Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].CO.[CH3:6][O:7][CH:8]([C:13]([O:15]C)=O)[C:9](OC)=[O:10].C(O)(=O)C.[CH:21]([NH2:23])=[NH:22]>>[CH3:6][O:7][C:8]1[C:13]([OH:15])=[N:22][CH:21]=[N:23][C:9]=1[OH:10]
Reactant: COC(=O)C(OC)C(=O)OC
Reactant: N=CN
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1c(O)ncnc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.8 %

Procedure:
A 2-liter, three-necked, round-bottomed flask equipped with a mechanical stirrer and a reflux condenser was dried at 100° C. and cooled to 25° C. under N2. Methanol (260 mL) was added, followed by a solution of sodium methoxide in methanol (25% by weight, 670 mL, 3.10 mol). The resulting solution was cooled to 0° C. Dimethyl methoxymalonate (151 g, 0.930 mol) was added in one portion, followed by formamidine acetate (100 g, 0.96 mol). The temperature was kept below 10° C. The resulting suspension was then stirred at 0° C. for 30 min, and refluxed for 1 h. The resulting suspension was cooled to 0° C. and quenched with concentrated HCl (250 mL) over 30 min, during which time the temperature was kept below 10° C. Stirring was continued at 5° C. for 30 min. The suspension was then filtered. The filter cake was re-suspended in water (1000 mL) and refluxed until a nearly clear solution was obtained. The solution was filtered while hot. The filtrate was cooled to 0-5° C. and stirred for 1 h. The solid precipitate was collected by filtration, washed with cold methanol (500 mL), and dried in a vacuum oven at 50° C. for 1 h to give the title compound (96.2 g, 73% yield) as a white solid. Exact Mass calculated for C5H6N2O3: 142.0, LCMS m/z=143.2 (M+H+); 1H NMR (400 MHz, DMSO-d6) δ 3.63 (s, 3H), 7.81 (s, 1H), 11.75 (br s, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[C:23]([F:26])([F:25])[F:24].C([O-])([O-])=O.[K+].[K+]>CC#N>[F:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:2]2[C:11]3[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:18][C:17]=1[C:23]([F:24])([F:25])[F:26]
Reactant: Oc1ccc(F)c(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1cccc2c(Cl)nccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cccc2c(Oc3ccc(F)c(C(F)(F)F)c3)nccc12
Yield: 101.4 %

Procedure:
The title compound was prepared following the procedure described in Intermediate-6, step-1 using 1-chloro-5-nitroisoquinoline (Step-1, Intermediate-1, 500 mg, 2.38 mmol), 4-fluoro-3-(trifluoromethyl)phenol (859 mg, 4.77 mmol) and K2CO3 (821 mg, 5.95 mmol) in CH3CN (5 mL) to afford 850 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.84 (d, J=8.4 Hz, 1H), 8.71 (d, J=7.8 Hz, 1H), 8.19 (d, J=6.3 Hz, 1H), 8.01-7.92 (m, 2H), 7.87 (m, 1H), 7.76 (m, 1H), 7.66 (t, J=9.6 Hz, 1H); MS (m/z): 353.20 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.ClCCC[N:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30](=[O:32])[CH3:31])=[CH:29][C:24]=2[O:23][C:22]1=[O:33].C([O-])([O-])=O.[K+].[K+].C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([N:21]4[C:25]5[CH:26]=[CH:27][C:28]([C:30](=[O:32])[CH3:31])=[CH:29][C:24]=5[O:23][C:22]4=[O:33])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(=O)c1ccc2c(c1)oc(=O)n2CCCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(=O)c1ccc2c(c1)oc(=O)n2N1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.0 g, 9 mmol), N-(3-chloropropyl)-6-acetyl-2-benzoxazolinone (2.4 g, 9 mmol), K2CO3 (3.6 g), a few crystals of KI, and acetonitrile (50 ml) was stirred and refluxed for 13 hours. The reaction was poured into water, and a dark, brown solid that separated was collected to afford 3.3 g of crude product. The solid was chromatographed on a Waters Prep 500 HPLC. Concentration of appropriate fractions afforded 2.3 g of a yellow solid, and recrystallization from ethyl acetate yielded 1.2 g (31%) of N-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-6-acetyl-2-benzoxazolinone, m.p.=152°-154° C.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:10][C@H:9]([O:11]C(=O)C)[CH2:8][N:7]1[S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl>C1COCC1>[OH:3][CH2:4][C@@H:6]1[N:7]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:8][C@@H:9]([OH:11])[CH2:10]1
Reactant: CCOC(=O)[C@H]1C[C@H](OC(C)=O)CN1S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2C[C@@H](O)C[C@@H]2CO)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cold solution of 4-acetoxy-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxylic acid ethyl ester (3) (0.65 g, 1.83 mmol) in THF (10 mL) is added LiAlH4 (0.135 g, 3.66 mmol) portion wise. Then the reaction mixture is stirred at room temperature for 1 h. After completion of the reaction, it is cooled to 0° C. and then pH of reaction mixture is adjusted to 3 by adding 6N HCl (0.65 mL). The mixture is concentrated, and the residue is triturated with water (8 mL), the solid precipitated out is filtered, washed with cold water (2×4 mL), and dried under reduced pressure to give compound (4) as white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][NH:11][C:12](=[O:32])[C@H:13]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:14][N:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[O:17])[C:3]=1[F:33].[CH2:34]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)[CH3:35].C(N(C(C)C)CC)(C)C>CS(C)=O>[CH:27]1([CH2:26][C@@H:13]([C:12]([NH:11][NH:10][C:4]2[C:3]([F:33])=[C:2]([N:39]3[CH2:40][CH2:41][N:36]([CH2:34][CH3:35])[CH2:37][CH2:38]3)[N:7]=[C:6]([O:8][CH3:9])[N:5]=2)=[O:32])[CH2:14][N:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[O:17])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: COc1nc(Cl)c(F)c(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)n1
Reactant: CCN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCN1CCN(c2nc(OC)nc(NNC(=O)[C@H](CC3CCCC3)CN(C=O)OCc3ccccc3)c2F)CC1
Yield: 83.9 %

