Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([CH:8]([OH:24])[C@H:9]1[O:13][C@@H:12]([N:14]2[CH2:19][N:18]([CH3:20])[C:17](=[O:21])[NH:16][C:15]2=[O:22])[CH2:11][C@@H:10]1[OH:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:31](Cl)(=[O:43])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.O>[Si:1]([CH:8]([OH:24])[C@H:9]1[O:13][C@@H:12]([N:14]2[CH2:19][N:18]([CH3:20])[C:17](=[O:21])[NH:16][C:15]2=[O:22])[CH2:11][C@:10]1([C:31](=[O:43])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[OH:23])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CN1CN([C@H]2C[C@H](O)[C@@H](C(O)[Si](C)(C)C(C)(C)C)O2)C(=O)NC1=O
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCC(=O)[C@]1(O)C[C@H](N2CN(C)C(=O)NC2=O)O[C@@H]1C(O)[Si](C)(C)C(C)(C)C
Temperature: 10 °C
Yield: 88.7 %

Procedure:
To a solution consisting of 3.59 gm. (0.010 mole) of 1-(5-tert-butyldimethylsilyl-2-deoxy-β-D-ribofuranosyl)-5-methyl-5,6-dihydro-s-triazine-2,4-(1H,3H)-dione and 30 ml. A.R. pyridine that had been cooled to 5° C. was added, with stirring, 2.55 gm. (0.0116 mole) of freshly distilled lauroyl chloride. This reaction mixture was stirred for 18 hours at 25° C. Then it was cooled to 10° C. and 3 ml. water was added. This mixture was stirred at 25° C. while the solvents were removed by evaporation under reduced pressure. The residue thus obtained was dispersed in a solvent mixture consisting of 100 ml. chloroform and 50 ml. saturated aqueous sodium bicarbonate. The aqueous and organic phases were allowed to stabilize and the organic phase was saved. It was washed two times with 50 ml. portions of saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The dried chloroform solution was filtered and the filter was washed with chloroform. The filtrate and washings were combined and the chloroform was removed by evaporation under reduced pressure. There was thus obtained 4.8 gm. (88.7% yield) of 1-(5-tert-butyldimethylsilyl-3-lauroyl-2-deoxy-β-D-ribofuranosyl)-5,6-dihydro-5-methyl-s-triazine-2,4-(1H,3H)-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([C:18]([C:20]3[C:28]4[CH:27]=[N:26][CH:25]=[N:24][C:23]=4[NH:22][CH:21]=3)=[O:19])[CH:17]=2)=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:36][C:37]([NH2:39])=[O:38]>CN(C=O)C>[NH2:39][C:37](=[O:38])[CH2:36][N:22]1[C:23]2[N:24]=[CH:25][N:26]=[CH:27][C:28]=2[C:20]([C:18]([C:16]2[CH:17]=[C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:13]=[N:14][CH:15]=2)=[O:19])=[CH:21]1
Reactant: NC(=O)CBr
Reactant: O=C(Cc1ccc(Cl)cc1)Nc1cncc(C(=O)c2c[nH]c3ncncc23)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC(=O)Cn1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To a stirred solution of 2-(4-chlorophenyl)-N-[5-(7H-pyrrolo[2,3-d]pyrimidin-5-ylcarbonyl)pyridin-3-yl]acetamide (Example 308, 50 mg, 0.13 mmol) in DMF (1 ml) was added Cs2CO3 (75 mg, 0.23 mmol) followed by 2-bromoacetamide (21.3 mg, 0.154 mmol). The reaction was then stirred at room temperature overnight. The reaction was quenched with water (5 mL) and extracted with EtOAc (3×5 mL). The organics were combined, washed with water (5 mL) then brine (5 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. Purification by preparative HPLC gave the title compound in 59% yield, 34 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][C:21](O)=[O:22])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH:19]=[CH:20][C:21]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:22])=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C=CC(=O)O)cc2)=C(C)C1=O
Reactant: C1COCCN1
Product: COC1=C(OC)C(=O)C(Cc2ccc(C=CC(=O)N3CCOCC3)cc2)=C(C)C1=O
Yield: 43.1 %

