Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:26]1[C:30]2[C:31]3[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=3[O:33][CH2:34][CH2:35][C:29]=2[CH:28]=[C:27]1[C:40](Cl)=[O:41]>O1CCCC1>[Si:1]([O:8][CH2:9][CH2:10][N:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:40]([C:27]1[S:26][C:30]2[C:31]3[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=3[O:33][CH2:34][CH2:35][C:29]=2[CH:28]=1)=[O:41])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCNc1ccccc1Cl
Reactant: O=C(Cl)c1cc2c(s1)-c1ccccc1OCC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccccc1Cl
Reaction time: 8 h
Yield: 71.9 %

Procedure:
To a solution of N-(2-(tert-butyldimethylsilyloxy)ethyl)-2-chloroaniline (0.145 g, 0.508 mmol) and triethylamine (0.113 mL, 0.812 mmol) in tetrahydrofuran (1 mL, 10 mmol) was added a solution of 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbonyl chloride (0.107 g, 0.406 mmol) in tetrahydrofuran (4 mL). The reaction was stirred overnight and concentrated in vacuo. Aqueous work up gave a yellow solid which was purified on silica by MPLC to give 150 mg of N-(2-(tert-butyldimethylsilyloxy)ethyl)-N-(2-chlorophenyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)=[CH:4][C:3]=1[O:21][CH3:22]>CN(C=O)C.CCO.[Pd]>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:12][CH2:13]2)=[CH:4][C:3]=1[O:21][CH3:22]
Reactant: COc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 10% Pd/C (0.068 g) in DMF (2 mL) under nitrogen was added a solution of tert-butyl 4-(4-amino-3-methoxyphenyl)-5,6-dihydropyridine-1(2H)-carboxylate (I33) (2.0 g, 6.5 mmol) in EtOH (50 mL) and the resulting suspension was stirred under an atmosphere of hydrogen at room temperature for 24 hours. The reaction mixture was filtered through celite, washing with ethyl acetate (100 mL). The filtrate was evaporated to dryness to give the title compound (I26) (1.42 g, 72%) as a light brown solid; 1H NMR (400 MHz, CDCl3) δ 6.66-6.58 (m, 3H), 4.21 (s, 2H), 3.76-3.66 (m, 4H), 2.53 (tt, J=12.1, 3.5 Hz, 1H), 1.84-1.75 (m, 2H), 1.55 (tdd, J=11.5, 6.4, 3.1 Hz, 1H), 1.47 (s, 9H).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:10][S:9][C:8]=1[C:19]([F:22])([F:21])[F:20])(=O)=O.[F:23][C:24]1[CH:25]=[C:26]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:27]=[C:28]([F:31])[C:29]=1O.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[C:7]([CH2:6][O:5][C:29]3[C:28]([F:31])=[CH:27][C:26]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:25][C:24]=3[F:23])=[C:8]([C:19]([F:22])([F:21])[F:20])[S:9][CH:10]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Reactant: CS(=O)(=O)OCc1c(-c2ccc(Cl)cc2)csc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cc(F)c(OCc2c(-c3ccc(Cl)cc3)csc2C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed [4-(4-chlorophenyl)-2-(trifluoromethyl)thiophen-3-yl]methyl methanesulfonate (636 mg, 1.72 mmol, 1.00 equiv), ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate (514 mg, 2.23 mmol, 1.30 equiv), potassium carbonate (712 mg, 5.15 mmol, 3.00 equiv), N,N-dimethylformamide (10.0 mL). The resulting solution was stirred overnight at 25° C. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:6). The resulting solution was diluted with 20 mL of H2O. The resulting solution was extracted with 4×20 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4). This resulted in 0.865 g (100%) of ethyl 3-(4-[[4-(4-chlorophenyl)-2-(trifluoromethyl)thiophen-3-yl]methoxy]-3,5-difluorophenyl)propanoate as colorless oil. Mass spectrum (ESI, m/z): Calcd. for C23H18C1F5O3S, 505.1 (M+H). found 505.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH3:11])=[CH:4][C:3]=1[N+:13]([O-])=O.CC(O)C.Cl.[H][H]>[Pd].CO>[CH2:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH2:13])[CH:4]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCC(=O)c1ccc(C)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: CCCCc1ccc(C)c(N)c1