Procedure:
[(2R)-3-{2-[6-Chloro-5-fluoro-2-(methyloxy)-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide (0.150 g, 0.31 mmol), commercially available 1-ethylpiperazine (0.080 mL, 0.63 mmol) and diisopropylethylamine (0.054 mL, 0.31 mmol) were stirred in DMSO (2 mL) overnight at 65° C. The reaction mixture was then purified by RP-HPLC to provide ((2R)-2-(cyclopentylmethyl)-3-{2-[6-(4-ethyl-1-piperazinyl)-5-fluoro-2-(methyloxy)-4-pyrimidinyl]hydrazino}-3-oxopropyl)[(phenylmethyl)oxy]formamide as a red solid (0.145 g, 83%). LCMS: (M+H)+=558.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:17]2[N:25](S(C3C=CC=CC=3)(=O)=O)[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)=[CH:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][C:5]=1[F:35].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:17]2[NH:25][C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)=[CH:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][C:5]=1[F:35]
Reactant: COC(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3[nH]2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.6 %

Procedure:
A mixture of 4-[1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-2-fluoro-benzoic acid methyl ester (360 mg, 0.71 mmol) and tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 3 ml) was stirred at 25° C. for 16 h. The reaction was quenched with a saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate (2×100 mL), washed with a saturated aqueous ammonium chloride solution (3×50 mL), brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 4-[2-cyclopentyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-vinyl]-2-fluoro-benzoic acid methyl ester (250 mg, 96%) as a white solid which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:4][C:5]([CH3:28])([CH3:27])[C:6]([NH:8][NH:9][C:10](=[O:26])[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=2)[CH:12]=1)=O)(=[O:3])[CH3:2].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>N1C=CC=CC=1>[C:1]([O:4][C:5]([CH3:28])([C:6]1[O:26][C:10]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=3)[CH:12]=2)=[N:9][N:8]=1)[CH3:27])(=[O:3])[CH3:2]
Reactant: CSc1ccc(Nc2cc(C(=O)NNC(=O)C(C)(C)OC(C)=O)ccn2)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CSc1ccc(Nc2cc(-c3nnc(C(C)(C)OC(C)=O)o3)ccn2)cc1
Yield: 40.3 %

