Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:52])[CH:4]([NH:18][C:19](=[O:51])[CH2:20][NH:21][C:22](=[O:50])[C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:24]=1[NH:30][C:31]1([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([Cl:49])[CH:44]=2)[C:39]2[C:34](=[CH:35][C:36]([Cl:40])=[CH:37][CH:38]=2)[NH:33][C:32]1=[O:41])[CH2:5][CH2:6][CH2:7][CH:8](N)[NH:9]C(OC(C)(C)C)=O>C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3](=[O:52])[CH:4]([NH:18][C:19](=[O:51])[CH2:20][NH:21][C:22](=[O:50])[C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:24]=1[NH:30][C:31]1([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([Cl:49])[CH:44]=2)[C:39]2[C:34](=[CH:35][C:36]([Cl:40])=[CH:37][CH:38]=2)[NH:33][C:32]1=[O:41])[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9]
Reactant: COC(=O)C(CCCC(N)NC(=O)OC(C)(C)C)NC(=O)CNC(=O)c1ccc(Br)cc1NC1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(CCCCN)NC(=O)CNC(=O)c1ccc(Br)cc1NC1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21

Procedure:
The rac-(S)-6-Amino-2-(2-{4-bromo-2-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoylamino}-acetylamino)-6-tert-butoxycarbonylamino-hexanoic acid methyl ester (200 mg, 0.25 mmol) in 5 mL of TFA was stirred at room temperature for 0.5 hour, and concentrated in vacuo. The residue was added by 10 mL of DCM, then rinsed with 20 mL of water. The organic layer was dried over Na2SO4, and concentrated in vacuo, then purified by flash column chromatopgraphy to 146 mg white solid. MS: 704 (M+H)+.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]([F:18])([F:17])[CH2:8][CH2:9][CH2:10][S:11][C:12]1[S:13][CH:14]=[CH:15][N:16]=1.CC(N(C)C)=O.O>C(Cl)(Cl)Cl>[Cl:4][C:14]1[S:13][C:12]([S:11][CH2:10][CH2:9][CH2:8][C:7]([Cl:6])([F:17])[F:18])=[N:16][CH:15]=1
Reactant: FC(F)(Cl)CCCSc1nccs1
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: ClC(Cl)Cl
Product: FC(F)(Cl)CCCSc1ncc(Cl)s1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
A solution of sulfuryl chloride (2.94 g) and chloroform (10 ml) was added dropwise over a period of one hour to a stirred mixture of 2-(4-chloro-4,4-difluorobutylthio)thiazole (4.85 g), and dimethylacetamide (47 g) maintained at 45° C. under a nitrogen atmosphere and the resultant mixture stirred for a further one hour. A further aliquot of sulfuryl chloride (0.58 g) dissolved in chloroform (5.0 ml) was then added over 45 minutes and the mixture stirred for a further 30 minutes. After cooling the reaction mixture to the ambient temperature water (50 ml) was added and the mixture extracted with hexane (3×50 ml). The hexane solution was washed with water (50 ml), saturated aqueous sodium bicarbonate solution (50 ml) and water (50 ml) and then dried over anhydrous magnesium sulfate. Removal of the solvent by evaporation under reduced pressure yielded of 5-chloro-2-(4-chloro-4,4-difluorobutylthio)thiazole (5.0 g, 87%).
Reaction SMILES: Br.[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=3)=[CH:16][C:15](=[O:26])[C:11]([C:12]([OH:14])=[O:13])=[CH:10]2)=[CH:5][CH:4]=1.[OH-].[Na+]>O>[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)=[CH:16][C:15](=[O:26])[C:11]([C:12]([OH:14])=[O:13])=[CH:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(=O)c(C(=O)O)cn2-c2ccc(F)cc2)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cn(-c2ccc(F)cc2)c(-c2ccc(O)cc2)cc1=O
Temperature: 25 °C
Yield: 78.2 %