Procedure:
A mixture of 34 parts of 1-(4-methyl-3-nitrophenyl)1-butanone, 24 parts of 2-propanol saturated with hydrochloric acid and 400 parts of methanol is hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. Water is added to the residue and the whole is alkalized with ammonium hydroxide. The product is extracted with 2,2'-oxybispropane. The extract is dried, filtered and evaporated, yielding 25.5 parts of 5-butyl-2-methylbenzenamine as a residue.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[NH:16]([CH3:29])[C@H:17]([C:25]([O:27][CH3:28])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1>>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([N:16]([CH3:29])[C@H:17]([C:25]([O:27][CH3:28])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CN[C@@H](Cc1ccccc1)C(=O)OC
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Product: COC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 77 %

Procedure:
Condensation of BocProOH (4.30 g.) and HMePheOMe (2.74 g.) by the mixed anhydride method using diphenylphosphinyl chloride gave BocPro-MePheOMe in 77% yield. Demethylation of BocPro-MePheOMe (3.0 g.) using aqueous sodium hydroxide gave BocPro-MePheOH in 83% yield. Condensation of BocPro-MePheOH (1.71 g.) and HPheOBz (2.14 g.) using dicyclohexylcarbodiimide and N-hydroxysuccinimide gave BocPro-MePhe-PheOBz in 76% yield. Debenzylation of BocPro-MePhe-PheOBz (2.0 g.) by hydrogenation with palladium catalyst gave BocPro-MePhe-PheOH in 100% yield.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9](=O)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[NH:13][NH2:14]>>[CH3:10][CH:9]=[C:8]([NH:14][NH:13][C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)/C=C/c1ccccc1
Reactant: CC(C)(C)OC(=O)NN
Product: CC=C(Cc1ccccc1)NNC(=O)OC(C)(C)C

Procedure:
This compound was prepared by the method of Ghali et al. (J. Org. Chem., 1981, 46, 5413-5414) in about 65% overall yield, from trans-4-phenyl-3-buten-2-one and t-butyl carbazate, after crystallization of the crude product from hexane; melting point=76-79° C.; NMR (CDCl3) 1.24 (d, 3H, CH3); 1.45 (s, 9H, t-butyl CH3); 3.78 (m, 2H, propenyl CH-1, carbazate NH-3); 5.8-6.29 (m, 2H, carbazate NH-2, propenyl CH-2); 6.53 (d, 1H, propenyl CH-3); 7.3 (m, 5H, aromatic).
Reaction SMILES: [CH:1]1([S:7][CH:8]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=2)[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([N:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][C:19]([O:27][CH3:28])=[C:20]([O:25][CH3:26])[CH:21]=3)[CH2:16]2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>O1CCCC1>[CH:1]1([S:7][CH:8]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][C:19]([O:27][CH3:28])=[C:20]([O:25][CH3:26])[CH:21]=3)[CH2:16]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C(CCCCC(=O)N2CCc3cc(OC)c(OC)cc3C2)SC2CCCCC2)cc1OC
Solvent: C1CCOC1
Product: COc1ccc(C(CCCCCN2CCc3cc(OC)c(OC)cc3C2)SC2CCCCC2)cc1OC

