Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16]O)=[CH:12][C:11]=2[C:18]2([CH2:23][O:24][CH3:25])[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.S(Cl)([Cl:28])=O>C(Cl)Cl>[Cl:28][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:3]2[C:2]([F:1])=[CH:7][N:6]=[C:5]([O:8][CH3:9])[CH:4]=2)=[C:11]([C:18]2([CH2:23][O:24][CH3:25])[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:12]=1
Reactant: COCC1(c2cc(CO)ccc2-c2cc(OC)ncc2F)CCCC1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COCC1(c2cc(CCl)ccc2-c2cc(OC)ncc2F)CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (4-(5-fluoro-2-methoxypyridin-4-yl)-3-(1-(methoxymethyl)cyclopentyl)phenyl)methanol (71.0 mg, 206 μmol) DMF (10 uL), and DCM (4.0 mL) was slowly added thionyl chloride (15.0 μL, 206 μmol) at 0° C. After addition, the resulting mixture was stirred at room temperature for 1 hour. The solvent was removed providing the product which was used in the next step. MS ESI (pos.) m/e: 364.2 (M+H)+.
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].O[C:17]1[CH:18]=[CH:19][C:20]2[CH2:26][CH:25]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:24]3[CH:33]=[CH:34][CH:35]=[CH:36][C:23]=3[CH2:22][C:21]=2[CH:37]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CCOCC>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[CH:18]=[CH:19][C:20]2[CH2:26][CH:25]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:24]3[CH:33]=[CH:34][CH:35]=[CH:36][C:23]=3[CH2:22][C:21]=2[CH:37]=1)(=[O:5])=[O:4]
Reactant: CCOC(=O)CC1Cc2ccc(O)cc2Cc2ccccc21
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)CC1Cc2ccc(OS(=O)(=O)C(F)(F)F)cc2Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
Trifluoromethanesulfonic anhydride (0.45 mL, 2.68 mmol) was added dropwise to a solution of ethyl (±)-10,11-dihydro-3-hydroxy-5H-dibenzo[a,d]cycloheptene-10-acetate (611.7 mg, 2.06 mmol) and 2,6-lutidine (0.48 mL, 4.12 mmol) in anhydrous CH2Cl2 (10.3 mL) at -78° C. under argon. After 0.5 h, the reaction was warmed to RT and stirred for 1 h. The yellow solution was diluted with Et2O (50 mL) and washed sequentially with 1.0 N HCl (5 mL), 5% NaHCO3 (5 mL), and brine (5 mL). Drying (MgSO4), concentration, and silica gel chromatography (20% EtOAc/hexanes) gave the title compound as a colorless oil (808.9 mg, 92%): TLC Rf (20% EtOAc/hexanes) 0.58; 1H NMR (250 MHz, CDCl3) δ 6.98-7.30 (m, 7H), 4.35 (d, J=15.2 Hz, 1H), 4.19 (q, J=7.1 Hz, 2H), 3.91 (d, J=15.2 Hz, 1H), 3.78-3.95 (m, 1H), 3.37 (dd, J=15.2, 4.1 Hz, 1H), 3.02 (dd, J=15.2, 9.6 Hz, 1H),2.70 (dd, J=15.8, 4.8 Hz, 1H), 2.53 (dd, J=15.8, 9.6 Hz, 1H), 1.27 (t, J=7.1 Hz, 3H); FTIR (CCl4) 1735, 1493, 1427, 1250, 1215, 1144,961,856 cm-1 ; MS (ES) m/e 451.1 (M+Na)+, 446.2 (M+NH4)+, 429.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][N:8]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]([O:17]CC2C=CC=CC=2)=[O:16])=[CH:9]1)([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.CCO.[Pd]>[C:1]([O:5][C:6](=[O:25])[CH2:7][N:8]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]([OH:17])=[O:16])=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1cc(C(=O)OCc2ccccc2)ccc1=O
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Cn1cc(C(=O)O)ccc1=O