Procedure:
A solution of 1,1-dimethyl-2-[2-[2-[[4-(methylthio)phenyl]amino]isonicotinoyl]hydrazino]-2-oxoethyl acetate (624 mg, 1.55 mmol) and p-toluenesulfonyl chloride (888 mg, 4.66 mmol) in pyridine (15 mL) was stirred at 90-95° C. overnight. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=10/1-0/1) and recrystallized from hexane/ethyl acetate to give the title compound (240 mg, yield 40%) as yellow crystals.
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:17](=[O:18])[N:16]([CH3:19])[C:15]2[C:14](=[O:20])[NH:13][C:12](=[O:21])[N:11]([CH3:22])[C:10]1=2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[H-].[Na+].[C:25]([O:28][C@H:29]([CH3:35])[CH2:30][CH2:31][CH2:32][CH2:33][I:34])(=[O:27])[CH3:26].O>CS(C)=O>[C:25]([O:28][C@H:29]([CH3:35])[CH2:30][CH2:31][CH2:32][CH2:33][I:34])(=[O:27])[CH3:26].[C:25]([O:28][C@H:29]([CH3:35])[CH2:30][CH2:31][CH2:32][CH2:33][N:13]1[C:14](=[O:20])[C:15]2[N:16]([CH3:19])[C:17](=[O:18])[N:9]([CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[C:10]=2[N:11]([CH3:22])[C:12]1=[O:21])(=[O:27])[CH3:26]
Reactant: Cn1c(=O)n(COC(=O)C(C)(C)C)c2c1c(=O)[nH]c(=O)n2C
Agent: CC(=O)O[C@H](C)CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(n(C)c1=O)n(COC(=O)C(C)(C)C)c(=O)n2C
Reaction time: 0.25 h
Yield: 94 %

Procedure:
To a stirring solution of 9-pivaloyloxymethyl-3,7-dimethyluric acid (0.14 g, 0.45 mmol) in dimethylsulfoxide (10 ml) was added sodium hydride (12 mg, 0.47 mmol) in one portion. The solution was stirred for 15 minutes. (R)-5-Acetoxy-1-iodohexane (0.13 g, 0.47 mmol) in dimethylsulfoxide (1 ml) was added. The solution of (R)-5-acetoxy-1-iodohexane was prepared according to methods described in U.S. patent application Ser. No. 09/002,345, which is incorporated herein by reference. After stirring at room temperature for 24 hours, water (25 ml) was added and the aqueous solution was extracted with ethyl acetate (3×15 ml). The combined extracts were washed with saturated aqueous sodium chloride solution (15 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica eluting with ethyl acetate to give (R)-1-(5-acetoxyhexyl)-9-pivaloyloxymethyl-3,7-dimethyluric acid (0.10 g, 50% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](Cl)=[O:19])=[CH:14][N:13]=1>N1C=CC=CC=1>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:1][C:18](=[O:19])[C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[N:13][CH:14]=1
Reactant: Nc1nc2ccccc2s1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: c1ccncc1
Product: O=C(Nc1nc2ccccc2s1)c1ccc(Cl)nc1

Procedure:
Using 2-amino-benzothiazole and 2-chloropyridine-5-carboxylic acid chloride in pyridine the title compound was obtained as a white solid (97% yield), MS: m/e=290.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:22][CH3:23])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])=[CH:8][C:7]=2[CH:21]=1.C(N(CC)CC)C.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([O:44][CH3:45])[C:41]=1[O:42][CH3:43])[C:36](Cl)=[O:37]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([O:22][CH3:23])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:36](=[O:37])[C:35]4[CH:34]=[C:33]([O:32][CH3:31])[C:41]([O:42][CH3:43])=[C:40]([O:44][CH3:45])[CH:39]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:8][C:7]=2[CH:21]=1
Reactant: COc1cc2c(cc1OC)CCCC(C(=O)N1CCNCC1)=C2
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)CCCC(C(=O)N1CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)CC1)=C2
Temperature: 0 °C
Yield: 67.1 %

Procedure:
To a mixture of 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)piperazine (1.2 g), triethylamine (0.5 g) and methylene chloride (20 ml) is added dropwise, with stirring under ice-cooling, a solution of 3,4,5-trimethoxybenzoyl chloride (1.0 g) in methylene chloride (25 ml). The reaction mixture is stirred for one hour at room temperature. The reaction mixture is pourd into ice-water (100 ml), and extracted with methylene chloride. The organic layer is washed with water, dried and concentrated under reduced pressure. The concentrate is crystallized from ethyl acetatehexane to give 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)-4-(3,4,5-trimethoxybenzoyl)piperazine (1.3 g), as obtained in Example 62, as colorless prisms, m.p. 164°-165° C.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]([C:19]4[N:24]=[CH:23][C:22]5[N:25](CC6C=CC(OC)=CC=6)[CH:26]=[N:27][C:21]=5[CH:20]=4)[CH3:18])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1>C(O)(C(F)(F)F)=O>[N:27]1[C:21]2[CH:20]=[C:19]([CH:17]([NH:16][C:12]3[N:11]=[C:10]([NH:9][C:6]4[CH:5]=[C:4]([CH:1]5[CH2:3][CH2:2]5)[NH:8][N:7]=4)[CH:15]=[CH:14][N:13]=3)[CH3:18])[N:24]=[CH:23][C:22]=2[NH:25][CH:26]=1
Reactant: COc1ccc(Cn2cnc3cc(C(C)Nc4nccc(Nc5cc(C6CC6)[nH]n5)n4)ncc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(Nc1nccc(Nc2cc(C3CC3)[nH]n2)n1)c1cc2nc[nH]c2cn1
Temperature: 70 °C
Yield: 46.1 %

