Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:6]([F:15])=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2.N1C=CC=CC=1.[Br:23]Br>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:6]([F:15])=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([Br:23])=[CH:8]2
Reactant: COC(=O)Cc1ccc2ncccc2c1F
Reactant: BrBr
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)Cc1ccc2ncc(Br)cc2c1F

Procedure:
To a solution of (5-fluoro-quinolin-6-yl)-acetic acid methyl ester (2.0 g, 9 mmol) in CCl4 (20 ml) and pyridine (1.48 ml, 18 mmol) was added bromine (0.9 ml, 18 mmol) dropwise at 5° C. The solution was heated to reflux for 20 minutes. After cooling, the reaction was quenched by sat. aq. NaHCO3 and the mixture extracted with dichloromethane and concentrated. The residue was purified by flash column chromatography to return the title compound (1.8 g, 66%). 1H-NMR (CDCl3, 300 MHz): 8.9 (d, 1H), 8.5 (d, 1H), 7.8 (d, 1H), 7.6 (m, 1H), 3.9 (d, 2H), 3.7 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([OH:11])=[O:10])[S:5][C:6]=1[CH2:7][CH3:8].S(=O)(=O)(O)O.O.[CH3:18]O>>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:18])=[O:10])[S:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1sc(C(=O)O)cc1Br
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCc1sc(C(=O)OC)cc1Br
Temperature: 50 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
To a solution of 4-bromo-5-ethyl-2-thiophenecarboxylic acid (1 g, 4.25 mmol) in methanol (21.27 ml) was added sulfuric acid (0.23 mL, 4.25 mmol). The resulting solution was stirred at 50° C. for 48 h. H2O (50 mL) was added and the reaction was cooled to 0° C. in an ice-bath. The pH was adjusted to 12 and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and used directly without further purification providing methyl 4-bromo-5-ethyl-2-thiophenecarboxylate (1.060 g, 4.25 mmol, 100% yield): LCMS (ES) m/e 248, 250 (M, M+2)+.
Reaction SMILES: [C:1]([O-])(C)(C)C.[K+].CI.[CH2:9]([O:11][C:12](=[S:18])[CH2:13][C:14]([CH2:16][CH3:17])=[O:15])[CH3:10]>O1CCCC1>[CH2:9]([O:11][C:12](=[S:18])[CH:13]([CH3:1])[C:14]([CH2:16][CH3:17])=[O:15])[CH3:10]
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=S)CC(=O)CC
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=S)C(C)C(=O)CC
Temperature: 60 °C
Reaction time: 12 h
Yield: 80.3 %

Procedure:
First 12.3 g (0.11 mol) of potassium tert.-butanolate and then 15.6 g (0.11 mol) of methyl iodide were added to a solution of 17.6 g (0.1 mol) of 4-methylthioacetoacetic acid ethyl ester in 100 ml of tetrahydrofuran, while cooling. The mixture was subsequently stirred at 60° C. for 12 hours, the solvent was then distilled off in vacuo, 200 ml of methylene chloride were added to the residue and the solution was extracted by shaking twice with 100 ml of water each time. The organic phase was dried over sodium sulphate and evaporated in vacuo. The residue was distilled in vacuo. 14 g (74% of theory) of 2-methyl-4-methylthioacetoacetic acid ethyl ester with a boiling point of 95°-99° C./2 mm Hg were thus obtained. ##STR6##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Cl[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[O:12])[CH:7]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: O=C(CCl)c1ccc(F)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(Cn1cc(Cl)cnc1=O)c1ccc(F)cc1
Yield: 7.6 %

