Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8](O)([CH3:10])[CH3:9].S(Cl)(Cl)=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([CH3:10])=[CH2:9]
Reactant: CC(C)(O)c1ccncc1Br
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: C=C(C)c1ccncc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
To a stirred solution of Intermediate 42A (1.25 g) in pyridine (38 mL) at 0° C. was added thionyl chloride (38.5 mL, 526.5 mmol). The reaction mixture was then stirred at room temperature overnight, quenched with saturated aqueous sodium bicarbonate solution and extracted with CH2Cl2 (2×20 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (80 g BIOTAGE® column, eluting with hexane:CH2Cl2/4:6) to provide Intermediate 42 (705 mg, 61.5% yield). MS (ES): m/z=198.1 [M+H]+. Intermediate 42 was used in the synthesis of Example 227.
Reaction SMILES: O[C:2]1([C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][N:16]=2)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.S(Cl)(Cl)=O>N1C=CC=CC=1>[F:24][C:21]([F:22])([F:23])[C:19]1[CH:18]=[CH:17][N:16]=[C:15]([C:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4][CH:3]=2)[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc(C(F)(F)F)ccn2)CC1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccn2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 53.3 %

Procedure:
To a solution of tert-butyl 4-hydroxy-4-[4-(trifluoromethyl)pyridin-2-yl]piperidine-1-carboxylate (2.00 g, 2.31 mmol) in pyridine (15.9 mL) cooled in an ice bath was slowly added thionyl chloride (0.84 mL, 12 mmol). The mixture was allowed to warm to room temperature and stirred overnight (17 h). The brown reaction mixture was quenched with ice water and extracted with methylene chloride three times. The combined extracts were dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel (0-10% B over 25 min. Bottle A=hexanes, Bottle B=EtOAc) to give 404 mg (53%) of desired product as light brown oil. LC-MS calculated for C16H19F3N2O2: (M+H) 329; found 273.1 (M-tBu+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][C:5]2=[CH:8][N:9]([CH2:11][C:12]([NH:16][C:17](=[O:29])[C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)([C:14]#[N:15])[CH3:13])[N:10]=[C:4]2[CH:3]=1.[Cl:30]N1C(=O)CCC1=O>C(#N)C>[C:14]([C:12]([NH:16][C:17](=[O:29])[C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:20][CH:19]=1)([CH3:13])[CH2:11][N:9]1[C:8]([Cl:30])=[C:5]2[N:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]2=[N:10]1)#[N:15]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C#N)(Cn1cc2ncc(Cl)cc2n1)NC(=O)c1ccc(OC(F)(F)F)cc1
Solvent: CC#N
Product: CC(C#N)(Cn1nc2cc(Cl)cnc2c1Cl)NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 60 °C
Yield: 89 %

Procedure:
A mixture of N-[2-(6-Chloro-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide (134 mg described in Example 155), and N-chlorosuccinimide (51 mg) in acetonitrile (3.5 mL) was heated to 60° C. overnight. The mixture was concentrated under reduced pressure to yield a residue that was purified by chromatography (SiO2, heptane/EA) to afford the title compound as white solid (129 mg, 89%). MS (ES): M/Z [M+H]=458. 1H NMR: (400 MHz, DMSO-d6): 1.78 (s, 3H), 5.10-5.20 (m, 2H), 7.53 (d, J=8.3 Hz, 2H), 7.97 (d, J=8.8 Hz, 2H), 8.43 (d, J=2.0 Hz, 1H), 8.59 (d, J=2.0 Hz, 1H) and 8.99 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −57.1 (s, 3F).
Reaction SMILES: [CH2:1]([NH2:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([NH:11][CH2:1][C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: NCc1ccc2c(c1)OCO2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCc1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 103.5 %

