Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([CH2:16][O:17][C:18]([CH3:27])([CH3:26])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:11]1)(C(C)(C)C)(C)C.O.CC(OC)(C)C>C1COCC1>[OH:8][CH2:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([CH2:16][O:17][C:18]([CH3:27])([CH3:26])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:11]1
Reactant: CC(C)(C)OC(=O)C(C)(C)OC[C@H]1CCC[C@@H](CO[Si](C)(C)C(C)(C)C)C1
Solvent: C1CCOC1
Solvent: O
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)C(C)(C)OC[C@H]1CCC[C@@H](CO)C1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 45.1 %

Procedure:
4.5 g of tert-butyl 2-[cis-3-(tert-butyidimethylsilanyloxymethyl)cyclohexyl-methoxy]-2-methylpropionate (synthesis analogously to tert-butyl 2-[cis-3-(tert-butyldimethylsilanyloxymethyl)cyclohexylmethoxy]-2-methylpropionate in Example 55) are dissolved in 85 ml of THF, 2.24 g of TBAF trihydrate are added and the mixture is stirred at 60° C. for 90 min. Water and MTBE are added, the phases are separated and the organic phase is dried over MgSO4 and concentrated. The residue is chromatographed on silica gel (heptane/ethyl acetate 1:1), which gives 1.45 g of tert-butyl 2-[cis-3-hydroxymethylcyclohexylmethoxy]-2-methylpropionate. C16H30O4 (286.42), MS (ESI): 287 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH3:25])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>>[CH2:31]([O:30][C:28]([N:24]([CH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:20])([F:22])[F:21])[CH:17]=[CH:18][C:13]=1[C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:2])=[O:26])[CH:6]=1)[CH3:25])=[O:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Reactant: O=C(Cl)OCc1ccccc1
Product: COc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1CN(C)C(=O)OCc1ccccc1

Procedure:
{2′-[(Benzyloxycarbonyl-methyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-27) was prepared by following the procedures of Example 7 and using (6-methoxy-2′-methylaminomethyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and benzyl chloroformate.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:15])[C:8]=2[N+:12]([O-])=O)[N:3]=1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:15])[C:8]=2[NH2:12])[N:3]=1
Reactant: Cc1ccc2c([N+](=O)[O-])c(C)ccc2n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(N)c(C)ccc2n1
Yield: 73.3 %

Procedure:
To a solution of 2,6-dimethyl-5-nitro-quinoline (192 mg, 0.95 mmol) in ethanol (9.3 mL) and water (4.7 mL) were added iron powder (280 mg, 5.0 mmol) and NH4Cl 280 mg, 5.2 mmol). The mixture was heated at reflux for 2 h, then cooled filtered. The filtrate was concentrated under reduced pressure, and the aqueous residue was extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. Purification of the residue by flash column (hexane/ethyl acetate gradient) gave 2,6-dimethyl-quinolin-5-ylamine (120 mg, 73%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[O:24][N:23]=[C:22]([CH2:25][O:26][CH3:27])[N:21]=3)[CH2:16][CH2:15]2)[CH:5]=[C:4]([F:28])[C:3]=1[CH2:29][C:30]([O:32]C)=[O:31].CO.[OH-].[Li+].Cl>O1CCCC1.O>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[O:24][N:23]=[C:22]([CH2:25][O:26][CH3:27])[N:21]=3)[CH2:16][CH2:15]2)[CH:5]=[C:4]([F:28])[C:3]=1[CH2:29][C:30]([OH:32])=[O:31]