Procedure:
In 7 ml of 47% by weight hydrobromic acid was suspended 0.2 g of 1-(4-fluorophenyl)-6-(4-methoxyphenyl)-4-oxo-1,4-dihydronicotinic acid was suspended, and the suspension was refluxed for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with 10 ml of water, adjusted to a pH of 12 with a 20% by weight aqueous sodium hydroxide solution, and washed with 20 ml of chloroform. This aqueous solution was then adjusted to a pH of 6.0 with acetic acid and the precipitated crystals were collected by filtration, and washed with water to obtain 0.15 g of 1-(4-fluorophenyl)-6-(4-hydroxyphenyl)-4-oxo-1,4-dihydronicotinic acid having a melting point of 185°-193° C.
Reaction SMILES: [C:1]1([C:7]2[C:8]([N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)=[C:9]3[CH:15]=[N:14][NH:13][C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[I:31]I>CN(C=O)C.CCOC(C)=O>[I:31][C:15]1[C:9]2[C:10](=[N:11][CH:12]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]=2[N:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]2)[NH:13][N:14]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]ncc23)CC1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]nc(I)c23)CC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 79.7 %

Procedure:
A mixture of tert-butyl 4-(5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (3 g, 7.75 mmol) and powdered potassium hydroxide (1.28 g, 19.4 mmol) in DMF (20 mL) was treated with iodine (3.93 g, 15.5 mmol), and the mixture was heated at 60° C. After 4 hours, the mixture was cooled to room temperature and treated with powdered KOH (700 mg, 10.7 mmol) and I2 (1.97 g, 7.75 mmol). The mixture was stirred at 60° C. for 1 hour. The mixture was cooled to room temperature, diluted with EtOAc (200 mL) and successively washed with saturated Na2S2O3 solution (2×20 mL) and water (2×50 mL). The organic layer was separated, dried (MgSO4), filtered, and concentrated in vacuo. The residue obtained was crystallized from boiling CH3CN to provide tert-butyl 4-(3-iodo-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (3.12 g, 79.7% yield) as a solid. LCMS (APCI+) m/z 506 (M+H)+, Retention time=4.04 minutes.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:22][CH2:21][C:9]2[N:10]3[C:19]4[C:18]([C:8]=2[CH2:7]1)=[CH:17][CH:16]=[CH:15][C:14]=4[NH:13][C:12](=[O:20])[CH2:11]3)=[O:5])[CH3:2].C1NC2C(=CC=CC=2)NC1=O.O=C1CCN(C(OCC)=O)CC1.N1C2C(=CC=CC=2)C=C1.[BH3-]C#N.[Na+].[OH-].[Na+]>C(O)(C(F)(F)F)=O.O>[O:20]=[C:12]1[CH2:11][N:10]2[C@H:9]3[CH2:21][CH2:22][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][C@H:8]3[C:18]3[C:19]2=[C:14]([CH:15]=[CH:16][CH:17]=3)[NH:13]1
Reactant: CCOC(=O)N1CCc2c(c3cccc4c3n2CC(=O)N4)C1
Agent: CCOC(=O)N1CCC(=O)CC1
Agent: O=C1CNc2ccccc2N1
Agent: [BH3-]C#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CC(=O)N3
Temperature: 0 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
The procedure described in Example 4, Steps E through G, was utilized to prepare ethyl-2-oxo-2,3,9,10-tetrahydro-1H-pyrido[3′,4′:4,5]-pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate from the corresponding amine, 1,3,4-trihydroquinoxalin-2-one, and ethyl 4-oxopiperidinecarboxylate. This indole (5.74 g, 19.2 mmol) was dissolved in TFA (100 mL). The reaction was cooled to 0° C. NaCNBH3 (3.96 g, 63.0 mmol) was added in small portions over 30 min, keeping the temperature less than 5° C. The reaction was stirred at r.t. for 4 hr. Ice was added to the reaction flask, and the reaction was basified with 50% NaOH until pH=12. Water (80 mL) was added to dissolve the precipitate. The reaction was extracted with CHCl3 (3×200 mL). The combined organic layers were washed with brine, dried, and concentrated to afford ethyl (6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (4.41 g, 77%). 1H NMR (CDCl3, 300 MHz) δ 8.45 bs, 1H), 6.86 (d, J=7.4 Hz, 1H), 6.74 (dd, J=7.7 Hz, 7.7 Hz, 1H), 6.63 (d, J=7.3 Hz, 1H), 4.15 (q, J=7.0 Hz, 2H), 3.89-3.993 (m, 2H), 3.41-3.47 (m, 2H), 3.33-3.41 (m, 2H), 3.12-3.31 (m, 1H), 2.69-2.75 (m, 2H), 1.90-1.92 (m, 2H), 1.28 (t, J=7.3 Hz, 3H) ppm. MS-APcI: 302 [MH]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([S:14][CH3:15])[CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N:16]1[CH:21]=[CH:20][CH:19]=[C:18](/[CH:22]=[CH:23]/[C:24](O)=[O:25])[CH:17]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([S:14][CH3:15])[CH2:12][NH:13][C:24](=[O:25])/[CH:23]=[CH:22]/[C:18]2[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(O)/C=C/c1cccnc1
Reactant: COc1ccc(C(CN)SC)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(CNC(=O)/C=C/c2cccnc2)SC)cc1OC
Reaction time: 0.17 h
Yield: 52.3 %

