Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[CH:8]=[C:7]([O:17][CH3:18])[C:6]=12.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC(C1C=C(C(C)C)C(C2C(P(C(C)(C)C)C(C)(C)C)=CC=CC=2)=C(C(C)C)C=1)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:19]([NH:26][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[CH:8]=[C:7]([O:17][CH3:18])[C:6]=12)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: COc1cc(-c2cnn(C)c2)cn2ncc(Br)c12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1cc(-c2cnn(C)c2)cn2ncc(NCc3ccccc3)c12
Temperature: 100 °C
Reaction time: 12 h

Procedure:
3-bromo-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (25.0 mg, 0.081 mmol), benzyl amine (12.0 mg, 0.011 mmol), tris[dibenzylideneacetone]dipalladium (0) (1.9 mg, 0.0020 mmol), and tert-butyl X-phos (3.5 mg, 8.1 mmol) were suspended in toluene (1.6 ml), sparged with argon for 3 minutes, then heated to 100° C. After 12 hours, the reaction mixture was concentrated. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.05% TFA to give N-benzyl-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-amine 1H NMR (500 MHz, DMSO-d6) δ 8.23 (s, 1H); 8.17 (s, 1H); 7.91 (s, 1H); 7.38 (d, 2H); 7.29 (t, 2H); 7.25 (s, 1H); 7.20 (t, 1H); 6.44 (s, 1H); 4.92 (t, 1H); 4.23 (d, 2H); 3.93 (s, 3H); 3.83 (s, 3H). LRMS (ESI) calculated for C19H20N5O [M+H]+, 334.2; found 334.1.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[S:10][C:11]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16]Cl)=[CH:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][O:27][C:23]=2[CH:22]=1.C(O)(=O)C(O)=O.S1C2C=CC=CC=2C(N2CCN(CCCC(C3SC4SCCNC(=O)C=4C=3)=O)CC2)=N1>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[S:10][C:11]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16][N:31]3[CH2:30][CH2:29][CH:28]([C:25]4[C:24]5[CH:34]=[CH:35][C:21]([F:20])=[CH:22][C:23]=5[O:27][N:26]=4)[CH2:33][CH2:32]3)=[CH:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2sc(C(=O)CCCCl)cc2C1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: O=C(CCCN1CCN(c2nsc3ccccc23)CC1)c1cc2c(s1)SCCNC2=O
Agent: O=C(O)C(=O)O
Product: CC(=O)N1CCc2sc(C(=O)CCCN3CCC(c4noc5cc(F)ccc45)CC3)cc2C1
Yield: 34.2 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 1.8 g of 5-acetyl-2-(4-chlorobutyryl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine and 1.6 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 1.0 g of 5-acetyl-2-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine as an oil, m.p. 235° C. as hydrochloride 1/2 hydrate thereof.
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:16])=[C:4]([NH:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C(=O)([O-])[O-:18].[K+].[K+].OO>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[C:3]([I:16])=[C:4]([NH:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:5]([C:8]([NH2:9])=[O:18])=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CCC(CC)Nc1c(C#N)ncc(Cl)c1I
Agent: OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCC(CC)Nc1c(C(N)=O)ncc(Cl)c1I
Temperature: 25 °C
Yield: 85 %

Procedure:
