Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Si:26]([O:33][CH2:34][CH2:35]I)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].C(OCC)(=O)C>O1CCCC1.CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:35][CH2:34][O:33][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCCI
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCO[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (3.06 g, 9.67 mmol) and sodium hydride (0.43 g, 60% in oil, 10.64 mmol) in tetrahydrofuran (60 mL) and dimethylformamide (6 mL). After 2 hours, add 2-(t-butyldimethylsilyloxy)ethyl iodide (2.78 g, 9.67 mmol). After 20 hours, heat to reflux. After 4 hours, cool to ambient temperature and add ice to quench. Evaporate in vacuo to remove most of the tetrahydrofuran. Partition the evaporated reaction mixture between ethyl acetate (250 mL) and water (200 mL). Separate the layers and extract the organic layer with water. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give 1-(t-butoxycarbonyl)-4-(1-(2-(t-butyldimethylsilyloxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane: Rf=0.58 (silica gel, ethyl acetate).
Reaction SMILES: [CH3:1][C:2]1([CH3:46])[CH2:7][O:6][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C@:17](O)([CH2:18][C@@H:19]([O:35][C:36](=[O:44])[NH:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH2:20][C@@H:21]3[O:29][C:30](=[O:34])[N:31]([CH3:33])[CH3:32])[CH:16]=[CH:15]4)[CH2:12][CH2:11]2)[CH3:9])[O:4][CH2:3]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:46][C:2]1([CH3:1])[CH2:3][O:4][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([O:35][C:36](=[O:44])[NH:37][C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)[CH2:20][C@@H:21]3[O:29][C:30](=[O:34])[N:31]([CH3:32])[CH3:33])=[CH:16][CH:15]=4)[CH2:12][CH2:11]2)[CH3:9])[O:6][CH2:7]1
Reactant: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3C=C[C@@]4(O)C[C@@H](OC(=O)Nc5ccccc5)C[C@H](OC(=O)N(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC(=O)Nc5ccccc5)C[C@H](OC(=O)N(C)C)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 10 h
Yield: 29.4 %

Procedure:
In 10 ml of toluene was dissolved 350 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α-(N,N-dimethylcarbamoyl)oxy-3β-(N-phenylcarbamoyl)oxypregn-6-en-5α-ol, followed by addition of 50 mg of pyridinium p-toluenesulfonate. The mixture was stirred in an atmosphere of argon gas at room temperature for 10 hours. The reaction mixture was then worked up in the same manner as Example 124 to give 100 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α-(N,N-dimethylcarbamoyl)oxy-3β-(N-phenylcarbamoyl)oxypregna-5,7-diene showing the following physical properties.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5][NH:4][CH2:3]1.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>>[CH3:1][C:2]1([CH3:21])[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5][N:4]([C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([F:22])=[CH:24][CH:25]=2)[CH2:3]1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)C1=CNCC(C)(C)c2c1[nH]c1ccccc21
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1ccccc21

Procedure:
As described in Example 2, the title compound was prepared from ethyl 1,1-dimethyl-1,2,3,6-tetrahydro-azepino[4,5-b]indole-5-carboxylate and 4-fluorobenzoyl chloride. 1H-NMR (DMSO-d6): δ 10.82 (1H, s), 7.76 (1H, d), 7.65 (1H, s), 7.61 (2H, dd), 7.54 (1H, d), 7.35 (2H, app t), 7.09 (1 H, app t), 6.98 (1 H, app t), 4.22 (2H, q), 3.97 (2H, brs), 1.52 (6H, s), 1.17 (3H, t); MS(ESI): 407 (MH+).
Reaction SMILES: CI.[C:3](=O)([O-])[O-].[K+].[K+].[OH:9][C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=1>CC(C)=O>[CH3:3][S:16][C:13]1[CH:14]=[CH:15][C:10]([OH:9])=[CH:11][CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(S)cc1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CSc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.3 %