Procedure:
A mixture of N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-(1-(3-(4-methoxybenzyl)-3H-imidazo[4,5-c]pyridin-6-yl)ethyl)pyrimidine-2,4-diamine (130 mg, 0.27 mmol) in TFA (3 mL) was heated at 70° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC to afford 45 mg (46%) of N2-(1-(3H-imidazo[4,5-c]pyridin-6-yl)ethyl)-N4-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>[Pd].C(O)C>[C:6]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=[C:4]([NH2:1])[CH:5]=1
Reactant: O=[N+]([O-])c1cccc(-c2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(-c2ccccc2)c1
Reaction time: 3 h

Procedure:
Palladium on carbon (10%, 0.70 g, 0.658 mmol) was added to a Parr hydrogenator bottle. The bottle was purged with nitrogen. Next, 3-nitro-1,1′-biphenyl (10 g, 50.2 mmol) and 190 mL ethanol were added to the bottle. The material was hydrogenated on a Parr hydrogenator. After 3 h, the reaction mixture was filtered through Celite® and the Celite® washed with dichloromethane. The filtrate was evaporated, obtained a brown oil, 8.69 g, assume quantitative yield (8.49 g).
Reaction SMILES: Br[CH:2]([F:16])[CH2:3][CH:4]([N+:13]([O-:15])=[O:14])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[OH:17][C:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.C1(C)C=CC=CC=1>[OH:17][C:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=2)[CH2:23][CH2:22][N:21]([CH:2]([F:16])[CH2:3][CH:4]([N+:13]([O-:15])=[O:14])[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:20][CH2:19]1
Reactant: O=C(c1ccccc1)C(CC(F)Br)[N+](=O)[O-]
Reactant: OC1(c2cccc(C(F)(F)F)c2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(c1ccccc1)C(CC(F)N1CCC(O)(c2cccc(C(F)(F)F)c2)CC1)[N+](=O)[O-]
Yield: 48.6 %

Procedure:
A mixture of 9.4 g of γ-bromo-4-fluoro-2-nitrobutyrophenone, 7.1 g of 4-hydroxy-4-(3-trifluoromethylphenyl)piperidine, 4.0 of potassium carbonate, a catalytic amount of potassium iodide and 60 ml of toluene was stirred at room temperature for 10 hours. The resulting mixture was diluted with water and extracted with toluene-ethyl acetate (1:1), and the organic layer was extracted with cold 30% hydrochloric acid. The hydrochloric acid layer was washed with toluene, made alkaline with 20% aqueous sodium hydroxide solution under cooling and extracted with ethyl acetate. The extracts were washed with water, dried over anhydrous sodium sulfate and concentrated to yield 6.4 g of γ-[4-hydroxy-4-(3-trifluoromethylphenyl)piperidino]-4-fluoro-2-nitrobutyrophenone as a residual oil, which was converted into its hydrochloride by a conventional manner. M.P. 200°-209° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:25]2[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]2=[O:35])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([C:13]([O:15]N2C3C=CC=CC=3N=N2)=O)[N:10]=[CH:9]1.[CH3:36][NH:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1>CN(C=O)C.C(=O)(O)[O-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]([N:25]2[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]2=[O:35])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([C:13]([N:37]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[CH3:36])=[O:15])[N:10]=[CH:9]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(-n3cnc(C(=O)On4nnc5ccccc54)c3)c(F)c2)C(=O)O1
Reactant: CNCc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2ccc(-n3cnc(C(=O)N(C)Cc4ccccn4)c3)c(F)c2)C(=O)O1
Yield: 22 %

