Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:29])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][S:26][CH3:27])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:28])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.[OH:30]O>C(O)(=O)C.C(OCC)(=O)C>[O:29]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][S:26]([CH3:27])=[O:30])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:28])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: OO
Reactant: CSCCNc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(C)cc12
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCS(C)=O)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methyl-N-[2-(methylsulfanyl)ethyl]quinolin-4-amine (300 mg, 0.70 mmol) in acetic acid (2 mL) was added hydrogen peroxide (0.5 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with ethyl acetate (10 mL), washed with a saturated aqueous solution of sodium bicarbonate, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC to afford the desired product. MS obsd. (ESI+) [(M+H)+] 444, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.99 (d, J=7.07 Hz, 1 H), 7.88 (dd, J=7.83, 1.26 Hz, 1 H), 7.70-7.60 (m, 2 H), 7.47 (td, J=7.64, 1.14 Hz, 1 H), 7.34 (d, J=8.34 Hz, 1 H), 7.25 (dd, J=8.34, 1.52 Hz, 1 H), 6.98 (t, J=5.56 Hz, 1 H), 6.14 (s, 1 H), 5.09 (brs, 2 H), 4.5 (brs, 2 H), 3.81-3.56 (m, 4 H), 3.20-3.07 (m, 1 H), 3.04-2.92 (m, 1 H), 2.65 (s, 3 H), 2.35 (s, 3 H).
Reaction SMILES: C(OCC)(=O)C1C(=CC=CC=1)C(OCC)=O.[CH3:17][C:18]1[NH:23][C:22](=[O:24])[C:21](C(O)=O)=[CH:20][C:19]=1[C:28]1[N:29]=[C:30]([CH3:33])[S:31][CH:32]=1.C>>[CH3:17][C:18]1[NH:23][C:22](=[O:24])[CH:21]=[CH:20][C:19]=1[C:28]1[N:29]=[C:30]([CH3:33])[S:31][CH:32]=1
Reactant: Cc1nc(-c2cc(C(=O)O)c(=O)[nH]c2C)cs1
Agent: CCOC(=O)c1ccccc1C(=O)OCC
Product: Cc1nc(-c2ccc(=O)[nH]c2C)cs1
Temperature: 150 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
C-5. 6-Methyl-5-(2-methyl-4-thiazolyl)-2(1H)-pyridinone--To a 100 ml portion of boiling diethyl phthalate was added 20 g of 1,2-dihydro-6-methyl-5-(2-methyl-4-thiazolyl)-2-oxo-3-pyridinecarboxylic acid and the resulting dark solution was heated for about 15 minutes and then cooled to about 150° C., treated with decolorizing charcoal and filtered. The filtrate was diluted with 350 ml of n-hexane (no solid precipitated) and then extracted with 300 ml of 3% aqueous sodium hydroxide solution. The aqueous phase was separated and acidified with acetic acid, yielding no precipitate. The acidic solution was concentrated on a rotary evaporator to a volume of about 100 ml and allowed to stand at room temperature overnight. The resulting crystalline yellow solid that had separated was collected, washed with water, dried and then recrystallized from isopropyl alcohol-ether to produce 6.8 g of 6-methyl-5-(2-methyl-4-thiazolyl)-2-(1H)-pyridinone, m.p. 188°-190° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[NH2:31][CH2:32][CH:33]1[CH2:35][CH2:34]1>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:29])[C:15]2[O:14][CH:13]([CH2:12][NH:31][CH2:32][CH:33]3[CH2:35][CH2:34]3)[CH2:17][C:16]=2[CH:18]=1
Reactant: NCC1CC1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4c(C)cccc4C)c3O2)cc1
Product: Cc1cccc(C)c1-c1cc(Cl)cc2c1OC(CNCC1CC1)C2

Procedure:
The title compound was prepared (0.058 g, 45%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.338 mmol) and (aminomethyl)cyclopropane (0.50 g, 6.77 mmol). mp 203-205° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:12])([F:11])[C:5]([O:7][CH2:8][CH2:9]Cl)=[O:6]>>[F:3][C:4]([F:12])([F:11])[CH:5]1[O:7][CH2:8][CH2:9][O:6]1
Reactant: O=C(OCCCl)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Product: FC(F)(F)C1OCCO1
Reaction time: 8 h
Yield: 29.9 %