Procedure:
To a solution of piperonylamine (6.07 g, 38.95 mmol) and triethylamine (5.37 g, 53.12 mmol) in dichloromethane (100 ml) at 0° C. was added methanesulfonyl chloride (4.14 g, 35.41 mmol). The reaction was stirred at 0° C. for 1 hour. The mixture was then diluted with dichloromethane (100 ml) and washed with 1 N HCl (2×100 ml). The organic layer was dried (MgSO4), the solid was filtered and the filtrate was concentrated to give N-(3,4-methylenedioxy)benzyl-methanesulfonamide as a grey solid (8.4 g, 92% yield).
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[F:12][C:13]([F:24])([F:23])[C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[O:15]>C1COCC1>[F:24][C:13]([F:12])([F:23])[C:14]1([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[CH2:8][O:15]1
Reactant: O=C(c1ccc(F)cc1)C(F)(F)F
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Fc1ccc(C2(C(F)(F)F)CO2)cc1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 2,2,2-trifluoro-1-(4-fluorophenyl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Reaction SMILES: [CH:1]1([C:7]2[CH:26]=[CH:25][C:10]([O:11][CH2:12][C@H:13]3[O:24][C:16]4=[N:17][C:18](=[O:23])[C@H:19]([CH2:21][CH3:22])[CH2:20][N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C1(C)C=CC=CC=1.[O-2].[Mn+4].[O-2]>[CH:1]1([C:7]2[CH:26]=[CH:25][C:10]([O:11][CH2:12][C@H:13]3[O:24][C:16]4=[N:17][C:18](=[O:23])[C:19]([CH2:21][CH3:22])=[CH:20][N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC[C@@H]1CN2C[C@@H](COc3ccc(C4CCCCC4)cc3)OC2=NC1=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCc1cn2c(nc1=O)O[C@H](COc1ccc(C3CCCCC3)cc1)C2
Yield: 5.5 %

Procedure:
To a solution of (2S,6R)-2-(4-cyclohexyl-phenoxymethyl)-6-ethyl-2,3,5,6-tetrahydro-oxazolo[3,2-a]pyrimidin-7-one (108 mg, 0.41 mmol) in toluene (2 ml) was added manganese(IV) oxide (360 mg, 4.1 mmol). The reaction mixture was heated at reflux for three days. The reaction mixture was filtered without cooling and the filtrate concentrated and loaded on a silica gel column. The column was eluted with 2-7% isopropanol/methylene chloride to afford 8 mg of (S)-2-(4-cyclohexyl-phenoxymethyl)-6-ethyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one. [α]D25 −22.40 (c 0.5, CHCl3).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([OH:16])=O)=[N:6]1)[CH:2]([CH3:4])[CH3:3].[NH2:17][C:18]1[S:19][CH:20]=[CH:21][N:22]=1>>[S:19]1[CH:20]=[CH:21][N:22]=[C:18]1[NH:17][C:14]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[N:6]=1)=[O:16]
Reactant: Nc1nccs1
Reactant: CC(C)Cn1nc(C(=O)O)c2ccccc21
Product: CC(C)Cn1nc(C(=O)Nc2nccs2)c2ccccc21
Yield: 36.6 %

Procedure:
1-(Isobutyl)-indazole-3-carboxylic acid (340 mg) was obtained from methyl indazole-3-carboxylate (0.5 g, 2.84 mmol) and 1-iodo-2-methylpropane (0.33 mL, 2.84 mmol) following general procedures G and E. 1-(Isobutyl)-indazole-3-carboxylic acid thiazol-2-ylamide (66 mg) was prepared from 1-(isobutyl)-indazole-3-carboxylic acid (130 mg, 0.60 mmol) and 2-aminothiazole (150 mg, 1.5 mmol) following the general procedure H.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:17][C@H:18]3[CH2:22][CH2:21][C:20](=[O:23])[CH2:19]3)[C:14](O)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.Cl.[CH:58]1([C:62]2[O:66][N:65]=[CH:64][C:63]=2[NH2:67])[CH2:61][CH2:60][CH2:59]1>CN(C)C=O.C(O)C.[C].[Pd].O>[CH:58]1([C:62]([C:63]2[NH:67][C:14]([CH:13]([C:10]3[CH:9]=[CH:8][C:7]([S:4]([CH:1]4[CH2:2][CH2:3]4)(=[O:6])=[O:5])=[CH:12][CH:11]=3)[CH2:17][C@H:18]3[CH2:22][CH2:21][C:20](=[O:23])[CH2:19]3)=[N:65][CH:64]=2)=[O:66])[CH2:61][CH2:60][CH2:59]1
Reactant: Nc1cnoc1C1CCC1
Reactant: O=C1CC[C@H](CC(C(=O)O)c2ccc(S(=O)(=O)C3CC3)cc2)C1
Agent: [Pd]
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CC[C@H](CC(c2ccc(S(=O)(=O)C3CC3)cc2)c2ncc(C(=O)C3CCC3)[nH]2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 45 %