Temperature: 23 °C
Reaction time: 0.75 h

Procedure:
A solution of benzyl 1-(2-(tert-butoxy)-2-oxoethyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (924 mg, 2.69 mmol) in EtOAc (20 mL) and EtOH (5 mL) was treated with palladium 10 wt. % on activated carbon (143 mg, 0.135 mmol) under nitrogen. The reaction vessel was purged through 3 vacuum-hydrogen cycles, and was stirred under a hydrogen balloon at 23° C. After 45 min, the reaction was filtered through Celite® brand filter agent, the filter cake washed with MeOH (100 mL), the filtrates were combined and concentrated, affording the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.02-13.68 (br. s., 1H), 8.49 (br. s., 1H), 7.83 (d, J=9.39 Hz, 1H), 6.44 (d, J=9.19 Hz, 1H), 4.68 (br. s., 2H), 1.41 (s, 9H). MS (ESI, positive ion) m/z: 276.0 (M+H).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=2)[CH:6]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3([CH3:36])[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)[CH2:19][CH:18]2[CH3:37])[CH2:5]1.[CH3:38]I>O1CCCC1>[CH3:38][O:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([F:16])([F:14])[F:15])[CH:11]=2)[CH:6]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3([CH3:36])[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]3)[CH2:19][C@@H:18]2[CH3:37])[CH2:5]1
Reactant: CC1CN(C2(C)CCN(C(=O)OC(C)(C)C)CC2)CCN1C1CC(O)c2cc(C(F)(F)F)ccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1CC(N2CCN(C3(C)CCN(C(=O)OC(C)(C)C)CC3)C[C@@H]2C)c2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
To a suspension of sodium hydride (150 mg, 3.75 mmol) in tetrahydrofuran (15 mL) was added a solution of tert-butyl 4-{4-[3-hydroxy-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidine-1-carboxylate (92 mg, 0.185 mmol) in tetrahydrofuran (5 mL). The reaction mixture was stirred at room temperature for 1 h before methyl iodide (0.50 mL, 8.05 mmol) was added. The reaction was continuously stirred at room temperature overnight and quenched by addition of 10 mL of water and 10 mL of EtOAc. The organic phase was separated and the aqueous layer was extracted with EtOAc twice (2×15 mL). The combined extracts were washed with brine, dried over Na2SO4, and evaporated under reduced pressure to give the crude product (81 mg, 85%) which was used directly for the next step. LC-MS [M+1]=511.3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:21]=[CH:20][C:19]3[C:18]([CH:22]([CH3:24])[CH3:23])=[CH:17][CH2:16][C:15]([CH3:26])([CH3:25])[C:14]=3[CH:13]=2)=[CH:7][CH:6]=1)[CH3:2].[CH:28](=O)[CH3:29]>>[CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH2:28][CH3:29])[C:12]2[CH:21]=[CH:20][C:19]3[C:18]([CH:22]([CH3:23])[CH3:24])=[CH:17][CH2:16][C:15]([CH3:25])([CH3:26])[C:14]=3[CH:13]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Nc2ccc3c(c2)C(C)(C)CC=C3C(C)C)cc1
Reactant: CC=O
Product: CCOC(=O)c1ccc(N(CC)c2ccc3c(c2)C(C)(C)CC=C3C(C)C)cc1

Procedure:
Following General Procedure M, 4-(5-isopropyl-8,8-dimethyl-7,8-dihydro-naphthalen-2-ylamino)-benzoic acid ethyl ester (Compound 79, 10 mg, 0.06 mmol), was reacted with acetaldehyde to give the title compound as a yellow oil.