Procedure:
A mixture of 0.959 g of 2-[6-(cyclohexylthio)-6-(3,4-dimethoxyphenyl)-1-oxohexyl]-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline and 0.35 mL of borane-methylsulfide complex (10M) in 10 mL of tetrahydrofuran is heated under reflux for 2 hour, cooled and quenched with methyl alcohol. The volatiles are removed in vacuo. The residue is taken up in 10 mL of ethyl alcohol, 8 mL of 1N sodium hydroxide is added and the resulting mixture is heated under reflux for 2 hours. The solution is cooled, diluted with water and extrated with ethyl acetate. The ethyl acetate extract is washed with brine, dried and filtered. The filtrate is evaporated to yield an oil. This oil is purified by flash chromatography using 2% methyl alcohol in methylene chloride affording 0.71 g of the desired product as a light yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35]([CH3:40])=[CH:34]2>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[N:5]=[CH:4][N:3]=[C:2]2[O:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35]([CH3:40])=[CH:34]2
Reactant: Cc1cc2cc(O)ccc2[nH]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN(C)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCCN(C)S(C)(=O)=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 35.3 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazoline (360 mg, 1.00 mm ol), (prepared as described for the starting material in Example 152), potassium carbonate (215 mg, 1.56 mmol) and 5-hydroxy-2-methylindole (162 mg, 1.10 mmol) in DMF (8.0 ml) was stirred at 100° C. for 5 hours and allowed to cool to ambient temperature. The solvent was removed by evaporation and the residue was purified by silica column chromatography eluting with methanol (2.5 to 5%) in dichloromethane. The resulting solid was recrystallised from ethyl acetate, filtered and washed with diethyl ether to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazoline (166 mg, 35%).
Reaction SMILES: [CH2:1]([Si:3](Cl)([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[Br:9][CH2:10][C@@H:11]([C:13]1[CH:24]=[CH:23][C:16]2[O:17][C:18]([CH3:22])([CH3:21])[O:19][CH2:20][C:15]=2[CH:14]=1)[OH:12].N1C=CN=C1.CCCCCC>CN(C=O)C>[Br:9][CH2:10][C@H:11]([O:12][Si:3]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:1][CH3:2])[C:13]1[CH:24]=[CH:23][C:16]2[O:17][C:18]([CH3:22])([CH3:21])[O:19][CH2:20][C:15]=2[CH:14]=1
Reactant: CC[Si](Cl)(CC)CC
Reactant: CC1(C)OCc2cc([C@@H](O)CBr)ccc2O1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC[Si](CC)(CC)O[C@@H](CBr)c1ccc2c(c1)COC(C)(C)O2
Temperature: 15 °C
Yield: 99.9 %

Procedure:
Triethylsilyl chloride (205 g) was added dropwise to a stirred mixture of (1R)-2-Bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (350 g) and imidazole (108.5 g) in DMF (875 ml) at 5° C. Upon complete addition the mixture was warmed to 15° C. and stirred, at this temperature for 1 h. n-Hexane (3500 ml) was then added to the mixture which was washed with water (3×1750 ml). The organic layer was dried over anhydrous MgSO4 before being filtered and concentrated under reduced pressure to give the title compound (488.6 g) as an oil, δ (DMSO-d6) 7.18 (1H, d, J 8.2 Hz), 7.10 (1H, s), 6.75 (1H, d, J 8.2 Hz), 4.83 (1H, m), 4.78 (2H, d, J 6.9 Hz), 3.55 (2H, m), 1.45 (6H, s), 0.84 (9H, t, J 8.1 Hz), 0.51 (6H, m).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6].[CH3:12][O:13][C@H:14]1[C@@H:19]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][CH2:17][NH:16][CH2:15]1.C(N(CC)CC)C>CN(C)C=O>[CH3:12][O:13][C@H:14]1[C@@H:19]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][CH2:17][N:16]([CH2:2][CH2:3][CH2:4][C:5]([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[O:6])[CH2:15]1
Reactant: O=C(CCCCl)N1CCCC1
Reactant: CO[C@@H]1CNCC[C@@H]1NCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CO[C@@H]1CN(CCCC(=O)N2CCCC2)CC[C@@H]1NCc1ccccc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
A mixture of 43.9 parts of 1-(4-chloro-1-oxobutyl)pyrrolidine, 55.1 parts of cis-3-methoxy-N-(phenylmethyl)-4-piperidinamine, 37.8 parts of N,N-diethylethanamine and 900 parts of N,N-dimethylformamide was stirred overnight at 70° C. Another portion of 4.4 parts of 1-(4-chloro-1-oxobutyl)pyrrolidine was added and stirring was continued overnight at 70° C. The reaction mixture was evaporated and the residue was taken up in a mixture of water and sodium carbonate. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 53.1 parts (59.0%) of cis-1-[4-[3-methoxy-4-[(phenylmethyl)amino]-1 piperidinyl]-1-oxobutyl]pyrrolidine as a residue (int. 42).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Cl[C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20][CH:21]1[CH2:23][CH2:22]1.O>ClCCl>[CH2:10]([O:9][C:7](=[O:8])[C:6]([C:18]1[CH:17]=[CH:16][C:15]([S:20][CH:21]2[CH2:22][CH2:23]2)=[C:14]([Br:13])[CH:19]=1)=[O:12])[CH3:11]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Brc1ccccc1SC1CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(=O)c1ccc(SC2CC2)c(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.1 %