Procedure:
A solution of 5-chloropyrimidin-2-one (1.309 g) and 2-chloro-4'-fluoroacetophenone (1.726 g) in triethylamine (2 ml) and ethanol (50 ml) was stirred and heated at reflux for 11/2 hours. After evaporation of solvents, the residue was triturated with water (100 ml). The resulting collected solid was crystallised from ethanol then acetone, but still required purification, by preparative thin-layer chromatography on silica developed in chloroform-ethanol (25:1 v/v), before crystallisation from propan-2-ol to give the title pyrimidinone (204 mg,); 196°-202°; λmaxEtOH 245 nm (ε 17780), 333 nm (ε 2090), λinf 236 nm (ε 15230), 280 nm (ε 980).
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C@H:11]([C:22]([N:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26]([OH:28])=[O:27])=[O:23])[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1.[NH:32]([C:54]([O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:55])[C@H:33]([C:44](ON1C(=O)CCC1=O)=[O:45])[CH2:34][C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[NH:37][CH:36]=1.CC(S[As](C)C)([C@@H](N)C(O)=O)C.OS([O-])(=O)=O.[K+]>C(OCC)(=O)C.CC(N(C)C)=O>[NH:32]([C:54]([O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:55])[C@H:33]([C:44]([NH:10][C@H:11]([C:22]([N:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26]([OH:28])=[O:27])=[O:23])[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)=[O:45])[CH2:34][C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[NH:37][CH:36]=1
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)ON1C(=O)CCC1=O)OCc1ccccc1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC[C@H]1C(=O)O
Agent: C[As](C)SC(C)(C)[C@@H](N)C(=O)O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC[C@H]1C(=O)O)OCc1ccccc1
Temperature: 5 °C

Procedure:
DMA, 1.05 equivalents of DIPEA (Mw=129.2) and 1.05 equivalents of H-Trp-Pro-OH (Mw=301.3; purity=91.0%) were mixed at room temperature for at least 30 min until a solution had formed. The reaction mixture was then diluted with ethyl acetate and cooled to 5±5° C. Once this temperature was reached, 1.00 equivalent of Z-Trp-OSu (Mw=435.45; purity=98.0%) was added and stirring continued for at least 30 min before the solution was left to warm up to room temperature again. After the completion of the reaction was confirmed by HPLC, 0.2 eq of, DMAPA (N,N′-Dimethylaminopropylamine, Mw=102.2 g/mol) were added. The reaction mixture was diluted with ethyl acetate and washed with a 5% (weight) aqueous NaCl solution containing 2 equivalents of KHSO4. The organic phase was further washed first with a 5% (weight) aqueous NaCl solution and finally with water. The organic phase was partially concentrated in vacuo and the residue was suspended in ethyl acetate and further concentrated in order to eliminate the remaining water. The concentrated peptide solution was added in small portions to a cold (0±5° C.) mixture of MTBE/petroleum ether (45-55) (1/1) and the precipitate was kept at 0±5° C. for at least 30 min before filtration. After filtration, it was then washed with petroleum ether (45-55) and dried in vacuo at 45° C. A white solid was finally obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]C(=O)C(C)(C)C)=[C:5]([CH3:16])[C:4]=1[C:17]([F:20])([F:19])[F:18].[OH-].[K+].[OH-].[Na+]>C(O)CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([CH3:16])[C:4]=1[C:17]([F:18])([F:20])[F:19]
Reactant: COc1ccc(NC(=O)C(C)(C)C)c(C)c1C(F)(F)F
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Product: COc1ccc(N)c(C)c1C(F)(F)F
Reaction time: 20 h
Yield: 49.2 %

