Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3](=[C:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=O)O.[CH:18]1[C:23]([NH:24][NH2:25])=[CH:22][CH:21]=[C:20]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:19]=1.Cl>C(O)C>[F:1][C:2]([F:17])([F:16])[C:3]1[C:5]2[C:6](=[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]3=[CH:13][CH:14]=2)[N:24]([CH:23]2[CH2:22][CH:21]=[C:20]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:19]=[CH:18]2)[N:25]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=C1C(=C(O)C(F)(F)F)CCc2ccccc21
Agent: Cl
Solvent: CCO
Product: NS(=O)(=O)C1=CCC(n2nc(C(F)(F)F)c3ccc4ccccc4c32)C=C1
Yield: 71.2 %

Procedure:
A 100 mL one neck round bottomed flask equipped with reflux condenser, nitrogen inlet and provisions for magnetic stirring was charged with 3,4-dihydro-2-[2,2,2-trifluoro-1-hydroxyethylidene]-1(2H)-naphthalenone from Step 1 (1.21 g, 5.0 mmol), 4-sulfonamidophenylhydrazine hydrochloride (1.12 g, 5.0 mmol) and 25 mL of absolute ethanol. The solution was warmed to reflux for 15 hours, cooled and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water and with brine, dried over anhydrous MgSO4, filtered and reconcentrated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and isooctane to give 1.4 g (71%) of pure 4,5-dihydro-4-[3-(trifluoromethyl)-1H-benz[g]indazol-1-yl]benzenesulfonamide: mp 257°-258° C.; 1H NMR (CDCl3 /CD3OD, 4:1) δ 2.7 (m, 2H), 2.9 (m, 2H), 6.6 (m, 1H), 6.9 (m, 1H), 7.1 (m, 1H), 7.16 (m, 1H), 7.53 (m, 2H), 7.92 (m, 2H); 19F NMR CDCl3 δ-62.5. FAB-MS M+H=394.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][OH:5].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]2[NH:1][CH2:2][C:3]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:4][O:5]2)=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: NCC(CO)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Clc1ccc(C2NCC(c3ccccc3)(c3ccccc3)CO2)cc1

Procedure:
This product is obtained by reacting 3-amino-2,2-diphenyl-1-propanol with 4-chlorobenzaldehyde in refluxing toluene in the presence of p-toluenesulphonic acid for 5 hours.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([C:14](=[O:34])[N:15]([CH:31]2[CH2:33][CH2:32]2)[CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[CH:18]=2)[CH2:11][C@H:10]([NH2:35])[CH2:9]1)=O)(C)(C)C.Cl[C:37]1[CH:42]=[C:41]([Cl:43])[N:40]=[CH:39][N:38]=1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.N1C(C)=CC=CC=1C>CC#N>[CH:31]1([N:15]([CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[CH:18]=2)[C:14]([C@@H:12]2[CH2:11][C@H:10]([NH:35][C:37]3[CH:42]=[C:41]([Cl:43])[N:40]=[CH:39][N:38]=3)[CH2:9][NH:8][CH2:13]2)=[O:34])[CH2:32][CH2:33]1
Reactant: COCCCn1cc(CN(C(=O)[C@@H]2C[C@H](N)CN(C(=O)OC(C)(C)C)C2)C2CC2)c2ccccc21
Reactant: Clc1cc(Cl)ncn1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: CC#N
Product: COCCCn1cc(CN(C(=O)[C@H]2CNC[C@@H](Nc3cc(Cl)ncn3)C2)C2CC2)c2ccccc21

Procedure:
The title compound is prepared analogously as described in Example 154 using (3S*,5R*)-3-Amino-5-{cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-piperidine-1-carboxylic acid tert-butyl ester and 4,6-dichloropyrimidine followed by deprotection of Boc using TMSOTf and 2,6-lutidine. MS: 497 (Cl35) [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 2.77 min.
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:16][CH2:15]2)[CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O>[Ni].CCOC(C)=O>[N:20]1([CH:17]2[CH2:18][CH2:19][N:14]([C:7]3[CH:8]=[CH:9][C:10]([NH2:11])=[C:5]([O:4][CH2:3][CH:2]([CH3:26])[CH3:1])[CH:6]=3)[CH2:15][CH2:16]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)COc1cc(N2CCC(N3CCCCC3)CC2)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CC(C)COc1cc(N2CCC(N3CCCCC3)CC2)ccc1N
Reaction time: 1 h
Yield: 37.8 %