To a solution of 5-chloro-4-iodo-3-(pentan-3-ylamino)picolinonitrile (55 mg, 0.16 mmol) in DMSO (1 mL) was added solid potassium carbonate (210 mg, 0.64 mmol). The mixture was cooled in an ice water bath (0° C.) and aqueous hydrogen peroxide (30%, 0.5 mL) was added. The reaction was allowed to warm to room temperature and monitored by LCMS. After the reaction was complete, the reaction mixture was diluted with EtOAc, and the organic layer was washed repeatedly with water. The organic layer was then dried over sodium sulfate, filtered and concentrated in vacuo. The residue was filtered through a silica gel plug to provide the title compound as a white solid (50 mg, 83%). m/z=368.1 [M+H]+ and 1H NMR.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(CC(O)=O)(CCC=C(C)C)(C=C)C.[C:23]([O:26][C:27]([CH3:36])([CH2:30][CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])[CH:28]=[CH2:29])(=[O:25])[CH3:24].[CH:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][C:38]=1[C:47](Cl)=[O:48]>C1COCC1>[CH:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][C:38]=1[C:47](=[O:48])[CH2:24][C:23]([O:26][C:27]([CH3:36])([CH2:30][CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])[CH:28]=[CH2:29])=[O:25]
Reactant: C=CC(C)(CCC=C(C)C)OC(C)=O
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: C=CC(C)(CCC=C(C)C)CC(=O)O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC(C)(CCC=C(C)C)OC(=O)CC(=O)c1ccc2ccccc2c1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
Lithium diisopropylamide (101.0 mL of a 2.0 M solution, 0.202 mol) is placed into a 500 mL three-necked round-bottomed flask fitted with a magnetic stirrer, internal thermometer, argon inlet, and-addition funnel. The flask is placed in a dry ice-acetone bath. 3,7-Dimethyl-1,6-octadien-3-yl acetate (linalyl acetate) in the amount of (18.66 g, 0.095 mol) is dissolved in THF (5 mL) and the resulting solution added to the flask over 45 min. Once addition is complete, the mixture is stirred for an additional 15 min before being treated with a solution of 2-naphthoyl chloride in the amount of (17.43 g, 0.090 mol) dissolved in THF (25 mL) over 30 min. The mixture is warmed to -20° C. and stirred at that temperature for 18 h. After warming to 0° C., the mixture is quenched with 20% HCl (53 mL). The mixture is poured into a separatory funnel containing ether (150 mL) and water (250 mL). The aqueous layer is extracted with ether (150 mL). The combined organic layers are washed with saturated NaHCO3 solution (2×100 mL), water (2×150 mL) and brine (150 mL), dried over MgSO4 and filtered. The solvent is removed by rotary evaporation to give an orange/red oil. The oil is purified by column chromatography (elution with 5% ethyl acetate dissolved in petroleum ether) to give an oil. Purity of the product is determined by thin layer chromatography and GC analysis and the structure confirmed by mass spectrometry, 1H and 13C NMR.
Reaction SMILES: [F:1][C:2]1[C:10]2[C:9]([NH2:11])=[CH:8][C:7]([Sn](C)(C)C)=[CH:6][C:5]=2[N:4]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[N:3]=1.Br[C:26]1[CH:31]=[CH:30][N:29]=[C:28]2[N:32]([S:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)(=[O:38])=[O:37])[C:33]([CH3:35])=[CH:34][C:27]=12>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C>[F:1][C:2]1[C:10]2[C:9]([NH2:11])=[CH:8][C:7]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]4[N:32]([S:36]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)(=[O:37])=[O:38])[C:33]([CH3:35])=[CH:34][C:27]=34)=[CH:6][C:5]=2[N:4]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[N:3]=1
Reactant: Cc1cc2c(Br)ccnc2n1S(=O)(=O)c1ccccc1
Reactant: C[Sn](C)(C)c1cc(N)c2c(F)nn(S(=O)(=O)c3ccccc3)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cc2c(-c3cc(N)c4c(F)nn(S(=O)(=O)c5ccccc5)c4c3)ccnc2n1S(=O)(=O)c1ccccc1
Temperature: 120 °C
Reaction time: 1.33 h

Procedure:
