Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1.[F:19][C:20]1[CH:34]=[CH:33][CH:32]=[CH:31][C:21]=1[CH2:22][N:23]1[CH2:28][C:27](=[O:29])[NH:26][C:25](=[O:30])[CH2:24]1>>[ClH:1].[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([CH:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][N:26]3[C:25](=[O:30])[CH2:24][N:23]([CH2:22][C:21]4[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=4[F:19])[CH2:28][C:27]3=[O:29])[CH2:5][CH2:6]2)=[O:18])=[CH:12][CH:13]=1
Reactant: O=C1CN(Cc2ccccc2F)CC(=O)N1
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCCl)CC1
Product: Cl
Product: O=C(c1ccc(F)cc1)C1CCN(CCN2C(=O)CN(Cc3ccccc3F)CC2=O)CC1

Procedure:
This compound was prepared from 1-(2-chloroethyl)-4-(4-fluorobenzoyl)piperidine and 4-(2-fluorobenzyl) piperazine 2,6-dione according to the process described in Example 3, Stage B.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH:17](OCC)OCC>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[S:8][CH:16]=[CH:17][C:4]=2[CH:3]=1
Reactant: CCOC(CBr)OCC
Reactant: Sc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Brc1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromobenzenethiol (24.7 g) in acetone (100 ml) was added potassium carbonate (18.5 g), then 2-bromo-1,1-diethoxyethane (19.5 ml) was added dropwise thereto, the solution was stirred overnight at room temperature, then acetone was added thereto. The solution was filtered, and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system). To a solution of the resulting 1-bromo-4-(2,2-diethoxyethylsulfanyl)benzene (32.5 g) in chlorobenzene (350 ml) was added polyphosphoric acid (60 ml), and then the solution was stirred for 2 hours at 140° C. The reaction mixture was poured into an ice, extracted with ethyl acetate, then sequentially washed with aqueous ammonia, water and brine, dried over anhydrous magnesium sulfate, the solvent was evaporated in vacuo, the resulting residue was purified by silica gel column chromatography (hexane) to provide 5-bromobenzo[b]thiophene (13.7 g). By referring to the synthetic method of Tetrahedron Lett., 1993, 34, 1007, to 5-bromobenzo[b]thiophene (13.7 g) was added sodium methoxide (28% solution in methanol) (200 ml). Copper(I) bromide (13.5 g) and ethyl acetate (40 ml) were sequencially added thereto followed by stirring for 4.5 hours at 80° C. Ethyl acetate and water were sequentially added thereto, the solution was stirred, then filtered through celite pad, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, the solvent was evaporated in vacuo, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (9.2 g).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[C@H:11]([CH3:16])[CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:24](B(CC)CC)[CH3:25].O>CN(C)C=O.O1CCCC1>[CH2:24]([C:2]1[C:10]2[N:9]3[C@H:11]([CH3:16])[CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1)[CH3:25]
Reactant: CCB(CC)CC
Reactant: C[C@@H]1CNC(=O)c2cc3cc(F)cc(Br)c3n21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(F)cc2cc3n(c12)[C@H](C)CNC3=O
Temperature: 50 °C

Procedure:
6.2 g (R)-6-bromo-8-fluoro-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one was dissolved in 150 ml N,N-dimethylformamide under argon. 1.43 g (Dppf)PdCl2, 39 g caesium carbonate and 41.6 ml of a 1M solution of triethylborane in tetrahydrofuran were added. The mixture was heated 15 h at 50° C., allowed to cool to room temperature and poured into water. The aqueous mixture was extracted with ethyl acetate. The combined organic phases washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on reversed phase silica gel (6:4 to 3:7 water/methanol) to afford the title product as an off-white solid. Yield: 1.8 g. ISP-MS: m/e 247.3 ([M+H]+).
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:18][N:19]([CH3:23])[C:20](Cl)=[O:21]>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:18][N:19]([CH3:23])[C:20]([NH:10][O:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:21]
Reactant: CN(C)C(=O)Cl
Reactant: NOCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(=O)NOCc1ccccc1
Yield: 42 %

