Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[C:14](=[O:18])[C:15]([OH:17])=[O:16].[Mg].[CH3:20]I.Cl>CCOCC.C(O)(=O)C>[CH3:20][C:14]([OH:18])([C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:12][C:13]=2[CH:1]=1)[C:15]([OH:17])=[O:16]
Reactant: CI
Reactant: O=C(O)C(=O)c1ccc2c(c1)Cc1ccccc1-2
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(O)(C(=O)O)c1ccc2c(c1)Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A cooled solution of fluorene-2-glyoxylic acid (4.5 g) in ether (150 ml) is treated dropwise over a 45 minute period with Grignard reagent prepared from magnesium (2.1 g) and methyl iodide (6.5 ml) in ether (145 ml). The mixture is then stirred for 2 hours at room temperature and poured into ice water. The mixture is treated with 250 ml 50% acetic acid and finally acidified to pH 2.0 with 10% HCl. The ether layer is separated, and the aqueous extracted with additional ether. The combined ether extracts are washed with sodium chloride solution and water, dried (MgSO4) and evaporated to give the title compound (3.7 g, mp 164°-168°). Recrystallization from ethvl acetate-hexane raises the mp to 170°-171°, λKBr 3400 cm-1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=2)=[N:4][C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].Cl[C:22]1[CH:23]=[CH:24][C:25]2[N:26]([C:28]([N+:31]([O-:33])=[O:32])=[CH:29][N:30]=2)[N:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:3]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:22]3[CH:23]=[CH:24][C:25]4[N:26]([C:28]([N+:31]([O-:33])=[O:32])=[CH:29][N:30]=4)[N:27]=3)=[C:14]([O:19][CH3:20])[CH:13]=2)=[N:4][C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]
Reactant: COc1cc(CNc2nc(C)nc(C)c2Cl)ccc1O
Reactant: O=[N+]([O-])c1cnc2ccc(Cl)nn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(CNc2nc(C)nc(C)c2Cl)ccc1Oc1ccc2ncc([N+](=O)[O-])n2n1

Procedure:
In analogy to the method described in example 1, 1.25 g (4.25 mmol) of 4-[(5-chloro-2,6-dimethyl-pyrimidin-4-ylamino)methyl]-2-methoxyphenol (from example B3), 0.86 g (4.25 mmol) of 6-chloro-3-nitroimidazo[1,2-b]pyridazine and 3.0 g (21.25 mmol) of potassium carbonate are reacted in 25 ml of dimethylformamide. After chromatography on silica gel (mobile phase: gradient toluene/dioxane 5:1 to 2:1) and crystallization from methylene chloride/methanol, 1.24 g (64%) of the title compound are isolated as a pale beige solid. m.p.: 229-232° C.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([OH:19])[CH:12]=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16].[CH3:20][C:21]1[N:22]=[C:23]([CH3:44])[N:24]2[C:29]=1[C:28](N1C=NC=N1)=[N:27][C:26]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([N+:41]([O-:43])=[O:42])[CH:36]=1)=[N:25]2>O1CCCC1>[CH3:20][C:21]1[N:22]=[C:23]([CH3:44])[N:24]2[C:29]=1[C:28]([O:19][C:11]1[CH:12]=[C:13]([O:17][CH3:18])[C:14]([O:15][CH3:16])=[C:9]([O:8][CH3:7])[CH:10]=1)=[N:27][C:26]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([N+:41]([O-:43])=[O:42])[CH:36]=1)=[N:25]2
Reactant: Cc1nc(C)n2nc(-c3cccc([N+](=O)[O-])c3)nc(-n3cncn3)c12
Reactant: COc1cc(O)cc(OC)c1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(Oc2nc(-c3cccc([N+](=O)[O-])c3)nn3c(C)nc(C)c23)cc(OC)c1OC

