Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]1[CH:33]=[CH:32][C:17]2[C:18]([CH:21]3[CH2:26][CH2:25][N:24]([CH:27]([CH2:30][CH3:31])[CH2:28]O)[CH2:23][CH2:22]3)=[N:19][O:20][C:16]=2[CH:15]=1.[C:34]1(=[O:44])[NH:38][C:37](=[O:39])[C:36]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOCC>[F:13][C:14]1[CH:33]=[CH:32][C:17]2[C:18]([CH:21]3[CH2:26][CH2:25][N:24]([CH:27]([CH2:30][CH3:31])[CH2:28][N:38]4[C:37](=[O:39])[C:36]5=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]5[C:34]4=[O:44])[CH2:23][CH2:22]3)=[N:19][O:20][C:16]=2[CH:15]=1
Reactant: CCC(CO)N1CCC(c2noc3cc(F)ccc23)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(CN1C(=O)c2ccccc2C1=O)N1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 7.6 %

Procedure:
A solution of diethyl azodicarboxylate (DEAD, 4.9 g, 28.3 mmol) in THF (50 ml) was added dropwise to a solution of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butanol (6.9 g, 23.6 mmol), phthalimide (4.16 g, 1.2 eq), and triphenylphosphine (7.4 g, 28.3 mmol) in THF (200 ml) at room temperature. The solution was stirred at room temperature for 24 hours. After the reaction, the solvent was stripped to dryness. The residue was stirred in ether (200 ml) and the insolubles were removed by filtration. The oily residue from concentration of the ether solution was purified by two flash chromatography (SiO2, 75 g, eluted with dichloromethane, DCM, and 1-2% CH3OH in DCM) and (100 g of SiO2 ; eluted with DCM, 11, and 1% CH3OH in DCM, 1.2 l). Two close compounds were separated and the top compound on TLC (1.6 g) was recrystallized from isopropyl ether to yield 0.76 g of white crystals, m.p. 86°-88° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][C:15]4[C:21]5[C:22]([O:26]CCC6C=CC([N+]([O-])=O)=CC=6)=[N:23][CH:24]=[N:25][C:20]=5[S:19][C:16]=43)=[N:11]2)[CH2:4][CH2:3]1.C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][C:15]4[C:21]5=[C:22]([OH:26])[N:23]=[CH:24][N:25]=[C:20]5[S:19][C:16]=43)=[N:11]2)[CH2:4][CH2:3]1
Reactant: CN1CCN(CCn2cc3c(n2)CCc2c-3sc3ncnc(OCCc4ccc([N+](=O)[O-])cc4)c23)CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: CN1CCN(CCn2cc3c(n2)CCc2c-3sc3ncnc(O)c23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.9 %

Procedure:
To a solution of 2-[2-(4-methylpiperazin-1-yl)ethyl]-6-[2-(4-nitrophenyl)ethoxy]-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazole (4.12 g, 7.93 mmol) in pyridine (100 mL) was added DBU (4.83 g, 31.72 mmol) and the resulting reaction mixture was stirred at room temperature overnight. Analytical HPLC showed no more starting material present and two new peaks appeared. Solvents were evaporated and the residue was dissolved in water and CH2Cl2. pH of the aqueous layer was adjusted to about 7. The organic phase contains the N-alkylated side product and no desired product. The desired product is in the aqueous phase. After separation of the layers, the pH of the aqueous was further adjusted to about 10 and it was concentrated to dryness. The resulting solid was washed with MeOH, then small amount of water, and air dried to afford a light yellow solid (0.79 g, 27%) as the desired product. The MeOH filtrates were concentrated to give a yellow solid, which was washed with EtOAc, air-dried to give another batch of desired product (1.5 g, 36%) as a light yellow solid. 1H-NMR (D2O) δ 7.82 (s, 1H), 7.56 (s, 1H), 4.26 (t, 2H), 3.30 (broad, 4 h), 3.21 (t, 2H), 3.07 (broad, 4H), 2.99 (t, 2H), 2.78 (s, 3H), 2.67 (t, 2H); LCMS RT=0.30 min; [M+H]+=371.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:23](O)=[O:24]>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH:23]=[O:24])=[C:4]([OH:10])[CH:3]=1
Reactant: COc1ccc(O)cc1Cl
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1cc(C=O)c(O)cc1Cl
Temperature: 85 °C

