Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.C1(C)C(S(O)(=O)=O)=CC=CC=1.C(OC([NH:20][C@@H:21]([CH2:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[CH2:22][N:23]([CH2:33][CH2:34][CH2:35][CH3:36])[C:24]([O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])=[O:25])=O)(C)(C)C>CCO.CCOCC>[NH2:20][C@@H:21]([CH2:37][CH:38]1[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]1)[CH2:22][N:23]([CH2:33][CH2:34][CH2:35][CH3:36])[C:24]([O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:30])[CH3:31])=[O:25]
Reactant: CCCCN(C[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(=O)OCC[Si](C)(C)C
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: CCCCN(C[C@@H](N)CC1CCCCC1)C(=O)OCC[Si](C)(C)C
Yield: 151.6 %

Procedure:
A solution of toluenesulfonic acid monohydrate (199.4 mg, 1.0 mmol) in absolute EtOH (1.0 mL) was added to a solution of (2S)-2-(tert-butoxycarbonylamino)-1-(N-butyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-3-cyclohexylpropane (468.5 mg, 1.03 mmol) in Et2O (10 mL). This solution was placed in a flask on a rotary evaporator and the Et2O was removed at rt. The flask was then lowered into the water bath (temperature: 60° C.) and the selective removal of the Boc group proceeded concurrently with removal of the remainder of solvent to afford (2S)-2-amino-1-(N-butyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-3-cyclohexylpropane (556.7 mg, 98%) as a white solid.
Reaction SMILES: [CH2:1]([N:5]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6](=[S:10])[O:7]CC)[CH:2]([CH3:4])[CH3:3].S(OCC)(O[CH2:19][CH3:20])(=O)=O>>[CH2:11]([N:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[C:6](=[O:10])[S:7][CH2:19][CH3:20])[CH:12]([CH3:13])[CH3:14]
Reactant: CCOC(=S)N(CC(C)C)CC(C)C
Reactant: CCOS(=O)(=O)OCC
Product: CCSC(=O)N(CC(C)C)CC(C)C
Temperature: 160 °C
Yield: 92 %

Procedure:
43.4 g. (0.2 mole) of O-ethyl N,N-diisobutyl-thiocarbamate are introduced into a 100 ml. round-bottomed flask, and 2.5 g. of diethyl sulfate are added. The mixture is refluxed for 90 minutes on an oil bath heated to 160°C, and thereafter the product is isolated by vacuum distillation. 39.8 g. (92 %) of S-ethyl N,N-diisobutyl-thiocarbamate are obtained; b.p.: 137°-138°C/20 Hgmm., nD25 = 1.4689.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13].[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]=[C:21]1[S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]=[C:21]1[S:29]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:31])=[O:30]
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: COC(=O)c1ccccc1CSc1ccccc1N
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1CSc1ccccc1NS(=O)(=O)c1cc2ccccc2o1
Yield: 74.1 %

Procedure:
Following General Procedure B, the title compound (803 mg, 74%) was prepared from methyl 2-(((2-aminophenyl)thio)methyl)benzoate (652 mg, 2.39 mmol) and benzofuran-2-sulfonyl chloride (816 mg, 3.78 mmol) in pyridine (10 ml).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[F:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1>O>[F:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]([N:1]=[O:3])[CH2:13][C:14]([OH:16])=[O:15])=[CH:10][CH:11]=1
Reactant: O=C(O)CNc1ccc(F)cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=NN(CC(=O)O)c1ccc(F)cc1
Reaction time: 6 h

Procedure:
Sodium nitrite (3.97 g), 57.5 mmol) in 10 mL water was added to a suspension of N-(4-fluorophenyl)glycine 9.25 g (54.7 mmol) in water (50 mL) under nitrogen. The reaction mixture was stirred until clear, ca. 6 hours. Acidification to pH 3 with HCl precipitated the product which was filtered and washed with water (50 mL) and dried to afford the title product.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]#[N:19])=[CH:5]2)[CH2:3][CH2:2]1.[C:20]([O:24][C:25]([NH:27][CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C>C(#N)C>[C:20]([O:24][C:25]([NH:27][CH:28]1[CH2:32][CH2:31][N:30]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]#[N:19])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=2[F:16])[CH2:29]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: N#Cc1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(c2c(F)cc3c(=O)c(C#N)cn(C4CC4)c3c2F)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 93.2 %