Procedure:
To a stirred slurry of benzyloxyamine hydrochloride (3.19 g, 20 mmol) in the THF (40 ml) at room temperature under nitrogen was added triethylamine (6.13 ml). This slurry was stirred, and dimethylcarbamyl chloride (1.84 ml) was added rapidly. 4-(N,N-dimethylamino)pyridine (1.0 g, 0.4 equiv.) was added, and the mixture was stirred for 20 hours. The mixture was filtered, and the filtrate evaporated. Purification by chromatography on silica provided N,N-dimethyl-N'benzyloxyurea as a colorless oil (1.62 g, 42% yield).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](Cl)(=[O:18])[C:15](Cl)=[O:16].Cl>C1(C)C=CC=CC=1>[C:8]1([N:7]2[C:1]3[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:15](=[O:16])[C:14]2=[O:18])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C1C(=O)N(c2ccccc2)c2ccccc21
Temperature: 60 °C
Yield: 94.2 %

Procedure:
The title compound is prepared following the procedures of Bryant, N. M., III et al. Syn Commun, 23, 1617-25 (1993) as follows. A solution of diphenylamine (26.6 g, 157 mmol) in toluene (65 mL) is added slowly to a solution of oxalyl chloride (14.8 mL, 170 mmol) in toluene (35 mL) while cooling in an ice-water bath to maintain the temperature below 40° C. The resulting brown slurry is heated at 55-65° C. for 1 hr. CAUTION: There is vigorous evolution of hydrogen chloride gas. Approximately 100 mL of solvent is removed by distillation (it contains unreacted oxalyl chloride) and the residue is heated overnight at 118-125° C. The reaction is cooled and then poured into ice-water (200 mL), extracted with ethyl acetate (4×250 mL). The combined extract is dried, filtered and concentrated to give 1-phenyl-1H-indole-2,3-dione (33.0 g, 94% yield). H-NMR 7.70 (1H, d), 7.58 (3H, d), 7.43 (3H, m), 7.19 (1H, t), 6.90 (1H, d).
Reaction SMILES: [O:1]1[CH2:18][CH:2]1[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)[CH:8]=[CH:9][CH:10]=1.CO.[CH:21]([NH2:24])([CH3:23])[CH3:22]>CCOCC>[OH:1][CH:2]([CH2:18][NH:24][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)N
Reactant: O=C1CCC(c2cccc(OCC3CO3)c2)=NN1
Solvent: CO
Solvent: CCOCC
Product: CC(C)NCC(O)COc1cccc(C2=NNC(=O)CC2)c1
Yield: 95.8 %

Procedure:
A stirred mixture of 6-[3-(2,3-epoxypropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone (10 g, 0.04 mole), methanol (100 ml), and isopropylamine (20.8 ml, 0.24 mole) was heated under reflux for 90 minutes. Evaporation of the solution under reduced pressure gave a white solid which, when treated with ether, gave crude 6-[3-(2-hydroxy-3-isopropylaminopropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone (11.7 g, 94%, m.p. 137°-141° C). The hemisulphate, recrystallised from aqueous methanol-ether, had m.p. 256°-258° C.
Reaction SMILES: [SiH4].Cl.[Cl:3][Si:4]([Cl:10])([Cl:9])[Si](Cl)(C)C.[Cl:11][Si:12]([Cl:18])([Cl:17])[Si](C)(C)C.[Cl:19][Si](Cl)(C)[Si](C)(C)C>>[SiH4:4].[Cl:11][SiH:12]([Cl:18])[Cl:17].[Si:4]([Cl:10])([Cl:19])([Cl:9])[Cl:3]
Reactant: C[Si](C)(C)[Si](C)(Cl)Cl
Reactant: C[Si](C)(C)[Si](Cl)(Cl)Cl
Reactant: C[Si](C)(Cl)[Si](Cl)(Cl)Cl
Agent: Cl
Agent: [SiH4]
Product: Cl[SiH](Cl)Cl
Product: Cl[Si](Cl)(Cl)Cl
Reaction time: 20 h
Yield: 40 %
Yield: 20 %