Procedure:
The above prepared 3-chloro-4-methoxy-phenol (2.379 g, 13.5 mmol, corrected for purity) was dissolved in 21 mL of trifluoroacetic acid and treated with hexamethylene tetramine (2.313 g, 1.25 eq.), and the mixture was then stirred at 85° C. over night. Cooling, pouring onto crashed ice, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, heptane/AcOiPr=82/18), followed by crystallization from heptane/AcOEt, produced finally 1.030 g of the title compound as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7]([CH:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[OH:10])=[N:8][C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[OH-].[Na+].[CH:31](O)([CH3:33])[CH3:32]>>[F:1][C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7]([CH:9]([O:10][CH:31]([CH3:33])[CH3:32])[C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:20])([F:19])[F:21])=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: OC(c1ccc(OC(F)(F)F)cc1)c1nc2cc(F)ccc2[nH]1
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)OC(c1ccc(OC(F)(F)F)cc1)c1nc2cc(F)ccc2[nH]1
Temperature: 160 °C

Procedure:
The compound of Example 1 (123 mg) was dissolved in isopropanol (2 mL), and concentrated sulfuric acid (41 mg) was added thereto. The mixture was heated at 140° C. for one hour and at 160° C. for 2 hours by means of a microwave reaction apparatus. The reaction mixture was basified with a 10% aqueous solution of sodium hydroxide and extracted with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (10% to 100% ethyl acetate/hexane), and thus the title compound (66 mg) was obtained as a colorless solid.
Reaction SMILES: [O:1]=[C:2]1[N:8]2[CH:4]([S:5][C:6]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)=[C:7]2[C:9]([O:11]CC2C=CC([N+]([O-])=O)=CC=2)=[O:10])[CH2:3]1.C(=O)(O)[O-].[Na+:37]>O1CCOCC1.O.[Pd]>[O:1]=[C:2]1[N:8]2[CH:4]([S:5][C:6]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:32])[F:30])[CH:24]=3)=[C:7]2[C:9]([O-:11])=[O:10])[CH2:3]1.[Na+:37]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)C1=C(Oc2cccc(C(F)(F)F)c2)SC2CC(=O)N12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C([O-])C1=C(Oc2cccc(C(F)(F)F)c2)SC2CC(=O)N12

Procedure:
A mixture of a solution of 602 mg of 4-nitrobenzyl 7-oxo-3-(3-trifluoromethylphenoxy)-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate in dioxan and 108 mg sodium bicarbonate in water, and 10% palladium/charcoal was hydrogenated at 50 psi at 25° for 60 minutes.
Reaction SMILES: O[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[CH2:13]([CH:15]1[O:17][CH2:16]1)Br.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CCCCCC.CC(C)=O.CCCCCC.CC(C)=O>[CH2:13]([C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1)[CH:15]1[O:17][CH2:16]1
Reactant: O=c1ccc2ccc(O)cc2o1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: O=c1ccc2ccc(CC3CO3)cc2o1

Procedure:
The intermediate 7-glycidylcoumarin was prepared in a reaction flask equipped with a reflux condenser containing 16.2 g 7-hydroxycournarin, 15.8 g epibromohydrin, 13.8 g potassium carbonate and 270 mL acetone. The reaction solution was boiled and refluxed overnight, cooled, treated with 100 mL 5% NaOH aqueous solution, and extracted three times with 80 mL methylene chloride. After evaporating the solvent, a crude yellow solid was obtained. The crude solid (1.5 g) was dissolved in a solution of 30 mL hexane and 20 mL acetone at 50° C. The hexane/acetone solution was then cooled at 0° C. for 2 to 3 hr. White crystals formed and were collected by filtering and dried to a white powder. Yield: 290 mg; melting point: 110-112° C.; Rf=0.6 (8% v/v ethyl acetate/CHCl3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10]([CH3:15])([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:10]([CH3:15])([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(C)(C)C1
Temperature: 25 °C

Procedure:
To a solution of 18.5 g (82.0 mmol) 3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester in 150 mL DCM at RT was added 30.0 mL (174 mmol) DIPEA. The mixture was cooled with ice and a solution of 14.0 mL (93.2 mmol) benzyl chloroformate in 60 mL DCM was added dropwise. The reaction mixture was stirred at RT over night and quenched with saturated aqueous sodium bicarbonate solution. The product was extracted with DCM. The organic layers were combined, dried over sodium sulfate and concentrated in vacuo.
Reaction SMILES: N1C=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]2)=[CH:3]C=1.S(Cl)(Cl)=O.[NH2:20][C:21]1[CH:36]=[C:35]([C:37]([O:39][CH3:40])=[O:38])[CH:34]=[CH:33][C:22]=1[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1)=[O:24]>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([NH:25][C:23](=[O:24])[C:22]2[CH:33]=[CH:34][C:35]([C:37]([O:39][CH3:40])=[O:38])=[CH:36][C:21]=2[NH:20][C:13]([CH:10]2[CH2:9][CH2:8][N:7]([CH:4]([CH3:3])[CH3:5])[CH2:12][CH2:11]2)=[O:15])=[N:27][CH:28]=1
Reactant: O=C(O)C1CCN(c2ccncc2)CC1
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c(N)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c(NC(=O)C2CCN(C(C)C)CC2)c1