Procedure:
This example illustrates a process of the invention only. A suspension of 9.6 g (0.20 mol) of 50% NaH in mineral oil in 150 mL of DM$0 was stirred at 15°-20° while 35.4 g (0.20 mol) of 2-chloroethyl trifluoroacetate were added dropwise. The resulting mixture was stirred overnight while the reaction temperature was maintained below 30° . The reaction mixture was then heated to 50° at 0.33 kPa (2.5 mm) to drive off volatile products which were recovered. Fractionation of the volatiles gave 8.5 g (30% yield) of 2-trifluoromethyl-1,3-dioxolane, b.p. 87°-93° . IR (CCl4): 3000 and 2910 (sat'd CH), 1200-1100 cm-1 (CF,C--O). NMR (CCl4): 1H 5.13 (q, JHF 4Hz, IH, CH) and 4.07 ppm (s, 4H, ring OCH2). Anal.: Calcd. for C4H5F3O2 : C, 33.81; H, 3.55. Found: C, 33.68; H, 3.39
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[C:3]([CH2:11][OH:12])[N:2]=1>[O-2].[O-2].[Mn+4].C(Cl)Cl>[CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[C:3]([CH:11]=[O:12])[N:2]=1
Reactant: OCc1cc2c(cn1)CCCC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cc2c(cn1)CCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
A solution of 5,6,7,8-tetrahydro-3-isoquinolinylmethanol (572 mg, 3.50 mmol) in (DCM) (10 ml) at rt under argon was treated with manganese dioxide (3.047 g, 35.0 mmol) and then stirred at rt for 2 h. The reaction mixture was then filtered through a thin pad of Kieselguhr, eluting with DCM (50 ml), the organic extracts were evaporated to give the crude product as a brown oil (435 mg, 77%).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[N:9](CC3C=CC(OC)=CC=3OC)[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]2[NH:31]C(=O)OC(C)(C)C)[N:3]=1.[BrH:39]>CC(O)=O>[NH2:31][C@H:26]1[CH2:27][CH2:28][CH2:29][CH2:30][C@H:25]1[NH:24][C:4]1[N:3]=[C:2]([Br:39])[C:7]2[C:8](=[O:22])[NH:9][CH2:10][C:6]=2[C:5]=1[F:23]
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(Cl)c3C2=O)c(OC)c1
Reactant: Br
Solvent: CC(=O)O
Product: N[C@H]1CCCC[C@H]1Nc1nc(Br)c2c(c1F)CNC2=O
Temperature: 90 °C
Reaction time: 6 h
Yield: 30 %