Procedure:
N-[4-methoxy-2-methyl-3-(trifluoromethyl)phenyl]-2,2-dimethylpropanamide (3.15 g, 10.9 mmol) and potassium hydroxide (3.20 g, 57.1 mmol) were slowly heated to 160° C. in ethylene glycol (31.0 ml) and stirred for 20 hours while maintaining the temperature. The reaction solution was portioned and extracted with water and chloroform, and the organic phase was extracted with a 1N aqueous hydrochloric acid solution to obtain an aqueous phase. This aqueous phase was made basic with a 2N aqueous sodium hydroxide solution and extracted three times with chloroform. The combined organic phase was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain 4-methoxy-2-methyl-3-(trifluoromethyl)-aniline (1.10 g, 49%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:11][C:12]2[N:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][N:13]=2)[CH:7]=[CH:8][C:9]=1[CH3:10])[CH3:2].C1COCC1.O.[Cl-].[NH4+]>[Fe].O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:11][C:12]2[N:17]=[CH:16][C:15]([NH2:18])=[CH:14][N:13]=2)[CH:7]=[CH:8][C:9]=1[CH3:10])[CH3:2]
Reactant: CCOc1cc(Oc2ncc([N+](=O)[O-])cn2)ccc1C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(Oc2ncc(N)cn2)ccc1C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
Fe powder (89 mg, 1.598 mmol) was added to a solution of 2-{[3-(ethyloxy)-4-methylphenyl]oxy}-5-nitropyrimidine (Intermediate 91, 110 mg) in a mixture THF/water (9 mL/3 mL) followed by ammonium chloride (86 mg, 1.598 mmol). The reaction mixture was stirred overnight under nitrogen. The reaction mixture was poured into water and the iron was filtrated. Ethyl acetate was used to wash the solid filtrated. The filtrate was extracted with ethyl acetate (3 times). The combined ethyl acetate layers were dried over sodium sulphate and concentrated to give the title compound (94 mg) which was directly used in the next step.
Reaction SMILES: [CH:1]([O:3][CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[NH:7][C:6]([CH3:13])([CH3:12])[CH2:5]1)=[CH2:2].[C:14](OC(=O)C)(=[O:16])[CH3:15]>N1C=CC=CC=1>[CH:1]([O:3][CH:4]1[CH2:5][C:6]([CH3:13])([CH3:12])[N:7]([C:14](=[O:16])[CH3:15])[C:8]([CH3:11])([CH3:10])[CH2:9]1)=[CH2:2]
Reactant: CC(=O)OC(C)=O
Reactant: C=COC1CC(C)(C)NC(C)(C)C1
Solvent: c1ccncc1
Product: C=COC1CC(C)(C)N(C(C)=O)C(C)(C)C1

Procedure:
40 g of 2,2,6,6-tetramethyl-4-piperidyl vinyl ether were dissolved in 270 ml of dry pyridine and 200 ml of acetic anhydride were added. The mixture was warmed slowly and finally was refluxed for 36 hours. The volatile constituents were evaporated off under a water pump vacuum on a boiling water bath and the residue was distilled under a high vacuum. Boiling point 88°/0.1 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][NH:6][C:7]([C:9]1[S:13][C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]2=[O:20])=[N:11][C:10]=1[CH3:21])=[O:8].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][NH:6][C:7]([C:9]1[S:13][C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:31][CH:32]=3)[C:15]2=[O:20])=[N:11][C:10]=1[CH3:21])=[O:8]
Reactant: Cc1nc(N2CCCCC2=O)sc1C(=O)NCc1cccc(F)c1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Product: Cc1nc(N2CCCC(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)NCc1cccc(F)c1
Yield: 41 %

Procedure:
Following the procedure as described in Example 2, making variation as required to use N-(3-fluorobenzyl)-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide in place of N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide to react with 1-(bromomethyl)-4-(trifluoromethyl)benzene, the title compound was obtained as a white solid in 41% yield: mp 177-178° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.52 (d, J=8.1 Hz, 2H), 7.30-7.27 (m, 3H), 7.10-6.92 (m, 3H), 6.11 (t, J=5.6 Hz, 1H), 4.56 (d, J=5.6 Hz, 2H), 4.33-4.21 (m, 1H), 4.00-3.88 (m, 1H), 3.53-3.56 (m, 1H), 2.94-2.73 (m, 2H), 2.62 (s, 3H), 2.11-1.95 (m, 1H), 1.94-1.75 (m, 2H), 1.62-1.43 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 171.7, 162.9, 162.7, 156.9, 152.4, 143.2, 140.6, 130.3, 129.6, 128.9, 125.9, 125.5, 125.4, 123.3, 122.4, 119.3, 114.7, 114.5, 48.0, 43.9, 43.3, 37.3, 24.9, 21.3, 17.4; MS (ES+) m/z 506.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=1.P([O-])([O-])(O)=O.[Na+].[Na+].[Br:17]Br>O>[CH3:1][O:2][C:3]1[N:4]=[C:5]([CH3:9])[C:6]([Br:17])=[CH:7][CH:8]=1
Reactant: BrBr
Reactant: COc1cccc(C)n1
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: O
Product: COc1ccc(Br)c(C)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.2 %