Procedure:
To a solution of the crude oily 2-(3,4-dimethoxy-phenyl) -2-(methylthio)ethylamine (0.96 g) and trans-3-(3-pyridyl) acrylic acid (0.63 g, 4.2 mmol) in dimethylformamide (10 ml), diethylphosphoric cyanide (0.69 ml) and triethylamine (1.17 ml) were sequentially added under ice-cooling and stirred for 10 minutes under ice-cooling. Aqueous sodium bicarbonate solution was added to the reaction mixture and extracted with ethyl acetate. The organic layers were combined, washed with water and aqueous saturated sodium chloride solution and dried over magnesium sulfate. The solvent was distilled out under reduced pressure and the residue was purified by silica gel column chromatography (hexane: chloroform:ethanol=8:2:1) to yield the titled compound (788 mg, 47%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][C@H:4](/[CH:8]=[CH:9]/[C:10](=[O:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]1[CH2:19][C:20]#[C:21][CH2:22][O:23][CH2:24][C:25]#[N:26].[H][H]>[Pd].CO>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([CH2:8][CH2:9][C:10](=[O:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]1[CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]#[N:26]
Reactant: N#CCOCC#CCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: N#CCOCCCCN1C(=O)CCC[C@@H]1CCC(=O)Cc1ccccc1
Reaction time: 19 h
Yield: 56.1 %

Procedure:
Palladium on carbon (10 wt. %, 7 mg) was added to a solution of {4-[(R)-2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-but-2-ynyloxy}-acetonitrile (35 mg, 0.10 mmol) in MeOH (3.0 mL). A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 19 h. The reaction mixture was filtered through celite, washing with MeOH, and the filtrate was concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→2% MeOH/CH2Cl2, gradient) afforded 20 mg (56%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:11]([Cl:12])=[CH:10][N:9]=[C:8]([NH:13][C@H:14]([CH2:22][N:23]=[N+]=[N-])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:7]1=[O:26])[CH3:2].Cl[Sn]Cl>CO.C1COCC1>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:11]([Cl:12])=[CH:10][N:9]=[C:8]([NH:13][C@H:14]([CH2:22][NH2:23])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:7]1=[O:26])[CH3:2]
Reactant: CCOC(=O)Cn1c(Cl)cnc(N[C@H](CN=[N+]=[N-])Cc2ccccc2)c1=O
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)Cn1c(Cl)cnc(N[C@H](CN)Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-[3-(1-azidomethyl-2-phenyl-ethylamino)-6-chloro-2-oxo-2H-pyrazin-1-yl]-acetic acid ethyl ester (5.67 g, 14.5 mmol) in MeOH (80 ml) and THF (40 ml) was added SnCl2 (4.1 g, 21.8 mmol) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo, azeotroped with CH2Cl2, and purified by flash chromatography (silica gel, 6% MeOH containing 10% NH4OH in CH2Cl2 to 10%) to give (S)-[3-(1-aminomethyl-2-pheny-ethylamino)-6-chloro-2-oxo-2H-pyrazin-1-yl]-acetic acid ethyl ester as a beige solid. 1H NMR (CDCl3, 400 MHz): δ 7.35–7.15 (m, 5H); 6.92 (s, 1H); 6.17 (bd, J=8.5 Hz, 1H); 4.88 (s, 2H));); 4.35–4.15(m, 3H); 3.00–2.70 (m, 4H); 1.32 (t, J=6.9 Hz, 3 H); rotation: [α]d=−82.6° (c=0.42, MeOH).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][C:9]1[CH:10]=[C:11]([NH:36][C:37]([C:39]2[C:40](=[O:52])[N:41]([C:45]3[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=3)[CH:42]=[CH:43][CH:44]=2)=[O:38])[CH:12]=[CH:13][C:14]=1[O:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][CH:17]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C=O>C(Cl)Cl>[F:8][C:9]1[CH:10]=[C:11]([NH:36][C:37]([C:39]2[C:40](=[O:52])[N:41]([C:45]3[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=3)[CH:42]=[CH:43][CH:44]=2)=[O:38])[CH:12]=[CH:13][C:14]=1[O:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][N:33]([CH3:2])[CH2:32][CH2:31]3)=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][CH:17]=1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: COc1cc2c(Oc3ccc(NC(=O)c4cccn(-c5ccc(F)cc5)c4=O)cc3F)ccnc2cc1OCC1CCNCC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc(NC(=O)c4cccn(-c5ccc(F)cc5)c4=O)cc3F)ccnc2cc1OCC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of N-(3-fluoro-4-(6-methoxy-7-(piperidin-4-ylmethoxy)quinolin-4-yloxy)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide TFA salt (22 mg, 0.030 mmol) and NaBH(OAc)3 (40 mg) in CH2Cl2 was added HCHO (0.1 mL of 33% solution) and the reaction mixture was stirred at rt for 6 h. Direct purification by preparative HPLC afforded the desired product as a white TFA salt solid (11 mg, 50%). 1H NMR (CDCl3) δ 12.16 (s, 1H), 8.77 (dd, 1H, J=7.7, 2.2 Hz), 8.55 (d, 1H, J=6.1 Hz), 8.08 (d, 1H, J=1.6 Hz), 8.06 (dd, 1H, J= 12.1, 1.6 Hz), 7.64-7.27 (m, 8H), 6.71 (d, 1H, J=6.6 Hz), 6.66 (t, 1H, J=6.6 Hz), 4.27 (d, 2H, J=5.5 Hz), 4.07 (s, 3H), 3.66 (d, 2H, J=12.1 Hz), 2.81 (s, 3H), 2.87-1.97 (m, 7H); MS(ESI+) m/z 627.4 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1C2C(=CC=C(C(=O)C)C=2)N[CH:5]=1.[F:16][C:17]1[C:18](I)=[C:19]([CH:21]=[C:22]([F:25])[C:23]=1[F:24])[NH2:20]>>[F:16][C:17]1[C:23]([F:24])=[C:22]([F:25])[CH:21]=[C:19]2[C:18]=1[C:4]([CH2:3][CH2:2][NH2:1])=[CH:5][NH:20]2
Reactant: CC(=O)c1ccc2[nH]cc(CCN)c2c1
Reactant: Nc1cc(F)c(F)c(F)c1I
Product: NCCc1c[nH]c2cc(F)c(F)c(F)c12