Procedure:
In a water bath, methyl iodide (18.5 ml) and potassium carbonate (28.7 g) were added to an acetone (250 ml) solution of 4-hydroxythiophenol (25 g), and stirred at room temperature for 5 hours. The salt was removed by filtration, the solvent was evaporated away under reduced pressure, diethyl ether was added, and extracted with aqueous 2 N sodium hydroxide solution. The obtained aqueous layer was made acidic with aqueous 6 N hydrochloric acid solution, extracted with diethyl ether, and the organic layer was washed with aqueous saturated sodium chloride solution. After dried, the solvent was evaporated away under reduced pressure to obtain 4-(methylsulfanyl)phenol (27.3 g) as a pale yellow solid. In a water bath, 30% hydrogen peroxide water (67 ml) was gradually and added dropwise to an acetic acid (130 ml) solution of 4-(methylsulfanyl)phenol (27.3 g). After the addition, this was gradually heated up to 100° C., and stirred for 1 hour. The reaction solution was restored to room temperature, and neutralized with saturated sodium bicarbonate water. This was extracted with ethyl acetate, and washed with saturated sodium bicarbonate water and saturated saline water. After dried, the solvent was evaporated away to obtain the entitled compound as a pale yellow solid.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:22][CH:21]=1.IC.Cl>O1CCCC1.CN(P(N(C)C)N(C)C)C.CCCCCC>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:1])[C:27]([OH:29])=[O:28])=[CH:22][CH:21]=1
Reactant: O=C(O)Cc1ccc(-c2ccccc2F)cc1
Reactant: CC(C)NC(C)C
Agent: CN(C)P(N(C)C)N(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CI
Product: CC(C(=O)O)c1ccc(-c2ccccc2F)cc1
Reaction time: 0.25 h

Procedure:
Diisopropylamine (16.4 ml) was dissolved in tetrahydrofuran (100 ml) and then a hexane solution (30.3 ml, 1.66 M) of n-butyllithium was added under ice-cooling, after which the resulting mixture was stirred for 15 minutes. Subsequently, thereto was added under ice-cooling a solution obtained by dissolving the above carboxylic acid (13.44 g) in tetrahydrofuran (100 ml), and thereafter, hexamethylphosphorus triamide (40 ml) was added, after which the resulting mixture was stirred under ice-cooling for one hour. Further, iodomethane (3.63 ml) was added and the resulting mixture was stirred for 3 hours. To the reaction mixture was added 10% hydrochloric acid (500 ml) and then the solution was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, then dried over sodium sulfate and thereafter concentrated under reduced pressure, to obtain 2-(2'-fluoro-biphenyl-4-yl)-propionic acid (16.64 g).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]3[C:13](=[O:14])[N:12]([CH2:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:11](=[O:23])[C:9]3=2)[NH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+].[CH3:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Cl)=[CH:36][CH:35]=1>CN(C)C=O>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]3[C:13](=[O:14])[N:12]([CH2:15][CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:11](=[O:23])[C:9]3=2)[N:4]([CH2:38][C:37]2[CH:40]=[CH:41][C:34]([O:33][CH3:32])=[CH:35][CH:36]=2)[N:3]=1
Reactant: O=C1c2cnc3[nH]nc(Br)c3c2C(=O)N1CCc1ccccc1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(Br)c3c4c(cnc32)C(=O)N(CCc2ccccc2)C4=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
To a solution of 1-bromo-7-phenethylpyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)-dione (500 mg, 1.34 mmol) in anhydrous N,N-dimethylformamide (5 ml), cesium carbonate (2.19 g, 6.7 mmol) and sodium iodide (27 mg, 0.2 mmol) were added followed p-methoxybenzyl chloride (0.18 mL, 2 mmol). The reaction mixture was stirred at room temperature for 2 hours. After completion of reaction (TLC and LCMS), the reaction mixture was poured over ice and extracted with ethyl acetate (3×50 ml). The combined organic layer was dried over sodium sulfate and evaporated under reduced pressure to give a residue which was purified by column chromatography on silica gel using a gradient of 0-20% ethyl acetate-hexanes to afford 1-bromo-3-(4-methoxybenzyl)-7-phenethylpyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)-dione (400 mg, 60%) as a solid. 1H NMR (400 MHz, CDCl3): δ 9.00 (s, 1H), 7.35 (d, 2H), 7.20-7.30 (m, 5H), 6.80 (d, 2H), 5.70 (s, 2H), 3.95 (t, 2H), 3.80 (s, 3H), 3.00 (t, 2H); LCMS: [M+H] 491.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([NH2:15])[CH:9]=2)[CH2:7][CH2:6]1)=[O:4].Cl[C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl.O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]3[O:14][C:17](=[O:19])[NH:15][C:10]=3[CH:9]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(c2ccc(O)c(N)c2)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1(c2ccc3oc(=O)[nH]c3c2)CC1
Yield: 61.3 %

