Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C1COCC1>[Cl:17][C:12]1[CH:11]=[C:10]([CH:9]2[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4][CH:3]2[CH2:2][NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CN)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CNS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 106.9 %

Procedure:
To a solution of tert-butyl (6RS,7RS)-6-(aminomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (144 mg) in THF (1.5 mL) were added triethylamine (0.08 mL) and methanesulfonyl chloride (66 mg), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (186 mg).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:5]2[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([F:21])=[CH:23][CH:24]=3)[N:3]=[CH:4]2)=[CH:12][CH:13]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(C)(C)c1ccc(Cn2cnc(N)c2C(N)=O)cc1
Product: CC(C)(C)c1ccc(Cn2cnc(NC(=O)c3ccc(F)cc3)c2C(N)=O)cc1
Yield: 56 %

Procedure:
An amidation reaction and post-treatment were carried out under the same conditions as in Example 1, using 2.63 g (9.66 mmol) of 4-amino-1-(4-t-butylbenzyl)-5-imidazolecarboxamide which was prepared in the same manner as in Example 57 and 4-fluorobenzoyl Chloride instead of benzoyl chloride to obtain 2.13 g of 1-(4-t-butylbenzyl)-4-(4-fluorobenzoylamino)-5-imidazolecarboxamide (yield 56%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[CH:5]=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][CH:33]([N:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)[CH2:32][CH2:31]2)[CH:27]=[CH:26][C:23]=1[CH:24]=O>>[CH3:20][O:21][C:22]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][CH:33]([N:36]3[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]3)[CH2:32][CH2:31]2)[CH:27]=[CH:26][C:23]=1[C:24]1[NH:1][C:2]2=[N:3][CH:4]=[CH:5][C:6]([NH:9][C@@H:10]3[C@@H:15]4[CH2:16][C@@H:12]([CH:13]=[CH:14]4)[C@@H:11]3[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1C=O
Reactant: NC(=O)[C@@H]1[C@H](Nc2ccnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)ccnc2[nH]1
Yield: 17.7 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50.0 mg, 0.193 mmol) and 2-methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-benzaldehyde (67.3 mg, 0.212 mmol) were reacted to produce 19 mg (20%) of the title compound. mp: 185-195° C., 1H NMR (300 MHz, DMSO-d6): 11.84 (s, 1H), 7.99 (d, J=9 Hz, 1H), 7.87 (d, J=5 Hz, 1H), 7.65 (s, 1H), 7.16 (s, 1H), 6.72 (d, J=8 Hz, 1H), 6.67 (d, J=8 Hz, 1H), 6.58 (s, 1H), 6.37 (d, J=5 Hz, 1H), 6.32 (s, 2H), 3.95 (s, 3H), 3.90 (d, J=12 Hz, 2H), 2.87-2.74 (m, 4H), 2.59 (d, J=8 Hz, 1H), 2.33 (m, 4H), 2.23 (d, J=8 Hz, 1H), 2.14 (s, 3H), 1.86 (d, J=12 Hz, 2H), 1.50 (q, J=12 Hz, 2H), 1.42 (d, J=8 Hz, 1H). MS: 557 (M+H), HPLC: 1.58 min (G method).
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][C:11]1([CH3:38])[CH2:16][CH:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:14][C:13]([CH3:37])([CH3:36])[NH:12]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C(C)=CC=CC=1>[Cl:3][C:2]1[N:1]=[C:8]([N:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:15]2[CH2:14][C:13]([CH3:37])([CH3:36])[NH:12][C:11]([CH3:38])([CH3:10])[CH2:16]2)[N:7]=[C:5]([N:17]([CH:15]2[CH2:16][C:11]([CH3:38])([CH3:10])[NH:12][C:13]([CH3:36])([CH3:37])[CH2:14]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[N:4]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCCCCCCCCCCCCCCCCCNC1CC(C)(C)NC(C)(C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCCCCCCCCCN(c1nc(Cl)nc(N(CCCCCCCCCCCCCCCCCC)C2CC(C)(C)NC(C)(C)C2)n1)C1CC(C)(C)NC(C)(C)C1