Procedure:
To a suspension of aluminum chloride (40.2 g) in dichloromethane (1200 mL) was added dropwise ethyl chloro(oxo)acetate (32.3 g) at 0° C., followed by stirring at the same temperature for 1 hour. To the reaction mixture was added dropwise a solution of 1-bromo-2-(cyclopropylsulfanyl)benzene (49.3 g) in dichloromethane (280 mL) while keeping it at 5° C. or lower, followed by stirring at room temperature for 1 hour. The reaction mixture was cooled to 0° C., and water was added thereto to stop the reaction. The reaction mixture was extracted with ethyl acetate and the organic layer was sequentially washed with water, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine. The solution was dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel chromatography to obtain ethyl[3-bromo-4-(cyclopropylsulfanyl)phenyl](oxo)acetate (29.8 g).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH:12]([OH:15])[CH2:13][CH3:14]>CN(C)C=O>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:14][CH2:13][CH2:12][OH:15])[N:5]=1)([O-:3])=[O:2]
Reactant: CCC(O)Br
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccn(CCCO)n1
Yield: 47.5 %

Procedure:
To a solution of 3-nitro-1H-pyrazole (prepared in example 3, 200 mg, 1.77 mmol) in anhydrous N,N-dimethylformamide (2 mL), a 60% dispersion of sodium hydride in mineral oil (92 mg, 2.30 mmol) was added while stirring under nitrogen. After the effervescence ceased and the mixture was stirred for an additional 30 min, bromopropanol (208 μL, 2.30 mmol) was added. The mixture was continued to stir under nitrogen for an additional 2 h. The solvent was removed in vacuo and purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 2% methanol/methylene chloride to 5% methanol/methylene chloride) afforded 3-(3-nitro-pyrazol-1-yl)-propan-1-ol (144 mg, 48%) as an oil: H1-NMR (400 MHz, CDCl3) δ 2.09 (2H, m), 2.84 (1H, s), 3.60 (2H, t, J=5.8 Hz), 4.32 (2H, t, J=6.8 Hz), 6.82 (1H, D, J=2.4 Hz), 7.51 (1H, d, J=2.4 Hz).
Reaction SMILES: CS([O-])(=O)=O.[C:6]1(=[O:13])[O:12][C:10](=[O:11])[CH2:9][O:8][CH2:7]1.[NH2:14][CH2:15][CH2:16][CH2:17][OH:18]>>[OH:18][CH2:17][CH2:16][CH2:15][NH:14][C:10](=[O:11])[CH2:9][O:8][CH2:7][C:6]([OH:12])=[O:13]
Reactant: O=C1COCC(=O)O1
Reactant: NCCCO
Agent: CS(=O)(=O)[O-]
Product: O=C(O)COCC(=O)NCCCO