Procedure:
1-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carbonitrile (5.04 g) and 3-(tertbutyloxycarbonylamino)pyrrolidine (3.96 g) were combined in acetonitrile (48 ml). The mixture was heated to reflux at which point all the solids dissolved. After refluxing for 15-20 minutes a precipitate formed. Stirring was continued at reflux overnight (22 hours). Triethylamine (6 ml) was then added and refluxing continued another seven hours before cooling to room temperature. The solid was collected by filtration and then washed with acetonitrile (15 ml) followed by a solution of triethylamine (5 ml) in acetonitrile (5 ml). The solid was dried under vacuum at 50° C. to give 7-[3-(tert-butyloxycarbonylamino)pyrrolidin-1-yl]-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carbonitrile (7.65 g, 93%), mp 249°-250° C. (dec).
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[C:21]([NH:22][C:23](=[O:30])[CH2:24][CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:20][N:19]=[C:18]3[N:31]([S:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)(=[O:36])=[O:35])[CH:32]=[CH:33][C:17]=23)[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1>[C:37]1([S:34]([N:31]2[C:18]3=[N:19][CH:20]=[C:21]([NH:22][C:23](=[O:30])[CH2:24][CH:25]4[CH2:26][CH2:27][CH2:28][CH2:29]4)[C:16]([NH:15][CH:12]4[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]4)=[C:17]3[CH:33]=[CH:32]2)(=[O:36])=[O:35])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2c(NC(=O)CC3CCCC3)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(CC1CCCC1)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 4.0 M solution of HCl in 1,4-dioxane (10 ml) was added to a solution of 4-[1-benzenesulfonyl-5-(2-cyclopentyl-acetylamino)-1H-pyrrolo[2,3-b]pyridin-4-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (0.222 g, 0.382 mmol) in 1,4-dioxane (10 ml) at 25° C. The reaction mixture was stirred at 25° C. for 1 h, then was concentrated under reduced pressure to afford crude N-[1-benzenesulfonyl-4-(piperidin-4-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-cyclopentyl-acetamide (hydrochloride salt) as a white solid. This material was used in the next step below without additional purification or characterization.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1.[N:18]1([CH2:24][CH2:25]O)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(OCC)C>[C:14]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:25][CH2:24][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:9][CH:8]=2)[N:5]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(O)cc2)n1
Reactant: OCCN1CCOCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)c1cc(N)n(-c2ccc(OCCN3CCOCC3)cc2)n1
Temperature: 25 °C
Yield: 43.1 %

Procedure:
A solution of 4-(5-amino-3-tert-butyl-pyrazol-1-yl)-phenol (WO2005/110994, 0.462 g, 2 mmol), 2-morpholin-4-yl-ethanol (0.327 g, 2.5 mmol) and triphenylphosphine (1.05 g, 4 mmol) in THF (5 mL) under a nitrogen atmosphere was treated with diisopropyl azodicarboxylate (0.808 mg, 4 mmol). The reaction mixture was stirred at RT for 16 H, then diluted with diethyl ether. The organic layer was washed with water. The resulting aqueous layer was basified with potassium carbonate and extracted with EtOAc. The resulting organic layer was washed with aq. citric acid solution, and the resulting aqueous layer was basified with potassium carbonate, and extracted with EtOAc (three times). The resulting organic layer was dried (Na2SO4), evaporated to dryness then sonicated with diethyl ether (10 mL) and filtered to give the title compound (0.297 g, 43%) as a white solid. LCMS (Method 5): Rt 0.41, 2.16 min, m/z 345 [MH+]. 1H NMR (400 MHz, CDCl3): δ 7.46-7.39 (2 H, m), 6.98-6.93 (2 H, m), 5.50 (1 H, s), 4.15-4.08 (2 H, m), 3.75 (4 H, t, J 4.5), 3.63 (2 H, bs), 2.83-2.78 (2 H, m), 2.59 (4 H, t, J 4.3), 1.34-1.26 (9 H, m).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1[CH:18]=[O:19].O.[SH-].[Na+]>C(O)C>[CH:18]([C:3]1[CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:5][C:6]2[C:11]([CH:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:19]
Reactant: O=CC1=C(Cl)c2ccccc2OC1c1ccccc1
Agent: [Na+]
Agent: [SH-]
Solvent: CCO
Solvent: O
Product: O=CC1=Cc2ccccc2OC1c1ccccc1
Reaction time: 8 h

Procedure:
A mixture of 26 g 4-chloro-3-formyl-flav-3-ene and 7.1 g sodium hydrosulfide hydrate in 400 ml ethanol is refluxed for 3 hours and allowed to stand overnight at room temperature. The reaction mixture is evaporated to dryness and the residue dissolved in methylene chloride. The precipitate is filtered and the organic solution is evaporated. The residue is recrystallized in a mixture of hexane and toluene. Pure 4-(2"H-3"-formyl-2"-phenyl-1"-benzopyran-4"-yl-thio)-3-formyl-flav-3-ene is obtained as yellow crystals; m.p. 193°-194° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[CH:10]=[C:9]([C:11]([OH:14])([CH3:13])[CH3:12])[S:8][C:6]=2[N:7]=1.[CH3:21][C:22]1[N:39](COCC[Si](C)(C)C)[C:25]2=[N:26][CH:27]=[C:28](C3OC(C)(C)C(C)(C)O3)[CH:29]=[C:24]2[N:23]=1.C[Si](C)(C)CCOCN1C2C=C(C3N=C(N4CCOCC4)C4C=C(C(O)(C)C)SC=4N=3)C=CC=2N=C1C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:21][C:22]1[NH:39][C:25]2=[N:26][CH:27]=[C:28]([C:2]3[N:3]=[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:5]4[CH:10]=[C:9]([C:11]([OH:14])([CH3:13])[CH3:12])[S:8][C:6]=4[N:7]=3)[CH:29]=[C:24]2[N:23]=1
Reactant: CC(C)(O)c1cc2c(N3CCOCC3)nc(Cl)nc2s1
Reactant: Cc1nc2cc(C3OC(C)(C)C(C)(C)O3)cnc2n1COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1nc2ccc(-c3nc(N4CCOCC4)c4cc(C(C)(C)O)sc4n3)cc2n1COCC[Si](C)(C)C
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1nc2cc(-c3nc(N4CCOCC4)c4cc(C(C)(C)O)sc4n3)cnc2[nH]1