Procedure:
A mixture of tert-butyl (1S,2R)-2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (200 mg, 0.364 mmol) and hydrobromic acid in HOAc (10 mL) was stirred at 90° C. for 6 h. The mixture was concentrated under reduced pressure, and the resulting crude material was reconstituted in MeOH (1.0 mL) and was purified via preparative HPLC eluting with water (0.05% TFA) and ACN (15-30% gradient, 0.035% TFA). The collected fractions were combined and ACN was removed via rotary evaporation. The resulting aqueous solution was neutralized with saturated aqueous NaHCO3, washed with EtOAc (2×200 mL), dried over Na2SO4, and filtered. The organic phase was stripped to dryness via rotary evaporation to yield the title compound (38 mg, 30%). [M+H] calc'd for C13H16BrFN4O, 343. found, 343.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.CC(C)([O-])C.[K+].C[O:13][C:14]([C:16]1[CH:21]=[N:20][C:19](Br)=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[N:17]=1)=[O:15]>O1CCCC1>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:18]2[N:17]=[C:16]([C:14]([OH:15])=[O:13])[CH:21]=[N:20][C:19]=2[O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[CH:28][CH:27]=1
Reactant: OCC1CC1
Reactant: COC(=O)c1cnc(Br)c(-c2ccc(F)cc2)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)c1cnc(OCC2CC2)c(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyclopropyl-methanol (2.2 g, 30.6 mmol, 10.0 eq) was dissolved in dry tetrahydrofuran (10 ml, 20 vol) and potassium tert-butoxide (3.4 g, 30.6 mmol, 10.0 eq) added portion-wise. After stirring for 15 minutes at room temperature 5-bromo-6-(4-fluoro-phenyl)-pyrazine-2-carboxylic acid methyl ester (0.95 g, 3.06 mmol, 1.0 eq) was added drop-wise as a tetrahydrofuran (10 ml) solution. The reaction mixture was stirred overnight at room temperature or until deemed complete by HPLC-MS analysis. The solution was concentrated in vacuo and the residue re-dissolved in ethyl acetate (20 ml). The resulting solution was washed with water (5 ml) and the aqueous phase extracted with ethyl acetate (10 ml). The combined organic phases were dried over magnesium sulphate, filtered and concentrated in vacuo to afford 6-(4-fluoro-phenyl)-5-cyclopropylmethoxy-pyrazine-2-carboxylic acid. Yield=0.89 g (75%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.[CH3:11][N:12]1[CH2:16][CH2:15][C@H:14](O)[CH2:13]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([CH:7]=1)[O:8][C@@H:14]1[CH2:15][CH2:16][N:12]([CH3:11])[CH2:13]1
Reactant: CN1CC[C@H](O)C1
Reactant: COc1ccc(Br)cc1O
Product: COc1ccc(Br)cc1O[C@@H]1CCN(C)C1
Yield: 58.4 %

Procedure:
The title compound was prepared by the method outlined for Preparative Example 63 using 5-bromo-2-methoxy-phenol (1.00 g, 4.926 mmol) and (S)-1-methyl-pyrrolidin-3-ol (601 mg, 5.94 mmol) to afford titled compound as a colorless solid (823 mg, 58%). LC/MS (Method B) 1.18 min, [M+1]+ 286/288.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH3:30])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[CH:24]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.BrC1C=CC([C@@H](N2CC[C@@](C3C=CC(F)=CC=3)(C)OC2=O)C)=CC=1.CC1C=C(B(O)O)C=CN=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:30])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[CH:24]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2ccc([C@H](C)N3CC[C@](C)(c4ccc(F)cc4)OC3=O)cc2)ccn1
Agent: C[C@@H](c1ccc(Br)cc1)N1CC[C@](C)(c2ccc(F)cc2)OC1=O
Agent: Cc1cc(B(O)O)ccn1
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@@](C)(c4ccc(F)cc4)OC3=O)cc2)ccn1