Procedure:
A solution of 175.17 mg (1.04 mmol) of potassium tert-butoxide and 287.53 mg (1.56 mmol) of 3,4,5-trimethoxyphenol in 20 ml of tetrahydrofuran is stirred for 30 min. 350 mg (1.04 mmol) of 5,7-dimethyl-2-(3-nitrophenyl)-4-(1H-1,2,4-triazol-1-yl)imidazo[5,1-f][1,2,4]triazine from example 12A are added thereto and the mixture is heated for 2 h to 70° C. After cooling, the solvent is removed and the residue is taken up and extracted with dichloromethane and 1N sodium hydroxide solution. The organic phase is separated off, dried and the crude product is purified by flash chromatography. (Eluent: dichloromethane/methanol 100:1).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([C:15]3[C:16]([NH:34][C:35]4[CH:36]=[N:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=4)=[N:17][CH:18]=[C:19]([C:21]([N:24]4[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]4)([CH3:23])[CH3:22])[CH:20]=3)[N:12]=[C:11]([CH3:43])[N:10]=2)=CC=1.OS(C(F)(F)F)(=O)=O.[OH-].[Na+]>FC(F)(F)C(O)=O>[CH3:42][O:41][C:38]1[N:37]=[CH:36][C:35]([NH:34][C:16]2[C:15]([C:13]3[N:12]=[C:11]([CH3:43])[N:10]=[C:9]([NH2:8])[N:14]=3)=[CH:20][C:19]([C:21]([N:24]3[CH2:25][CH2:26][N:27]([S:30]([CH3:33])(=[O:31])=[O:32])[CH2:28][CH2:29]3)([CH3:23])[CH3:22])=[CH:18][N:17]=2)=[CH:40][CH:39]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)(C)N4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(C(C)(C)N3CCN(S(C)(=O)=O)CC3)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 80 °C
Yield: 26.7 %

Procedure:
A solution of N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(2-(4-(methylsulfonyl)piperazin-1-yl)propan-2-yl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.034 g, 0.045 mmol) in trifluoroacetic acid (1 mL) was treated with triflic acid (0.032 mL, 0.361 mmol). The light yellow reaction was sealed and heated at 80° C. After 30 min the reaction was cooled with ice and basified with 10 N NaOH, then partitioned between water and DCM. The aqueous layer was extracted with DCM (3×) and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. This material was dissolved in DMSO and purified by prep HPLC (5-70% MeCN/H2O with 0.1% TFA). Product-containing fractions were concentrated, then treated with sat'd aq. NaHCO3 and DCM. The aq. layer was extracted with DCM (3×) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give 4-(2-(6-methoxypyridin-3-ylamino)-5-(2-(4-(methylsulfonyl)piperazin-1-yl)propan-2-yl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.006 g, 0.012 mmol, 25.9% yield) as a yellow solid. m/z (ESI, +ve ion) 514 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.70 (s, 1H); 8.83 (d, J=2.5 Hz, 1H); 8.53 (d, J=2.7 Hz, 1H); 8.45 (d, J=2.5 Hz, 1H); 8.19 (dd, J=8.9, 2.8 Hz, 1H); 7.61-7.93 (m, 2H); 6.81 (d, J=9.0 Hz, 1H); 3.84 (s, 3H); 3.01-3.16 (m, 4H); 2.86 (s, 3H); 2.48-2.63 (m, 4H); 2.44 (s, 3H); 1.36 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13]3)[CH:5]=[C:6]([F:9])[C:7]=1[OH:8].C1C(=O)N([Cl:28])C(=O)C1>C1COCC1>[Cl:28][C:16]1[C:17]2[C:12](=[CH:11][C:10]([C:4]3[CH:3]=[C:2]([F:1])[C:7]([OH:8])=[C:6]([F:9])[CH:5]=3)=[CH:19][CH:18]=2)[CH:13]=[CH:14][C:15]=1[OH:20]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Oc1ccc2cc(-c3cc(F)c(O)c(F)c3)ccc2c1
Solvent: C1CCOC1
Product: Oc1ccc2cc(-c3cc(F)c(O)c(F)c3)ccc2c1Cl