Procedure:
A mixture of 1′-{3-[(2-methylpropyl)oxy]-4-nitrophenyl}-1,4′-bipiperidine (4.00 g, 11.1 mmol) and Raney nickel (0.500 g) in EtOAc was stirred under H2 (1 atm.) for 1 h. The mixture was filtered through a pad of Celite®, concentrated and recrystallized from EtOAc/hexanes to provide the title compound (1.40 g, 4.20 mmol, 39%). MS (M+H) 332.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@:19]([CH2:32][CH:33]=O)([C:28]([O:30][CH3:31])=[O:29])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1.[CH3:35][NH2:36].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@:19]([CH2:32][CH2:33][NH:36][CH3:35])([C:28]([O:30][CH3:31])=[O:29])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1
Reactant: COC(=O)[C@]1(CC=O)CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1C(=O)OC(C)(C)C
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNCC[C@@]1(C(=O)OC)CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1C(=O)OC(C)(C)C

Procedure:
The reaction was performed on the two separated batches of 1-(1,1-dimethylethyl) 2-methyl (2R,5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-2-(2-oxoethyl)-1,2-pyrrolidinedicarboxylate obtained from the previous step (D37, Procedure 1). The first batch (109 g) was dissolved in MeOH (440 mL) and MeNH2 in MeOH 2M solution (347 mL) was added. AcOH (11 mL) was added. NaBH(OAc)3 (49 g) was added portion wise after 10 minutes. More NaBH(OAc)3 (14.7 g) was added portion wise at 25° C. The reaction mixture was quenched with 28% aqueous malic acid (200 mL) followed by AcOEt (1000 mL). K2CO3 was added up to pH˜9. Organic phase was concentrated to dryness, re-dissolved in EtOAc (500 mL) and extracted with 20% citric acid (4×300 mL). The combined aqueous phases were treated with EtOAc (500 mL) and solid K2CO3 was added until pH˜9. The phases were separated and the organic phase was dried under Na2SO4 and evaporated to dryness to afford the title compound (80 g). The second batch (180 g) was dissolved in MeOH (628 mL) and MeNH2 in MeOH 2M solution (300 mL) was added. AcOH (31 mL) was added. NaBH(OAc)3 (78.8 g) was added portionwise at 0° C. after 10 minutes. The reaction mixture was quenched with saturated NH4Cl (890 mL) and EtOAc (890 mL). The phases were separated and the aqueous was extracted with EtOAc (4×300 mL). The organic phase was dried over Na2SO4, concentrated to dryness, re-dissolved in EtOAc (500 mL) and extracted with 20% citric acid (6×150 mL). The combined aqueous phases were treated with EtOAc (600 mL) and solid K2CO3 was added until pH 8/9. The Phases were separated and the organic phase dried over Na2SO4 and evaporated to dryness to afford the title compound (78 g). 1H NMR (400 MHz, DMSO-d6) δ(ppm): 7.55 (m, 1H); 7.42 (m, 3H); 7.25 (m, 2H); 6.98 (m, 2H); 5.14 (m, 2H); 4.85-4.69 (2m, 1H); 3.75-3.73 (2s, 3H); 2.36 (bs, 3H) 2.80-2.25 (m, 2H); 2.20-2.00 (m, 3H); 1.70 (m, 1H); 1.32-1.00 (2s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:4]=1[NH2:5].CN(C=O)C.[CH2:18]([O:25][C:26](Cl)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:4]=1[NH:5][C:26](=[O:27])[O:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1cc([N+](=O)[O-])ccc1N
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: COc1cc([N+](=O)[O-])ccc1NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
2-Methoxy-4-nitroaniline, 51 g (0.3 mol), was dissolved in 135 ml of acetone containing 12 g of MgO, and 65 ml of commercial benzylchloroformate was slowly added to the stirred mixture. After 4 hours the flask was warmed to redissolve the precipitate and the mixture was stirred overnight. DMF (100 ml) was added, and the mixture was heated to dissolve all of the product before being filtered through celite. After dilution with 250 ml of ethanol the hot solution was further diluted with water until almost cloudy, and allowed to cool. The pale yellow crystals were collected, washed well with 50% aqueous ethanol, and dried. Yield 86.0 g, 94%, m.p. 130°-131° C.