Procedure:
methanesulfonate by (a) reacting diglycolic anhydride and 3-aminopropanol to produce [2-(3-hydroxypropyl)amino-2-oxoethoxy]acetic acid, (b) heating to cyclize the latter to obtain 4-(3-hydroxypropyl)-3,5-dioxomorpholine, (c) esterifying the latter with methanesulfonyl chloride to produce 3-(3,5-dioxomorpholino)propyl methanesulfonate and (d) reacting the mesylate with 4-[bis(2-bromo-p-tolyl)methyl]piperidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:10])[CH3:9].[BrH:13].OO.S([O-])([O-])=O.[Na+].[Na+]>>[Br:13][C:5]1[CH:6]=[C:7]([CH:8]([CH3:10])[CH3:9])[C:2]([F:1])=[CH:3][C:4]=1[O:11][CH3:12]
Reactant: COc1ccc(C(C)C)c(F)c1
Reactant: Br
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Product: COc1cc(F)c(C(C)C)cc1Br
Temperature: 27.5 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
The crude 3-fluoro-4-isopropylanisole solution from the previous step (100 ml, 0.82 M, 82 mmol) was stirred at 20° C. in the dark. Aqueous 48 wt % HBr (16.6 g, 98.5 mmol) and aqueous 35 wt % hydrogen peroxide (14.0 g, 144 mmol) were added concomitantly over 40 min. The reaction mixture was maintained at 25-30° C. during the addition. The mixture was stirred at 30° C. for 3 h and then was cooled to 5° C. Sodium sulfite (4.2 g) was added in portions over 30 min while maintaining the quench temperature at <20° C. The aqueous layer was removed, and the organic layer was washed with 2 M KHCO3 (20 ml), concentrated, and flushed with heptane (50 ml) at 30-40° C. under reduced pressure to afford 2-bromo-4-isopropyl-5-fluoroanisole as a pale yellow liquid in 98% yield.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[C:14](=O)[CH2:15]Br)C.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([NH2:26])=[O:25]>>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:18])=[C:8]([C:14]2[N:26]=[C:24]([C:23]3[CH:27]=[CH:28][CH:29]=[C:21]([O:20][CH3:19])[CH:22]=3)[O:25][CH:15]=2)[CH:9]=1
Reactant: CCOC(=O)COc1ccc(Br)cc1C(=O)CBr
Reactant: COc1cccc(C(N)=O)c1
Product: COc1cccc(-c2nc(-c3cc(Br)ccc3OCC(=O)O)co2)c1

Procedure:
Title compound was prepared from [4-bromo-2-(2-bromoacetyl)phenoxy]acetic acid ethyl ester and 3-methoxybenzamide according to GP5 and GP3: LC/MS (an10p8) Rt 2.68 min, m/z 404 [M+H]+; 1H NMR (CDCl3): δ 3.87 (s, 1H), 4.89 (s, 2H), 7.09 (m, 2H), 7.4-7.7 (m, 4H), 8.22 (s, 1H), 8.89 (s, 1H), 13.3 (br s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH:7]=1.[H-].[Na+].CS(C)=O.Cl[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1>O1CCCC1>[CH3:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[CH:7]=[C:2]([O:1][C:26]3[N:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=2)=[CH:13][CH:12]=1
Reactant: Clc1ncccn1
Reactant: COC(=O)c1cc(O)cc(-c2ccc(C)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Oc2ncccn2)cc(-c2ccc(C)cc2)c1