Procedure:
A mixture of 2-methoxy-6-methylpyridine (17.0 g, 138 mmol) and a solution of disodium hydrogen phosphate (0.15M in water, 250 mL) was stirred at room temperature. Bromine (7.1 mL, 138 mmol) was added dropwise over 15 min via an addition funnel. The reaction mixture was then stirred at room temperature for 4 h. The clear colorless solution was diluted with water (500 mL) and extracted with dichloromethane (200 mL) three times. The combined organic layers were dried over MgSO4, filtered and solvent was removed in vacuo from the filtrate to give a yellow liquid. Flash chromatography on silica gel (EtOAc:hexane:1:20) and removal of solvent from the desired combined fractions afforded a clear colorless liquid (15.4 g): 1H-NMR (CDCl3, 300 MHz): δ 7.60 (d, 1H, J=8), 6.46 (d, 1H, J=8), 3.89 (s, 3H), 2.54 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:11]2[C:6](=[C:7]([CH3:16])[CH:8]=[C:9]([C:13](O)=[O:14])[C:10]=2[CH3:12])[S:5](=[O:18])(=[O:17])[CH2:4][CH2:3]1.S1C2C(=CC=CC=2)CCC1C(O)=O.[CH2:33]([N:35]1[C:39]([OH:40])=[CH:38][CH:37]=[N:36]1)[CH3:34].OC1NN=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)(CC)(C)C>[CH3:1][C:2]1([CH3:19])[C:11]2[C:6](=[C:7]([CH3:16])[CH:8]=[C:9]([C:13]([C:38]3[CH:37]=[N:36][N:35]([CH2:33][CH3:34])[C:39]=3[OH:40])=[O:14])[C:10]=2[CH3:12])[S:5](=[O:17])(=[O:18])[CH2:4][CH2:3]1
Reactant: Cc1cc(C(=O)O)c(C)c2c1S(=O)(=O)CCC2(C)C
Reactant: CCn1nccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)C1CCc2ccccc2S1
Agent: O=C([O-])[O-]
Solvent: CCC(C)(C)O
Product: CCn1ncc(C(=O)c2cc(C)c3c(c2C)C(C)(C)CCS3(=O)=O)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
7.4 Grams (0.026 mol) of 4,4,5,8-tetramethylthiochroman-6-carboxylic acid-1,1-dioxide corresponding to thiochroman carboxylic acid (IIIc), 3.4 g (0.03 mol) of 1-ethyl-5-hydroxypyrazole corresponding to 5-hydroxypyrazole (II) and 6.22 g (0.03 mol) of DCC (N,N'-dicyclohexylcarbodiimide) were all together added to 50 ml of tert-amyl alcohol, and the mixture was stirred at room temperature for 30 minutes. Then, 1.8 g (0.013 mol) of anhydrous potassium carbonate was added. The reaction mixture was allowed to react at 80° C. for 8 hours, and the reaction solvent was distilled off under reduced pressure. The resultant residue was dispersed in a 5% potassium carbonate aqueous solution and ethyl acetate to separate it into two layers. Further, the aqueous layer was adjusted to a pH of 1 with 5% hydrochloric acid, and the formed solid was recovered by filtration to give 6.13 g (yield 62%) of 4,4,5,8-tetramethyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide (Compound Ic-1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:28])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C:10](=[O:21])[C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:8]2)=[O:4].[Br:29]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:28])=[C:7]2[C:12](=[C:13]([Br:29])[N:14]=1)[N:11]([CH2:15][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1)[C:10](=[O:21])[C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CC2CCCC2)c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2CC2CCCC2)c1O
Yield: 71.2 %

Procedure:
A mixture of 1-cyclopentylmethyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (147 mg, 0.39 mmol) and N-bromosuccinimide (76 mg, 0.43 mmol) in CH2Cl2 (1.5 mL) was refluxed for 3 h. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (5-15% EtOAc/hexanes+1% AcOH) to give 127 mg of the title compound as a yellow solid. MS: (−) m/z 455.21, 457.17 (M-1, 79/81Br).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:19]2[C:18](=[O:24])[CH2:17][C@@:16]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:15])[CH:13]=[CH2:14])[CH2:3]1>[Pd].C(OCC)(=O)C>[OH:1][C@@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:19]2[C:18](=[O:24])[CH2:17][C@@:16]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:15])[CH2:13][CH3:14])[CH2:3]1
Reactant: C=CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Yield: 93.6 %