Procedure:
Isomer 2 of the title compound, (R)-6-(4-fluorophenyl)-6-methyl-3-((S)-1-(4-(2-methylpyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one, was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-methyl-1,3-oxazinan-2-one and 2-methylpyridine-4-boronic acid following a procedure analogous to that described in Example 64. LC-MS Method 1 tR=1.18, m/z=405 (M+1); 1H NMR (CDCl3) 8.83 (s, 1H), 7.72 (s, 1H), 7.66 (s, 1H), 7.48 (d, 2H, J=7.3 Hz), 7.32 (br m, 2H), 7.16 (d, 2H, J=6.7), 7.04 (t, 2H, J=7.6 Hz), 5.77 (q, 1H, J=6.7 Hz), 3.05 (br m, 1H), 2.89 (s, 3H, 2.42-2.32 (m, 2H), 2.23 (br m, 1H), 1.64 (s, 3H), 1.59 (d, 3H, J=6.7 Hz).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].[O:14]=[S:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:31][C@H:30]([CH2:32][NH:33][C:34](=[O:36])[CH3:35])[O:29][C:28]3=[O:37])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1.CN1CCOCC1>ClCCl>[O:14]=[S:15]1(=[O:4])[CH:16]=[CH:17][CH:18]([C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:31][C@H:30]([CH2:32][NH:33][C:34](=[O:36])[CH3:35])[O:29][C:28]3=[O:37])=[CH:23][CH:22]=2)[CH2:19][CH2:20]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCS(=O)CC3)cc2)C(=O)O1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(=O)NC[C@H]1CN(c2ccc(C3C=CS(=O)(=O)CC3)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoroacetic anhydride (2.98 mL, 21.1 mmol) is added dropwise at room temperature to a solution of N-[[(5S)-3-[4-(tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (2.46 g, 7.02 mmol; prepared as described in International Publication WO 97/09328) and N-methylmorpholine (3.86 mL, 35.1 mmol) in dichloromethane (60 mL). The reaction mixture is stirred overnight at room temperature and then evaporated to dryness. The resulting crude N-[[(5S)-3-[4-(3,4-dihydro-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (2.77 g) is dissolved in tetrahydrofuran (100 mL) and peracetic acid (7.01 mL of a 32% solution in acetic acid) added dropwise at 0° C. The reaction mixture is allowed to warm to room temperature, stirred overnight, and then evaporated to dryness. The residue is purified by flash column chromatography (ethyl acetate) to give the title compound as white solid.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:6][CH:5]=1.[C:23]([C:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=1)#[CH:24]>CCCCCCC>[C:25]1([C:23]#[C:24][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:9][CH:8]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=1
Reactant: C#CC1=CCCCC1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(OC(F)(F)F)cc2)cc1
Solvent: CCCCCCC
Product: FC(F)(F)Oc1ccc(C#CC2=CCCCC2)cc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 4-trifluoromethoxy-phenyl ester and 1-ethynyl-cyclohexene following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane; yield (110 mg, 83%); 1H NMR δ (CDCl3): 7.41 (d, J=8.38 Hz, 2H), 7.21 (d, J=8.37 Hz, 2H), 6.28 (m, 1H), 2.17 (dm, 4H), 1.63 (dm, 4H); LCMS m/z: 266.
Reaction SMILES: [CH:1]1([O:5][C:6]2[CH:7]=[N:8][N:9]([CH:13]([CH2:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:14]([OH:16])=O)[C:10](=[O:12])[CH:11]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:23][C:24]1([CH3:36])[O:28][C@H:27]([CH2:29][N:30]2[CH:34]=[CH:33][C:32]([NH2:35])=[N:31]2)[CH2:26][O:25]1>>[CH:1]1([O:5][C:6]2[CH:7]=[N:8][N:9]([CH:13]([CH2:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:14]([NH:35][C:32]3[CH:33]=[CH:34][N:30]([CH2:29][C@@H:27]4[CH2:26][O:25][C:24]([CH3:36])([CH3:23])[O:28]4)[N:31]=3)=[O:16])[C:10](=[O:12])[CH:11]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(OC2CCC2)cc1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC3CCCC3)n3ncc(OC4CCC4)cc3=O)n2)O1

Procedure:
Using the method described in Example 49, 2-(4-cyclobutoxy-6-oxo-6H-pyridazin-1-yl)-3-cyclopentyl-propionic acid (Intermediate 72) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded 2-(4-cyclobutoxy-6-oxo-6H-pyridazin-1-yl)-3-cyclopentyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-propionamide as an off-white solid as a mixture of diastereomers (0.38 g, 24%).
Reaction SMILES: [C:1]([NH:4][C:5]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[CH:16]=1)(C([O-])=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]>C1(C)C=CC=CC=1>[C:1]([NH:4][CH:5]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[CH:16]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc2c(c1)CCCC2)(NC(C)=O)C(=O)[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1ccc2c(c1)CCCC2)NC(C)=O