Procedure:
To a solution of 1-(3-amino-4-hydroxy-phenyl)-cyclopropanecarboxylic acid methyl ester (2.0 g, 9.6 Mmol) in THF (40 mL) was added triphosgene (4.2 g, 14 mmol) at room temperature. The mixture was stirred for 20 minutes at this temperature before water (20 mL) was added dropwise at 0° C. The resulting mixture was extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give 1-(2-oxo-2,3-dihydro-benzooxazol-5-yl)-cyclopropanecarboxylic acid methyl ester (2.0 g, 91%), which was directly used in the next step. 1H NMR (CDCl3, 300 MHz) δ 8.66 (s, 1H), 7.13-7.12 (m, 2H), 7.07 (s, 1H), 3.66 (s, 3H), 1.68-1.65 (m, 2H), 1.24-1.20 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][C@@H:11]([OH:13])[CH2:10][N:9]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23](O)=[O:24])=[C:16]3[N:15]=2)[CH:5]=[CH:6][CH:7]=1.[CH:26]1([NH2:29])[CH2:28][CH2:27]1>>[CH:26]1([NH:29][C:23]([C:22]2[CH:21]=[N:20][N:17]3[CH:18]=[CH:19][C:14]([N:9]4[CH2:10][C@H:11]([OH:13])[CH2:12][C@@H:8]4[C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[N:15][C:16]=23)=[O:24])[CH2:28][CH2:27]1
Reactant: NC1CC1
Reactant: O=C(O)c1cnn2ccc(N3C[C@H](O)C[C@@H]3c3cccc(F)c3)nc12
Product: O=C(NC1CC1)c1cnn2ccc(N3C[C@H](O)C[C@@H]3c3cccc(F)c3)nc12
Yield: 66 %

Procedure:
Prepared by the method described in Example 1 using 5-((2R,4R)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid and substituting tert-butyl amine with cyclopropylamine to provide the final product as a white solid (15 mg, 66% yield). MS (apci) m/z=382.1 (M+H).
Reaction SMILES: C(O[C:6](=[O:20])[NH:7][C@H:8]([CH:17]1[CH2:19][CH2:18]1)[C:9]([N:11]1[CH2:14][CH:13]([C:15]#[N:16])[CH2:12]1)=[O:10])(C)(C)C.FC(F)(F)C(O)=O.[Br:28][C:29]1[N:30]=[C:31]2[C:37](C(O)=O)=[CH:36][N:35]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:32]2=[N:33][CH:34]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl.C(OCC)(=O)C.O>[C:15]([CH:13]1[CH2:12][N:11]([C:9](=[O:10])[C@H:8]([NH:7][C:6]([C:37]2[C:31]3[C:32](=[N:33][CH:34]=[C:29]([Br:28])[N:30]=3)[N:35]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[CH:36]=2)=[O:20])[CH:17]2[CH2:18][CH2:19]2)[CH2:14]1)#[N:16]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(Br)cnc21
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CC(C#N)C1)C1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CC(C#N)C2)C2CC2)c2nc(Br)cnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.7 %