Procedure:
Using a similar procedure to that described in Example 275, 1-(4-pyridinyl)piperidin-4-ylcarboxylic acid (2.0 g, 9.7 mmol), thionyl chloride (1.4 mL, 19 mmol), and 2-amino-N-(5-chloropyridin-2-yl)-4-methoxycarbonylbenzamide (2.8 g, 9.2 mmol) afforded, after purification by column chromatography (SiO2: 5 to 10% [2.0 N ammonia in methanol]:methylene chloride), 0.40 g (9%) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)=[O:8].[OH-].[Na+].O.[CH:25]1([N:31]=[C:32]=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CC(C)=O>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:32]([NH:31][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:33])(=[O:19])=[O:20])=[CH:14][CH:13]=1)=[O:8]
Reactant: O=C=NC1CCCCC1
Reactant: NS(=O)(=O)c1ccc(CCNC(=O)N2CCCC2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(NC1CCCCC1)NS(=O)(=O)c1ccc(CCNC(=O)N2CCCC2=O)cc1
Reaction time: 2 h

Procedure:
5 g of 4-[2-(oxo-pyrrolidine-1-carboxamido)-ethyl]-benzenesulfonamide are dissolved in 100 ml of acetone with 0.65 g of NaOH and water. 2.3 g of cyclohexyl-isocyanate are added dropwise with agitation and ice cooling, and agitation is continued for 2 hours at room temperature. Subsequently, the substantial amount of acetone is distilled off under reduced pressure, the aqueous solution is acidified and the product is reprecipitated from dilute ammonia. The N-(4-[2-(2-oxo-pyrrolidine-1-carboxamido)-ethyl]-benzenesulfonyl)-N'-cyclohexyl urea is recrystallized from dilute ethanol, and has a melting point of 189°-190° C.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:5]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:6])[CH2:3][NH2:4].C(NCC)C>C(Cl)Cl>[NH2:1][C@H:2]([C:5]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:6])[CH2:3][NH2:4]
Reactant: NC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCNCC
Product: NC[C@H](N)C(=O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 1-L round bottom flask is charged with Fmoc-Dap-Z, CH2Cl2 (122 mL) and diethylamine (61 mL, Acros). The solution is stirred at room temperature and the completion monitored by HPLC. After 7h, the mixture is concentrated (bath temp. <30° C.). The residue is suspended in CH2Cl2 (300 mL) and concentrated. This is repeated twice. To the residue is added MeOH (20 mL) and CH2Cl2 (300 mL), and the solution is concentrated. The residue is suspended in CH2Cl2 (100 mL) and toluene (400 mL), concentrated, and the residue left under vacuum overnight to give product.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH:13]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]1>>[Br:1][C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[N:4][C:5]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]2)=[N:6][CH:7]=1
Reactant: FC(F)(F)c1nc(Cl)ncc1Br
Reactant: O=C1CCNCCN1
Product: O=C1CCN(c2ncc(Br)c(C(F)(F)F)n2)CCN1
Yield: 82.3 %