Procedure:
To a solution (30 mL) of 2-[4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propanic acid in N,N-dimethylformamide were added N,N-diisopropylethylamine (1.89 mL), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo(4,5-b)pyridinium 3-oxide hexafluorophosphate (1.52 g) and 5-cyclobutylisoxazol-4-amine hydrochloride (0.669 g), and the mixture was stirred at room temperature for 20 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=70:30-100:0, volume ratio). The obtained crude product was dissolved in ethanol (30 mL), palladium carbon (1.00 g) was added, and the mixture was purged with hydrogen (5 atm) and stirred at room temperature for 2 hr and at 50° C. for 2 hr. The reaction mixture was filtered to remove the catalyst, sodium hydroxide (0.160 g) was added to the filtrate, and the mixture was heated under reflux for 1.5 hr. To the reaction mixture was added ammonium chloride (0.243 g), and the mixture was cooled to room temperature and stirred at room temperature for 16 hr. The reaction mixture was concentrated, the obtained residue was suspended in acetone and the suspension was filtered to remove insoluble materials. The filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=60:40-100:0, volume ratio) to give the title compound (0.720 g, yield of 3 steps 45%) as a colorless oil. MS: 441 (MH+).
Reaction SMILES: [C:1]([O:5][C@@H:6]1[C@@H:10]([CH2:11][O:12][C:13](=[O:16])[CH2:14][CH3:15])[O:9][C@@H:8]([N:17]2[CH:24]=[C:23]([F:25])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:7]1)(=[O:4])[CH2:2][CH3:3].C(N(CC)CC)C.[F:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](Cl)=[O:38]>O1CCOCC1>[F:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37]([N:20]1[C:21](=[O:22])[C:23]([F:25])=[CH:24][N:17]([C@@H:8]2[O:9][C@H:10]([CH2:11][O:12][C:13](=[O:16])[CH2:14][CH3:15])[C@@H:6]([O:5][C:1](=[O:4])[CH2:2][CH3:3])[CH2:7]2)[C:18]1=[O:19])=[O:38]
Reactant: CCC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OC(=O)CC
Reactant: O=C(Cl)c1cccc(F)c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)n(C(=O)c3cccc(F)c3)c2=O)C[C@@H]1OC(=O)CC
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
2.0 Grams of 2'-deoxy-3',5'-di-O-propionyl-5-fluorouridine are dissolved in 25 ml of dry dioxane and the solution is ice cooled. 2 Milliliters of triethylamine and 1.8 g of 3-fluorobenzoyl chloride are added to the solution and the mixture is subjected to reaction at room temperature for 15 minutes and then at 60° C. for 30 minutes. The reaction liquid is worked up in the same manner as described in Example 1 whereby 2.05 g (yield: 71.5%) of powdery 3-(3-fluorobenzoyl)-2'-deoxy-3', 5'-di-O-propionyl-5-fluorouridine are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:13])[C:9]([CH3:12])=[C:10](I)[C:3]=12.[CH3:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21](B3OC(C)(C)C(C)(C)O3)[CH:22]=2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)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>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH3:13])[C:9]([CH3:12])=[C:10]([C:21]3[CH:22]=[C:23]4[C:18]([CH2:17][CH2:16][N:15]4[CH3:14])=[CH:19][CH:20]=3)[C:3]=12
Reactant: Cc1c(I)c2c(Br)ccnc2n1C
Reactant: CN1CCc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1c(-c2ccc3c(c2)N(C)CC3)c2c(Br)ccnc2n1C
Temperature: 65 °C
Reaction time: 3 h
Yield: 15.1 %