Procedure:
[(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-carbamic acid tert-butyl ester (0.99 g, 3.54 mmol) was dissolved in 24 mL of dichloromethane and cooled in an ice bath. Trifluoroacetic acid (10.6 mL) was added slowly and the reaction was then stirred at room temperature. After 3 h., the reaction was judged complete by TLC and was then evaporated under high vacuum. The residue was dissolved in 34 mL of acetonitrile to which was then added 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1.28 g, 3.44 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.21 g, 3.78 mmol) and N,N-diisopropylethylamine (2.1 mL, 12 mmol). The reaction was stirred for 18 h and then water and ethyl acetate were added. The layers were separated and the aqueous layer was extracted once more with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (methanol/dichloromethane). The resultant viscous oil was triturated with hexanes to provide 0.93 g (50%) of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide as a white solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:8]1([SH:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH:2]1([S:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Ic1ccccc1
Reactant: SC1CCCCC1
Product: c1ccc(SC2CCCCC2)cc1

Procedure:
The general procedure was used to convert iodobenzene and cyclohexylmercaptan to the title product. Purification by flash chromatography (hexane as the eluent) gave the analytically pure product as a clear oil (297 mg, 77% yield). 1H NMR (300 MHz, CDCl3) δ 7.44 (dd, J=6.97, 2H; Ha, Ha′), 7.35–7.22 (m, 3H; Hb, Hb′, Hc,), 3.19–3.11 (m, 1H; Hd), 2.04 (m, 2H; He, Hi), 1.82 (m, 2H; He′, Hi′), 1.65 (m, 1H; Hg), 1.48–1.26 (m, 5H; Hh, Hf, Hh′, Hf′, Hg′). 13C NMR (75 MHz, CDCl3) δ 135.11 (C1), 131.75 (C3, C5), 128.64 (C2, C6), 126.46 (C4), 46.44 (C7), 33.26 (C8, C12), 25.97 (C10), 25.69 (C9, C11). Anal. Calcd. for C12H16S: C, 74.94; H, 8.39; S, 16.67; Found C, 75.06; H, 8.40; S, 16.54.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:20])[CH3:19])=[CH:13][CH:12]=2)=O)=[CH:5][CH:4]=1.[CH3:21][C:22]1([CH3:31])[CH2:27][C:26]([CH3:29])([CH3:28])[CH2:25][C:24](=O)[CH2:23]1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[C:24]2[CH2:25][C:26]([CH3:29])([CH3:28])[CH2:27][C:22]([CH3:31])([CH3:21])[CH2:23]2)[C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:20])[CH3:19])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2ccc(NC(C)=O)cc2)cc1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(NC(C)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To a stirred suspension of zinc powder (0.39 g, 5.94 mmol) in THF (15 mL) was slowly added TiCl4 (0.33 mL, 2.97 mmol) via syringe at RT under a nitrogen atmosphere. The mixture was heated at reflux for 2 h. A solution of N-(4-{[4-(methyloxy)phenyl]carbonyl}phenyl)acetamide (56) (0.20 g, 0.74 mmol) and 3,3,5,5-tetramethylcyclohexanone (0.35 g, 2.23 mmol) in THF (4 mL) was added to the mixture. The reaction mixture was heated at reflux with stirring under a nitrogen atmosphere for 1 h. The reaction mixture was allowed to cool to room temperature. To the reaction mixture was slowly added 10% aqueous K2CO3 (15 mL). The reaction mixture was filtered through a pad of Celite and the pad washed with EtOAc (100 mL). The filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was further extracted with EtOAc (25 mL). The combined organic phase washed with water, brine, dried (Na2SO4) filtered, and the filtrate was concentrated to give the crude product as yellow oil. The crude product was purified by chromatography on a silica gel column eluted with a gradient from hexanes to 40% EtOAc:hexanes to give 0.27 g (93%) of compound 57 as colorless viscous oil. 1H NMR (400 MHz, CDCl3): δ 0.91 (s, 6H), 0.92 (s, 6H), 1.27 (s, 2H), 1.96 (s, 2H), 1.97 (s, 2H), 2.16 (s, 3H), 3.78 (s, 3H), 6.80 (d, J=8.6 Hz, 2H), 7.06 (d, J=8.8 Hz, 2H), 7.10 (d, J=8.5 Hz, 2H), 7.39 (d, J=8.5 Hz, 2H). LCMS (ESI): m/z 392 (M+H)+, 390 (M−H)−.
Reaction SMILES: [C:1]([O:7]CC)(=O)[CH2:2][C:3]([CH3:5])=O.[CH3:10][C:11]1[CH:12]=[C:13]([NH2:16])[NH:14][N:15]=1>>[CH3:10][C:11]1[CH:12]=[C:13]2[NH:16][C:3]([CH3:5])=[CH:2][C:1](=[O:7])[N:14]2[N:15]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1cc(N)[nH]n1
Product: Cc1cc2[nH]c(C)cc(=O)n2n1