Reaction SMILES: [CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23](O)=[O:24].[OH:26][CH2:27][CH2:28][CH2:29][CH2:30][NH2:31].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[OH:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:23](=[O:24])[CH2:22][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([O:20][CH3:21])[CH:5]=2)[N:10]([C:11](=[O:12])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:2]=1[CH3:1]
Reactant: NCCCCO
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)c(CC(=O)NCCCCO)c(C)n2C(=O)c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
To a stirred solution of indomethacin (3.57 g, 10 mmol) in DMF was added 4-hydroxybutylamine (4.64 g), HOBt (2.02 g, 15 mmol), DIPEA (3.88 g, 30 mmol), EDCI (2.10 g, 11 mmol) at 25° C. The resultant solution was stirred for 16 h at 25° C. Removal of solvent in vacuo afforded a residue, where 100 mL water was added and extracted with EtOAc (3×75 mL). Combined organic layers were dried over Na2SO4. Solvent was evaporated completely and the obtained mass was dissolved in CH2Cl2 (40 mL), then HCl (gas) was bubbled for 2 h at 25° C. Removal of solvent in vacuo afforded a yellow residue, where n-hexane was added (20 mL) and stirred for 30 min to a make good slurry, which was filtered to afford the desired N-(4-hydroxybutyl)-2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetamide as yellow solid (2.5 g, 70%). 1H NMR (500 MHz, DMSO-d6) δ 1.44-1.52 (m, 2H, CCH2CC), 1.53-1.59 (m, 2H, CCCH2C), 2.23 (s, 3H, CH3), 3.03-3.08 (m, 2H, CH2CCC), 3.52 (s, 2H, CH2CO), 3.75 (s, 3H, OCH3), 3.77-3.78 (m, 2H, CCCCH2), 4.53 (br s, 1H, OH), 6.684 (dd, J=9, 2.4 Hz, 1H, indolyl H-6), 6.916 (d, J=9 Hz, 1H, indolyl H-7), 7.144 (d, J=2.4 Hz, 1H, indolyl H-4), 7.64 (d, J=8.7 Hz, 2H, p-chlorobenzoyl H-3, H-5), 7.67 (d, J=8.7 Hz, 2H, p-chlorobenzoyl H-2, H-6), 8.24 (br s, 1H, NHCO). Mass (ESI) (M+Na) calcd for C23H25ClN2O4Na 451.15; found 451.04.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[CH:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[CH:16]([C:26]([NH:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:27])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:37].N1C=CC=CC=1.[CH3:44][S:45](Cl)(=[O:47])=[O:46].C(OCC)(=O)C>O>[CH2:30]([O:29][NH:28][C:26]([CH:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:37])[N:8]([CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]2[NH:1][S:45]([CH3:44])(=[O:47])=[O:46])[CH:17]1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])=[O:27])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CS(=O)(=O)Cl
Reactant: NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2ccccc2)C1c1ccc(Cl)cc1Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2ccccc2)C1c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of 538 mg of (3RS,4RS)-2-{(1SR,2SR)-2-aminocyclohexyl}-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 2.5 ml of pyridine was added 0.15 ml of methanesulfonyl chloride, followed by stirring at room temperature for 6 hours. Ethyl acetate and water were added thereto to carry out a liquid separation operation, and the organic layer was washed with a 1 M aqueous hydrochloric acid solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:chloroform) and then recrystallized from ethyl acetate-hexane to obtain 206 mg of (3RS,4RS)—N-(benzyloxy)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless powdered crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[C:9]([OH:16])=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=[O:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:26][CH3:27].[Cl-].[NH4+]>C(#N)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[C:9]([O:16][CH2:26][CH3:27])=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=[O:12])=[CH:4][CH:3]=1
Reactant: CCI
Reactant: O=Cc1cccc(OCc2ccc(Cl)cc2)c1O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1c(C=O)cccc1OCc1ccc(Cl)cc1
Temperature: 98 °C
Reaction time: 18 h