Reaction SMILES: [CH:1]1([CH:7]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=O)=[CH:27][CH:26]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[S:10][C:9]=2[CH3:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:34][NH:35][CH2:36][CH2:37][C:38]([O:40]CC)=[O:39].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[OH-].[Na+]>CN(C)C=O.C(O)C.O1CCCC1.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29]([N:35]([CH3:34])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:31])=[CH:27][CH:26]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=3)[S:10][C:9]=2[CH3:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC
Reactant: Cc1sc(-c2ccc(C(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1sc(-c2ccc(C(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 36 h
Yield: 75.7 %

Procedure:
To a mixture of 4-[(cyclohexyl{2-methyl-5-[4-(trifluoromethyl)phenyl]thiophen-3-yl}methyl)amino]benzoic acid (326 mg) synthesized above, ethyl 3-(methylamino)propanoate (108 mg), 1-hydroxybenzotriazole monohydrate (126 mg) and triethylamine (115 μL) in N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (158 mg), and the mixture was stirred at room temperature for 1.5 days. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give colorless oil. To a mixture of the obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 2.5 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title compound (291 mg, 76%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:10])=[C:5]([C:7]([OH:9])=O)[N:6]=1.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.C[O:24][C:25](=[O:76])[C@@H:26]([NH:43][C:44]([C@@H:46]1[CH2:55][C:54]2[CH:53]=[C:52]3[O:56][CH2:57][C@H:58]([C:60]4[CH:65]=[CH:64][CH:63]=[C:62]([O:66][CH2:67][C:68]5[CH:73]=[CH:72][C:71]([Cl:74])=[C:70]([Cl:75])[CH:69]=5)[CH:61]=4)[O:59][C:51]3=[CH:50][C:49]=2[CH2:48][NH:47]1)=[O:45])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH3:41])[C:36]=2[CH3:42])=[CH:30][CH:29]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCN=C=NCCCN(C)C.Cl.CCOC(C)=O.CO>[Cl:75][C:70]1[CH:69]=[C:68]([CH:73]=[CH:72][C:71]=1[Cl:74])[CH2:67][O:66][C:62]1[CH:61]=[C:60]([C@H:58]2[CH2:57][O:56][C:52]3=[CH:53][C:54]4[CH2:55][C@@H:46]([C:44]([NH:43][C@@H:26]([CH2:27][C:28]5[CH:29]=[CH:30][C:31]([O:34][C:35]6[CH:40]=[CH:39][N:38]=[C:37]([CH3:41])[C:36]=6[CH3:42])=[CH:32][CH:33]=5)[C:25]([OH:76])=[O:24])=[O:45])[N:47]([C:7]([C:5]5[N:6]=[C:2]([CH3:1])[O:3][C:4]=5[CH3:10])=[O:9])[CH2:48][C:49]=4[CH:50]=[C:51]3[O:59]2)[CH:65]=[CH:64][CH:63]=1
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1cccc(OCc2ccc(Cl)c(Cl)c2)c1)CO3
Reactant: Cc1nc(C(=O)O)c(C)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1nc(C(=O)N2Cc3cc4c(cc3C[C@H]2C(=O)N[C@@H](Cc2ccc(Oc3ccnc(C)c3C)cc2)C(=O)O)OC[C@H](c2cccc(OCc3ccc(Cl)c(Cl)c3)c2)O4)c(C)o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
2,5-Dimethyl-oxazole-4-carboxylic acid (6 mg) was taken in 1 mL of anhydrous DCM and EDCl (9 mg), HOBT (7 mg) and (S)-2-({(3S,8S)-3-[3-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester dihydrochloride (25 mg) and stirred for 5 minutes. The reaction mixture was cooled to 0° C. and DIEA (25 mg) was added and reaction was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was loaded onto a silica gel column (1:3 EtOAc:hexanes to 4% MeOH in 1:1 EtOAc:hexanes) to get purified (S)-2-{[(3S,8S)-3-[3-(3,4-Dichloro-benzyloxy)-phenyl]-7-(2,5-dimethyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester (23 mg). This was hydrolyzed according to General Procedure B to give the title compound (19 mg). LCMS (m/z): 878.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[NH:5][CH3:6].C(N(CC)CC)C.[Br:18][C:19]1[C:20]([Cl:29])=[CH:21][C:22]([F:28])=[C:23]([CH:27]=1)[C:24](Cl)=[O:25]>C(Cl)Cl>[Br:18][C:19]1[C:20]([Cl:29])=[CH:21][C:22]([F:28])=[C:23]([CH:27]=1)[C:24]([N:5]([C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[O:2][CH3:1])[CH3:6])=[O:25]
Reactant: O=C(Cl)c1cc(Br)c(Cl)cc1F