Procedure:
Synthesised from 5-bromo-2-chloro-4-(trifluoromethyl)pyrimidine (1.14 g, 4.35 mmol) and 1,4-diazepan-5-one (490 mg, 4.30 mmol) in accordance with General Method B, giving the title compound (1.20 g, 81%) as a white solid. δH (300 MHz, DMSO-d6) 8.79 (s, 1H), 7.71 (t, J 4.8 Hz, 1H), 3.90 (m, 4H), 3.21 (m, 2H), 2.54 (m, 2H). LC-MS (pH 3) MH+ m/z 339.0, RT 1.93 minutes. LC-MS (pH 10) MH+ m/z 339.0, RT 1.91 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(#N)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:10])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(N)c(S(N)(=O)=O)c1
Solvent: c1ccncc1
Solvent: CC#N
Product: CS(=O)(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,5-Diaminobenzenesulfonamide (Example 17c, 11.16 g, 59.61 mmol) was dissolved in acetonitrile (300 mL) and pyridine (7.07 g, 89.41 mmol) was added. Methanesulfonyl chloride (7.17 g, 62.59 mmol) was added dropwise over a period of 10 min and the reaction mixture was stirred for 16 h at 25° C. after which time a precipitate had formed. Most of the acetonitrile was removed in vacuo and water (200 mL) was added to afford a clear solution. The product slowly started to precipitate and the mixture was placed in an ice bath for 3 h. The precipitate was collected by vacuum filtration and dried under high vacuum to afford the desired product, 2-amino-5-methanesulfonylamino-benzenesulfonamide (also made in Examples 3d and 3d′) (11.1 g, 41.84 mmol, 70.2% yield) as a brown solid. 1H NMR (400 MHz, CD3OD) δ: 2.89 (3H, s), 6.82 (1H, d, J=8.5 Hz), 7.20 (1H, dd, J1=8.5 Hz, J2=2.5 Hz), 7.58 (1H, d, J=2.5 Hz). LC-MS (ESI) calcd for C7H11N3O4S2 265.02. found 266.0 [M+H+].
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16]N)=[CH:12][CH:11]=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[F:9][C:10]1[CH:15]=[CH:14][C:13]2[NH:16][C:2]3[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=3[C:12]=2[CH:11]=1
Reactant: NNc1ccc(F)cc1
Reactant: O=c1cc(O)cc[nH]1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1[nH]ccc2[nH]c3ccc(F)cc3c12
Yield: 18.1 %

Procedure:
4-Hydroxypyridin-2(1H)-one (1 g, 0.009 mol) and (4-fluorophenyl)hydrazine (3.6 g, 0.027 mol) in diphenyl ether (20 mL) were heated at 250° C. for 5 hours to afford the crude product. Purification by washing with hexane, followed by column chromatography on silica gel (1.5% methanol in DCM) afforded 330 mg of the product (17.36% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][C:10]2([O:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([NH2:17])[CH3:16]>>[CH2:1]([N:8]1[CH2:14][CH2:13][C:10]([CH2:11][NH:17][CH2:15][CH3:16])([OH:12])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN
Reactant: c1ccc(CN2CCC3(CO3)C2)cc1
Product: CCNCC1(O)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.2 g (53.9 mmol) of 5-benzyl-5-aza-1-oxaspiro-[2,4]heptane are added dropwise to 60 ml of aqueous ethylamine solution (50%) and the mixture is stirred overnight at room temperature. The batch is then concentrated and the residue is distilled.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([F:25])[CH:15]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH3:26])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1>CO.C(Cl)Cl.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([F:25])[CH:15]=[C:16](/[CH:21]=[CH:22]\[CH2:23][OH:24])[CH:17]=3)[N:12]([CH3:26])[CH:11]=2)=[O:9])=[CH:27][CH:28]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)cc(F)c21
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(/C=C\CO)cc(F)c21

Procedure:
A mixture of N-(4-chlorobenzyl)-8-fluoro-1,4-dihydro-6-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-3-quinolinecarboxamide from Example No. 8 (0.200 g) and Pd/C (10%, 0.040 g) in MeOH (10 mL) and CH2Cl2 (10 mL) is placed on a Parr shaker under 50 psi of H2 for 6 h. The reaction mixture is filtered through Celite and concentrated in vacuo. Recrystallization from EtOAc gave the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12]2[S:13][C:14]([C:23]3[N:27]=[CH:26][N:25]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][O:29]4)[N:24]=3)=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=2)=[C:5]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][N:4]2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][C:46]([F:50])([F:49])[CH2:45][CH2:44]1>>[F:49][C:46]1([F:50])[CH2:47][CH2:48][N:43]([CH2:42][CH2:41][O:10][C:7]2[CH:8]=[CH:9][N:4]3[N:3]=[C:2]([CH3:1])[C:11]([C:12]4[S:13][C:14]([C:23]5[N:27]=[CH:26][N:25]([CH:28]6[CH2:33][CH2:32][CH2:31][CH2:30][O:29]6)[N:24]=5)=[C:15]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)[N:16]=4)=[C:5]3[CH:6]=2)[CH2:44][CH2:45]1
Reactant: Cc1nn2ccc(O)cc2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Reactant: FC1(F)CCN(CCCl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nn2ccc(OCCN3CCC(F)(F)CC3)cc2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Yield: 90.9 %