Procedure:
1-(3-(2-aminoethyl)-1H-indol-5-yl)ethanone can be prepared according to method D step II, III, IV and V starting from 3,4,5-trifluoro-2-iodoaniline.
Reaction SMILES: N[CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[O:11])=[C:6]([Cl:9])[CH2:7][S:8][C@H:3]12.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=[O:28].Cl>C(N(CC)CC)C>[O:28]=[C:2]1[C:23](=[O:24])[N:4]2[C:5]([C:10]([O:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=3)=[O:11])=[C:6]([Cl:9])[CH2:7][S:8][C@H:3]12
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)C1=C(Cl)CS[C@@H]2C(=O)C(=O)N12

Procedure:
4-Nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate, trifluoromethanesulfonic anhydride, triethylamine and hydrochloric acid were reacted in the same manners as those of Examples 1-4 to give 4-nitrobenzyl 7-oxo-3-chloro-3-cephem-4-carboxylate (monohydrate). Mp. 105°-106° C. (dec.).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:31]2[O:32][C@@H:30]2[C@@:29]2([CH3:33])[C:7](=[CH:8][C@@H:9](OC(=O)C)[C@@H:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:34])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2[O:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][O:18]2)[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].C(O[C@H]1[C@@H]2O[C@@H]2[C@@]2(C)C(=C[C@@H](OC(OC)=O)[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C2OCC(C)(C)CO2)C)C1)(=O)C>>[C:1]([O:4][C@H:5]1[C@@H:31]2[O:32][C@@H:30]2[C@@:29]2([CH3:33])[C:7](=[CH:8][CH:9]=[C:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:34])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2[O:18][CH2:19][C:20]([CH3:24])([CH3:23])[CH2:21][O:22]2)[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1C=C2C[C@@H](OC(C)=O)[C@@H]3O[C@@H]3[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCC(C)(C)CO4)CC[C@H]3[C@H]12
Agent: COC(=O)O[C@@H]1C=C2C[C@@H](OC(C)=O)[C@@H]3O[C@@H]3[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCC(C)(C)CO4)CC[C@H]3[C@H]12
Product: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Yield: 46.9 %