Procedure:
3α-Hydroxy-21-methylene-5α-pregnane-11,20-dione(850 mg) was hydrogenated over 10% palladium on carbon catalyst (80 mg) in ethyl acetate for 1 hour. The catalyst was filtered off and the solvent removed in vacuo to give title compound (800 mg) as a white solid identical with the material of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=2[O:16][CH2:17][C@@H:18]2[NH:22][CH2:21][C@H:20]([OH:23])[CH2:19]2)[N:9]=[CH:8][N:7]=1.[C:30](O)(=[O:33])[CH2:31][OH:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=2[O:16][CH2:17][C@@H:18]2[N:22]([C:31](=[O:32])[CH2:30][OH:33])[CH2:21][C@H:20]([OH:23])[CH2:19]2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc(OC[C@H]2C[C@@H](O)CN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Reactant: O=C(O)CO
Product: COc1cc(OC[C@H]2C[C@@H](O)CN2C(=O)CO)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Yield: 46 %

Procedure:
The procedure described in Example 20 was repeated using (3R,5R)-5-[({4-[3-chloro-4-fluoroanilino]-7-methoxyquinazolin-5-yl}oxy)methyl]pyrrolidin-3-ol (209 mg) with glycolic acid (42 mg) to give the title compound as a white solid in 46% yield; NMR spectrum (DMSO-d6) 10.01 (s, 1H), 8.48 (s, 1H), 8.22 (dd, 1H), 7.74-7.69 (m, 1H), 7.43 (t, 1H), 6.84 (d, 1H), 6.78 (d, 1H), 5.29-5.28 (m, 1H), 4.73-4.68 (m, 1H), 4.64-4.59 (m, 2H), 4.44-4.42 (m, 1H), 4.34-4.31 (m, 1H), 4.06-4.05 (m, 2H), 3.93 (s, 3H), 3.64 (dd, 1H), 3.45 (s, 1H), 2.25-2.12 (m, 1H), 1.99-1.95 (m, 1M); Mass spectrum MH+ 477.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][C:5](=[O:18])[N:6]([CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[C:7]=1[CH3:8].[C:20]([O:24][C:25](=[O:36])[NH:26][C@H:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:28]O)([CH3:23])([CH3:22])[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:20]([O:24][C:25](=[O:36])[NH:26][C@H:27]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:28][N:4]1[C:3](=[O:19])[C:2]([Br:1])=[C:7]([CH3:8])[N:6]([CH2:9][C:10]2[C:11]([F:17])=[CH:12][CH:13]=[CH:14][C:15]=2[F:16])[C:5]1=[O:18])([CH3:21])([CH3:22])[CH3:23]
Reactant: Cc1c(Br)c(=O)[nH]c(=O)n1Cc1c(F)cccc1F
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(Br)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1F
Yield: 49 %