Procedure:
To a solution of 4-bromo-3-iodo-1,2-dimethyl-1H-pyrrolo[2,3-b]pyridine (D27) (580 mg, 1.653 mmol) in ACN (9 mL) was added 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline (557 mg, 2.148 mmol), bis(triphenylphosphine)palladium(II) chloride (116 mg, 0.165 mmol) and 9 mL of sodium carbonate (2N aqueous solution). The reaction mixture was stirred at 65° C. for 3 hours. The reaction mixture was diluted with water (30 mL), the aqueous layer was then extracted with ethyl acetate (50 mL×3). The organic layers were combined, passed through a hydrophobic frit and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-30% ethyl acetate in cyclohexane to give an impure material which was further purified by column chromatography on silica gel, eluting with a gradient of 0-20% ethyl acetate in cyclohexane to afford the title compound (89 mg). LCMS (A): m/z (M+H)+ 356/358, C18H18BrN3 requires 355/357 (acidic).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:18][CH2:17][CH2:16][NH:15][C:14]=3[CH:19]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][C:22]#[N:23].C(N(CC)C(C)C)(C)C.ClCCl>C(Cl)(Cl)Cl.O>[C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:18][CH2:17][CH2:16][N:15]([CH2:21][C:22]#[N:23])[C:14]=3[CH:19]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc2c(c1)NCCO2
Reactant: N#CCBr
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: N#CCN1CCOc2ccc(S(=O)(=O)c3ccccc3)cc21
Temperature: 25 °C
Yield: 98.9 %

Procedure:
To a solution of 6-benzenesulfonyl-3,4-dihydro-2H-benzo[1,4]oxazine (0.200 g., 0.727 mmol) in 0.5 mL chloroform was added bromoacetonitrile (0.100 mL, 1.45 mmol) and N,N-diisopropyl ethylamine (0.190 mL, 1.1 mmol). The solution was refluxed for 18 hours and cooled to room temperature. To the reaction mixture was added 15 mL dichloromethane and 20 mL water. The fractions were separated, and the organic fraction was washed with 50 mL water. The organic fraction was dried over Na2SO4, concentrated in vacuo, and the residue purified by flash chromatography (10-50% ethyl acetate in hexanes) to give 0.246 g (0.719 mmol, 99%) of (6-benzenesulfonyl-2,3-dihydro-benzo[1,4]oxazin-4-yl)-acetonitrile as a clear oil. MS: 315 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:23])=O)=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:25])[CH3:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:32])CC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([S:21][CH2:23][F:32])=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:25])[CH3:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)c1ccc([C@H]2OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]2CF)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](CF)[C@@H](c2ccc(SCF)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.1 %