Procedure:
A solution of 12.0 g of cyanuric chloride in 100 ml of xylene was added dropwise at 20°-25° C. to a solution of 54.0 g of 2,2,6,6-tetramethyl-4-(octadecylamino)piperidine in 200 ml of xylene. The resulting mixture was then heated under reflux for 8 hours, after which it was neutralised with an aqueous solution of potassium carbonate and then extracted with benzene. The extract was dried over anhydrous potassium carbonate and then the solvent was distilled off. The resulting residue was purified by column chromatography through silica gel, eluted with a 20:1:1 by volume mixture of ethyl acetate, ethanol and triethylamine, to give the title compound in the form of crystals. These were recrystallised from ethyl acetate, giving the purified title compound in the form of colourless crystals melting at 68°-70° C.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][O:14]CC3C=CC(OC)=CC=3)=[CH:9][C:8]=2[C:24]([F:27])([F:26])[F:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)(C(F)(F)F)=O.C(Cl)Cl.CCOC(C)=O>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][C:8]=2[C:24]([F:25])([F:26])[F:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(COCc2ccc(C3CCCCC3)c(C(F)(F)F)c2)cc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OCc1ccc(C2CCCCC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The obtained 1-cyclohexyl-4-(4-methoxy-benzyloxymethyl)-2-trifluoromethyl-benzene is dissolved in a mixture of TFA and DCM (8 mL, 1:1 v/v). After stirring at room temperature for 2 h, all volatile materials are evaporated and the residue obtained is dissolved in EtOAc and washed with saturated aqueous NaHCO3. The organic layer is separated, washed with saturated aqueous NaCl and dried over Na2SO4. After concentration, the residue is purified by silica gel chromatography (20% ethyl acetate in hexanes) to give (4-cyclohexyl-3-trifluoromethyl-phenyl)-methanol as a colorless oil.
Reaction SMILES: [C:1]([S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][C:20](=[O:22])[CH3:21])[N:14]=[CH:13][CH:12]=[C:11]2[Cl:23])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.C(Cl)Cl>[C:1]([S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][CH:20]([OH:22])[CH3:21])[N:14]=[CH:13][CH:12]=[C:11]2[Cl:23])(=[O:6])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(=O)COc1cc2nccc(Cl)c2cc1S(=O)(=O)C(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(O)COc1cc2nccc(Cl)c2cc1S(=O)(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.2 %