Reactant: COCc1noc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)OC)c(F)c3)CC2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COCc1noc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)O)c(F)c3)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl (2,6-difluoro-4-{2-[(1S,2R)-2-{1-[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]piperidin-4-yl}cyclopropyl]ethoxy}phenyl)acetate (0.500 g, 10.7 mmol) in 14 ml anhydrous tetrahydrofuran was added by 7 ml methanol and 7 ml water. Lithium hydroxide (0.3129 g, 5.37 mmol) was added into the reaction mixture, and the reaction was stirred at RT overnight. 1 M hydrochloric acid was added to adjust the pH to 4. The volatiles were removed under vacuum, and the remaining aqueous layer was extracted with dichloromethane (3×20 ml). The organics were combined, dried over magnesium sulphate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified on Biotage column (50 g silica gel) using a gradient eluent of 0-70% ethyl acetate in hexanes (700 ml) to afford the title compound. LC/MS (m/z) 432.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[O:44][CH2:43][CH2:42][C@H:18]4[S:19](=[O:41])(=[O:40])[C:20]([CH3:39])([CH3:38])[C:21]([N:23](C(OC(C)(C)C)=O)C(=O)OC(C)(C)C)=[N:22][C@:17]4([CH3:45])[C:15]=3[CH:16]=2)=[O:9])=[N:6][CH:7]=1.CC(C)([O-])C.[K+].[CH2:52]([OH:55])[C:53]#[CH:54].C(O)(C(F)(F)F)=O>CN(C=O)C.C(Cl)Cl>[NH2:23][C:21]1[C:20]([CH3:38])([CH3:39])[S:19](=[O:41])(=[O:40])[C@@H:18]2[CH2:42][CH2:43][O:44][C:14]3[CH:13]=[CH:12][C:11]([NH:10][C:8]([C:5]4[CH:4]=[N:3][C:2]([O:55][CH2:52][C:53]#[CH:54])=[CH:7][N:6]=4)=[O:9])=[CH:16][C:15]=3[C@@:17]2([CH3:45])[N:22]=1
Reactant: C#CCO
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc(NC(=O)c4cnc(Cl)cn4)ccc3OCC[C@H]2S(=O)(=O)C1(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: C#CCOc1cnc(C(=O)Nc2ccc3c(c2)[C@@]2(C)N=C(N)C(C)(C)S(=O)(=O)[C@@H]2CCO3)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a solution of tert-butyl N-[(4aR,11bR)-10-[(5-chloropyrazine-2-carbonyl)amino]-3,3,11b-trimethyl-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (126 mg, 0.190 mmol) in DMF (2 mL) was added a mixture of potassium tert-butoxide (63.9 mg, 0.569 mmol) in propargyl alcohol (0.224 mL, 3.79 mmol). The reaction was stirred at ambient temperature for 1 h. The reaction mixture was partitioned between water and ethyl acetate, and the organic layer was concentrated. The crude residue was diluted with DCM (3 mL) and TFA (0.292 mL, 3.79 mmol) was added and the reaction was stirred at ambient temperature. After 1 h, the reaction mixture was diluted with DCM, washed with saturated aqueous sodium bicarbonate, and concentrated. The crude product was purified by column chromatography, eluting with 20-80% (3:1 ethyl acetate/ethanol) in heptane, to provide N-((4aR,11bR)-2-amino-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-10-yl)-5-(prop-2-yn-1-yloxy)pyrazine-2-carboxamide (82 mg, 0.170 mmol, 89% yield) as an off-white powder. MS m/z=484.0 (M+H).