3-Fluoro-1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (660 mg), Pd(PPh3)4 (168 mg) and 4-bromo-2-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (613 mg) were weighed into a microwave vial and DMF (10 ml) was added. The mixture was heated to 120° C. overnight. The mixture was then cooled to RT and the solvent was removed in vacuo. The crude material was dried in a vacuum oven overnight. The resulting dark brown oil was purified by FlashMaster II. The crude material was dissolved in chloroform and added to the top of 2×100 g silica SPE cartridges that were subsequently eluted with 0-100% ethyl acetate:cyclohexane over 80 min. The product-containing fractions were combined and the solvent removed in vacuo to give the title compound, 357 mg as a cream solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[F:11].C([O-])([O-])=O.[K+].[K+].[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN1C(=O)CCC1>C(OCC)(=O)C>[F:11][C:3]1[CH:4]=[C:5]([NH2:8])[CH:6]=[CH:7][C:2]=1[O:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Nc1ccc(Oc2ccccc2)c(F)c1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
1,2-difluoro-4-nitro-benzene Compound 132a (1.3 g, 8.2 mmol), K2CO3 (1.2 g, 9.0 mmol) and phenol Compound 132b (0.84 g, 9.0 mmol.) were combined with 10 mL of NMP in a sealed pressure tube. The reaction was heated in a microwave at 140° C. for 50 min. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over NaSO4, then filtered and concentrated down to an oil. The crude oil in ethyl acetate (25 mL) was added to 10% Pd/C (1.3 g) and placed under 40 psi of hydrogen in a Parr apparatus for 1 hr. The solution was then filtered through Celite and concentrated to give 3-fluoro-4-phenoxy-phenylamine Compound 132c (1.9 g). MS 204 (MH+). An alternative procedure for making Compound 132c is described in U.S. Pat. No. 3,652,665. Using the procedure of Example 1, 3-fluoro-4-phenoxy-phenylamine Compound 132c was used in place of Compound 1e to prepare 4-chloro-6-(3-fluoro-4-phenoxy-phenylamino)-pyrimidine-5-carbonitrile Compound 132d. Using the procedure of Example 1, Compound 132d was carried forward in place of 4-chloro-6-(3-chloro-4-fluoro-phenylamino)-pyrimidine-5-carbonitrile Compound 1f to prepare 5-(3-fluoro-4-phenoxy-phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5,6,8-tetraaza-acenaphthylene-2-carboxylic acid Compound 112. MS 423 (MH+). Compound 112 was carried forward in place of Compound 1 and 4-morpholin-4-ylmethyl-phenylamine Compound 3e was used in place of 4-piperidin-1-ylmethyl-phenylamine Compound 1k to give Compound 113. MS 597 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:12])[NH:7]2.[H-].[Na+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:12])[N:7]2[CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1
Reactant: O=c1ccc2c(Br)cccc2[nH]1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)ccc3c(Br)cccc32)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 106.6 %

Procedure:
To a solution of 5-bromoquinolin-2(1H)-one (0.84 g, 2.29 mmol) in DMF (20 mL) at room temperature was added sodium hydride (0.57 g, 14.22 mmol) and 4-methoxybenzyl chloride (1.24 mL, 9.10 mmol). Upon completion of addition, the reaction mixture was stirred at room temperature for 2 d, and then heat to 75° C. where it stirred for 2 h. After cooling to room temperature, the reaction mixture was quenched with water, and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was purified by flash chromatography (0 to 30% ethyl acetate:hexanes) to afford the title compound (0.84 g, 40% yield) as a white powder. LCMS, [M+H]+=344.0. 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J=9.8 Hz, 1H), 7.44 (dd, J=6.6, 2.2 Hz, 1H), 7.28-7.23 (m, 3H), 7.14 (d, J=8.2 Hz, 1H), 6.89 (d, J=9.8 Hz, 1H), 6.83 (d, J=8.6 Hz, 2H), 5.5 (s, 2H), 3.76 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: Cc1cccc(N)c1