Procedure:
The title compound was prepared by reacting 6-(3,5-difluoro-4-hydroxyphenyl)-2-naphthol (300 mg, 1.10 mmol) and NCS (155 mg, 1.16 mmol) in THF (30 mL) according to method C to yield 264 mg (78%) of grey solid: mp 209–210° C.; 1H NMR (DMSO-d6): δ 7.32 (1H, d, J=8.89 Hz), 7.50–7.61 (2H, m), 7.83 (1H, d, J=8.96 Hz), 7.92 (1H, dd. J=8.94 Hz, J=1.59 Hz), 8.05 (1H, d, J=8.88 Hz), 8.22 (1H, d, J=1.19 Hz), 10.36 (1H, s), 10.54 (1H, s); MS (ESI) m/z 305/307 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([C:20]#[C:21][Si](C)(C)C)[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH2:15])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.C([O-])([O-])=O.[K+].[K+]>CO.C1COCC1>[C:20]([C:18]1[CH:17]=[CH:16][C:3]([NH:4][C:5]2[C:6]([C:13]([NH2:15])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=2)=[C:2]([F:1])[CH:19]=1)#[CH:21]
Reactant: Cn1cc(C(N)=O)c(Nc2ccc(C#C[Si](C)(C)C)cc2F)cc1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1ccc(Nc2cc(=O)n(C)cc2C(N)=O)c(F)c1
Yield: 73 %

Procedure:
4-{2-Fluoro-4-[(trimethylsilyl)ethynyl]anilino}-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide was reacted with K2CO3 in MeOH/THF as for example 12, step B. The resulting crude product was purified by column chromatography on silica gel (50% acetone/CH2Cl2 as eluant) to give 4-(4-ethynyl-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a pale yellow-orange solid (73%), m.p. (CH2Cl2/MeOH) 269-272° C. 1H NMR [(CD3)2SO, 400 MHz] δ 10.60 (s, 1H), 8.37 (s, 1H), 7.91 (br s, 1H), 7.51 (t, J=8.4 Hz, 1H), 7.48 (br s, 1H), 7.46 (dd, J=11.4, 1.7 Hz, 1H), 7.33 (dd, J=8.3, 0.9 Hz, 1H), 5.71 (s, 1H), 4.25 (s, 1H), 3.37 (s, 3H). Anal. Calcd for C15H12FN3O2.0.25H2O: C, 62.2; H, 4.4; N, 14.5. Found: C, 62.6; H, 4.1; N, 14.6.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[CH2:13]([NH:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:13]([N:20]([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)[CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(CNCCCN2CCOCC2)cc1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(CCN(CCCN2CCOCC2)Cc2ccccc2)cc1
Temperature: 65 °C

Procedure:
A suspension of 1-(2-bromoethyl)-4-nitrobenzene (0.314 g, 1.366 mmol), N-benzyl-3-morpholinopropan-1-amine (0.128 g, 0.546 mmol), and potassium carbonate (0.189 g, 1.366 mmol) in dimethylformamide (1.821 ml) was heated at 65° C. for 20 hours. The reaction was partitioned in ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by flash chromatography to provide the title compound.
Reaction SMILES: CC(C)([O-])C.[K+].[Si:7]([O:14][C@@H:15]1[C@H:19]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:18][C@@H:17]([O:29][C:30]2[CH:35]=[CH:34][N:33]=[C:32](Cl)[CH:31]=2)[CH2:16]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[NH2:37][C@@H:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40][CH2:39]1>COCCOC.CCOC(C)=O>[Si:7]([O:14][C@@H:15]1[C@H:19]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:18][C@@H:17]([O:29][C:30]2[CH:35]=[CH:34][N:33]=[C:32]([NH:37][C@@H:38]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH2:40][CH2:39]3)[CH:31]=2)[CH2:16]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: N[C@H]1CCc2ccccc21
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ccnc(Cl)c2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ccnc(N[C@H]3CCc4ccccc43)c2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 0.08 h
Yield: 94.8 %

