])[CH2:22][CH2:21][CH2:20][CH2:19]5)[NH:13][C:10]4=[N:11][CH:12]=3)=[CH:6][CH:5]=2)(=[O:35])=[O:36])[CH2:30][CH2:29]1)[CH3:27]
Reactant: NC1=NC(CCc2nc3cc(-c4ccccc4)cnc3[nH]2)CCCC1
Reactant: CCN1CCN(S(=O)(=O)c2ccc(-c3cnc4[nH]c(CCC5CCCCC(=S)N5)nc4c3)cc2)CC1
Agent: N
Solvent: CO
Product: CCN1CCN(S(=O)(=O)c2ccc(-c3cnc4[nH]c(CCC5CCCCC(N)=N5)nc4c3)cc2)CC1

Procedure:
The title compound is synthesized as described for 7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-4,5,6,7-tetrahydro-3H-azepin-2-ylamine (compound 1) from 157 mg of 7-(2-{6-[4-(4-ethyl-piperazine-1-sulfonyl)-phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}-ethyl)-azepane-2-thione (compound A7) and 6.90 ml of methanol containing ammonia (strength: 7.0 M) at 50° C. for 90 hours. Purification by flash chromatography on LiChroprep-NH2® (eluent gradient: ethyl acetate/0-100 vol. % 2-propanol) affords 28 mg of the title compound as an amorphous solid of m.p. 199° C. ESI-MS: 528.2 (MNH4+), 510.4 (MH+), TLC: Rf=0.30 (LiChroprep-NH2® HPTLC, neat methanol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:14][C:13](=S)[C:12]3[CH:11]=[C:10]([CH3:16])[S:9][C:8]=3[NH:7][C:6]=2[CH:17]=1.FC(F)(F)S(OC)(=O)=O.[CH3:27][O:28][CH2:29][CH2:30][C@H:31]1[CH2:36][NH:35][CH2:34][CH2:33][NH:32]1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]=[C:13]([N:35]3[CH2:34][CH2:33][NH:32][C@@H:31]([CH2:30][CH2:29][O:28][CH3:27])[CH2:36]3)[C:12]3[CH:11]=[C:10]([CH3:16])[S:9][C:8]=3[NH:7][C:6]=2[CH:17]=1
Reactant: COCC[C@H]1CNCCN1
Reactant: Cc1cc2c(s1)Nc1cc(F)ccc1NC2=S
Agent: COS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: COCC[C@H]1CN(C2=Nc3ccc(F)cc3Nc3sc(C)cc32)CCN1
Temperature: 90 °C

Procedure:
Suspend 6-fluoro-2-methyl-4,9-dihydro-3-thia-4,9-diazabenzo[f]azulene-10-thione (500 mg, 1.9 mmol) in dichloromethane (30 ml), stir under nitrogen and cool in an ice/water bath. Add methyl trifluoromethanesulfonate (500 μl), and stir overnight. Concentrate the reaction mixture under reduced pressure, take up in pyridine (10 ml) and add (S)-2-(2-methoxyethyl)piperazine (400 mg, 2.78 mmol) and stir the reaction mixture under nitrogen and heat at 90° C. for three days. Concentrate the reaction mixture under reduced pressure and purify by flash column chromatography on silica gel (eluent dichloromethane/methanol) to give the desired as a yellow solid 727 mg: Mass Spectrum (FIA) 375 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([C:15]([OH:17])=O)=[CH:5][CH:4]=1.[CH3:18][O:19][C:20](=[O:40])[CH2:21][N:22](C(C1C2C(=CC(OC)=CC=2)C(OC)=CC=1)=S)[CH3:23]>>[CH3:18][O:19][C:20](=[O:40])[CH2:21][N:22]([C:15]([C:6]1[C:7]2[C:12](=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:17])[CH3:23]
Reactant: COC(=O)CN(C)C(=S)c1ccc(OC)c2cc(OC)ccc12
Reactant: COc1ccc2c(C(=O)O)ccc(OC)c2c1
Product: COC(=O)CN(C)C(=O)c1ccc(OC)c2cc(OC)ccc12

Procedure:
By following serially the procedures of examples 2 and 3 and using an equivalent amount of 4,6-dimethoxy-1-naphthalenecarboxylic acid of example 61 instead of 5-bromo-1-naphthalenecarboxylic acid; N-[(4,6-dimethoxy-1-naphthalenyl)thioxomethyl]-N-methylglycine methyl ester (I, R1 and R2 =CH3, R3 =4-CH3O, R4 =6-CH3O and R5 =H); mp 105°-107° C.; NMR (CDCl3) δ3.05 (s, 3H), 3.85 (s, 3H), 3.90 (s, 3H), 4.0 (s, 3H), 4.8 (2d, J=20 Hz, 2H), 7.3 (m, 5H); was obtained via N-[(4,6-dimethoxy-1-naphthalenyl)carbonyl]-N-methylglycine methyl ester; NMR (CDCl3) δ2.75 (s, 1H), 3.7 (s, 3H), 3.9 (s, 3H), 4.0 (s, 3H), 4.35 (s, 2H), 7.4 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([C:8]2[N:16]=[C:15]3[C:11](=[N:12][N:13]=[N:14]3)[C:10](=[O:17])[N:9]=2)[CH:7]=1.C(OCC)C.[C:25]([CH2:28][C:29](=O)[CH3:30])(=[O:27])[CH3:26]>>[C:25]([CH:28]=[C:29]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([C:8]2[N:16]=[C:15]3[C:11](=[N:12][N:13]=[N:14]3)[C:10](=[O:17])[N:9]=2)[CH:7]=1)[CH3:30])(=[O:27])[CH3:26]
Reactant: COc1ccc(N)cc1C1=NC(=O)C2=NN=NC2=N1
Reactant: CC(=O)CC(C)=O
Solvent: CCOCC
Product: COc1ccc(NC(C)=CC(C)=O)cc1C1=NC(=O)C2=NN=NC2=N1

Procedure:
A stirred suspension of 2-(5-amino-2-methoxyphenyl)-8-azapurin-6-one (1.34 g) in acetylacetone (15 ml) was heated at reflux for one hour. The mixture was then cooled and poured into diethyl ether (100 ml). The precipitated solid was filtered off and recrystallised twice from ethanol with the aid of charcoal to give 2-[5-(1-acetylprop-1-en-2-ylamino)-2-methoxyphenyl]-8-azapurin-6-one (1.2 g), m.p. 239°-240° C. (with decomposition).