Procedure:
To a solution of (4R,5R)-4-Fluoromethyl-5-(4-methanesulfinyl-phenyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.0 g, 2.69 mmol) in DCM (50 mL) is cooled to 0° C. followed by addition of SbCl3 (0.018 g, 0.081 mmol) and DAST (0.6 mL, 4.582 mmol). The resulting reaction mixture is stirred at RT for 16 h. After completion reaction mixture is quenched with aqueous bicarbonate solution and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, concentrated and purified by combi-flash chromatography (12 g column) using 8% ethyl acetate in n-Hexane as an eluent to afford title compound (564 mg) as colorless oil. 1H-NMR (400 MHz, DMSO): δ 1.41 (s, 9H), 1.48 (s, 3H), 1.61 (s, 3H), 377-.382 (m, 1H), 4.42-4.53 (m, 1H), 4.76-4.92 (m, 1H), 5.06 (d, J=7.36 Hz, 1H), 5.99 (d, J=52.32 Hz, 2H), 7.46-7.51 (m, 4H). LC-MS (m/z): M+H=374.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:9])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:10](Cl)(=[O:20])[C:11]1[CH:19]=[CH:18][C:17]2[O:16][CH2:15][O:14][C:13]=2[CH:12]=1>>[Cl:1][C:2]1[C:3]([O:9][C:10](=[O:20])[C:11]2[CH:19]=[CH:18][C:17]3[O:16][CH2:15][O:14][C:13]=3[CH:12]=2)=[CH:4][C:5]([O:8][C:10](=[O:20])[C:11]2[CH:19]=[CH:18][C:17]3[O:16][CH2:15][O:14][C:13]=3[CH:12]=2)=[N:6][CH:7]=1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Product: O=C(Oc1cc(OC(=O)c2ccc3c(c2)OCO3)c(Cl)cn1)c1ccc2c(c1)OCO2
Yield: 4 %

Procedure:
The general procedure of Example 45 was followed using 2.00 g of 5-chloro-4-hydroxy-2-pyridone and 3.80 g of piperonyloyl chloride, thereby producing 180 mg of the title compound in a yield of 3%.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][C:4]1[N:5]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=1.[NH2:22][C@@H:23]([CH3:40])[CH2:24][N:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:37]=[C:36]([F:38])[C:33]([C:34]#[N:35])=[C:32]([Cl:39])[CH:31]=2)=[N:26]1>>[Cl:39][C:32]1[CH:31]=[C:30]([C:27]2[CH:28]=[CH:29][N:25]([CH2:24][C@@H:23]([NH:22][C:9]([C:7]3[N:8]=[C:4]([CH2:3][C:2]([F:1])([F:21])[F:20])[N:5]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=3)=[O:11])[CH3:40])[N:26]=2)[CH:37]=[C:36]([F:38])[C:33]=1[C:34]#[N:35]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)nc1CC(F)(F)F
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn(COCC[Si](C)(C)C)c(CC(F)(F)F)n1

Procedure:
The title compound was prepared using the procedure described in Example 32(e) starting from 2-(2,2,2-trifluoroethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic acid (0.98 mmol, 320 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.98 mmol, 273 mg). The product was purified by flash-chromatography. Yield 310 mg. LC-MS: [M+1]=585.25.
Reaction SMILES: [N:1]1[C:2]([CH2:10][OH:11])=[N:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12>C(O)C.[Pd]>[N:1]1[C:2]([CH2:10][OH:11])=[N:3][N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=12
Reactant: OCc1nc2ccccn2n1
Agent: [Pd]
Solvent: CCO
Product: OCc1nc2n(n1)CCCC2

Procedure:
[1,2,4]Triazolo[1,5-a]pyridin-2-ylmethanol (prepared as described in Example 82, step a)) (150 mg, 1.0 mmol) in ethanol (10 ml) was hydrogenated on a Parr apparatus at 50 psi over 10% palladium on carbon (150 mg) overnight. The catalyst was separated by filtration, then the filtrate was concentrated in vacuo to yield (5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)methanol as a white solid (153 mg). Data for the title compound: 1H NMR (360 MHz, CDCl3) δ 1.97 (2H, m), 2.07 (2H, m), 2.90 (2H, t, J=6.3 Hz), 3.00 (1H, br s), 4.13 (2H, t, J=6.0 Hz), 4.70 (2H, s); MS (ES+) m/e 154 [MH]+.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[I-].[Li+].[C:11]1([C@H:17]2[C@H:22]([O:23][CH3:24])[C@H:21]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[CH2:20][CH2:19][C:18]2=[O:35])[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1>CS(C)=O.C1COCC1>[C:11]1([C@H:17]2[C@H:22]([O:23][CH3:24])[C@H:21]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[CH2:20][CH2:19][C@:18]32[O:35][CH2:2]3)[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1
Reactant: C[S+](C)(C)=O
Reactant: COc1ccc(CO[C@@H]2CCC(=O)[C@@H](C3=CCCCC3)[C@@H]2OC)cc1
Agent: [H-]
Agent: [I-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CO[C@@H]2CC[C@]3(CO3)[C@@H](C3=CCCCC3)[C@@H]2OC)cc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 48.2 %