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].C[C@]12CC[C@H]3[C@@H](CCC4[C@]3(C)C=CC(=[O:41])C=4)[C@@H]1CCC2=O.C[C@]12CC=C3[C@@H](CCC4[C@]3(C)CCC(=O)C=4)[C@@H]1CCC2=O>>[OH:41][C@:17]12[CH2:18][CH2:19][C@@:2]3([CH3:1])[C@@H:6]([CH2:5][CH2:4][C:3]3=[O:21])[C@@H:7]1[CH2:8][CH2:9][C:10]1[C@:15]2([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Product: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)CC[C@@]12O

Procedure:
We have carried on investigations with attention to the fact that corticoids can be prepared through fewer steps from the aforementioned androst-4-ene-3,17-dione, androsta-1,4-diene-3,17-dione or androsta-4,9(11) -diene-3,17-dione which has recently be produced inexpensively and in a large scale from 9α-hydroxy-androst-4ene-3,17-dione which has also recently be produced by a fermentative process.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:31][CH3:32])=[C:10]([CH2:19][NH:20][C:21]([CH:23]([CH2:27][CH2:28][CH2:29][CH3:30])[C:24]([OH:26])=O)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH2:33][CH2:34][C:35]1[CH:36]=[CH:37][C:38]([F:62])=[C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:48]3[CH2:53][CH2:52][N:51](C(OC(C)(C)C)=O)[C@@H:50]([CH3:61])[CH2:49]3)[CH:42]=2)[CH:40]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:27]([CH:23]([C:24]([NH:33][CH2:34][C:35]1[CH:40]=[C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:48]3[CH2:53][CH2:52][NH:51][C@@H:50]([CH3:61])[CH2:49]3)[CH:42]=2)[C:38]([F:62])=[CH:37][CH:36]=1)=[O:26])[C:21]([NH:20][CH2:19][C:10]1[C:11]([NH:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[C:6]2[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]2=[N:8][C:9]=1[CH2:31][CH3:32])=[O:22])[CH2:28][CH2:29][CH3:30]
Reactant: C[C@H]1CN(Cc2cccc(-c3cc(CN)ccc3F)c2)CCN1C(=O)OC(C)(C)C
Reactant: CCCCC(C(=O)O)C(=O)NCc1c(CC)nc2c(cnn2CC)c1NC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(C(=O)NCc1ccc(F)c(-c2cccc(CN3CCN[C@@H](C)C3)c2)c1)C(=O)NCc1c(CC)nc2c(cnn2CC)c1NC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12 %

Procedure:
A mixture of 2-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]hexanoic acid, 1,1-dimethylethyl (2S)-4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (424 mg, 0.98 mmol), HBTU (535 mg, 1.41 mmol) and Et3N (0.82 mL, 5.89 mmol) in DCM (3 mL) was stirred at room temperature overnight. The reaction was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were then washed with water followed by a brine wash. The organic layer was then concentrated under vacuum to give a crude residue: LC-MS m/z 841 (M+H)+. The crude residue was dissolved in 25% TFA in DCM (2 mL) and stirred at RT for 2 h. It was purified with a Gilson HPLC (with 0.1% TFA condition) eluting with 10 to 70% CH3CN in water at a flowrate of 20 mL/min. The fractions were combined and then converted to the free base with saturated NaHCO3. The organic layer was dried over sodium sulfate, filtered and then concentrated to give 2-butyl-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-{[(3S)-3-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]propanediamide as a solid (59 mg, 12%). LC-MS m/z 741 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[C@H:12]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11](=[O:24])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9].[C:25]1([C:31](N)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.N(OCC(C)C)=O.S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCl>[CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[C@H:12]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:11](=[O:24])[N:6]2[C:7]=1[C:8]([O:10][C:31]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:9]
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Agent: CC(C)CON=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1=C(C(=O)OC(c2ccccc2)(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Yield: 50 %