Procedure:
To a mixture of 3-(4-chloro-benzyloxy)-2-hydroxy-benzaldehyde (63, 110 mg, 0.42 mmol), potassium carbonate (150 mg, 1.1 mmol) in acetonitrile (8 mL) was added iodoethane (0.2 mL, 2.5 mmol) at room temperature. The mixture was stirred at 98° C. for 18 hours. The reaction mixture was poured into a solution of saturated ammonium chloride and was extracted with ethyl acetate. The organic layer was collected, washed with brine, and dried over magnesium sulfate. After removal of solvent, a light yellow solid was obtained (64, 116 mg, 95%).
Reaction SMILES: [Br-].[C:2]([CH2:9][P+:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3].[OH-].[Na+]>O>[C:2]([CH:9]=[P:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3]
Reactant: CC(C)(C)OC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 16 h
Yield: 95.2 %

Procedure:
A suspension of the carbo-t-butoxymethyl triphenylphosphonium bromide (55.8 g, 122 mmol) in water (400 ml) was treated with sodium hydroxide (4.7 g, 117 mml) in water (100 ml). The mixture was stirred for 16 hours and the solid collected to give 43.7 g (95% of theory) of carbo-t-butoxymethylene triphenylphosphorane.
Reaction SMILES: [Br:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH3:21])[N:11]([NH:13]C(=O)OC(C)(C)C)[CH:12]=1.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25]>ClCCl>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[Br:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH3:21])[N:11]([NH2:13])[CH:12]=1
Reactant: Cc1nc(-c2cnn(C)c2Br)cn1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(-c2cnn(C)c2Br)cn1N
Reaction time: 2.5 h

Procedure:
tert-Butyl [4-(5-bromo-1-methyl-1H-pyrazol-4-yl)-2-methyl-1H-imidazol-1-yl]carbamate (5.00 g, 14.0 mmol) was dissolved in dichloromethane (120 mL), treated with trifluoroacetic acid (20.9 mL, 281 mmol), and stirred for 2.5 hours. After removal of volatiles in vacuo, the oily residue was diluted with diethyl ether (100 mL). The resulting suspension was stirred for 30 minutes at room temperature, and then the solid was collected and washed with diethyl ether to provide the product as an off-white solid. Yield: 4.98 g, 13.5 mmol, 96%. LCMS m/z 256.3 (M+1). 1H NMR (500 MHz, CD3OD) δ 2.65 (s, 3H), 3.95 (s, 3H), 7.68 (s, 1H), 7.86 (s, 1H).
Reaction SMILES: [Si]([O:8][C:9]1([CH3:31])[CH2:12][N:11]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])[O:21][C:20]3=[O:29])=[CH:15][C:14]=2[F:30])[CH2:10]1)(C(C)(C)C)(C)C.F.C(=O)([O-])[O-].[Na+].[Na+].O1CCNC1=O>C(#N)C.ClCCl.CO.C(Cl)(Cl)Cl>[F:30][C:14]1[CH:15]=[C:16]([N:19]2[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])[O:21][C:20]2=[O:29])[CH:17]=[CH:18][C:13]=1[N:11]1[CH2:10][C:9]([OH:8])([CH3:31])[CH2:12]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CC(C)(O[Si](C)(C)C(C)(C)C)C3)c(F)c2)C(=O)O1
Agent: *CC(*)C
Agent: F
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CC(C)(O)C3)c(F)c2)C(=O)O1

Procedure:
A solution of (S)-N-[[3-[4-[3-[(tert-butyldimethylsilyl)oxy]-3-methyl-1-azetidinyl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (0.550 g, 1.22 mmol) in acetonitrile (20 mL) in a polypropylene bottle was treated with 40% aqueous hydrofluoric acid (5 mL) at ambient temperature. After 16 h TLC analysis (5% methanol/chloroform) revealed the deprotection was essentially complete. The reaction mixture was transferred to an erlenmeyer flask along with some dichloromethane (150 mL). The stirred mixture was carefully treated with saturated aqueous sodium carbonate (300 mL, gas evolution). After gas evolution ceased, the mixture was transferred to a separatory funnel and the phases separated. The aqueous phase was neutralized to pH 7 by the addition of 6N hydrochloric acid and extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. Radial chromatography over silica gel, eluting with 5% methanol/chloroform, afforded, after concentration of appropriate fractions, 0.374 g (91%) of the title oxazolidinone antibacterial agent as a white solid with mp 152°-153° C. and MS(EI) 337 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[CH:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1>>[CH:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH2:4][C:3]4[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:2]=4[Cl:1])[CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(Cc3ccc(Cl)cc3Cl)CC2)nn1