Procedure:
5-Bromo-1-(2,6-difluoro-benzyl)-6-methyl-1H-pyrimidine-2,4-dione (synthesized according to the method of BMCL 2004 14(19) 4967-4973) (2.77 g, 8.37 mmol), ((R)-2-hydroxy-1-phenyl-ethyl)-carbamic acid tert-butyl ester (2.08 g, 8.78 mmol), and triphenylphosphine (3.29 g, 12.5 mmol) were added to anhydrous tetrahydrofuran (70 mL) and stirred for a short time. To this solution was slowly added diethylazodicarboxylate (1.95 mL, 12.5 mmol), followed by stirring at room temperature for 12 hrs in a nitrogen atmosphere. Following concentration, the residue was purified using silica gel chromatography (eluent: hexane/ethyl acetate, 2/1) and dried in a vacuum to afford 2.26 g of the compound as a white foam (yield 49%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:38]=[CH:37][CH:36]=[CH:35][C:5]=1[C:6]([C:8]1[CH:12]=[C:11]([CH2:13][CH3:14])[S:10][C:9]=1[N:15]1[C:19]([CH3:20])=[N:18][N:17]=[C:16]1[CH2:21][NH:22][C:23]([C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[C:28]([O:30]C)=[O:29])=[O:24])=[O:7]>CO>[Cl:3][C:4]1[CH:38]=[CH:37][CH:36]=[CH:35][C:5]=1[C:6]([C:8]1[CH:12]=[C:11]([CH2:13][CH3:14])[S:10][C:9]=1[N:15]1[C:19]([CH3:20])=[N:18][N:17]=[C:16]1[CH2:21][NH:22][C:23]([C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[C:28]([OH:30])=[O:29])=[O:24])=[O:7]
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)c2cccc(C(=O)OC)c2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)c2cccc(C(=O)O)c2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
Methanol (13 ml) and a 2M sodium hydroxide aqueous solution (2.5 ml) were added to methyl 3-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethylcarbamoyl)benzoate (1.3 g), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated, and the residue was partitioned between water and ethyl acetate. The aqueous layer was taken out, and citric acid was added to adjust the aqueous solution to pH 3. The solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from a mixed solvent of ethyl acetate and diisopropyl ether to give 1.05 g of 3-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethylcarbamoyl)benzoic acid.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].[F:14][C:15]1[CH:16]=[C:17]([N:29]2[CH2:33][C@H:32]([CH2:34][NH:35][C:36](=[O:38])[CH3:37])[O:31][C:30]2=[O:39])[CH:18]=[C:19]([F:28])[C:20]=1[CH:21]1[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]1.CN1CCOCC1>ClCCl>[O:27]=[S:24]1(=[O:4])[CH:25]=[CH:26][CH:21]([C:20]2[C:19]([F:28])=[CH:18][C:17]([N:29]3[CH2:33][C@H:32]([CH2:34][NH:35][C:36](=[O:38])[CH3:37])[O:31][C:30]3=[O:39])=[CH:16][C:15]=2[F:14])[CH2:22][CH2:23]1
Reactant: CC(=O)NC[C@H]1CN(c2cc(F)c(C3CCS(=O)CC3)c(F)c2)C(=O)O1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2cc(F)c(C3C=CS(=O)(=O)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
Trifluoroacetic anhydride (2.24 ml, 15.8 mmol) was added dropwise at room temperature to a solution of N-[[(5S)-3-[3,5-difluoro-4-(tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (2.04 g, 5.28 mmol and N-methylmorpholine (2.90 ml, 26.4 mmol) in dichloromethane (50 ml). The reaction mixture was stirred overnight at room temperature and then evaporated to dryness. The resulting crude N-({(5S)-3-[4-(3,4-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (1.95 g) was dissolved in tetrahydrofuran (100 ml) and peracetic acid (5.6 ml of a 32% solution in acetic acid, 26.4 mmol) added dropwise at 0° C. The reaction mixture was allowed to warm to room temperature, stirred overnight, and then evaporated to dryness. The residue was purified by flash column chromatography (ethyl acetate) to give white solid (1.80 g, 85%)
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])=[N:9][CH:10]=1)=[N+]=[N-].C(OCC)(=O)C.C(O)C.[H][H]>[C].[Pd].ClCCl>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[C:8]2[N:9]=[CH:10][C:5]([CH2:4][NH2:1])=[CH:6][CH:7]=2)(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: [H][H]
Reactant: [N-]=[N+]=NCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Yield: 38.7 %

Procedure:
Under an argon atmosphere, 5-azidomethyl-2-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridine (77 mg, 0.177 mmol), palladium carbon (14 mg), and ethyl acetate (2 ml) were added to ethanol (10 ml). The resulting mixture was stirred for 50 minutes in a hydrogen atmosphere of 1 atmospheric pressure. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography. A fraction obtained from the dichloromethane:methanol=10:1 eluate was concentrated under reduced pressure to give the title compound (28 mg, 0.0685 mmol, 39%) as a white powder.