Procedure:
To a mixture of [1,3-bis(2,6-diisopropylphenyl)imidazolidin-2-yl](chloro)[(2,3-η)-(1Z)-1-phenylprop-1-ene-2,3-diyl]palladium(2+) (7.8 mg, 0.000012 mol) and potassium tert-butoxide (73.7 mg, 0.000656 mol) under an atmosphere of argon was added 4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-cyclopentyl]oxy}-2-chloropyridine (281.8 mg, 0.0005968 mol) in 1 ml DME. The solution was stirred for 5 mins, then (S)-(+)-1-aminoindane (0.10 mL, 0.000776 mol) in 1.0 ml DME was added dropwise over 15 min. The solution was stirred overnight, then dissolved in 50 mL EtOAc, washed with water, and concentrated. The residue was purified by flash chromatography (30% EtOAc/hexanes) to afford the title compound (0.3219 g, 95%) as a white solid.
Reaction SMILES: C[O-].[Na+].P(=O)([O-])O[C:6]([CH2:15][CH3:16])(CC)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:19][O:20][C:21]1[CH:22]=C([CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1)C=O>CN(C=O)C>[CH3:19][O:20][C:21]1[CH:22]=[C:16]([CH:15]=[CH:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1
Reactant: CCC(CC)(O[PH](=O)[O-])c1ccccc1
Reactant: COc1cc(C=O)cc(OC)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C=Cc2ccccc2)cc(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
16.5 g (0.3 mol) of sodium methanolate are added at 0° C. to a solution of 60 g (0.29 mol) of crude diethylbenzyl phosphonate in 415 ml of anhydrous DMF. Then, at 0° C., a total of 50.0 g (0.3 mol) of 3,5-dimethoxybenzaldehyde is added in portions. After stirring for 1 hour at room temperature and heating for 1 hour under reflux, the product is precipitated by the addition of 660 ml of water/methanol (mixture ratio 2:1). Recrystallisation from water/methanol (2:1) yields 3,5-dimethoxystilbene in the form of colourless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.[CH2:24]([N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[N:28]1)[C:25]#[CH:26]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:26]#[C:25][CH2:24][N:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=[N:28]3)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1
Reactant: Cc1nnc2n1-c1ccc(I)cc1C(c1ccccc1F)=NC2
Reactant: C#CCn1ncc2ccccc21
Product: Cc1nnc2n1-c1ccc(C#CCn3ncc4ccccc43)cc1C(c1ccccc1F)=NC2

Procedure:
This compound was obtained as described in example 17 by reaction of 6-(2-fluorophenyl)-8-iodo-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine with 1-(2-propynyl) 1H-indazole [ref. p. V. Tkachenko, I. I. popov, A. M. Simonov and Yu. V. Medvedov, Khim. Geterotsikl. Soedin. 11, 1542 (1975)]. The chromatographically isolated product was crystallized from ethyl acetate to give yellowish crystals with m.p. 148°-151° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[C:12](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>C(#N)C>[CH3:12][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CCC(=O)c1ccc(O)cc1
Agent: [K+]
Solvent: CC#N
Solvent: COS(=O)(=O)OC
Product: CCC(=O)c1ccc(OC)cc1
Temperature: 25 °C