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cccc(NC(=O)Cc2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
A solution of 4-bromophenylacetic acid (502 mg, 2.33 mmol), m-toluidine (0.25 mL, 2.33 mmol), HOBT (350 mg, 2.59 mmol), and N-methylmorpholine (0.51 mL, 4.64 mmol) in DMF (10 mL) was treated with EDCI (496 mg, 2.59 mmol), stirred overnight at room temperature, and poured into ice water. The resulting white precipitate was collected by filtration to give 672 mg of the desired product. MS (ESI(+)) m/e 304, 306 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][Si](C)(C)C)=[CH:9][CH:10]=2)[N:5]([CH3:18])[C:4](=[O:19])[C:3]=1[C:20]([NH:22][CH2:23][C:24]([O:26]C)=[O:25])=[O:21].CN(C)C=O.[F-].[Cs+].[H][H]>CO.[Pd]>[CH2:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:2]([OH:1])=[C:3]([C:20]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21])[C:4](=[O:19])[N:5]2[CH3:18])=[CH:10][CH:9]=1)[CH3:13]
Reactant: COC(=O)CNC(=O)c1c(O)c2ccc(C#C[Si](C)(C)C)cc2n(C)c1=O
Reactant: [H][H]
Agent: [Pd]
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: CN(C)C=O
Product: CCc1ccc2c(O)c(C(=O)NCC(=O)O)c(=O)n(C)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
To a stirred solution of methyl 2-(4-hydroxy-1-methyl-2-oxo-7-(2-(trimethylsilyl)ethynyl)-1,2-dihydroquinoline-3-carboxamido)acetate (0.59 g, 1.5 mmol) in N,N-dimethylformamide (5.0 mL, 1.5 mmol) and methanol (1.0 mL, 1.5 mmol) was added cesium fluoride (0.23 g, 1.5 mmol) under nitrogen. After stirring at room temperature for 1 hour, the mixture was concentrated to remove solvents. The resulting solid was adsorbed onto silica and purified using flash chromatography (15-80% EtOAc:Hex gradient) to afford a yellow solid. The solid was suspended in methanol (10 mL) with Pd/C (20 mol %) and exposed to hydrogen from a balloon for 16 h. The crude reaction mixture was filtered through Celite, and the filter pad was washed with dichloromethane (5×10 mL) under argon. The filtrate was concentrated to give a white solid that was further purified on silica by flash chromatography (100% chloroform). The solid was then treated with 5 N aqueous NaOH (3 mL) in THF (3 mL) for 5 hours. The mixture was acidified to pH 1 using 5 N aqueous HCl, and the resulting precipitate was collected by filtration. After washing the solid with water (5×10 mL) and ether (2×10 ml), the desired material was obtained after drying in a vacuum oven overnight at 50° C. (0.21 g, 38% yield, 3 steps).
Reaction SMILES: [CH2:1]([O:5][CH2:6][C@@H:7]([NH:12][C:13]([C@H:15]1[O:17][C@@H:16]1[C:18]([O:20]CC)=[O:19])=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10])[CH:2]([CH3:4])[CH3:3].C(=O)([O-])[O-].[Na+:27].[Na+]>C(O)C.O>[CH2:1]([O:5][CH2:6][C@@H:7]([NH:12][C:13]([C@H:15]1[O:17][C@@H:16]1[C:18]([O-:20])=[O:19])=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10])[CH:2]([CH3:3])[CH3:4].[Na+:27]
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@H](COCC(C)C)CC(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)COC[C@H](CC(C)C)NC(=O)[C@H]1O[C@@H]1C(=O)[O-]
Temperature: 25 °C
Yield: 148.1 %

Procedure:
Crude ethyl (2S,3S)-3-[[(1S)-1-isobutoxymethyl-3-methylbutyl]carbamoyl]oxirane-2-carboxylate (15.29 g) synthesized according to the process (acid chloride method) similar to that described in Patent reference 1 was dissolved in ethanol (24 mL). While the solution was stirred at room temperature, sodium carbonate (2.44 g) dissolved in water (24 mL) was dropped. After the solution was stirred at room temperature for 1 hour, it was further stirred at 90° C. to 95° C. for 2 hours. The solvent was distilled off under reduced pressure, and water (50 mL) was added to the residue. The obtained solution was washed with two portions of ethyl acetate (50 mL), and water was distilled off under reduced pressure. Acetone (400 mL) was dropped to the residue, and the obtained solution was stirred overnight at room temperature. The precipitated crystalline product was collected by filtration, washed with a mixture of 3% water-acetone (30 mL), washed again with acetone (30 mL), and dried in air to obtain white solid sodium (2S,3S)-3[[(1S)-1-isobutoxymethyl-3-methylbutyl]carbamoyl]oxirane-2-carboxylate (10.55 g, 70.3%). The NMR data of the solid product were the same as those in Example 9.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1.[CH:23]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH2:24].C(N(CC)CC)C.Cl>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:24]=[CH:23][S:25]([NH2:28])(=[O:27])=[O:26])[CH:16]=1
Reactant: C=CS(N)(=O)=O
Reactant: Nc1c(C(=O)c2cccc(Br)c2)cnn1-c1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1c(C(=O)c2cccc(C=CS(N)(=O)=O)c2)cnn1-c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 5-amino-4-(3-bromobenzoyl)-1-(4-fluorophenyl)pyrazole (1.5 g, 4.14 mmol) [prepared as described in Example 1 above], vinylsulfonamide (1.33 g, 12.4 mmol), bis(triphenylphosphine)palladium chloride (0.3 g, 0.42 mmol) and triethylamine (6 ml, 43 mmol) in dimethylformamide (18 ml) was heated at 100° C. under argon. After 16 h, the reaction mixture was cooled to room temperature and poured into 1 N hydrochloric acid. The product was extracted into ethyl acetate, washed with brine, dried over sodium sulfate and filtered. The organic layer was removed in vacuo and the residue was purified by flash chromatography (elution gradient: 40-80% ethyl acetate/hexane) to give 5-amino-4-[3-(2-aminosulfonylethenyl)benzoyl]-1-(4-fluorophenyl)pyrazole which was recrystallized from a mixture of methanol/ethyl acetate/hexane to give 0.78 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][C:11](=[CH2:13])[CH2:10][C@H:9]2[C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.[N+](=[CH2:19])=[N-]>CO.C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:12][C:11](=[CH2:13])[CH2:10][C@H:9]2[C:14]([O:16][CH3:19])=[O:15])=[CH:6][CH:7]=1
Reactant: C=[N+]=[N-]
Reactant: C=C1C[C@@H](C(=O)O)[C@H](c2ccc(Cl)cc2)C1
Solvent: CCOCC
Solvent: CO
Product: C=C1C[C@@H](C(=O)OC)[C@H](c2ccc(Cl)cc2)C1
Temperature: 0 °C

Procedure:
A 100 mL round bottom flask was equipped with a magnetic stir bar and charged with a solution of 1.188 g (5.02 mmol) of the product from Step A (the combined product of two experiments) dissolved in 20 mL of methanol was stirred and cooled to 0° C. with an external ice-water bath. A solution of diazomethane in diethyl ether was added slowly until the reaction mixture developed the persistent yellow color and TLC analysis (25% ethyl acetate-hexanes) indicated that esterification was complete. Excess diazomethane was quenched by dropwise addition of acetic acid, and volatiles were removed in vacuo. The residual clear oil was used directly in the next step without further purification.