Reactant: CNc1ccccc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1N(C)C(=O)c1cc(Br)c(Cl)cc1F
Temperature: 25 °C
Yield: 77.8 %

Procedure:
2-Methoxy-N-methylaniline (7.4 g, 53.8 mmol) and triethylamine (10.9 g, 107.7 mmol) were added to 5-bromo-4-chloro-2-fluoro-benzoyl chloride (Step 21D, 11.7 g, 43.1 mmol) in DCM (200 mL) at 0° C. The mixture was then allowed to warm to rt and concentrated. The mixture was partitioned in water and ethyl acetate. The organic layer was separated, washed with NaHSO4 solution, water and brine, and was dried. After filtration and concentration, the residue was purified via silica gel flash column chromatography eluting with ethyl acetate in hexane (50%) to give 5-bromo-4-chloro-2-fluoro-N-(2-methoxy-phenyl)-N-methyl-benzamide (12.5 g). MS: [M+H]+374.0/372.0; tR=2.70 min (method 1)
Reaction SMILES: O[CH:2]([N:7]1[C@H:10]([CH2:11][C:12](=[O:14])[CH3:13])[CH2:9][C:8]1=[O:15])[C:3]([O:5][CH3:6])=[O:4].N1C(C)=CC=CC=1C.S(Cl)([Cl:26])=O>O1CCCC1>[Cl:26][CH:2]([N:7]1[C@H:10]([CH2:11][C:12](=[O:14])[CH3:13])[CH2:9][C:8]1=[O:15])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(O)N1C(=O)C[C@H]1CC(C)=O
Reactant: O=S(Cl)Cl
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: COC(=O)C(Cl)N1C(=O)C[C@H]1CC(C)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of methyl 2-hydroxy-2-[(4R)-4-(2-oxopropyl)-2-oxoazetidin-1-yl]acetate (268 mg) in tetrahydrofuran (5 ml) was cooled to -40° C. 2,6-Lutidine (0.287 ml) and thionyl chloride (0.18 ml) were added, and the mixture was stirred for one hour, during which time the temperature was allowed to warm to 0° C. The mixture was filtered and the filtrate was concentrated in vacuo to give methyl 2-chloro-2-[(4R)-4-(2-oxopropyl)-2-oxoazetidin-1-yl]acetate. This product was diluted with benzene and concentrated in vacuo again. The residue was diluted with tetrahydrofuran (5 ml), and 2,6-lutidine (0.287 ml) and triphenylphosphine (650 mg) were added at 0° C. The mixture was stirred at room temperature for 15 hours, and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed on silica gel (10 g) eluting with a mixture of ethyl acetate and acetone (10:1-10:5) to give methyl 2-[(4R)-4-(2-oxopropyl)-2-oxoazetidin-1-yl]-2-(triphenylphosphoranylidene)acetate (350 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:14](=[O:19])C(F)(F)F)=[CH:7][N:8]2[CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.[OH-:20].[Na+]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:14]([OH:19])=[O:20])=[CH:7][N:8]2[CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: CCCn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Reactant: [OH-]
Agent: [Na+]
Product: CCCn1cc(C(=O)O)c2ccc(Cl)cc21
Temperature: 25 °C
Yield: 74 %

Procedure:
A mixture of 1-(6-chloro-1-propyl-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (277.1 mg, 0.81 mmol) in a 20% aqueous sodium hydroxide solution (2.7 mL) was heated under reflux for 17 h. At this time, the reaction was cooled to 25° C., partitioned between water (75 mL) and ethyl acetate (75 mL), and extracted with diethyl ether (1×50 mL). The aqueous layer was acidified to pH=1 with concentrated hydrochloric acid and then extracted with ethyl acetate (1×75 mL). The combined organic layers were washed with water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford 6-chloro-1-propyl-1H-indole-3-carboxylic acid (141.4 mg, 74%) as a cream-colored solid: mp 179-180° C.; EI-HRMS m/e calcd for C12H12ClNO2 (M+) 237.0556, found 237.0558.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[S:13]([NH2:16])(=[O:15])=[O:14])[CH:4]=[N:3]1.C[Al](C)C.[CH3:21][O:22][C:23]1[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([NH:30][C:31](=O)[O:32]C)[N:24]=1>C(Cl)Cl>[CH3:21][O:22][C:23]1[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([NH:30][C:31]([NH:16][S:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)(=[O:15])=[O:14])=[O:32])[N:24]=1
Reactant: COC(=O)Nc1nc(C)nc(OC)n1
Reactant: Cn1cc(-c2ccccc2S(N)(=O)=O)cn1
Agent: C[Al](C)C
Solvent: ClCCl