Procedure:
To a stirred solution of methyl 5-hydroxy-4′-methylbiphenyl-3-carboxylate (300 mg, 1.24 mmol) in tetrahydrofuran (20 mL) at 0° C. was added sodium hydride (60% in mineral oil, 55 mg, 1.37 mmol) over a period of 10 minutes. The reaction mixture was concentrated to afford a green solid. A microwave vial was charged with the resulting green solid, dimethyl sulfoxide (8 mL), and 2-chloropyrimidine (118 mg, 0.98 mmol). The mixture was subjected to microwave irradiation at 100° C. for 4 minutes. After cooling, the mixture was filtered through Celite and the filtrate was concentrated. The residue was purified by flash chromatography to afford the title compound.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.[NH2:26][CH2:27][CH2:28][SH:29].B(F)(F)F>O1CCCC1>[S:29]1[C:2]2([CH2:7][CH2:6][N:5]([C:8]3[CH:13]=[CH:12][C:11]([N:14]4[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]4=[O:24])=[CH:10][C:9]=3[F:25])[CH2:4][CH2:3]2)[NH:26][CH2:27][CH2:28]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Reactant: NCCS
Agent: FB(F)F
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)NCCS4)c(F)c2)C(=O)O1
Yield: 68 %

Procedure:
The title compound was prepared by reacting (S)—N-{3-[4-(4-oxo-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.0 mmol), 2-aminoethanethiol (1.0 mmol) and BF3. etherate (2.0 mmol) in tetrahydrofuran (10 ml) at a temperature 65° C. for 12 hours in 68% yield.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[CH:4][CH:3]=1.B.C1COCC1>>[NH2:13][CH2:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([NH2:1])=[CH:3][CH:4]=1
Reactant: N#Cc1ccc(N)c2ccccc12
Agent: B
Solvent: C1CCOC1
Product: NCc1ccc(N)c2ccccc12
Temperature: 70 °C
Reaction time: 19.5 h

Procedure:
To a vial containing 4-aminonaphthalene-1-carbonitrile (0.59 mmol) was added BH3.THF (1M solution (1.2 mmol). The vial was capped and stirred at 70° C. for 19.5 hours. The reaction was cooled down to room temperature and quenched by drop wise addition of methanol (2 mL), stirred at room temperature for 30 minutes, filtered and stirred with Dowex 50WX2-200 resin (1 g) for 26.5 hours. The resin was filtered, washed with methanol (20 mL) and 10% aqueous ammonia (50 mL). The solvent was removed under vacuum. The material was used without any further purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Cl:8].[C:9]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=1>>[Cl:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:15]([C:10]1[C:9]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:17])=[O:16]
Reactant: Cc1noc(N)c1Cl
Reactant: O=S(=O)(Cl)c1ccccc1-c1ccccc1
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccccc2)c1Cl
Yield: 74 %

Procedure:
N-(4-Chloro-3-methyl-5-isoxazolyl)-2-biphenylsulfonamide was prepared in the same manner as described in Example 10 from 5-amino-4-chloro-3-methylisoxazole and 2-biphenylsulfonyl chloride in 74% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 132-134° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.O.[C-:11]#[N:12].[K+]>C(O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][C:11]#[N:12])=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: ClCc1ccc(Cl)nc1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCc1ccc(Cl)nc1
Temperature: 50 °C

Procedure:
A solution of 5.2 g (32 mmol) of 2-chloro-5-chloromethylpyridine dissolved in 40 mL of ethanol was treated with 20 mL of water and 2.4 g (37 mmol) of potassium cyanide. The mixture was stirred and heated at 50° C. for 20 hours. The dark mixture was then partitioned between dichloromethane and water and the organic layer was washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure to yield 4.54 g (92%) of Preparatory Compound E, (6-chloro-3-pyridinyl)acetonitrile, as a dark brown liquid: 1H NMR (CDCl3) δ 8.38 (d, J=3.0 Hz, 1H), 7.71 (dd, J=3.0 and 7.6 Hz, 1H), 7.42 (d, J=7.6 Hz, 1H), 3.80 (s, 2H) ppm. GCMS: (EI) m/z 152 (M+).