Procedure:
In Step 1, ethyl acetoacetate and 5-methyl-2H-pyrazol-3-ylamine are condensed to form 2,5-dimethyl-4H-pyrazolo[1,5-a]pyrimidine-7-one (1) in refluxing acetic acid.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[S:11][S:12][C:13]([CH2:16][O:17][C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=2[Cl:28])=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(O)(=O)C>[OH:8][CH2:9][C:10]1[S:11][S:12][C:13]([CH2:16][O:17][C:18]2[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:19]=2[Cl:28])=[CH:14][CH:15]=1
Reactant: CC(C)(C)[Si](C)(C)OCC1=CC=C(COc2cc(C(F)(F)F)ccc2Cl)SS1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: OCC1=CC=C(COc2cc(C(F)(F)F)ccc2Cl)SS1
Reaction time: 5 h
Yield: 57 %

Procedure:
To a stirred solution of the 3-[(tert-butyldimethylsilyloxy)methyl]-6-[(2-chloro-5-trifluoromethyl-phenyloxy)methyl]-1,2-dithiin obtained above (290 mg, 0.62 mmol) in 8 mL of THF was added a solution of 4 mL of 1M tetrabutylammonium fluoride in THF and 2.5 mL of acetic acid. The reaction mixture was stirred for 5 h until TLC analysis showed the reaction to be complete. The reaction mixture was partitioned between 30 mL of water and 50 mL of ethyl acetate. The organic phase was washed with 3% aqueous sodium bicarbonate (50 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL) and then the combined organic layer was washed with water, dried over magnesium sulfate and concentrated to a small volume. The residue was chromatographed over a silica gel column (ethyl acetate-hexane, 1:3) to yield 120 mg (57%) of the title compound as a yellow solid. The compound was further purified by reverse phase HPLC (PRP-1 column, acetonitrile:water gradient), mp 94.2°-96° C.; 1H NMR (CDCl3):δ7.51 (d, J=8.4, 1 H), 7.22 (dd, J=6.8, J=2.0, 1 H), 7.16 (d, J=l.2, 1 H), 6.55 (d, J=6.0, 1 H), 6.5 (d, J=6.0, 1 H), 4.79 (s, 2 H), 4.31 (d, 2 H, J=5.6) 1.80 (t, J=6.0, 1 H); 13C NMR(CDCl3):δ153.69, 136.86, 136.49, 130.98, 130.85, 128.30, 127.54, 124.77, 119.13, 118.28, 111.03, 70.73, 64.53, MS (EI):354 (M+). Anal. calcd for C13H10ClF3O2S2 :C, 44.01; H, 2.84. Found:C, 43.74; H, 2.94.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C:10](=[CH2:12])[CH2:9][C@H:8]1[CH2:13][O:14][Si](C(C)(C)C)(C)C)=[O:6])[CH:2]=[CH2:3].Cl.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.[Cl-].[Na+].O>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C:10](=[CH2:12])[CH2:9][C@H:8]1[CH2:13][OH:14])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1CC(=C)C[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1CC(=C)C[C@H]1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a solution of (2S)-1-allyloxycarbonyl-2-(t-butyldimethylsilyloxymethyl)-4-methylenepyrrolidine (2.88 g) in ethyl acetate (100 ml) was added 6N hydrochloric acid (3.0 ml) at ambient temperature. After stirring for 1 hour at ambient temperature, to the mixture were added potassium carbonate (2.54 g) and brine (30 ml) with stirring. The organic layer was separated, washed in turn with aqueous sodium hydrogen carbonate and brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (40 ml) eluting with a mixture of n-hexane and ethyl acetate (3:1 V/V) to give (2S)-1-allyloxycarbonyl-2-hydroxymethyl-4-methylenepyrrolidine (1.78 g).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[S:19])[C:8]1[CH:13]=[C:12]([N:14]=[C:15]=[S:16])[C:11]([F:17])=[CH:10][C:9]=1[Cl:18])=[O:4].[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][NH:21]1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[S:19])[C:8]1[CH:13]=[C:12]([NH:14][C:15]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][NH:21]2)=[S:16])[C:11]([F:17])=[CH:10][C:9]=1[Cl:18])=[O:4]
Reactant: C1CCNNC1
Reactant: COC(=O)COC(=S)c1cc(N=C=S)c(F)cc1Cl
Solvent: Cc1ccccc1
Product: COC(=O)COC(=S)c1cc(NC(=S)N2CCCCN2)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
A solution of 4.8 g of the resulting 2-chloro-4-fluoro-5-isothiocyanatothiobenzoic acid (methoxycarbonylmethyl) ester in 50 ml of toluene is added dropwise, with stirring, at from 20° to 250° C. to a solution of 1.4 g of hexahydropyridazine in 20 ml of toluene. The batch is then stirred for a further 8 hours at room temperature and is then concentrated by evaporation in vacuo to yield 4.4 g of 2-chloro-4-fluoro-5-(1-hexahydropyridazinylthiocarbonylamino)-thiobenzoic acid (methoxycarbonylmethyl) ester in resinous form.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:4]=2[N:3]=1>N.CO>[Cl:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]2[OH:9])[C:5]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:4]=2[N:3]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Cl)ccc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Solvent: CO
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Cl)ccc32)[C@H](O)[C@@H]1O