Procedure:
The procedure of Example 17 was repeated except that 42.3 mg (0.0798 mmole) of 7α-acetoxy-20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregn-5-en-3β-yl acetate was used in lieu of 43.6 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-methoxycarbonyloxypregn-5-en-3β-yl acetate to give 17.6 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-yl acetate. In addition, 14.0 mg of 7α-acetoxy-20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregn-5-en-38-yl acetate was recovered. The yield of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-yl acetate was 70% based on consumed 7α-acetoxy-20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregn-5-en-3β-yl acetate. The 1H-NMR spectrum of the product 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-yl acetate was in agreement with that of the 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-yl acetate obtained in Example 17.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1.[C:23]([NH2:27])([CH3:26])([CH3:25])[CH3:24]>ClCCl.CN(C=O)C>[C:23]([NH:27][C:8]([C:5]1[N:6]=[CH:7][C:2]([Br:1])=[CH:3][N:4]=1)=[O:10])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1ncc(Br)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1ncc(Br)cn1
Temperature: 2.5 °C
Reaction time: 16 h
Yield: 75.4 %

Procedure:
5-Bromopyrimidine-2-carboxylic acid (1 g, 4.93 mmol) was suspended in dichloromethane (10 ml) and DMF (20 μl). Oxalyl chloride (520 μl, 5.91 mmol, 1.2 equiv.) was added drop wise at room temperature and the mixture was stirred for 16 hours. The reaction mixture was then cooled to 0-5° C. and pyridine (480 μl, 5.91 mmol, 1.2 equiv.) and tert-butyl amine (621 μl, 5.91 mmol, 1.2 equiv.) were added drop wise at 0-5° C. The mixture was stirred for 4 hours at room temperature. The reaction mixture was extracted with saturated NaHCO3 solution and dichloromethane. The organic layers were extracted with water and brine, dried over sodium sulfate and evaporated to dryness. The desired 5-bromo-pyrimidine-2-carboxylic acid tert-butylamide (960 mg, 76% yield) was obtained as a light yellow solid, MS: m/e=258.0/259.9 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:10])=[N:4][CH:5]=[C:6](Br)[C:7]=1[CH3:8].[Li]CCCC>C1COCC1>[Br:1][C:2]1[C:3]([NH2:10])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1c(Br)cnc(N)c1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccnc(N)c1Br
Temperature: -78 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
To a solution of 3,5-dibromo-4-methyl-pyridin-2-ylamine (3.38 g, 12.7 mmol) in THF (60 mL) cooled to −78° C. was added n-BuLi (1.9M in pentane) (13.4 mL, 25.4 mmol) to give an orange solution. The solution was stirred at −78° C. for 1 h and then quenched with water (10 mL). The pH of the mixture was adjusted to ˜12 with 10N NaOH and then extracted with CH2Cl2 (3×30 mL), dried (Na2SO4), filtered and concentrated in vacuo to give an orange oil. Purification by column chromatography on silica gel (Et2O) afforded 3-bromo-4-methyl-pyridin-2-ylamine (1.68 g, 71%) as a pale yellow solid. 1H NMR (CDCl3) δ 2.32 (s, 3H), 5.00 (br s, 2H), 6.52 (d, 1H, J=6.0 Hz), 7.84 (d, 1H, J=6.0 Hz).
Reaction SMILES: [C:1]([NH:9]/[C:10](=[CH:15]\[C:16]1[CH:21]=[CH:20][C:19]([O:22]C2C=CC=CC=2C)=[CH:18][CH:17]=1)/[C:11]([O:13]C)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>O1CCOCC1>[C:1]([NH:9]/[C:10](=[CH:15]\[C:16]1[O:22][C:19]([C:18]2[CH:17]=[CH:4][CH:3]=[CH:2][C:7]=2[CH3:6])=[CH:20][CH:21]=1)/[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)/C(=C/c1ccc(Oc2ccccc2C)cc1)NC(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ccccc1-c1ccc(/C=C(\NC(=O)c2ccccc2)C(=O)O)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 148.9 %