Procedure:
A mixture of 29.2 g (87.6 mmol) monoethyl 2-acetylamino-2-(5,6,7,8-tetrahydro-naphthalen-2-ylmethyl)-malonate and 400 mL toluene was refluxed for 5 h. The reaction mixture was then washed with 1 M NaOH and water, dried and evaporated down under reduced pressure.
Reaction SMILES: I[CH2:2][CH:3]([CH3:33])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11]([CH2:12][C@@H:13]([O:28][C:29]([O:31][CH3:32])=[O:30])[CH2:14][C@@H:15]2[O:23][C:24]([O:26][CH3:27])=[O:25])=[CH:10][CH:9]=3)[CH2:6][CH2:5]1.[C:34]1([S:40]([O-:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Na+]>CN(C)C=O>[CH3:33][CH:3]([C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11]([CH2:12][C@@H:13]([O:28][C:29]([O:31][CH3:32])=[O:30])[CH2:14][C@@H:15]2[O:23][C:24]([O:26][CH3:27])=[O:25])=[CH:10][CH:9]=3)[CH2:6][CH2:5]1)[CH2:2][S:40]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:42])=[O:41]
Reactant: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CI)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CS(=O)(=O)c5ccccc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Temperature: 40 °C
Reaction time: 7 h
Yield: 57.7 %

Procedure:
A mixture of 71 mg of 21-iodo-20-methyl-1α,3β-bis-(methoxycarbonyloxy)pregna-5,7-diene, 80 mg of sodium benzenesulfinate and 3 ml of dimethylformamide was stirred at 40° C. for 7 hours. The reaction mixture was subjected to the same isolation and purification procedure in Example 5 to give 42 mg of 20-methyl-1α,3β-bis(methoxycarbonyloxy)-21-phenylsulfonylpregna-5,7-diene, whose 1H NMR spectrum was identical with that obtained in Example 5.
Reaction SMILES: C([O:3][C:4](=O)[N:5]([C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH2:21][O:22][CH3:23])[N:16]=[C:15]([NH2:24])[C:14]=1[N+:25]([O-])=O)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C>C(O)C.[Pd]>[NH2:24][C:15]1[C:14]2[NH:25][C:4](=[O:3])[N:5]([CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH:18]=[C:17]([O:19][CH2:20][CH2:21][O:22][CH3:23])[N:16]=1
Reactant: CCOC(=O)N(Cc1ccccc1)c1cc(OCCOC)nc(N)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COCCOc1cc2c([nH]c(=O)n2Cc2ccccc2)c(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.6 %

Procedure:
[2-Amino-6-(2-methoxy-ethoxy)-3-nitro-pyridin-4-yl]-benzyl-carbamic acid ethyl ester (118 mg) was dissolved in ethanol (5 ml) and 10% Pd on carbon (15 mg) added. The reaction was stirred under a hydrogen atmosphere (50 psi) for 1 h at RT. The reaction mixture was then filtered through a Celite pad and evaporated. The crude was dissolved in glacial acetic acid (2 ml) and transferred to a microwave vial (Biotage, 0.5-2.0 ml). The vial was sealed and heated under microwave irradiation at 100° C. for 5 minutes. The resultant brown mixture was evaporated then solid loaded on silica and columned on Isco Companion on a silica column (4 g, Redisep), eluting with EtOAc:heptane, increasing the gradient linearly from 60:40 to 100% EtOAc over 8 column volumes (CVs) then isocratic at 100% EtOAc for 8 CVs. The desired fractions were combined and evaporated to provide the title compound as a white solid (50 mg).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[F:9].[CH3:10][C:11]1(C)[C:15](C)(C)OB(C(C)=C)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CC(N(C)C)=O.CCOC(C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[F:9][C:3]1[CH:4]=[CH:5][C:6]([NH2:8])=[N:7][C:2]=1[C:11]([CH3:15])=[CH2:10]
Reactant: Nc1ccc(F)c(Br)n1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: C=C(C)c1nc(N)ccc1F
Temperature: 150 °C