Procedure:
70 ml/h of high-boiling residue from the silane synthesis having a boiling point of greater than 150° C. and 25 I/h of gaseous hydrogen chloride were fed concurrently at room temperature and ambient pressure into an electrically heated laboratory fluidized-bed reactor having a length of 500 mm and an internal diameter of 40 mm, filled with 266 g of silicon, d(0.5): 70-80 μm. The temperature was set to 600° C. The high-boiling residue comprised 75 % of disilanes, a mixture of tetrachlorodimethyldisilane, trichlorotrimethyldisilane, dichlorotetramethyldisilane and other silanes. A more precise assignment was difficult because of the large number of by-products. After 20 hours of operation, the experiment was stopped without deposits having been formed. About 100 g/h of silane mixture comprising, as main constituents, about 20 % of trichlorosilane and about 40% of silicon tetrachloride was formed. After separation of the trichlorosilane and silicon tetrachloride, a silane cleavage product having the composition set forth in Table 1 was obtained during the experiment.
Reaction SMILES: [CH:1]#[C:2][CH3:3].[Br:4][C:5]1[CH:6]=[C:7](I)[C:8]([NH2:11])=[N:9][CH:10]=1.C(N(CC)CC)C>C1COCC1.[Cu]I>[Br:4][C:5]1[CH:6]=[C:7]([C:1]#[C:2][CH3:3])[C:8]([NH2:11])=[N:9][CH:10]=1
Reactant: C#CC
Reactant: Nc1ncc(Br)cc1I
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC#Cc1cc(Br)cnc1N
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Propyne (28 g, 700 mmol) was condensed into a pre-weighed flask cooled to ca. −40° C. containing THF (150 mL). The solution was added via cannula to a cooled (0-5° C.), degassed mixture of 5-bromo-3-iodo-pyridin-2-ylamine (139 g, 465 mmol), bis(triphenylphosphine)dichloropalladium(0) (16.3 g, 23.2 mmol), copper (I) iodide (5.3 g, 27.9 mmol) and triethylamine (141 g, 194 mL, 1.4 mol) in THF (1.25 L). The mixture was stirred at 0-5° C. for 30 minutes then for a further 30 minutes at ambient temperature. The solid was removed by filtration and the cake washed with THF. The filtrate was diluted with ethyl acetate and extracted with 2M hydrochloric acid (×3). The combined acid extract was washed with diethyl ether and then made basic by careful addition of potassium carbonate then extracted with diethyl ether (×3). The combined organic layer was dried (Na2SO4), filtered and evaporated to afford the title compound as a buff solid (91 g, 93%). 1H NMR (400 MHz, CDCl3): 8.01 (d, J=2.4 Hz, 1H), 7.55 (d, J=2.4 Hz, 1H), 4.96 (s, 2H), 2.11 (s, 3H).
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:9][C:10]1[CH:11]=[C:12]([CH:18]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:13]=[C:14]([CH2:16][CH3:17])[CH:15]=1.C(N(C(C)C)CC)(C)C.OS([O-])(=O)=O.[K+]>C(Cl)Cl>[C:31]([C:28]1[CH:29]=[CH:30][C:25]([NH:24][CH:18]([C:12]2[CH:13]=[C:14]([CH2:16][CH3:17])[CH:15]=[C:10]([NH:9][C:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:7])[CH:11]=2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:26][CH:27]=1)#[N:32]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(N)cc(CC)c1
Reactant: O=C(Cl)C1CCCC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(CC)cc(NC(=O)C2CCCC2)c1
Temperature: 25 °C
Yield: 66.4 %