Procedure:
To 3-methyl-7β-phenoxyacetamidoceph-3-em-4-carboxylic acid (3.43 g., 9.5 m. moles) in dichloromethane (50 ml) was added triphenylmethylamine (4.3 g., 16.6 m. moles), isobutyl nitrite (3.43 g., 33.2 m. moles) and anhydrous sodium sulphate (5 g) and the mixture heated 2 hours at 35°. The cooled solution was washed with 5% sodium bicarbontate (30 ml) and water (30 ml). The organic solution was evaporated to a solid, the solid slurried in toluene (40 ml) cooled, filtered and slurry-washed with cold toluene (15 ml) to yield the previously unreported title compound (2.88 g. 50.0% yield based on the input acid) m.pt. 182°, pure by t.l.c. The compound possessed ν max (1% CHBr3 solution) 3380 (NHCO), 1775 (β-lactam), 1723 (αβ-unsaturated ester) 1686 - 1518 Cm-1 (amide carbonyl); τ (11% CDCl3 solution) 2.2 - 3.2 (complex, phenyl rings + phenoxy ring + --NH), 5.41 (singlet, phenoxy methylene acetamido group, H2), 4.09 (doublet of doublets J 4.5, 9 Hz, C-7, H) 4.95 (doublet, J 4.5 Hz, H), 6.51 + 6.97 (two doublets [branches of a quartet]J 18 Hz, H2), 8.08 (singlet, C-3, H3). Found C, 70.63; H, 5.16 N, 4.52. C35H30N2O5S requires C, 71.18; H, 5.09; N, 4.75%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Cl-].[K+].[S:13](=O)(=[O:16])([OH:15])[OH:14]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: O=S(=O)(O)O
Agent: [Cl-]
Agent: [K+]
Product: O=[N+]([O-])c1cc(S(=O)(=O)O)ccc1F
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To 2-fluoronitrobenzene (2.33 g) was added fuming sulfuric acid (20 mL), and the mixture was stirred at 60° C. for 30 minutes. The reaction mixture was cooled to room temperature. The reaction mixture was poured into ice and potassium chloride (10 g), and the resulting mixture was stirred at room temperature for 30 minutes. The precipitated crystals were collected by filtration. The collected crystals were washed with water, and dried under reduced pressure to give 4-fluoro-3-nitrobenzenesulfonic acid (3.15 g). To phosphoryl chloride (85 mL) were added 4-fluoro-3-nitrobenzenesulfonic acid (3.15 g) and phosphorus pentachloride (2.82 g) under ice-cooling, and the mixture was heated at reflux overnight. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. To the residue was added ice water, and the resulting mixture was extracted with diethyl ether. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=3/1) to give the title compound (2.65 g).
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.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][C:26]1=[O:31].C(N(C(C)C)CC)(C)C.C(O)(C(F)(F)F)=O>CN1C(=O)N(C)CCC1>[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]([N:28]3[CH2:29][CH2:30][N:25]([CH3:24])[C:26](=[O:31])[CH2:27]3)[N:11]=2)=[O:13])=[CH:17][CH:18]=1
Reactant: CN1CCNCC1=O
Reactant: O=C(NCc1ccc(F)cc1)c1nc(Br)c2cccnc2c1O
Solvent: CN1CCCN(C)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2nc(C(=O)NCc3ccc(F)cc3)c(O)c3ncccc23)CC1=O
Temperature: 25 °C

Procedure:
A solution of 5-bromo-N-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide (0.20 g, 0.53 mmol), 1-methylpiperazin-2-one (0.21 g, 1.86 mmol) and diisopropylethylamine (0.19 mL, 1.06 mmol) in DMPU (2.0 mL) were heated at 135 C for 26 hr. Diisopropylethylamine (0.19 mL, 1.06 mmol) was added and the reaction heated at 135C for a further 24 hr. The reaction was cooled to room temperature, neutralized by the addition of TFA and purified by reverse phase HPLC. (Vydak C18, Gradient elution with Water:Acetonitrile 95:5 to 5:95 with 0.1% TFA at 30 mL/min over 15 mins). Lyophilization of the pure fractions afforded the title compound as an off white solid.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[F:14][CH:15]([CH2:18][NH2:19])[CH2:16][NH2:17].[S:20]1(=[O:32])(=[O:31])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH2:24][NH:23][CH2:22][CH2:21]1>>[O:32]=[S:20]1(=[O:31])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH2:24][N:23]([C:2]2[N:11]=[C:10]([NH:17][CH2:16][CH:15]([F:14])[CH2:18][NH2:19])[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=3)[N:3]=2)[CH2:22][CH2:21]1