Procedure:
To a solution 6-bromo-5-fluoro-pyridin-2-ylamine (850 mg, 4.45 mmol) in dimethylacetamide (13.5 mL) was added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.09 mL, 5.79 mmol), palladium tetrakis(triphenylphosphine) (514 mg, 445 μmol) and tribasic potassium phosphate (1.89 g, 8.9 mmol) in water (4 mL, 223 mmol). The mixture was sealed in a microwave vial and heated at 150° C. in a microwave for 15 min. Upon cooling, the mixture was diluted with EtOAc, washed with water and brine, concentrated on to silica gel, and chromatographed (20% to 100% EtOAc in hexanes) to give 5-fluoro-6-isopropenyl-pyridin-2-ylamine contaminated with catalyst-derived impurities (−800 mg) that was used directly in the next step without further purification.
Reaction SMILES: C1(C([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:50]([OH:51])[CH:41]6[CH:42]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:52]([CH3:54])[CH3:53])=[O:16])C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.[C].[Pd]>[CH2:44]([O:43][CH:42]1[CH:37]2[CH:38]3[O:39][C:35]([O:34][CH2:33][C:21]45[CH:20]6[CH2:29][C:28]([CH:30]=[O:31])([C:17]4([C:15]([OH:16])=[O:14])[C:18]([CH:52]([CH3:53])[CH3:54])=[CH:19]6)[CH:27]4[CH:23]([CH:24]([CH3:32])[CH2:25][CH2:26]4)[CH2:22]5)([CH:50]([OH:51])[CH:41]1[O:40]3)[O:36]2)[CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]
Reactant: CCCCCCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)O)OC2OC1C3O
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.9 %

Procedure:
14.1 mg of compound (46) was dissolved in 1.9 ml of ethyl acetate and allowed to react in the presence of a catalytic amount of 10% palladium-carbon under stirring under a hydrogen atmosphere at room temperature for 3 hours. The reaction solution was filtered, and the filtrate was concentrated in vacuo. The reaction product was charged onto a silica gel column (Kieselgel 60, Merck, 1.5φ×15 cm) and eluted with n-hexane-ethyl acetate (3:1) to give 6.0 mg of compound (47) as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([N+:18]([O-])=O)[C:15]([F:21])=[CH:14][C:13]=2[F:22])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8]>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[C:3]([C:12]2[C:13]([F:22])=[CH:14][C:15]([F:21])=[C:16]([NH2:18])[CH:17]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:9])([F:8])[F:10]
Reactant: Cn1nc(-c2cc([N+](=O)[O-])c(F)cc2F)c(Cl)c1C(F)(F)F
Agent: [Fe]
Solvent: CC(=O)O
Product: Cn1nc(-c2cc(N)c(F)cc2F)c(Cl)c1C(F)(F)F
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
A solution of 3.4 g (0.01 mole) 4-chloro-3-(2,4-difluoro-5-nitrophenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole in 50 mL acetic acid was heated to 80° C. under a nitrogen atmosphere. The heat and nitrogen were removed and 1.7 g (0.03 mole) iron powder was added in 3 portions over 5 min. The solution was stirred at 80° C. for an additional 30 min. The solution was cooled and filtered through Celite®. The filtrate was diluted with 100 mL water and extracted three times with ethyl acetate. The ethyl acetate extracts were washed with a saturated NaHCO3 solution, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified chromatographically using 35% ethyl acetate in hexane as the eluent to give 2.46 g (79%) of 5-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-2,4-difluorobenzenamine as a white solid, mp 82° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10]C)=[O:9])#[N:2].O.[OH-].[Li+].Cl>O1CCCC1.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([CH:12]=1)[C:8]([OH:10])=[O:9])#[N:2]
Reactant: COC(=O)c1cc(C#N)ccc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C#N)cc1C(=O)O
Yield: 99.1 %

Procedure:
A mixture of Example 25A (6.1 g, 31.9 mmol) and lithium hydroxide monohydrate (5.36 g, 128 mmol) in tetrahydrofuran (100 mL) and H2O (50 mL) was stirred at room temperature for 3 h. The reaction pH was adjusted to pH=3 with 3N HCl, and the mixture was extracted twice with isopropanol/CH2Cl2 (1:3). The organics were combined, dried (MgSO4), filtered and concentrated to afford 5.6 g (99%) of the title compound. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 4.15 (s, 3H) 7.17 (d, J=8.85 Hz, 1H) 7.86 (dd, J=8.85, 2.44 Hz, 1H) 8.47 (d, J=2.14 Hz, 1H).