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2-c2cnn(C)c2)n1
Yield: 17.6 %

Procedure:
By the procedure of Example 14, 2 g of 2-(1-methyl-1H-pyrazol-4-yl)benzenesulfonamide, prepared in Example 19, was reacted in 100 ml of methylene chloride with 0.7 g of trimethylaluminum (5 ml of 2M toluene solution) followed by 1.7 g of methyl (4-methoxy-6-methyl-1,3,5-triazin-2-yl)carbamate. After work up and evaporation of the methylene chloride solvent, the residue was triturated with ethyl acetate to yield 0.6 g of the title compound; m.p. 221°-224° C. The IR spectrum showed a carbonyl absorption at 1700 cm-1 indicative for a sulfonylurea.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].CCN(C(C)C)C(C)C.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][C:30]([OH:32])=O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(Cl)CCl>O1CCOCC1.CN(C)C1C=CN=CC=1>[CH3:5][O:4][N:3]([CH3:2])[C:30](=[O:32])[CH2:29][CH2:28][CH:25]1[CH2:24][CH2:23][N:22]([C:20]([O:19][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:21])[CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)O)CC1
Reactant: CNOC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: ClCCCl
Product: CON(C)C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
Molecular sieve pellets (4 Å), N,O-dimethylhydroxylamine hydrochloride (227 mg, 3.32 mmol), and DIEA (0.41 mL, 0.30 g, 2.4 mmol) were added to a solution of 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propionic acid (500 mg, 1.94 mmol, from Step A) in 1,4-dioxane (10 mL). 4-(Dimethylamino)pyridine (57 mg, 0.47 mmol) and EDC (483 mg, 2.52 mmol) were added and the mixture was stirred for 16 h at rt. The mixture was partitioned between EtOAc (50 mL) and 1 N aq. HCl (50 mL). The aqueous layer was extracted with EtOAc (50 mL). The organic layers were washed with sat'd NaCl (30 mL), dried (Na2SO4), decanted, and evaporated to give 583 mg of N-methoxy-N-methyl-3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propionamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:23]=[N:24][CH:25]=[C:26]([CH:31]=4)[C:27]([O:29]C)=O)=[N:14][CH:13]=[N:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.[NH3:32]>C(O)CCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:23]=[N:24][CH:25]=[C:26]([CH:31]=4)[C:27]([NH2:32])=[O:29])=[N:14][CH:13]=[N:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: N
Reactant: COC(=O)c1cncc(OCCCCc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Solvent: CCCCO
Product: NC(=O)c1cncc(OCCCCc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Temperature: 180 °C
Yield: 34.8 %

Procedure:
Methyl 5-{4-[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]butoxy}nicotinate (0.015 g, 0.034 mmol) and ammonia (3.00 mL, 20%, 0.02 mol) were mixed in 1-butanol (1.00 mL) and the resulting mixture was heated at 180° C. for 20 h. The solvent was removed by evaporation, and the product was purified by preparative HPLC to give 5 mg (36%) 5-{4-[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]butoxy}nicotinamide hydroformate as a white solid. MS [M+H]=423.1, LC/MS (EI) tR 3.45 min (Method D), 1H NMR (7% MeOD/CDCl3) δ (ppm) 8.92 (s, 1H), 8.50 (s, 1H), 8.25 (s, 1H), 7.62 (s, 1H), 7.40-7.30 (m, 3H), 7.10 (t, J=8.4 Hz, 2H), 3.84 (t, J=6.0 Hz, 2H), 2.66 (t, J=7.5 Hz, 2H), 1.75-1.58 (m, 2H), 1.59-1.45 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].[S:11](Cl)(=[O:14])(=[O:13])[NH2:12]>>[C:4]([C:3]1[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][S:11]([NH2:12])(=[O:14])=[O:13])#[N:5]
Reactant: N#Cc1c(N)cccc1F
Reactant: NS(=O)(=O)Cl
Product: N#Cc1c(F)cccc1NS(N)(=O)=O

Procedure:
Prepared as in Example 77a from 2-amino-6-fluorobenzonitrile and sulfamoyl chloride