Procedure:
3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]acrylic acid (200 mg, 0.58 mmol) obtained in Example 2 and morpholine (65 mg, 0.75 mmol) were used, and a method similar to that described in Example 3 was employed to obtain the title compound (102 mg, 0.25 mmol, yield 43%).
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:13])[C:9]([OH:23])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C(C([Sn])=C(CC[CH2:36][CH3:37])CCCC)CCC.[NH:39]1[CH2:44][CH2:43][NH:42][CH2:41][C:40]1=[O:45]>O1CCOCC1.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>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:12]([C:10]2[C:9]([OH:23])=[C:8]3[C:3]([CH:4]=[CH:5][CH:6]=[N:7]3)=[C:2]([CH2:44][CH2:43][N:42]3[CH2:37][CH2:36][NH:39][C:40](=[O:45])[CH2:41]3)[N:11]=2)=[O:13])=[CH:17][CH:18]=1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: O=C(NCc1ccc(F)cc1)c1nc(Br)c2cccnc2c1O
Reactant: O=C1CNCCN1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: O=C1CN(CCc2nc(C(=O)NCc3ccc(F)cc3)c(O)c3ncccc23)CCN1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture of 5-bromo-N-(4-fluorobenzyl)-8-hydroxy-[1,6]naphthyridine-7-carboxamide (0.40 g, 1.06 mmol), tri-n-butylvinyl tin (0.62 mL, 2.13 mmol), bis (triphenylphosphine)palladium(II) chloride (0.15 g, 0.21 mmol), 2-piperazinone (0.12 g, 1.17 mmol) in dioxane (10 mL) was purged with nitrogen and heated with stirring at 100° C. in a sealed tube for 24 hours. The resultant product mixture was filtered through a pad of Celite. The filtrate was concentrated under vacuum. The residue was dissolved in DMSO, and subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[C:9]([CH3:20])=[C:10]([CH2:14][CH2:15][CH2:16][C:17](O)=[O:18])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:25])=O>>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[C:9]([CH3:20])=[C:10]([CH2:14][CH2:15][CH2:16][C:17]([Cl:25])=[O:18])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1c(CCCC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Product: Cc1c(CCCC(=O)Cl)cccc1C(=O)c1ccc(Cl)cc1

Procedure:
A mixture of 8 g of 4-(3'-p-chlorobenzoyl-2'-methylphenyl)-butyric acid (Example V) and 80 ml of thionyl chloride was refluxed for 45 minutes and after removal of excess thionyl chloride under reduced pressure, 60 ml of benzene were added thereto. The traces of thionyl chloride were removed by entrainment with benzene. This operation was repeated 3 times. The residue was taken up in tetra-hydrofuran to obtain a solution of 4-(3'-p-chlorobenzoyl-2'-methyl-phenyl)-butyric acid chloride which was used as is for the next step.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:17].[C:18]1([CH2:24][C:25](=[NH:29])OCC)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C.C(Cl)(Cl)Cl>[ClH:17].[CH3:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:25](=[NH:29])[CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=N)Cc1ccccc1
Reactant: Cc1ccccc1COc1cccnc1N
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: Cc1ccccc1COc1cccnc1NC(=N)Cc1ccccc1
Yield: 9.5 %