Procedure:
To a suspension of 1-((6-(tert-butylsulfonyl)-4-chloroquinolin-7-yl)oxy)propan-2-one (100 mg, 0.281 mmol) in MeOH (2810 μl) was added NaBH4 (13.29 mg, 0.351 mmol) at rt. This was stirred at rt for 20 min. Removed solvent in vacuo. Redissolved in DCM and quenched with sat aq NH4Cl. Separated and extracted twice more with DCM. Washed combined organics with brine, then dried on MgSO4, filtered and concentrated providing 1-((6-(tert-butylsulfonyl)-4-chloroquinolin-7-yl)oxy)propan-2-ol (98.8 mg, 0.276 mmol, 98% yield) as an off-white foam. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (d, J=6.06 Hz, 3H) 1.33 (s, 9H) 4.00-4.20 (m, 3H) 4.81 (d, J=4.29 Hz, 1H) 7.74 (s, 1H) 7.76 (d, J=4.80 Hz, 1H) 8.65 (s, 1H) 8.94 (d, J=4.80 Hz, 1H). MS: m/z: 358.1 [M+H]+.
Reaction SMILES: OC[C:3]1([OH:25])[C:8]2=[N:9][C:10]([C:13]3[S:17][C:16]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)=[N:15][C:14]=3[CH3:24])=[CH:11][CH:12]=[C:7]2[O:6][CH2:5][CH2:4]1.I([O-])(=O)(=O)=O.[Na+]>O1CCOCC1.O.ClCCl>[CH3:24][C:14]1[N:15]=[C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[S:17][C:13]=1[C:10]1[N:9]=[C:8]2[C:3](=[O:25])[CH2:4][CH2:5][O:6][C:7]2=[CH:12][CH:11]=1
Reactant: Cc1nc(-c2cccnc2)sc1-c1ccc2c(n1)C(O)(CO)CCO2
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(-c2cccnc2)sc1-c1ccc2c(n1)C(=O)CCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
The crude 4-(hydroxymethyl)-6-[4-methyl-2-(3-pyridyl)thiazol-5-yl]-2,3-dihydropyrano[3,2-b]pyridin-4-ol from step e was dissolved in a 1:1 mixture of dioxane (40 mL) and H2O (40 mL), and sodium periodate (2.22 g, 10.76 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was diluted with dichloromethane (50 mL) and H2O (50 mL) and the two layers were separated. The organic layer was dried over Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel chromatography (CH2Cl2/MeOH=100/1) to afford the title compound as a yellow solid (1.7 g, two-step yield: 48%). 1H NMR (400 Mz, CDCl3): 2.76 (s, 3H); 3.02 (t, J=6.6, 2H); 4.66 (t, J=6.9, 2H); 7.49 (d, J=9, 1 H); 7.62-7.58 (m, 1H); 7.75 (d, J=8.7, 1 H); 8.45 (d, J=7.8, 1 H); 8.71 (d, J=3.9, 1H); 9.28 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([NH2:9])=[O:8])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:3]=1>COC(OC)(OC)CCCC>[CH2:3]([C:2]1[NH:1][C:2]2[N:6]([N:5]=[C:4]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[CH:3]=2)[C:7](=[O:8])[N:9]=1)[CH2:4][CH2:10][CH3:11]
Reactant: NC(=O)n1nc(-c2ccc(F)cc2)cc1N
Agent: CCCCC(OC)(OC)OC
Product: CCCCc1nc(=O)n2nc(-c3ccc(F)cc3)cc2[nH]1
Temperature: 25 °C
Yield: 123.1 %

Procedure:
A mixture of 5.0 g of the product of Example 3 and 20 ml of trimethylorthovalerate is heated at reflux for 30 minutes. The reaction mixture is cooled to room temperature and diluted with hexanes. The resulting solid is collected by filtration, washed with hexanes and dried to give 4.0 g of the desired product as a solid, m.p. 238° C.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7].N12CCCN=C1CCCCC2.[CH:43]([CH:45]=[CH2:46])=[O:44]>O1CCCC1.O>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:46][CH2:45][CH:43]=[O:44])[CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7]
Reactant: C=CC=O
Reactant: Cc1ccc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Solvent: O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(C[C@@H]2CN(CCC=O)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Temperature: -30 °C
Reaction time: 6 h

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (500 mg) and 1,8-diazabicyclo [5.4.0]undec-7-ene (1.5 μl) in tetrahydrofuran (2.5 ml) was cooled to −30° C. with stirring under nitrogen atmosphere. Acrolein (90%, 0.225 ml) was added to the mixture while maintaining the temperature at −20˜−40° C. for a period of 10 minutes and then the resulting mixture was stirred at 0° C. After 6 hours, the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. After evaporation of the solvent under reduced pressure, the resulting residue was chromatographed on a silica gel using a mixture of hexane and ethyl acetate as eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(2-formylethyl)piperazine (332 mg) as an oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[S:14][C:13]([C:15]3[N:16]=[C:17]4[C:23]([C:24]([C:26]5([CH3:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)=[O:25])=[CH:22][N:21](COCC[Si](C)(C)C)[C:18]4=[N:19][CH:20]=3)=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1.O.O.O.C([O-])(=O)C.[Na+]>ClCCl.FC(F)(F)C(O)=O>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([C:10]2[S:14][C:13]([C:15]3[N:16]=[C:17]4[C:23]([C:24]([C:26]5([CH3:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)=[O:25])=[CH:22][NH:21][C:18]4=[N:19][CH:20]=3)=[CH:12][CH:11]=2)=[O:9])[CH2:6][CH2:7]1
Reactant: CC1(C(=O)c2cn(COCC[Si](C)(C)C)c3ncc(-c4ccc(C(=O)N5CCC(O)CC5)s4)nc23)CCCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC1(C(=O)c2c[nH]c3ncc(-c4ccc(C(=O)N5CCC(O)CC5)s4)nc23)CCCCC1
Reaction time: 8 h
Yield: 75 %