Reaction SMILES: [C:1]1([S:7]([CH:10]([NH2:29])[C:11]2O[C:15]([C:17]([OH:19])=[O:18])=[C:14]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:13](=[O:28])[CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:30][NH2:31]>CO>[C:1]1([S:7]([CH:10]([NH2:29])[C:11]2[N:31]([CH3:30])[C:15]([C:17]([OH:19])=[O:18])=[C:14]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:13](=[O:28])[CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN
Reactant: NC(c1cc(=O)c(OCc2ccccc2)c(C(=O)O)o1)S(=O)(=O)c1ccccc1
Solvent: CO
Product: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(OCc2ccccc2)c1C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 65.08 %

Procedure:
To a stirred solution of 6-(benzene sulfonyl amino-methyl)-3-benzyloxy-4-oxo-4H-pyran-2-carboxylic acid (12-01) (640.0 mg, 1.54 mmol) in MeOH (5.0 mL) was added methylamine (2 M in methanol, 2.0 mL) at room temperature and the mixture was stirred for 6 h at room temperature. After completion of the reaction, the solvent was removed under reduced pressure to get the crude compound. It was then purified using normal column chromatography to get 6-(benzene sulfonyl amino-methyl)-3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (13-01) (430.0 mg, 65.08%) as a yellow solid.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][C:18](=[O:20])[C@H:17]3[C@@H:7]([CH2:8][CH2:9][C@@H:10]4[C@:15]3([CH3:16])[CH2:14][CH:13]=[CH:12][CH2:11]4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[C:21]([OH:23])=O.C(Cl)(=O)C([Cl:27])=O>C1C=CC=CC=1>[Cl:27][C:21]([C@H:3]1[CH2:4][CH2:5][C@H:6]2[C@H:7]3[C@H:17]([C:18](=[O:20])[CH2:19][C@:2]12[CH3:1])[C@:15]1([CH3:16])[C@H:10]([CH2:11][CH:12]=[CH:13][CH2:14]1)[CH2:9][CH2:8]3)=[O:23]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[C@]12CC=CC[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC(=O)[C@@H]12
Solvent: c1ccccc1
Product: C[C@]12CC=CC[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)Cl)[C@@]3(C)CC(=O)[C@@H]12

Procedure:
A solution of 5α-androst-2-en-11-one 17β-carboxylic acid (6.3g.) in dry benzene (200 ml.) and oxalyl chloride (15.75 ml.) was refluxed for 1.5 hr. The mixture was evaporated to give 17β-chlorocarbonyl-5α-androst-2-en-11-one as a gum which shaken with 880 ammonia (100 ml.), benzene (32 ml.) and water (32 ml.) After 1 hr. the mixture was extracted with ether. The ethereal solution was washed (H2O), dried and evaporated to give a froth. Crystallisation from chloroform/petrol afforded the title compound (1.9g.); m.p. 92°-96°; [α]D + 95.5°, (c 0.75).
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@@:5]3([CH3:35])[CH:9]([CH:10]4[CH2:11][C@H:12]([F:21])[C:13]5[C@@:18]([CH3:19])([C@:2]124)[CH:17]=[CH:16][C:15](=[O:20])[CH:14]=5)[CH2:8][C@@H:7]([CH3:22])[C@:6]3([O:26][C:27]([C:29]1[S:30][CH:31]=[CH:32][C:33]=1[CH3:34])=[O:28])[C:23]([OH:25])=[O:24].[CH2:36]1CCN2C(=NCCC2)CC1.S(OC)(OC)(=O)=O>C(OCC)(=O)C>[O:1]1[C@H:3]2[CH2:4][C@@:5]3([CH3:35])[CH:9]([CH:10]4[CH2:11][C@H:12]([F:21])[C:13]5[C@@:18]([CH3:19])([C@:2]124)[CH:17]=[CH:16][C:15](=[O:20])[CH:14]=5)[CH2:8][C@@H:7]([CH3:22])[C@:6]3([O:26][C:27]([C:29]1[S:30][CH:31]=[CH:32][C:33]=1[CH3:34])=[O:28])[C:23]([O:25][CH3:36])=[O:24]
Reactant: Cc1ccsc1C(=O)O[C@]1(C(=O)O)[C@H](C)CC2C3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@@]21C
Reactant: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)[C@@]1(OC(=O)c2sccc2C)[C@H](C)CC2C3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@@]21C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of Step 1 (11.1 g) is dissolved in ethyl acetate (200 mL). DBU (4.05 g) and dimethyl sulphate (3.36 g) are added sequentially and the reaction mixture is stirred at room temperature for 2 hours, then partitioned between ethyl acetate and water. The organic layer is washed with water and brine, dried over magnesium sulphate and evaporated. Crystallisation from methanol affords 3-methylthiophene-2-carboxylic acid (6S,9S,10S,11S,13S,16R,17R)-9,11-epoxy-6-fluoro-17-methoxycarbonyl-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl ester. Selected 1H-NMR signals (CDCl3) δ 0.90 (3H, d), 0.92 (3H, s), 1.40 (3H, s), 2.40 (3H, s), 3.65 (3H, s).