Procedure:
N-[(5S)-3-(3-fluoro-4-(4-(1-benzotriazolyloxy)carbonylimidazol-1-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide (prepared as detailed for Exarnples 49-80; 243 mg, 0.5 mM) dissolved in DMF (4 ml) was treated with 2-(N-methylaminomethyl)pyridine (68 mg, 0.55mM). The mixture was stirred under nitrogen, and heated to 55° for 18 hours. After cooling, the mixture was diluted with saturated sodium bicarbonate solution (20 ml), extracted with ethyl acetate (2×10 ml), the extract washed with water and dried over magnesium sulfate. After evaporation the residue was dissolved in dichloromethane and the solution chromatographed on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 20% methanol in dichloromethane. Relevant fractions were combined and evaporated to give title product (52 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[O:10][C:11]3[C:16]([C:17](=O)[CH:18]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:8])=[CH:5][CH:4]=1.[C:22]1([S:28]([N:31]=C=O)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[O:10][C:11]3[C:16]([C:17](=[N:31][S:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)(=[O:30])=[O:29])[CH:18]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:8])=[CH:5][CH:4]=1
Reactant: O=C=NS(=O)(=O)c1ccccc1
Reactant: COc1ccc(C(=O)c2cc(=O)c3ccccc3o2)cc1
Solvent: CC#N
Product: COc1ccc(C(=O)c2cc(=NS(=O)(=O)c3ccccc3)c3ccccc3o2)cc1

Procedure:
Combine 2-(4-methoxybenzoyl)-chromone (1 mmol) and benzenesulfonyl isocyanate (1.2 mmol) in acetonitrile (7.0 mL). Heat at reflux for 48 hours. Add methanol (5 mL) to quench the reaction. Evaporate in vacuo. Recrystallize to give the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:17]3[CH2:22][CH2:21][C:20]([OH:29])([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[ClH:30]>>[ClH:30].[CH2:9]1[C:10]2[C:15](=[CH:14][C:13]([N:17]3[CH2:18][CH2:19][C:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)([OH:29])[CH2:21][CH2:22]3)=[CH:12][CH:11]=2)[CH2:16][NH:8]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(N3CCC(O)(c4ccccc4)CC3)cc2C1
Agent: Cl
Product: OC1(c2ccccc2)CCN(c2ccc3c(c2)CNC3)CC1

Procedure:
Prepared in analogy to Example A3(e) from 5-(4-hydroxy-4-phenyl-piperidin-1-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and hydrochloric acid. Off-white solid. MS (m/e): 295.4 ([M+H]+, 100%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[CH2:8](Br)[CH:9]([CH3:11])[CH3:10].[OH-].[K+]>CO>[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][CH:9]([CH3:11])[CH3:10])=[N:5][N:6]=1
Reactant: CC(C)CBr
Reactant: Nc1nnc(S)s1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CSc1nnc(N)s1
Yield: 38.7 %

Procedure:
2-Amino-5-mercapto-1,3,4-thiadiazole (2.0 g), isobutyl bromide (2.1 g), and potassium hydroxide (0.8 g) were stirred in methanol (50 ml) overnight at room temperature. The reaction mixture was concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 1.1 g of the aimed compound.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:36]2([CH3:37])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:38])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:31])([CH3:30])[CH3:29])[CH3:22])[CH2:12][C@@H:11]([OH:39])[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@@H:9]1[C@@:36]2([CH3:37])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:38])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:31])([CH3:30])[CH3:29])[CH3:22])[CH2:12][C@@H:11]([OH:39])[CH2:10]1
Reactant: C[C@H](SCCCCC(C)(C)O)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H](SCCCCC(C)(C)O)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 61.5 %

Procedure:
Under the same conditions as in Example 9, the crude 1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-(5-hydroxy-5-methylhexylthio)pregna-5,7,16-triene (73.2 mg) obtained in Example 5, tetrahydrofuran (2 ml) and 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) were reacted and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, dichloromethane:ethanol=7:1, developed once) to give the title compound as a pale yellow oil (36.1 mg, 55%, 2 steps).
Reaction SMILES: [NH:1]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:2][C:3]([OH:5])=O.C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[CH2:46]([O:50][C:51]([N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1)=[O:52])[CH2:47][CH2:48][CH3:49].C([O-])(O)=O.[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH2:46]([O:50][C:51]([N:53]1[CH2:58][CH2:57][N:56]([C:3](=[O:5])[CH2:2][NH:1][C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:55][CH2:54]1)=[O:52])[CH2:47][CH2:48][CH3:49]
Reactant: CCCCOC(=O)N1CCNCC1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)CNC(=O)OCc2ccccc2)CC1
Reaction time: 12 h

Procedure:
To a solution of 5.62 g Z-Gly-OH (Benzyloxycarbonylamino-acetic acid) in 100 ml DMF were added 13.7 ml N-ethylmorpholine, 8.8 g TOTU and 5.0 g Piperazine-1-carboxylic acid butyl ester. After stirring for 12 h, aqueous NaHCO3 was added and the reaction mixture was diluted with ethyl acetate and washed with aqueous LiCl (4%) and 0.1 M HCl. The crude product obtained after evaporation of the solvent was purified by flash chromatography on silica using an ethyl acetate/heptane gradient. Yield: 6.34 g