Reactant: O=S1(=O)CCNCc2ccccc21
Reactant: NCC(F)CN
Reactant: Cc1ccc2nc(Cl)nc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)nc(NCC(F)CN)c2c1

Procedure:
The title compound was prepared in analogy to Example 56-1 in Scheme 23 by using 2,4-dichloro-6-methylquinazoline, 2-fluoropropane-1,3-diamine and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide. MS obsd. (ESI+) [(M+H)+] 430, 1H NMR (400 MHz, CD3OD) δ ppm 8.06-8.04 (d, J=7.6 Hz, 1 H), 7.93 (s, 1 H), 7.81-7.79 (d, J=7.6 Hz, 1 H), 7.69-7.65 (t, J=8 Hz, 2 H), 7.60-7.53 (m, 2 H), 5.32 (s, 2 H), 5.17-5.03 (d, J=28 Hz, 1 H), 4.52 (s, 2 H), 4.20-3.92 (m, 2 H), 3.67 (s, 2 H), 3.47-3.36 (m, 2 H), 2.44 (s, 3 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[C@H:12]([OH:15])[CH2:13][OH:14].N1C=CC=CC=1.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[C:22]([O:14][CH2:13][C@H:12]([C:3]1[C:4]([CH3:11])=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Br:1])[OH:15])(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc([N+](=O)[O-])cc(Br)c1[C@H](O)CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])cc(Br)c1[C@H](O)COC(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a suspension of (S)-1-(2-bromo-6-methyl-4-nitrophenyl)ethane-1,2-diol (65D) (6.96 g, 25.22 mmol) in DCM (100 ml), was added pyridine (5 mL) at 0° C. To the solution was added pivaloyl chloride (PivCl) slowly at 0° C. The reaction mixture was stirred at 0° C. for 5 min, then raised to rt, stirred at rt for 5 h. The reaction mixture was washed by sat. NaHCO3, extracted by DCM, dry over MgSO4, filtered, purified by silica gel column, eluting by 0-40% EtOAc in Hexanes to give 9.13 g of 65E. The product taken on without full characterization.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[CH2:9]([N:16]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:17]1[CH2:21][CH:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:19]([CH2:27][CH3:28])[CH2:18]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CI.[NH4+].[Cl-]>C1COCC1.C(Cl)Cl>[CH2:29]([N:16]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C@@H:17]1[CH2:21][C:20]([CH3:2])([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C@H:19]([CH2:27][CH3:28])[CH2:18]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1.[CH2:29]([N:16]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C@H:17]1[CH2:21][C:20]([CH3:2])([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C@@H:19]([CH2:27][CH3:28])[CH2:18]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCOC(=O)C1CC(N(Cc2ccccc2)Cc2ccccc2)CC1CC
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CI
Product: CCOC(=O)C1(C)C[C@@H](N(Cc2ccccc2)Cc2ccccc2)C[C@H]1CC
Product: CCOC(=O)C1(C)C[C@H](N(Cc2ccccc2)Cc2ccccc2)C[C@@H]1CC
Temperature: -78 °C
Reaction time: 1 h
Yield: 168.6 %

Procedure:
To a solution of LDA (1.8M in THF, 3.04 mL, 5.47 mmol) and THF (40 mL) at about −78° C. was added ethyl 4-(dibenzylamino)-2-ethylcyclopentanecarboxylate (1.0 g, 2.7 mmol, Preparation #EE.1) in THF (4 mL). The reaction mixture was stirred at about −78° C. for about 1 h. MeI (2.57 mL, 41.0 mmol) was added and reaction mixture was stirred at about −78° C. for about 1 h and was then warmed to about −40° C. DCM (150 mL) was added followed by saturated aqueous NH4Cl solution (50 mL). The layers were separated and the aqueous layer was extracted with DCM (2×30 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash silica gel chromatography eluting with a gradient of 0-10% EtOAc in DCM to give (2R,4S)-ethyl 4-(dibenzylamino)-2-ethyl-1-methylcyclopentanecarboxylate and (2S,4R)-ethyl 4-(dibenzylamino)-2-ethyl-1-methylcyclopentanecarboxylate (0.864 g, 84%). LC/MS (Table 2, Method a) Rt=2.25 min; MS m/z: 380 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7](=[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])[CH2:6][CH2:5]2.C([O-])([O-])=O.