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH:23]=[CH:24][CH:25]=[C:26]3[CH2:31][CH2:30][N:29](C(O)=O)[CH2:28][CH2:27]3)(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.O1CCOCC1>CO>[CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([S:20]([CH:23]=[CH:24][CH:25]=[C:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]3)(=[O:21])=[O:22])=[CH:18][CH:19]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(COc2ccc(S(=O)(=O)C=CC=C3CCN(C(=O)O)CC3)cc2)c2ccccc2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc(COc2ccc(S(=O)(=O)C=CC=C3CCNCC3)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 0.2 g (0.37 mmol) of tert-butyl ester of 4-{3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl]allylidene}piperidine-1-carboxylic acid (II-24a) obtained in Example 12 (12-2) in methanol (2.0 mL) was added 4N hydrochloric acid-dioxane solution (2.0 mL) at 0° C. and stirred for 2 hours at room temperature. The reaction mixture was then concentrated under a reduced pressure, treated with saturated aqueous sodium bicarbonate, extracted with chloroform, and dried over anhydrous magnesium sulfate. After drying, the solution was filtered, and the filtrate was concentrated under a reduced pressure to give crude 2-methyl-4-[4-(3-piperidin-4-ylidene-1-propene-1-sulfonyl)phenoxymethyl]quinoline. This was dissolved in dichloromethane (10 mL), treated with triethylamine (0.077 mL, 0.56 mmol) and pivaloyl chloride (0.058 g, 0.48 mmol) at 0° C., and stirred for 2 hours. The reaction mixture was then concentrated under a reduced pressure, diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over magnesium sulfate. The filtrate was concentrated under a reduced pressure to obtain 0.18 g (yield 94.7%) of 2,2-dimethyl-1-(4-{3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl]allylidene}piperidin-1-yl)propan-1-one (X-25). Its physical property is shown below.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=2[CH:13]=1.[N+:17]([O-])([OH:19])=[O:18]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:3]([N+:17]([O-:19])=[O:18])=[C:4]([C:14]([OH:16])=[O:15])[C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=2[CH:13]=1
Reactant: CN1C(=O)COc2c(C(=O)O)cc(Cl)cc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CN1C(=O)COc2c1cc(Cl)c([N+](=O)[O-])c2C(=O)O

Procedure:
To a solution of 60 g of 6-chloro-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid in 450 ml of concentrated sulfuric acid with cooling below 0° C. is added dropwise a mixture of 11.6 ml of fuming nitric acid and 11.6 ml of concentrated sulfuric acid at a temperature below 5° C. The resultant solution is stirred under ice-cooling for 2.5 hours and poured into ice-cold water. The precipitated crystals are collected by filtration and recrystallized from ethanol to give 6-chloro-3,4-dihydro-4-methyl-7-nitro-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid, melting at 257° C. with decomposition.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[C:4]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[N:3][CH:2]=1.N1C=CN=C1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN(C=O)C.O>[Si:26]([O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][NH:11][C:4]2[C:5]3[C:10](=[N:9][CH:8]=[CH:7][N:6]=3)[N:1]=[CH:2][N:3]=2)=[CH:15][CH:16]=1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: Oc1ccc(CCNc2ncnc3nccnc23)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CCNc2ncnc3nccnc23)cc1
Temperature: 2.5 °C
Reaction time: 20 h
Yield: 92.1 %

Procedure:
4-[2-(Pteridin-4-ylamino)-ethyl]-phenol (1.0 g, 3.7 mmol) was partially dissolved in dry DMF (75 mL), treated with imidazole (630 mg, 9.3 mmol), cooled to 0-5° C. and treated dropwise with a solution of t-butyldimethylsilyl chloride (680 mg, 4.5 mmol) in DMF (15 mL). After warming to 25° C. the mixture was stirred for 20 h, diluted with H2O (75 mL) and extracted with EtOAc. The extracts were washed with H2O, brine, dried (Na2SO4), filtered and concentrated in vacuo to give {2-[4-(tert-butyldimethylsilanyloxy)-phenyl]-ethyl}-pteridin-4-yl-amine (1.3 g) as a white solid: mp 164-165° C.; 1H NMR (300 MHz, CDCl3) δ 8.99 (s, 1H), 8.61 (s, 1H), 8.59 (s, 1H), 8.26 (d, J=5.9 Hz, 1H), 6.8-7.2 (m, 5H), 3.98 (t, J=6.2 Hz, 2H), 2.99 (t, 6.3 Hz, 2H), 1.02 (s, 6H), 0.18 (s, 9H).