Procedure:
A solution of [2-[5-(4-hydroxy-piperidine-1-carbonyl)-thiophen-2-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-(1-methyl-cyclohexyl)-methanone (0.032 g, 0.056 mmol) in 1 mL of dichloromethane and 1 mL of trifluoroacetic acid was stirred for 2 h, then concentrated. The residue was dissolved in 2 mL of ethanol and treated with sodium acetate trihydrate (0.076 g, 0.56 mmol). The mixture was stirred overnight, then concentrated to a residue. Column chromatography (0->50% EtOAc/hexanes) afforded 0.019 g (76%) of {2-[5-(4-hydroxy-piperidine-1-carbonyl)-thiophen-2-yl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-(1-methyl-cyclohexyl)-methanone as an off-white solid.
Reaction SMILES: [CH3:1][C@H:2]([CH2:8][OH:9])[CH2:3][S:4]([NH2:7])(=[O:6])=[O:5].[H-].[Na+].Cl[C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[CH:20][N:21]=2)[N:18]=1.Cl>CN(C=O)C>[CH3:1][C@@H:2]([CH2:3][S:4](=[O:6])(=[O:5])[NH2:7])[CH2:8][O:9][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[CH:20][N:21]=2)[N:18]=1
Reactant: C[C@H](CO)CS(N)(=O)=O
Reactant: Clc1ccc2nccn2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](COc1ccc2nccn2n1)CS(N)(=O)=O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
To a solution of 0.93 g of 2-(R)-methyl-3-hydroxy-1-propylsulfonamide in 50 ml of DMF was added by portions 0.48 g of sodium hydride, followed by stirring for 30 minutes at 70° C. The mixture to which 0.93 g of 6-chloroimidazo[1,2-b]pyridazine was added was refluxed for 5 hours. After cooling, the reaction mixture was adjusted to pH 6.0 with 1N-hydrochloric acid and concentrated to dryness under reduced pressure. The residue was subjected to a silica gel column chromatography, eluting with chloroform-methanol (10:1). The corresponding fractions were collected and concentrated to obtain 1.06 g of the title compound.
Reaction SMILES: [CH:1]1([C:4]2[C:13]3[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=3)[C:7](=O)[NH:6][N:5]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][N:6]=1
Reactant: COc1ccc2c(C3CC3)n[nH]c(=O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(C3CC3)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 4-cyclopropyl-7-methoxy-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:37])([F:36])[O:21][C:22]1[CH:23]=[C:24]([C:28]2[O:32][CH:31]=[N:30][C:29]=2[C:33](O)=[O:34])[CH:25]=[CH:26][CH:27]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:33]([C:29]3[N:30]=[CH:31][O:32][C:28]=3[C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:20]([F:36])([F:19])[F:37])[CH:23]=3)=[O:34])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1cccc(OC(F)(F)F)c1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3cccc(OC(F)(F)F)c3)n2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 01b: tR=1.04 min; [M+H]+=461.12.
Reaction SMILES: [OH:1][CH:2]([C:7]1[C:8]([CH3:29])=[N:9][C:10]2[N:11]([N:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:22]=2)[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C:3]([O:5][CH3:6])=[O:4].Cl(O)(=O)(=O)=O>C(OC(C)(C)C)(=O)C>[C:7]([O:1][CH:2]([C:7]1[C:8]([CH3:29])=[N:9][C:10]2[N:11]([N:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:22]=2)[C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)[C:3]([O:5][CH3:6])=[O:4])([CH3:8])([CH3:12])[CH3:2]
Reactant: COC(=O)C(O)c1c(C)nc2cc(-c3ccccc3)nn2c1-c1ccc(C)cc1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2cc(-c3ccccc3)nn2c1-c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 2-hydroxy-2-(5-methyl-2-phenyl-7-p-tolylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (6.20 mg, 0.016 mmol) in tert-butyl acetate (0.3 mL) at room temperature was added perchloric acid (0.008 mL, 0.128 mmol). The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was quenched with water and diluted with ethyl acetate. The organic phase was washed with saturated NaHCO3 and dried over sodium sulfate. The solvent was evaporated to give the title compound. The crude product was used directly for next step.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[CH:8]1[C:18]2[C:17](=[O:19])[NH:16][C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]=3[NH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1>CC(C)=O>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([N:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:18]=2[C:17](=[O:19])[NH:16][C:15]2[CH:20]=[CH:21][CH:22]=[CH:23][C:14]1=2)=[O:6]
Reactant: O=C1Nc2ccccc2Nc2ccccc21
Reactant: O=C(Cl)CCCCl
Solvent: CC(C)=O
Product: O=C1Nc2ccccc2N(C(=O)CCCCl)c2ccccc21