Procedure:
A mixture of 2-amino-3-(2-methylbenzyloxy)pyridine (5.2 g, 24.2 mmol) and ethyl phenylacetimidate hydrochloride (5.32 g, 26.7 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave an oil which was taken up in chloroform, filtered to remove an insoluble white solid, and purified by flash chromatography (chloroform/methanol) to obtain the product (0.85 g), m.p. 175°-178° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11](P(=O)(OCC)OCC)[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:28]([N:35]1[CH2:40][CH2:39][C:38](=O)[CH2:37][CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>C1COCC1>[C:14]1(/[CH:13]=[CH:12]/[CH:11]=[C:38]2[CH2:39][CH2:40][N:35]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:36][CH2:37]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOP(=O)(CC=Cc1ccccc1)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=C/C=C/c2ccccc2)CC1
Yield: 100.1 %

Procedure:
Lithium bis(trimethylsilyl)amide (1M sol. in THF, 2.63 mL, 2.63 mmol) was added at −60° C. under nitrogen atmosphere to a solution of diethyl cinnamylphosphonate (0.629 mL, 2.64 mmol). After 15 min. under stirring at the same temperature, N-Boc-4-piperidone (500 mg, 2.51 mmol) dissolved in THF (5 ml) was added. Stirring and cooling was maintained for 30 min and, after 2 h, the reaction mixture was quenched with water and with EtOAc. The combined extracts were washed, dried over Na2SO4 and evaporated to dryness affording the title product (752 mg), that was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN1CCCC1=O>[CH3:1][N:2]([CH3:23])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:36]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)(=[O:38])=[O:37])[CH2:19][CH2:18]3)=[O:16])=[CH:12][CH:13]=2)[CH2:4]1
Reactant: CN(C)C1CCN(c2ccc(NC(=O)C3CCNCC3)cc2)C1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CN(C)C1CCN(c2ccc(NC(=O)C3CCN(S(=O)(=O)c4ccccc4)CC3)cc2)C1
Reaction time: 12 h

Procedure:
Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide (70 mg) dissolved in N-methylpyrrolidone (2 ml) was mixed with potassium carbonate (45 mg) and benzenesulfonyl chloride (35 mg). After 12 hours, the mixture was filtered and the filtrate was purified by preparative HPLC. This resulted in the product with the molecular weight of 456.61 (C24H32N4O3S); MS (ESI): 457 (M+H+).
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].CS[CH2:9][N:10]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[N:11]1.[CH3:18]O>O>[CH3:18][S:3]([CH2:9][N:10]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[N:11]1)(=[O:5])=[O:2]
Reactant: CO
Reactant: O=S([O-])OO
Reactant: CSCn1ccc([N+](=O)[O-])n1
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)Cn1ccc([N+](=O)[O-])n1
Reaction time: 16 h
Yield: 80 %

Procedure:
Oxone (2.05 g, 3.36 mmol) was added to a mixture of 1-methylsulfanylmethyl-3-nitro-1H-pyrazole (194 mg, 1.12 mmol) in methanol (10 mL) and deionized water (100 μL) was allowed to proceed for 16 h with vigorous stirring. The solvent was removed in vacuo and the crude material was purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) afforded 1-methanesulfonylmethyl-3-nitro-1H-pyrazole as a white solid (184 mg, 80%).
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=2[CH:28]=O)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[CH:1]1([N:6]2[C:10]3=[N:11][C:28]([C:27]4[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=4[O:25][CH2:24][CH2:23][N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: O=Cc1ccccc1OCCN1CCOCC1
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccccc3OCCN3CCOCC3)nc(=O)c1-2
Temperature: 120 °C