Procedure:
Cyclopentanecarbonyl chloride (0.104 ml, 0.85 mmol) was added dropwise at 0° C. to a solution of the ethyl (RS)-(3-amino-5-ethyl-phenyl)-(4-cyano-phenylamino)-acetate (250 mg, 0.772 mmol) obtained in Example 223.4 and diisopropylethylamine (0.146 ml, 0.85 mmol) in CH2Cl2 (5 ml). The reaction mixture was warmed slowly (2 h.) to room temperature. A saturated aqueous solution of KHSO4 was added and the mixture was extracted with EtOAc. The organic phase was washed with H2O, dried and filtered, and the filtrate was concentrated. The residue was purified by chromatography (SiO2, hexanehexane/EtOAc 2:1). There were obtained 215 mg (66%) of ethyl (RS)-(4-cyano-phenylamino)-[3-(cyclopentanecarbonyl-amino)-5-ethyl-phenyl]-acetate as a colorless foam; MS: 418 ([M−H]−).
Reaction SMILES: [CH3:1][Si:2]([CH2:5][CH2:6][O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C@@H:24]([CH2:27][C:28]2[N:29]=[CH:30][NH:31][CH:32]=2)[CH2:25][OH:26])=[CH:18][CH:17]=1)=[O:9])([CH3:4])[CH3:3].C([N:35](CC)CC)C.[C:40](Cl)(=[O:45])[CH2:41][CH2:42][CH2:43][CH3:44]>C(Cl)Cl.CO>[NH:31]1[CH:32]=[C:28]([CH2:27][CH:24]([N:23]([CH2:22][C:19]2[CH:20]=[CH:21][C:16]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:8]([O:7][CH2:6][CH2:5][Si:2]([CH3:3])([CH3:4])[CH3:1])=[O:9])=[CH:17][CH:18]=2)[C:40](=[O:45])[CH2:41][CH2:42][CH2:43][CH3:44])[CH2:25][OH:26])[N:29]=[CH:30]1.[NH3:35]
Reactant: CCCCC(=O)Cl
Reactant: CCN(CC)CC
Reactant: C[Si](C)(C)CCOC(=O)c1ccccc1-c1ccc(CN[C@H](CO)Cc2c[nH]cn2)cc1
Solvent: ClCCl
Solvent: CO
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2C(=O)OCC[Si](C)(C)C)cc1)C(CO)Cc1c[nH]cn1
Product: N

Procedure:
Reaction of 0.45 g of N-[(2'-(trimethylsilylethoxycarbonyl)biphenyl-4-yl)methyl]-3-(imidazol-4-yl)-2-(S)-aminopropan-1-ol, 0.152 ml of triethylamine and 0.132 ml of valeryl chloride yields N-[3-(imidazol-4-yl)-1-hydroxy-2-propyl]-N-[(2'-(trimethylsilylethoxycarbonyl)biphenyl-4-yl)methyl]valeramide after flash chromatography (methylene chloride-methanol-conc. ammonia: 120-10-1). During working up, the aqueous phase is rendered slightly basic. FAB-MS: m/e=536 (M+H)+.
Reaction SMILES: N[N:2]([CH:10]=[NH:11])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23])=O.O.C[N:27](C)C=O>>[N+:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]1[N:27]=[C:10]([NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6])[NH:11][CH:13]=1)([O-:24])=[O:23]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N(N)C=N
Reactant: O=C(CBr)c1ccccc1[N+](=O)[O-]
Solvent: O
Product: CC(C)(C)OC(=O)Nc1nc(-c2ccccc2[N+](=O)[O-])c[nH]1
Temperature: 25 °C
Reaction time: 144 h
Yield: 36 %

Procedure:
tert-Butyl amino(imino)methylcarbamate (4.78 g; 30 mmol) was dissolved in N,N-dimethylformamide (30 mL), 2-bromo-2′-nitroacetophenone (2.44 g; 10 mmol) was added thereto, and the mixture was stirred for 144 hours at room temperature. To the reaction solution, water (100 mL) was added, and the precipitated powder was collected by filtration. The resulting powder was dissolved in ethyl acetate (200 mL), and the mixture was washed with saturated aqueous sodium bicarbonate solution (two times). The organic layer was dried over anhydrous magnesium sulfate and then distilled under reduced pressure. The resulting residue was dispersed in acetone/diethyl ether, collected by filtration and dried to give 1.09 g of the title compound (yield 36%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21]C4C=CC(C(O)=O)=CC=4OC)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1N=CC2N(C)C(=O)C(F)(F)CN(C3CCCC3)C=2N=1.[CH3:54][N:55]([CH3:66])[CH2:56][CH2:57][O:58][C:59]1[CH:65]=[CH:64][C:62](N)=[CH:61][CH:60]=1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:62]4[CH:64]=[CH:65][C:59]([O:58][CH2:57][CH2:56][N:55]([CH3:66])[CH3:54])=[CH:60][CH:61]=4)=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)CCOc1ccc(N)cc1
Agent: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Product: CN(C)CCOc1ccc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)cc1