Procedure:
A mixture of 4-chlorobutyryl chloride (3.5 g) and 10,11-dihydrodibenzo[b,e][1,4]diazepin-11-one (4.2 g) (J. Med. Chem., 1963, 6, 767) in acetone (90 ml) was heated under reflux for 8 hours and evaporated. The residue was purified by chromatography on silica using hexane plus 0-100% dichloromethane as eluant. Appropriate fractions were combined and evaporated and the residue triturated with hexane/dichloromethane to give the title compound as a colourless solid, 1.62 g (26%), m.p. 151°-152° C.
Reaction SMILES: [ClH:1].C(O)(C)C.[NH2:6][C:7]([NH2:9])=[S:8].[CH3:10][N:11]([CH2:13][C:14]1[S:18][C:17]([CH2:19]O)=[CH:16][C:15]=1[CH3:21])[CH3:12]>>[ClH:1].[ClH:1].[C:7]([S:8][CH2:19][C:17]1[S:18][C:14]([CH2:13][N:11]([CH3:12])[CH3:10])=[C:15]([CH3:21])[CH:16]=1)(=[NH:9])[NH2:6]
Reactant: Cc1cc(CO)sc1CN(C)C
Reactant: NC(N)=S
Agent: Cl
Solvent: CC(C)O
Product: Cc1cc(CSC(=N)N)sc1CN(C)C
Yield: 82 %

Procedure:
In 35 ml of 21% (by weight) hydrochloric acid-isopropanol solution was suspended 2.1 g of thiourea, and 5 g of 5-(dimethylamino)methyl-4-methyl-2-thenyl alcohol was added thereto, after which the resulting mixture was subjected to reaction under reflux for 15 hours. After the mixture was allowed to stand at room temperature, the crystals deposited were collected by filtration to obtain 7 g (yield 82%) of 2-amidinothiomethyl-5-(dimethylamino)methyl-4-methylthiophene dihydrochloride having a melting point of 212°-214° C. (decomp.). NMR (d6 -DMSO) δ values: 2.31 (3H, s, --CH3), 2.82 (6H, s, --CH3 ×2), 4.58 (2H, s, >CH2), 5.04 (2H, s, >CH2), 7.16 (1H, s, thiophene ring H), 9.76 (4H, bs, ##STR224## 11.01 (1H, bs, HCl)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12]([C:14]1[CH:18]=[C:17]([CH3:19])[S:16][C:15]=1Br)=[O:13].C(=O)([O-])[O-].[K+].[K+]>>[CH3:19][C:17]1[S:16][C:15]2[O:1][C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=3[NH:11][C:12](=[O:13])[C:14]=2[CH:18]=1
Reactant: Cc1cc(C(=O)Nc2cc([N+](=O)[O-])ccc2O)c(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc2c(s1)Oc1ccc([N+](=O)[O-])cc1NC2=O