Procedure:
Following the procedure of Example 11, making variations only as required to use 2,4-dichlorobenzyl chloride in place of 2-trifluoromethylbenzyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a light yellow solid (75% yield). 1H NMR (300 MHz, CDCl3) δ 7.95-8.02, 7.44, 7.38, 7.23, 6.93, 3.70-3.77, 3.60-3.63, 3.54, 2.60-2.65, 1.50, 0.74, 0.45, 0.08. MS (ES+) m/z 434 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([O:9][CH2:10][C@@H:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])=[N:4][O:5][C:6]=1[CH:7]=[O:8].P([O-])(O)(O)=[O:22].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>O.CC(O)(C)C>[C:16]([O:15][C:14]([NH:13][C@@H:11]([CH3:12])[CH2:10][O:9][C:3]1[C:2]([F:1])=[C:6]([C:7]([OH:22])=[O:8])[O:5][N:4]=1)=[O:20])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=P([O-])(O)O
Reactant: C[C@@H](COc1noc(C=O)c1F)NC(=O)OC(C)(C)C
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: C[C@@H](COc1noc(C(=O)O)c1F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
To a mixture of tert-butyl {(1S)-2-[(4-fluoro-5-formylisoxazol-3-yl)oxy]-1-methylethyl}carbamate (244 mg), sodium dihydrogen phosphate (305 mg), 2-methylbut-2-ene (449 mL), 2-methylpropan-2-ol (5 mL) and water (1 mL) was added sodium chlorite (115 mg) at room temperature, and the obtained mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with a mixed solvent of ethyl acetate/2-propanol (volume ratio 3/1). The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a white powder (256 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH:17]([C:23](=O)[CH2:24][CH2:25][CH3:26])[C:18](OCC)=[O:19])[CH3:16])=[CH:11][CH:10]=1)#[N:2].[O:28]1[C:32]2([CH2:37][CH2:36][CH:35]([NH:38][C:39]3[NH:43][CH:42]=[N:41][N:40]=3)[CH2:34][CH2:33]2)[O:31][CH2:30][CH2:29]1.N12CCCN=C1CCCCC2.C(N(CC)C1C=CC=CC=1)C>Cl>[O:28]1[C:32]2([CH2:33][CH2:34][CH:35]([N:38]3[C:18](=[O:19])[C:17]([CH:15]([C:12]4[CH:13]=[CH:14][C:9]([C:4]5[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=5)=[CH:10][CH:11]=4)[CH3:16])=[C:23]([CH2:24][CH2:25][CH3:26])[N:40]4[N:41]=[CH:42][N:43]=[C:39]34)[CH2:36][CH2:37]2)[O:31][CH2:30][CH2:29]1
Reactant: CCCC(=O)C(C(=O)OCC)C(C)c1ccc(-c2ccccc2C#N)cc1
Reactant: c1nnc(NC2CCC3(CC2)OCCO3)[nH]1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)c1ccccc1
Product: CCCc1c(C(C)c2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Temperature: 180 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
A mixture of ethyl 2-[1-(2′-cyanobiphenyl-4-yl)ethyl]-3-oxohexanoate (4.80 g), N-(1,4-dioxaspiro[4.5]dec-8-yl)-4H-1,2,4-triazol-3-amine (1.50 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL) and N,N-diethylaniline (20 mL) was stirred at 180° C. overnight, allowed to cool and poured into 1 M hydrochloric acid (100 mL), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow oil (1.50 g, 43%).
Reaction SMILES: C1([C:7]2O[N:10]=[C:9]([NH2:12])[N:8]=2)C=CC=CC=1.[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([N:18]2[CH:7]=[N:8][C:9]([NH2:12])=[N:10]2)=[CH:16][CH:15]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Nc1noc(-c2ccccc2)n1
Product: Nc1ncn(-c2ccc(Cl)cc2)n1

Procedure:
Prepared in analogy to example 18a), starting with 5-phenyl-[1,2,4]oxadiazol-3-ylamine and 4-chloroaniline. The title compound was obtained as brownish solid (Yield=54%). MS ISP (m/e): 195.1 (100) [(M+H)+].
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:41][C:42]([N:44]([CH3:51])[CH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1)=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:41][CH2:42][N:44]([CH3:51])[CH:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)=[CH:36][CH:37]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CN(C(=O)CCl)C1CCOCC1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN(C)C2CCOCC2)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 23.7 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (16 mg) and 2-chloro-N-methyl-N-(tetrahydropyran-4-yl)acetamide (10 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (4.1 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]([OH:16])([CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])C#C.CC(=CCCC(CCO)C)C.P(Cl)(Cl)Cl.P(Br)(Br)Br.C(OCC)(=O)CC(C)=O>>[CH3:15][CH:8]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:13])[CH3:14])[CH2:7][CH2:6][CH2:5][C:2](=[O:16])[CH3:1]
Reactant: C#CC(C)(O)CCCC(C)CCC=C(C)C
Agent: BrP(Br)Br
Agent: CC(C)=CCCC(C)CCO
Solvent: CCOC(=O)CC(C)=O
Solvent: ClP(Cl)Cl
Product: CC(=O)CCCC(C)CCC=C(C)C

Procedure:
3,7,11-trimethyldodeca-1-yn-10-en-3-ol can easily be synthesized by halogenating citronellol, which is used as a perfume, with phosphorus trichloride or phosphorus tribromide, reacting the halogenation product with ethyl acetoacetate to form 6,10-dimethylundeca-9-en-2-one, and subjecting it to ethynylation in the same manner as described above.