Procedure:
The title compound was synthesized using an analogous procedure to that described in connection with 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid from 2-Chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one and 4-(2-(dimethylamino)ethoxy)aniline. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44-1.79 (m, 6H) 1.93 (br. s, 2H) 2.20 (s, 6H) 2.59 (t, J=5.81 Hz, 2H) 3.32 (s, Hz, 3H) 3.88-4.10 (m, 4H) 4.68 (t, J=8.34 Hz, 1H) 6.85 (d, J=8.84 Hz, 2H) 7.55 (d, J=9.09 Hz, 2H) 8.18 (s, 1H) 9.20 (s, 1H). [M+H] calc'd for C23H30F2N6O2, 461. found 461.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:24](O)[CH2:25][OH:26].O>C1(C)C=CC=CC=1>[O:9]1[CH2:24][CH2:25][O:26][CH:8]1[C:5]1[C:4]([N+:10]([O-:12])=[O:11])=[CH:3][C:2]([F:1])=[CH:7][N:6]=1
Reactant: OCCO
Reactant: O=Cc1ncc(F)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(F)cnc1C1OCCO1
Temperature: 120 °C

Procedure:
To a solution of 5-fluoro-3-nitropicolinaldehyde (12.5 g, 73.48 mmol) in toluene (220 mL) were added p-toluene sulfonic acid (698 mg, 3.67 mmol) and ethylene glycol (20.7 mL, 367.43 mmol) at 25° C. The reaction mixture was heated to 120° C. for overnight and water was removed using dean-stark apparatus. Reaction mass was cooled to 25° C. Water was added to the reaction mass and extracted with EtOAc. Organic layer was washed with brine and dried over Na2SO4. The organic layer was concentrated in vacuo and purified by column chromatography on silica gel using 0-10% EtOAc in hexane to give 2-(1,3-dioxolan-2-yl)-5-fluoro-3-nitropyridine: 1H NMR (400 MHz, DMSO-d6): δ 4.02 (s, 4H), 6.22 (s, 1H), 8.939 (d, 1H, J=1.2 Hz); LC-MS (ESI) m/z 215.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[C:9]([CH3:10])=[CH:8][C:7]([O:11][CH2:12][CH2:13][CH3:14])=[CH:6][C:5]=1[OH:15].Br[CH2:18][C:19]1[CH:38]=[CH:37][C:22]([O:23][CH2:24][C:25]2[N:26]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:28][C:29]=2[CH3:30])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C.CCCCCC>[CH3:1][O:2][C:3](=[O:16])[C:4]1[C:5]([O:15][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28][C:29]=3[CH3:30])=[CH:37][CH:38]=2)=[CH:6][C:7]([O:11][CH2:12][CH2:13][CH3:14])=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CBr)cc1
Reactant: CCCOc1cc(C)c(C(=O)OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCOc1cc(C)c(C(=O)OC)c(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c1

Procedure:
A mixture of the title A compound, 2-hydroxy-6-methyl-4-propoxy-benzoic acid methyl ester (407 mg, 1.81 mmol), the title D compound, 4-(4-bromomethyl-phenoxymethyl)-5-methyl-2-phenyl-oxazole (650 mg, 1.81 mmol) and potassium carbonate (751 mg, 5.44 mmol) in DMF is stirred at RT overnight. The mixture is then partitioned between EtOAc and water. The organic layer is washed with brine, dried with magnesium sulfate and concentrated under vacuum to give the crude product. Chromatography on silica gel, using 10% EtOAc in hexane gives 2-methyl-6-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyloxy]-4-propoxy-benzoic acid methyl ester as a white foam: ESI-MS 502 [M+1]+.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:12]=2[NH2:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[CH3:25][O:26][C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)=[O:28].O>C(Cl)Cl>[C:1]1([S:7]([NH:10][C:11]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:12]=2[NH:13][C:33]([C:32]2[CH:36]=[CH:37][C:29]([C:27]([O:26][CH3:25])=[O:28])=[CH:30][CH:31]=2)=[O:34])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: Nc1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(=O)Nc2cc(Cl)ccc2NS(=O)(=O)c2ccccc2)cc1
Reaction time: 6 h
Yield: 79.1 %