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (0.95 g, 4.28 mmol), 2-[2-(4-morpholinyl)ethoxy]benzaldehyde (1.51 g) and xylenes (15 ml) was heated to 120° C. for 1 hour, then to 160° C. until the reaction was complete. The reaction mixture was then cooled to room temperature, the solvent was removed in vacuo, and the residue was purified by silica gel chromatography eluting with ethyl acetate (100%), followed by ethanol/ethyl acetate (1/1) to afford 1-cyclopentyl-3-ethyl-6-[2-[2-(4-morpholinyl)ethoxy]phenyl]pyrazolo[3,4-d]pyrimidin-4-one (Example 11 (b)), as an oil. The free base was then converted into its hydrochloride salt, which was recrystallized from ethanol and dried at 110° C. under high vacuum to afford 0.5 g of 1-cyclopentyl-3-ethyl-6-[2-[2-(4-morpholinyl)ethoxy]phenyl]pyrazolo[3,4-d]pyrimidin-4-one monohydrochloride, as an off-white powder, m.p. 235-237° C., labelled as Example 11 (c).
Reaction SMILES: O[C:2]1[C:3]([OH:12])=[C:4]([C:7]([CH2:10][CH3:11])=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:21]([O-:24])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:13]([O:12][C:3]1[CH:2]=[C:9]([O:24][CH2:21][C:2]2[CH:3]=[CH:4][CH:7]=[CH:8][CH:9]=2)[CH:8]=[C:7]([CH2:10][CH3:11])[C:4]=1[CH:5]=[O:6])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: CCc1ccc(O)c(O)c1C=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1C=O
Yield: 88 %