Procedure:
In the same manner as in Example 98 and using N-(2-hydroxy-5-nitrophenyl)-2-bromo-5-methyl-3-thiophenecarboxamide and potassium carbonate, 2-methyl-7-nitrothieno[2,3-b][1,5]benzoxazepin-4(5H)-one is obtained.
Reaction SMILES: [CH:1]1([N:4]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:5]([C:7]2[CH:8]=[N:9][C:10]([N:13]3[CH:17]=[CH:16][N:15]=[C:14]3[CH3:18])=[N:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1.Cl[C:26]1[N:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][N:27]=1>>[CH:1]1([N:4]([CH:19]2[CH2:24][CH2:23][N:22]([C:26]3[N:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][N:27]=3)[CH2:21][CH2:20]2)[C:5]([C:7]2[CH:12]=[N:11][C:10]([N:13]3[CH:17]=[CH:16][N:15]=[C:14]3[CH3:18])=[N:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCc1cnc(Cl)nc1
Reactant: Cc1nccn1-c1ncc(C(=O)N(C2CCNCC2)C2CC2)cn1
Product: CCc1cnc(N2CCC(N(C(=O)c3cnc(-n4ccnc4C)nc3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from 2-(2-methyl-imidazol-1-yl)-pyrimidine-5-carboxylic acid cyclopropyl-piperidin-4-yl-amide and 2-chloro-5-ethylpyrimidine following a procedure analogous to that described in Example 3. LC (method 10): tR=1.39 min; Mass spectrum (ESI+): m/z=433 [M+H]+.
Reaction SMILES: C1(C2C([CH:11]=[O:12])=CC(C(N3CCC(C4C=CC(C#N)=CC=4)CC3)=O)=C(C)C=2)CCC1.[Cl:30][C:31]1[C:39](I)=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[C:33]([CH3:41])[CH:32]=1.C1(C2C(C=O)=CC(C(O)=O)=C(C)C=2)CCC1>>[Cl:30][C:31]1[C:39]([CH:11]=[O:12])=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[C:33]([CH3:41])[CH:32]=1
Reactant: Cc1cc(C2CCC2)c(C=O)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reactant: Cc1cc(Cl)c(I)cc1C(=O)O
Agent: Cc1cc(C2CCC2)c(C=O)cc1C(=O)O
Product: Cc1cc(Cl)c(C=O)cc1C(=O)O

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 392.2, except 4-chloro-5-iodo-2-methylbenzoic acid (compound 471.1) was used in place of 4-cyclobutyl-5-iodo-2-methylbenzoic acid (compound 392.1).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].[Br:17]Br>CCOCC>[Br:17][CH2:2][C:1]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][C:7]=2[CH:8]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1cc2cc(C(C)(C)C)ccc2o1
Solvent: CCOCC
Product: CC(C)(C)c1ccc2oc(C(=O)CBr)cc2c1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
2-Acetyl-5-tert-butylbenzofuran (86.5 g) was dissolved in 800 ml of ether and, with stirring at room temperature, 63.9 g of bromine was dropped thereinto. When the crystals started to be separated, the reaction mixture was cooled with ice water. After completion of the dropping, the mixture was stirred for 30 minutes, the reaction mixture was poured into ice water and, until the crystals were dissolved, ethyl acetate was added thereto. The organic layer was washed with water for three times, dried over anhydrous magnesium sulfate, concentrated in vacuo and n-hexane was added to the residue to crystallize followed by filtrating to give 100.1 g of crystals. M.p. 100°-102° C.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([C:22](Cl)=[O:23])[CH2:18][CH2:19][CH2:20][CH3:21]>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:10][C:22]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:23])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCC(=O)Cl
Reactant: NC(=O)C(c1ccccc1)c1ccccc1
Product: CCCCCC(=O)NC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 87° C. and MS: m/e=309 (M+) was prepared in accordance with the general method of example 39 from 2,2-diphenylacetamide and pentanecarboxylic acid chloride.