Procedure:
The title compound has been prepared according to the similar manner described in 85-B (ii) using 2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}pyrazolo[1,5-a]pyridin-5-ol (100 mg, 0.218 mmol) obtained in Example 31-B-(i), potassium carbonate (75.3 mg, 0.545 mmol) and 1-(2-chloroethyl)-4,4-difluoropiperidine (80.0 mg, 0.436 mmol) obtained above. The crude product was purified by basic silica gel column chromatography (EtOAc/hexane=20/80→50/50) to give pure title compound (120 mg, 91%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[Br-].COC(C1C=CC=CC=1C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O.O1C=CC=C1C[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[CH2:54][C:55]([O:57][CH3:58])=[O:56].C(Cl)C1C=CC=CC=1.C1(CC([O-])=O)C=CC=CC=1.[C-]#N.[K+].C1(CC#N)C=CC=CC=1.S(=O)(=O)(O)O>CS(C)=O.CO>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[CH2:54][C:55]([O:57][CH3:58])=[O:56])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccccc1CCc1ccco1
Reactant: O=Cc1ccc(F)cc1
Agent: COC(=O)c1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CS(C)=O
Solvent: ClCc1ccccc1
Product: COC(=O)Cc1ccccc1CCc1ccc(F)cc1

Procedure:
Methyl 2-(2-[4-fluorophenyl]ethyl)phenylacetate was prepared from 4-fluorobenzaldehyde and (o-methoxycarbonylbenzyl)triphenylphosphonium bromide by a route similar to that described in Example 3 for the preparation of methyl 2-[2-(2-furyl)ethyl]phenylacetate. In this instance, the benzyl chloride was converted into the phenylacetate by treatment with potassium cyanide in DMSO and, then, methanolysis of the resulting phenylacetonitrile with sulphuric acid in methanol.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[N:21][C:20]([C:23]4[CH:24]=[N:25][N:26]([CH2:28][C:29](OCC)=[O:30])[CH:27]=4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.CO.[CH3:36][NH2:37]>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:12][CH2:13][N:14]([C:17]3[N:22]=[N:21][C:20]([C:23]4[CH:24]=[N:25][N:26]([CH2:28][C:29]([NH:37][CH3:36])=[O:30])[CH:27]=4)=[CH:19][CH:18]=3)[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: CCOC(=O)Cn1cc(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)cn1
Solvent: CO
Solvent: O
Product: CNC(=O)Cn1cc(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flask was placed ethyl 2-(4-(6-(4-(6-fluoroindolin-1-yl)piperidin-1-yl)pyridazin-3-yl)-1H-pyrazol-1-yl)acetate (45 mg, 0.1 mmol) and MeOH (2 mL) was added. Then, 40 wt % CH3NH2(aq) (8 mL) was added. The resulting mixture was stirred at room temperature for 30 min and H2O (10 mL) was added. The solid was filtered and washed with H2O (5 mL×3), then dried to yield 2-(4-(6-(4-(6-fluoroindolin-1-yl)piperidin-1-yl)pyridazin-3-yl)-1H-pyrazol-1-yl)-N-methylacetamide as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[CH:21](B1OC(C)(C)C(C)(C)O1)=[CH2:22]>>[CH2:21]([C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1)[CH3:22]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: CCc1nc(Nc2cc(C)[nH]n2)cc2cc(OC)ccc12

Procedure:
Similar procedure as described in example 330 was used, starting (1-Chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and ethenylboronic acid pinacol ester to give (1-Ethyl-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 283(MH+).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:12]=[CH:11][N:10]([C:13]3[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=3)[C:9](=[O:22])[CH:8]=2)[CH2:3][CH2:2]1.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([NH:30][C:19]([C:15]1[S:14][C:13]([N:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)=[CH:8][C:9]2=[O:22])=[N:17][C:16]=1[CH3:18])=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1nc(-n2ccc(OCCC3CC3)cc2=O)sc1C(=O)O
Reactant: NCc1ccccc1
Product: Cc1nc(-n2ccc(OCCC3CC3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 17 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 2-(4-(2-cyclopropylethoxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid to react with benzylamine, the title compound was obtained as a colorless solid in 17% yield: mp 172-174° C. (hexane/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.64 (d, J=8.1 Hz, 1H), 7.37-7.26 (m, 5H), 6.16 (dd, J=8.1, 2.5 Hz, 1H), 6.09 (t, J=5.6 Hz, 1H), 5.97 (d, J=2.5 Hz, 1H), 4.58 (d, J=5.6 Hz, 2H), 4.03 (t, J=6.6 Hz, 2H), 2.68 (s, 3H), 1.68 (q, J=6.6 Hz, 2H), 0.89-0.72 (m, 1H), 0.52-0.46 (m, 2H), 0.13-0.08 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 167.8, 162.2, 162.1, 153.6, 152.1, 137.7, 131.3, 128.8, 127.9, 127.7, 122.2, 104.1, 96.6, 69.1, 44.1, 33.6, 17.3, 7.5, 4.2; MS (ES+) m/z 410.2 (M+1).