Procedure:
1.9 g of dihydroxy-6-ethylbenzaldehyde, 3.48 ml of benzyl chloride and 4.7 g of K2CO3 are stirred in 5.2 ml of DMF at 90° for 2 h. The batch is diluted with EtOAc and washed with water. The organic phase is dried using Na2SO4, evaporated and chromatographed on silica gel. The uniform fractions are combined and evaporated. The oily residue solidifies on standing after a few days. Treatment with etheropetroleum ether 1:1 gives 3.5 g (88%) of 2,4-bisbenzyloxy-6-ethylbenzaldehyde, which discolours in air.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH3:42])([CH3:41])[C@H:13]3[C@:26]([CH3:29])([CH2:27][CH:28]=2)[C@@H:25]2[C@:16]([CH3:40])([C@@:17]4([CH3:39])[CH:22]([CH2:23][CH2:24]2)[C@H:21]2[C@H:30]([C:33]([CH3:35])=[CH2:34])[CH2:31][CH2:32][C@:20]2([C:36]([OH:38])=O)[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:7][CH:6]=1)=[O:4].C(Cl)(=O)C([Cl:46])=O>ClCCl>[Cl:46][C:36]([C@:20]12[CH2:32][CH2:31][C@@H:30]([C:33]([CH3:35])=[CH2:34])[C@@H:21]1[C@@H:22]1[C@@:17]([CH3:39])([CH2:18][CH2:19]2)[C@@:16]2([CH3:40])[C@@H:25]([C@:26]3([CH3:29])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:41])([CH3:42])[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[CH:28][CH2:27]3)[CH2:24][CH2:23]1)=[O:38]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)C(CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)Cl)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a flask containing (1R,3aS,5aR,5bR,7aR,11aS,11bR,13bR)-9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (0.1-4.2 mmol scale) was added oxalyl chloride (2M in dichloromethane) (10-50 equiv.). The solution was stirred at rt for 2-5 h and was stripped of solvent. The residue was dissolved in dichloromethane and concentrated two additional times, then was used with no additional purification in the next step. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.92 (d, J=8.55 Hz, 2H), 7.19 (d, J=8.24 Hz, 2H), 5.26-5.30 (m, 1H), 4.73 (d, J=1.53 Hz, 1H), 4.62-4.64 (m, 1H), 3.90 (s, 3H), 2.81 (td, J=11.14, 4.58 Hz, 1H), 2.47 (ddd, J=13.58, 3.20, 3.05 Hz, 1H), 2.19-2.28 (m, 2H), 2.10 (dd, J=17.09, 6.41 Hz, 1H), 1.85-1.99 (m, 1H), 1.68 (s, 3H), 1.00 (s, 6H), 0.98 (s, 3H), 0.92 (s, 3H), 0.92 (s, 3H), 0.84-1.83 (m, 17H). 13C NMR (126 MHz, CHLOROFORM-d) δ ppm 177.49, 167.35, 149.46, 148.81, 146.39, 130.17 (s, 2C), 128.61 (s, 2C), 128.03, 124.12, 110.40, 68.00, 52.99, 52.11, 49.78, 49.67, 46.11, 42.54, 41.86, 40.70, 38.00, 37.60, 36.39, 36.31, 33.64, 32.3, 29.98, 29.72, 29.54, 25.60, 21.37, 21.13, 19.86, 19.48, 16.59, 15.71, 14.89.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7](=[O:26])[C@@H:8]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C@@H:9]([O:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17])[CH2:10][CH3:11])[C@H:4]([C:27](=[O:44])[NH:28][C@:29]2([C:34](=[O:43])[NH:35][S:36]([C:39]3([CH3:42])[CH2:41][CH2:40]3)(=[O:38])=[O:37])[CH2:31][C@H:30]2C=C)[CH2:3]1>CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.ClCCCl>[CH2:10]([C@H:9]1[C@H:8]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:22])[CH3:23])[C:7](=[O:26])[N:5]2[CH2:6][C@H:2]([OH:1])[CH2:3][C@H:4]2[C:27](=[O:44])[NH:28][C@:29]2([C:34](=[O:43])[NH:35][S:36]([C:39]3([CH3:42])[CH2:40][CH2:41]3)(=[O:38])=[O:37])[CH2:31][C@H:30]2[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH3:11]
Reactant: C=CCCCO[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)NS(=O)(=O)C2(C)CC2)C[C@H]1C=C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: CC[C@@H]1OCCC/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2(C)CC2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@H]1NC(=O)OC(C)(C)C
Solvent: ClCCCl
Product: CC[C@@H]1OCCCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2(C)CC2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@H]1NC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a round-bottom flask equipped with a stir bar was added tert-butyl ((2S,3S)-1-((2S,4R)-4-hydroxy-2-(((1R,2S)-1-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)pyrrolidin-1-yl)-1-oxo-3-(pent-4-en-1-yloxy)pentan-2-yl)carbamate (all material from step 4, 480 mg, 0.749 mmol) and DCE (100 mL). The solution was sparged with nitrogen for 30 minutes. To the solution was added Hoveyda-Grubbs Catalyst 2nd Generation (23 mg, 0.037 mmol). The solution was stirred at 80° C. for 2 h, then was cooled to 45° C. and was stirred for 3 days. The solution was concentrated in vacuo and the resulting residue was subjected to C18 chromatography (water with 0.1% TFA:acetonitrile with 0.1% TFA, 60:40 to 0:100) to afford tert-butyl ((2R,6S,7S,13aS,14aR,16aS,Z)-7-ethyl-2-hydroxy-14a-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5,16-dioxo-2,3,5,6,7,9,10,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa[i]pyrrolo[1,2-e][1,5,8]oxadiazacyclopentadecin-6-yl)carbamate as a brown solid foam (100 mg, 22%). MS: MS m/z 613.4 (M++1).
Reaction SMILES: [C:1](OC(C)C)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17].[H][H]>[Cr].[Cu]>[CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18]
Reactant: [H][H]
Reactant: CC(C)CCCCCCCCCCCCCCC(=O)OC(C)C
Agent: [Cr]
Agent: [Cu]
Product: CC(C)CCCCCCCCCCCCCCCO
Temperature: 275 °C
Reaction time: 7 h
Yield: 83.5 %