Procedure:
To a solution of 4′-hydroxypropiophenone (1.0 g, 6.67 mmol) in acetonitrile (50.0 mL) was added potassium carbonate (7.17 g, 66.7 mmol) and the mixture heated to reflux for 90 min. After this time the reaction mixture was allowed to cool to room temperature and dimethyl sulphate (1.05 mL, 11.1 mmol) was added and the reaction mixture was heated to reflux for a further 19 h. After cooling the acetonitrile was evaporated under reduced pressure and the residue taken up in water and extracted with dichloromethane. The dichloromethane extract was dried (MgSO4) and evaporated under reduced pressure to give 4′-methoxypropiophenone as a yellow oil, (970 mg, 89%) 1H nmr (d6-DMSO, 300 MHz) 1.06, t (7.2 Hz), CH3; 2.95, q (7.2 Hz), CH2; 3.83, s, OMe; 7.02, d (6.9 Hz), H3′,5′; 7.93, d (6.9 Hz), H2′,6′. ESI (+ve) MS m/z 165 (M+H, 100%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C@:15]([OH:32])([CH2:16][C@@H:17]([O:28][C:29](=[O:31])[CH3:30])[CH2:18][C@@H:19]2[OH:27])[CH:14]=[CH:13]3)[CH2:10][CH2:9]1)[CH3:7].COC(OC)C(C)[C@@H]1[C@]2(C)[C@H]([C@H:41]3[C@H:51](CC2)[C@:49]2(C)[C@:44](O)(C[C@@H](O)C[C@@H:48]2[OH:56])[CH:43]=[CH:42]3)CC1>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C@:15]([OH:32])([CH2:16][C@@H:17]([O:28][C:29](=[O:31])[CH3:30])[CH2:18][C@@H:19]2[O:27][C:48](=[O:56])[C:49]2[CH:51]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:14]=[CH:13]3)[CH2:10][CH2:9]1)[CH3:7]
Reactant: COC(OC)C(C)[C@H]1CC[C@H]2[C@@H]3C=C[C@@]4(O)C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)O[C@H]1C[C@H](O)[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](C(C)C5OCCO5)CC[C@H]4[C@@H]3C=C[C@@]2(O)C1
Product: CC(=O)O[C@H]1C[C@H](OC(=O)c2ccccc2)[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](C(C)C5OCCO5)CC[C@H]4[C@@H]3C=C[C@@]2(O)C1
Yield: 92.8 %