Procedure:
385 mg (1.74 mmol) of trimethylsulphoxonium iodide are added to a suspension of sodium hydride (28 mg, 1.16 mmol) in 1 mL of DMSO. The mixture is stirred for 40 minutes, followed by successive addition of 1 mL of THF and 186 mg of anhydrous lithium iodide. The mixture is stirred for a further 30 minutes, cooled to 0° C., and 39 mg (0.11 mmol) of (2S,3S,4R)-2-(cyclohex-1-enyl)-3-methoxy-4-p-methoxybenzyloxy-cyclohexanone dissolved in 0.5 mL of THF are added. The bath is removed and the reaction is allowed to continue for 40 minutes at room temperature. After adding pH 7 buffer, extracton and evaporation of the solvents, the product is purified by chromatography on a preparative silica plate (eluent: 1:1 ether/pentane) to give 19 mg (45%) of (3R,4S,5S,6R)-4-(cyclohex-1-enyl)-5-methoxy-6-p-methoxybenzyloxy-1-oxaspiro[2,5]octane in the form of a colourless oil.
Reaction SMILES: [CH:1]1([S:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH:15][C@:16]34[CH2:50][CH2:49][C@@H:48]([C:51]([CH3:53])=[CH2:52])[C@@H:17]3[C@@H:18]3[C@@:31]([CH3:34])([CH2:32][CH2:33]4)[C@@:30]4([CH3:35])[C@@H:21]([C@:22]5([CH3:47])[C@@H:27]([CH2:28][CH2:29]4)[C:26]([CH3:37])([CH3:36])[C:25]([C:38]4[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=4)=[CH:24][CH2:23]5)[CH2:20][CH2:19]3)[CH2:9][CH2:8]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.CC(S(Cl)(=O)=O)C>>[CH:1]([S:4]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH:15][C@:16]23[CH2:50][CH2:49][C@@H:48]([C:51]([CH3:53])=[CH2:52])[C@@H:17]2[C@@H:18]2[C@@:31]([CH3:34])([CH2:32][CH2:33]3)[C@@:30]3([CH3:35])[C@@H:21]([C@:22]4([CH3:47])[C@@H:27]([CH2:28][CH2:29]3)[C:26]([CH3:36])([CH3:37])[C:25]([C:38]3[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=3)=[CH:24][CH2:23]4)[CH2:20][CH2:19]2)[CH2:9][CH2:8]1)(=[O:5])=[O:6])([CH3:3])[CH3:2]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(S(=O)(=O)C4CC4)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CC(C)S(=O)(=O)Cl
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(S(=O)(=O)C(C)C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(cyclopropylsulfonyl)piperazin-1-yl)ethyl)amino)-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]chrysen-9-yl)benzoic acid using propane-2-sulfonyl chloride as the reagent in Step 1. The product was isolated as a colorless oil (6 mg, 36%). LCMS: m/e 748.63 (M+H)+, 2.31 min (method 11). 1H NMR (400 MHz, Acetic) δ 7.99 (d, J=8.0 Hz, 2H), 7.26 (d, J=8.0 Hz, 2H), 5.33 (d, J=5.3 Hz, 1H), 4.82 (s, 1H), 4.71 (s, 1H), 3.80-3.55 (m, 8H), 3.49-3.25 (m, 5H), 2.92-2.68 (m, 1H), 2.32-1.04 (m, 22H), 1.73 (s, 3H), 1.32 (s, 3H), 1.30 (s, 3H), 1.17 (s, 3H), 1.10 (s, 3H), 1.05 (s, 3H), 0.98 (s, 3H), 0.96 (s, 3H).