Procedure:
To a solution of 2-phenylsulfonylamino-5-chloroaniline (90 mg; prepared in Reference Example 12.) and pyridine (0.05 ml) in methylene chloride (5 ml), 4-methoxycarbonylbenzoic acid chloride (70 mg) was added at room temperature in a stream of argon. The mixture was stirred for 6 hours. After the termination of reaction, water was added to the reaction mixture. The mixture was extracted with ethyl acetate. The organic layer was washed, dried over and concentrated under the reduced pressure. The residue was purified by the recrystallization from AcOEt-hexane mixture solvent to give the title compound (112 mg) having the following physical data.
Reaction SMILES: [O:1]=[C:2]([CH3:42])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:25]2[CH2:29][CH2:28][C@H:27]([C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)[O:26]2)[CH:10]=[C:11]([O:17]CC2C=CC=CC=2)[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5]>C(O)(=O)C.C(OCC)(=O)C.[Pd]>[O:1]=[C:2]([CH3:42])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:25]2[CH2:29][CH2:28][C@H:27]([C:30]3[CH:31]=[C:32]([O:40][CH3:41])[C:33]([O:38][CH3:39])=[C:34]([O:36][CH3:37])[CH:35]=3)[O:26]2)[CH:10]=[C:11]([OH:17])[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:5])=[O:6]
Reactant: CCCOc1c(OCc2ccccc2)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCOc1c(O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)=O
Reaction time: 0.75 h

Procedure:
A mixture of 1.2 g of 2-[3-oxopropylsulfonyl)-4-n-propoxy-5-benzyloxyphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (STEP J), 400 mg 10% Pd/C, 1-2 drops of acetic acid in 100 mL of ethyl acetate was stirred under H2 at 40 psi for 45 minutes. The reaction mixture was filtered over a bed of celite and evaporated in vacuo to yield the title compound: NMR(200 MHz, CDCl3) δ 1.10(t, CH2CH2CH3), 1.92(m, CH2CH2CH3), 1.9-2.6(m, 3-CH2 and 4-CH2), 2.40(s, CH3C(O)CH2), 3.86(s, OCH3), 3.90(s, 2 OCH3), 4.12(t, OCH2CH2CH3), 4.42(s, CH3C(O)CH2), 5.10-5.28(m, 2-CH and 5-CH), 6.64(s, 5-ArH), 7.35 and 7.47(2 d, 2-ArH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:19]([NH2:21])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:34]=[CH:33][CH:32]=[N:31]2)=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([N:30]3[CH:34]=[CH:33][CH:32]=[N:31]3)=[CH:28][CH:29]=2)[C@H:12]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:19]([NH2:21])=[O:20])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: BrCc1ccc(-n2cccn2)cc1
Reactant: NC(=O)[C@@H]1CCCCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Product: NC(=O)[C@@H]1CCCCC[C@@H]1N(Cc1ccc(-n2cccn2)cc1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 18 %

Procedure:
The titled compound (40 mg) was prepared in 18% yield from cis-2-(4-chlorobenzenesulfonylamino)-cycloheptanecarboxylic acid amide (150 mg, 0.45 mmol) and 1-(4-bromomethyl-phenyl)-1H-pyrazole according to the N-alkylation procedure described in Example 11: 1H NMR (DMSO-d6) δ 8.46 (s, 1 H), 7.79 (d, 2 H, J=12.0 Hz), 7.71 (m, 3 H), 7.62 (d, 2 H, J=8.0 Hz), 7.40 (d, 2 H), J=8.0 Hz), 7.33 (s br, 1 H), 6.70 (s br, 1 H), 6.54 (s, 1 H), 4.56 (AB2,2 H,Δv=16,Jab=96 Hz), 4.00 (m, 1 H), 2.78 (m, 1 H), 2.30 (m, 1 H), 1.73 (m, 2 H), 1.37 (m, 7 H); MS m/e 509.12 (M+Na)+.