[K+].[K+].Br.Br[CH2:29][CH2:30][C:31]1[N:32]=[CH:33][NH:34][CH:35]=1>CN(C=O)C.O>[NH:34]1[CH:35]=[C:31]([CH2:30][CH2:29][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[C:7](=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[CH2:6][CH2:5]3)[N:32]=[CH:33]1
Reactant: CC(=C1CCc2cc(O)ccc2C1=O)c1ccccc1
Reactant: BrCCc1c[nH]cn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=C1CCc2cc(OCCc3c[nH]cn3)ccc2C1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
The product obtained from Step 2 (0.180 g, 0.68 mmol) was dissolved in 5 mL of dry DMF and treated with K2CO3 (0.376 g, 2.72 mmol) and 4-(2-bromoethyl)imidazole hydrobromide (0.192 g, 0.75 mmol). After stirring overnight at room temperature, the reaction was diluted with water and extracted with EtOAc. The pooled extracts were washed well with aqueous 0.5N KOH, water and brine, and then dried, filtered, and concentrated. Purification of the residue (SiO2, 5% MeOH in DCM) afforded 0.120 g (49%) of the title compound as a light yellow foam. Conversion of this product to its HCl salt according to the method of Example 34 afforded 0.063 g of a light yellow powder, mp 170-172° C.: CI-MS m/e 359 (M+ +1).
Reaction SMILES: C([CH:8]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]1)[CH2:9][N:10]([CH:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17]1)[C:11]1[S:12][CH:13]=[CH:14][N:15]=1)C1C=CC=CC=1.ClC(OCC(C)C)=O.CO>ClCCCl>[CH2:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:24][CH:16]1[N:10]([C:11]1[S:12][CH:13]=[CH:14][N:15]=1)[CH2:9][CH2:8][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]1
Reactant: c1ccc(CC(CN(c2nccs2)C2Cc3ccccc3C2)C2CCCCN2)cc1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCCl
Solvent: CO
Product: c1ccc2c(c1)CC(N(CCC1CCCCN1)c1nccs1)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of compound 52 (0.688 g, 1.64 mmol) in DCE (15 mL) was added isobutyl chloroformate (0.53 mL, 4.94 mmol) at 0° C. and the solution was refluxed for 9.5 hours. Methanol (30 mL) was added and the mixture was allowed to stir at rt for 16 hours. The reaction mixture was concentrated under reduced pressure to provide compound 53.
Reaction SMILES: C([Si]([O:18][C@@H:19]1[C@H:26]2[C@H:22]([O:23][C:24]([CH3:28])([CH3:27])[O:25]2)[CH:21]=[C:20]1[F:29])(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[F:29][C:20]1[C@H:19]([OH:18])[C@@H:26]2[O:25][C:24]([CH3:27])([CH3:28])[O:23][C@@H:22]2[CH:21]=1
Reactant: CC1(C)O[C@@H]2[C@@H](C=C(F)[C@@H]2O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)O[C@@H]2[C@@H](C=C(F)[C@@H]2O)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tert-butyl((3aR,4R,6aR)-5-fluoro-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)diphenylsilane (5-5) (840 mg, 2.0 mmol, 1 eq) was dissolved in THF (10 mL) and TBAF (4.0 mL, 4.0 mmol, 2 equiv, 1M in THF) was added. The resulting mixture was stirred at ambient temperature for 2 hours. Upon disappearance of the starting material, the mixture was diluted with 50 mL EtOAc and washed with water (3×20 mL) and brine (20 mL). The organic layer was dried over MgSO4, filtered and concentrated. The crude residue was purified by flash chromatography (40 g SiO2, 0-60% EtOAc in hexanes) to yield (3aS,4R,6aR)-5-fluoro-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (5-6) as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 5.31 (s, 1H); 4.98 (td, J=6.0, 2.0 Hz, 1H); 4.74 (td, J=6.0, 3.0 Hz, 1H); 4.44 (s, 1H); 2.88 (brs, 1H); 1.49 (s, 3H); 1.41 (s, 3H).