Procedure:
Into a 20 liters autoclave were charged 4770 g of isopropyl isostearate [Emery 2310, commercially available from Emery Co., Ltd. U.S.A.] and 239 g of copper-chromium catalyst (product of Nikki Co., Ltd.). Hydrogen gas was charged into the reactor under a pressure of 150 kg/cm2 and the reaction mixture was heated up to 275° C. After hydrogenation under 150 kg/cm2 /275° C. for about 7 hours, the reaction product was cooled, followed by removing the catalyst residue by filtration to obtain 3500 g of crude product. The crude product was distilled under reduced pressure thereby obtaining 3300 g of colorless transparent isostearyl alcohol as a fraction of 80° to 167° C./0.6 mmHg. The thus obtained isostearyl alcohol (monomethyl-branched isostearyl alcohol) had an acid value of 0.05, a saponification value of 5.5, and a hydroxyl value of 181.4. IR analysis (liquid film) revealed absorptions at 3340 and 1055 cm-1 and NMR analysis (CCl4 solvent) revealed an absorption at (δ)=3.50 (broad triplet, --CH2 --OH). According to the gas chromatograph, the alcohol was chiefly composed of about 75% of an alcohol whose number of carbon atoms in the alkyl group was 18, with the remainder being made of alcohols having alkyl groups with 14 and 16 carbon atoms. The branched methyl group was located substantially at the center of the main alkyl chain in all the alcohol components.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9](O)[C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][N:11]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)C>S(Cl)(Cl)=O.CN(C)C=O>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:22][CH:21]=1
Reactant: COc1cccnc1C(O)c1cc(F)ccc1F
Reactant: Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1cccnc1C(Sc1ccc(Cl)cc1)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.8 %

Procedure:
After the 2-[(2,5-difluorophenyl)-hydroxymethyl]-3-methoxypyridine (251 mg, 1.0 mmol) obtained in Referential Example 9 was dissolved in thionyl chloride (2.0 ml), a catalytic amount of dimethylformamide was added to the resulting solution. The resulting mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added dioxane, followed by further concentration. The residue thus obtained was dissolved in dimethylformamide (10 ml). To the resulting solution were added 4-chlorobenzenethiol (289 mg, 2.0 mmol) and potassium carbonate (1.10 g, 8.0 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 50° C. for 1 hour. After the reaction mixture was cooled to room temperature, diethyl ether (50 ml) was added thereto. The resulting mixture was washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (hexane:ethyl acetate=10:1) to give the title compound (256 mg, 58%) as an oil.
Reaction SMILES: Cl.NO.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:22])[C:12](=[CH:18][N:19](C)C)[C:13]([CH:15]2[CH2:17][CH2:16]2)=[O:14])=[C:7]([N:23]([CH2:28][CH3:29])[S:24]([CH3:27])(=[O:26])=[O:25])[CH:6]=1>C(O)C>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:12]2[CH:18]=[N:19][O:14][C:13]=2[CH:15]2[CH2:17][CH2:16]2)=[O:22])=[C:7]([N:23]([CH2:28][CH3:29])[S:24]([CH3:27])(=[O:26])=[O:25])[CH:6]=1
Reactant: CCN(c1cc(Cl)ccc1C(=O)C(=CN(C)C)C(=O)C1CC1)S(C)(=O)=O
Agent: Cl
Agent: NO
Solvent: CCO
Product: CCN(c1cc(Cl)ccc1C(=O)c1cnoc1C1CC1)S(C)(=O)=O
Reaction time: 1 h
Yield: 22.9 %

Procedure:
Hydroxylamine hydrochloride (0.76 g) was added to a mixture of 1-[4-chloro-2-(N-ethyl-N-methylsulphonylamino)phenyl]-3-cyclopropyl-2-dimethylaminomethylenepropan-1,3-dione (3.83 g) in ethanol. The mixture was stirred for 1 hour and evaporated to dryness. The residue was dissolved in dichloromethane and washed with water, dried (magnesium sulphate) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography eluted with a mixture of cyclohexane, dichloromethane and ethyl acetate. The product was triturated with a mixture of ether and hexane and filtered to give 4-[4-chloro-2-(N-ethyl-N-methylsulphonylamino)benzoyl]-5-cyclopropylisoxazole (compound 4, 0.81 g) as a white solid, mp. 114-115.8° C.