Procedure:
The reaction and workup procedures of Example 105 were repeated except that 350 mg of 20-(1,3-dioxolan-2-yl)-3β-acetoxypregn-6-ene-1α,5α-diol was used in lieu of 400 mg of 21,21-dimethoxy-20-methylpregn-6-ene-1α,3β,5α-triol to give 400 mg of 20-(1,3-dioxolan-2-yl)-3β-acetoxy-1α-benzoyloxypregn-6-en-5α-ol showing the following physical properties.
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[CH:13]([C@@H:16]1[CH2:20][O:19][C:18](=[O:21])[N:17]1[C:22](=[O:25])[CH2:23][CH3:24])([CH3:15])[CH3:14].[CH3:26][O:27][C:28]1[C:36]([CH3:37])=[C:35]2[C:31]([C:32](=[O:38])[O:33][CH2:34]2)=[C:30]([O:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH3:45])[C:29]=1[CH2:46][CH:47]=[C:48](C)[CH2:49]CC(O)=O>CCCCCC.O1CCCC1>[CH3:26][O:27][C:28]1[C:36]([CH3:37])=[C:35]2[C:31]([C:32](=[O:38])[O:33][CH2:34]2)=[C:30]([O:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH3:45])[C:29]=1[CH2:46][CH2:47][CH:48]([CH3:49])[CH2:24][C@H:23]([CH3:1])[C:22]([N:17]1[C@H:16]([CH:13]([CH3:15])[CH3:14])[CH2:20][O:19][C:18]1=[O:21])=[O:25]
Reactant: [Li]CCCC
Reactant: CCC(=O)N1C(=O)OC[C@H]1C(C)C
Reactant: COCCOCOc1c(CC=C(C)CCC(=O)O)c(OC)c(C)c2c1C(=O)OC2
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCCOCOc1c(CCC(C)C[C@H](C)C(=O)N2C(=O)OC[C@H]2C(C)C)c(OC)c(C)c2c1C(=O)OC2
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of 1.38 molar n-butyllithium in hexane (11.8 ml) was added to diisopropylamine (2.45 ml) in tetrahydrofuran (50 ml) at -10° C. After 20 minutes, the solution was cooled to -78° C., and a solution of (R)-4-isopropyl-3-propionyl-2-oxazolidinone [prepared as described in J. Am. Chem. Soc., 103:2127 (1981)](3.23 g) in tetrahydrofuran (10 ml) was added. After 30 minutes (E) 4-(1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2-methylbut-2-enyl bromide (2.54 g) in tetrahydrofuran (12 ml) was added. The reaction temperature was allowed to reach -10° C. slowly, then maintained at that temperature for 3 hours. The reaction was quenched with 10% aqueous ammonium chloride then extracted with ethyl acetate. The extract was washed with 10% hydrochloric acid, dilute aqueous sodium bicarbonate and water, then dried and evaporated. The residue was chromatographed on silica gel, eluting with 2:1 hexane:acetone, to yield (E) 3-[6-(1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2-(S),4-dimethylhexanoyl)-4-(R)-isopropyl-2-oxazolidinone as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:32][C:33]1[CH:37]=[CH:36][N:35]([CH2:38][C:39]([CH3:49])([CH3:48])[O:40][CH2:41][C@@H:42]([OH:47])[CH2:43][N:44]([CH3:46])[CH3:45])[N:34]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:46][N:44]([CH3:45])[CH2:43][C@H:42]([OH:47])[CH2:41][O:40][C:39]([CH3:48])([CH3:49])[CH2:38][N:35]1[CH:36]=[CH:37][C:33]([NH:32][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10]2)=[O:30])=[N:34]1
Reactant: CN(C)C[C@H](O)COC(C)(C)Cn1ccc(N)n1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C[C@H](O)COC(C)(C)Cn1ccc(NC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 180.7 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), (S)-1-[2-(3-amino-pyrazol-1-yl)-1,1-dimethyl-ethoxy]-3-dimethylamino-propan-2-ol (370 mg, 1.44 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 950 mg, 2.5 mmol) and iPr2NEt (1.4 mL, 8 mmol) in CH2Cl2 (50 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, dried over Na2SO4 and filtered. The mixture was then concentrated and purified by reverse phase chromatography (15-95% of ACN/water) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-((5)-3-dimethylamino-2-hydroxy-propoxy)-2-methyl-propyl]-1H-pyrazol-3-yl}-amide (255 mg, 18%) as an off-white powder. The racemate mixture was submitted for SFC purification to of chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-((S)-3-dimethylamino-2-hydroxy-propoxy)-2-methyl-propyl]-1H-pyrazol-3-yl}-amide (85.1 mg, 6.1%) as an white powder. HRMS (ES+) m/z Calcd for C35H44Cl2F2N6O3+H [(M+H)+]: 705.2893. found: 705.2891. and chiral (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-((S)-3-dimethylamino-2-hydroxy-propoxy)-2-methyl-propyl]-1H-pyrazol-3-yl}-amide (23.1 mg, 20.8%) as an off-white powder. HRMS (ES+) m/z Calcd for C35H44Cl2F2N6O3+H [(M+H)+]: 705.2893. found: 705.2889.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CCN(CC)CC.[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:29])=[C:23]([S:25](Cl)(=[O:27])=[O:26])[CH:24]=1>C1COCC1>[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:29])=[C:23]([S:25]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)(=[O:27])=[O:26])[CH:24]=1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Reactant: C1CC2(CCN1)OCCO2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(F)cc1S(=O)(=O)N1CCC2(CC1)OCCO2
Reaction time: 1 h
Yield: 100.2 %

Procedure:
A stirred solution of 1,4-dioxa-8-azaspiro[4,5]decane (10.73 g, 75 mmol) and Et3N (8 mL, 57 mmol) in THF (150 mL) was cooled in an ice-water bath. To this mixture was slowly added 5-fluoro-2-methylbenzenesulfonyl chloride (10.5 g, 50.33 mmol) and stirred for 1 h and then cold bath was removed. After 15 h at room temperature, the reaction mixture was diluted with ether (200 mL), washed with 1N aq. HCl (2×50 mL), brine (50 mL), dried (Na2SO4), filtered and concentrated to give product as an off-white solid 15.9 g, 100%). 1H NMR (500 MHz, CDCl3) δ: 7.61 (1H, dd, J=8.6, 2.8 Hz), 7.28-7.26 (1H, m), 7.15 (1H, td, J=8.1, 2.8 Hz), 3.94 (4H, s), 3.35-3.32 (4H, m), 2.57 (3H, s), 1.78-1.76 (4H, m). HRMS (M+H) calcd for C14H19FNO4S: 316.1019; found: 316.1013.