Procedure:
A solution of 0.226 g (0.508 mmole) of 72 in 10 mL of NH3 /MeOH was stirred in a pressure bottle at room temperature for 5 hr. The reaction mixture was evaporated and coevaporated with MeOH (3×) to give a solid. This solid was recrystallized from MeOH to give 0.136 g (76%, based on C12H12Cl2N2O4MeOH) of 73 as white crystals. MP 102°-150° C. (melted over a large range of temperature). MS (Cl) m/e 319.0242 (37%, MH+ =319.0252). 1H NMR ((DMSO-d6): d 8.06 (d, 1, 7-H, J7-6 =9.0 Hz), 7.73 (d, 1, 4-H, J4-6 =2.0 Hz), 7.30 (dd, 1, 6-H), 5.89 (d, 1, 1'-H, J1-2 =8.0 Hz), 5.51 (d, 1, 2'-OH, J2'-2'OH =6-5 Hz), 5.29 (d, 1, 3'-OH J3'-3'OH =4.5 Hz),5.26 (t, 1, 5'-OH, J5'-5'OH =5-0 Hz), 4.45 (m, 1, 2'-H, J2'-3' =5.5 Hz), 4.12 (m, 1, 3'-H, J3'-4' =2.0 Hz), 3.99 (m, 1, 4'-H, J4'-5' =J4'-5" =3.5 Hz), 3.69 (m, 2, 5'-H and 5"-H, J5'-5" =12.0 Hz). 13C NMR ((DMSO-d6) d 142.36 (C3a), 141.40 (C2), 131.88 (C7a), 127.49 (C5), 123.32 (C6), 118.40 (C4), 114.51 (C7), 89.07 (C1'), 86.23 (C4'), 71.49 (C2'), 69.75 (C3'), 61.23 (C5').