Procedure:
To a solution of 1-methyl (Z)-2-(benzoylamino)-3-[4-(2-methylphenoxy)phenyl]prop-2-enoate (104 mg, 0.29 mmol), prepared as described above, in dioxane (5 mL) is added 1 N LiOH (5 mL). The reaction mixture is stirred at 25° C. for 3 hours. The dioxane is then removed under reduced pressure and the remaining reaction mixture poured into a separatory funnel. The aqueous layer is washed with diethyl ether and then acidified (pH=4) by treatment with 10% HCl causing a white precipitate to develop. A portion of ethyl acetate (50 mL) is added and the organic layer is separated, dried over sodium sulfate and concentrated to afford 75 mg of (Z)-2-(benzoylamino)-3-[5-(2-methylphenyl)-2-furyl]prop-2-enoic acid which does not require a further purification.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].[CH2:7]([OH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCOCC>[CH2:7]([O:14][C:1](=[O:5])[C:2]([Cl:4])=[O:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: OCc1ccccc1
Solvent: CCOCC
Product: O=C(Cl)C(=O)OCc1ccccc1
Yield: 94 %

Procedure:
Under N2, oxalyl chloride (262 ml) was dissolved in 1 liter anhydrous ether and heated to reflux, at which temperature benzyl alcohol (207 ml) was added over 70 minutes. After refluxing a further 16 hours, ether was stripped and the residue distilled at reduced pressure to yield 372 g (94%) of title product, b.p./0.7 mm 85° C.
Reaction SMILES: C[O:2]N=C1C2C(=CC=C(C(O)=O)C=2C)SCC1.[CH3:18][O:19][N:20]=[C:21]1[C:30]2[C:25](=[C:26](C)[CH:27]=[C:28]([C:32](C3C=NN(CC)C=3OS(CCC)(=O)=O)=[O:33])[C:29]=2[CH3:31])[S:24](=[O:50])(=[O:49])[CH2:23][CH2:22]1.OO.C(OCC)(=O)C>C(O)(=O)C>[CH3:18][O:19][N:20]=[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:32]([OH:33])=[O:2])[C:29]=2[CH3:31])[S:24](=[O:50])(=[O:49])[CH2:23][CH2:22]1
Reactant: CCCS(=O)(=O)Oc1c(C(=O)c2cc(C)c3c(c2C)C(=NOC)CCS3(=O)=O)cnn1CC
Reactant: CON=C1CCSc2ccc(C(=O)O)c(C)c21
Agent: OO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CON=C1CCS(=O)(=O)c2ccc(C(=O)O)c(C)c21
Yield: 97 %

Procedure:
1.0 Gram (4.0 mmol) of the 4-methoxyimino-5-methylthiochroman-6-carboxylic acid obtained in the above (2) was reacted with 1.3 g (12 mmol) of a 30% hydrogen peroxide aqueous solution in 5 ml of acetic acid at 100° C. for 1 hour. Ethyl acetate was added to the reaction product, and the mixture was washed with a saturated sodium chloride aqueous solution and then dried over sodium sulfate. The solvent was distilled off to give 1.1 g (yield 97%) of 4-methoxyimino-5-methylthiochroman-6-carboxylic acid-1,1-dioxide.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][N+:10]([O-])([C:11]3[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][N:12]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].P(Cl)(Cl)([Cl:30])=O>>[Cl:17][C:16]1[C:11]([N:10]2[C:6]3[CH:5]=[C:4]([Cl:30])[N:3]=[C:2]([Cl:1])[C:7]=3[CH:8]=[CH:9]2)=[N:12][CH:13]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][N+]1(c2ncc(C(F)(F)F)cc2Cl)C=Cc2c1ccnc2Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: FC(F)(F)c1cnc(-n2ccc3c(Cl)nc(Cl)cc32)c(Cl)c1
Temperature: 25 °C

Procedure:
4 -chloro-1-(3-chloro-5-trifluoromethylpyridin-2-yl) pyrrolo[3,2-c]pyridine N-oxide (Compound 4, 1.2 g, 3.4 mmol) was heated in phosphorus oxychloride (20 ml) under reflux for 18 hours. The mixture was cooled to room temperature, poured into ice-water, and the mixture made neutral by addition of solid sodium bicarbonate. The resulting mixture was extracted with dichloromethane, and the organic extracts combined, dried over magnesium sulfate, filtered and the filtrate evaporated in vacuo. The residue was further purified by flash column chromatography on silica gel to give 1-(3-chloro-5-trifluoromethylpyridin-2-yl)-4,6-dichloropyrrolo[3,2-c]pyridine (0.24 g) as a colorless oil.