Procedure:
2-(2-Chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)propan-2-ol (100 mg) was reacted with 161 mg of 3-(2-(trimethylsilyl)ethoxy)methyl)-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-imidazo[4,5-b]pyridine 54 via Example 6b and General Procedure A. Crude 2-(2-(1-((2-(trimethylsilyl)ethoxy)methyl)-2-methyl-1H-benzo[d]imidazol-6-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)propan-2-ol was then refluxed overnight with 2 equivalents of tetrabutylammoniumfloride in THF to remove the SEM protecting group. The crude material was then extracted with water and ethyl acetate. The organic layer was concentrated to dryness and then purified via reverse phase HPLC to give 5.1 mg of 414. MS (Q1) 411.2 (M)+
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[NH:26][N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.Cl.Cl.[CH3:29][O:30][C@@H:31]1[CH2:35][NH:34][CH2:33][C@H:32]1[NH2:36]>>[NH2:36][C@H:32]1[C@H:31]([O:30][CH3:29])[CH2:35][N:34]([C:2]2[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)=[CH:20][C:5]([C:6]([NH:8][C:9]3[CH:10]=[CH:11][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:13][CH:14]=3)=[O:7])=[CH:4][N:3]=2)[CH2:33]1
Reactant: CO[C@@H]1CNC[C@H]1N
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2ccn[nH]2)c1
Agent: Cl
Product: CO[C@@H]1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2ccn[nH]2)C[C@H]1N

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 38 using 6-chloro-5-(1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 38.1) and trans-4-methoxypyrrolidin-3-amine dihydrochloride (Stage 78.1) to afford a white solid. HPLC (Condition 7) tR=5.675 min, UPLC-MS (Condition 3) tR=0.78 min, m/z=463.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.58 (br. s, 2H) 2.83-2.98 (m, 1H) 3.07-3.18 (m, 1H) 3.21 (s, 3H) 3.26-3.43 (m, 2H) 3.45-3.59 (m, 2H) 6.39 (br. s, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.49-7.91 (m, J=8.60 Hz, 3H) 8.03 (br. s, 1H) 8.72 (br. s, 1H) 10.18 (s, 1H) 12.76-13.24 (m, 1H).
Reaction SMILES: [CH2:1]([CH:5]([C:11]([O:13]CC)=[O:12])[C:6]([O:8]CC)=O)[CH:2]([CH3:4])[CH3:3].[CH:16](/[S:24]([NH2:27])(=[O:26])=[O:25])=[CH:17]\[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:4][CH:2]([CH3:3])[CH2:1][CH:5]([C:6]([NH:27][S:24](/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:25])=[O:26])=[O:8])[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)C(CC(C)C)C(=O)OCC
Reactant: NS(=O)(=O)/C=C/c1ccccc1
Product: CC(C)CC(C(=O)O)C(=O)NS(=O)(=O)/C=C/c1ccccc1
Yield: 96.6 %

Procedure:
In the same manner as in Example 1 (1), the object compound was obtained using diethyl isobutylmalonate (10.0 g). This and trans-β-styrenesulfonamide (2.91 g) were condensed in the same manner as in Example 152 (3). The condensed product was subjected to hydrolysis in the same manner as in Example 1 (3) to give the title compound (4.99 g) as an oil.
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:33])[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19](O)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[CH:5][CH:4]=1.Cl>C(O)CCC>[ClH:1].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:33])[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][C:16](=[C:19]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: O=C(CCCN1CCC(C(O)(c2ccccc2)c2ccccc2)CC1)c1ccc(Br)cc1
Agent: Cl
Solvent: CCCCO
Product: O=C(CCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1)c1ccc(Br)cc1

Procedure:
A mixture of 20 g (0.038 mole) of 4'-bromo-4-[4-(α-hydroxy-α-phenylbenzyl)piperidino]butyrophenone hydrochloride, 500 ml of 37% HCl and 250 ml of n-butanol was refluxed for 3 hours after which the solvent and excess acid were removed under vacuum. The remaining residue was recrystallized from isopropyl alcohol to give the desired product, M.P. 228°-230° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:18])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:17])=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[N-:19]=[N+]=[N-].[Na+].S(=O)(=O)(O)O>C(Cl)Cl>[Br:1][C:2]1[C:3]([OH:18])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([CH3:17])(=[NH:19])=[O:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: CS(=O)c1ccc(Nc2ncc(Br)c(O)n2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=N)(=O)c1ccc(Nc2ncc(Br)c(O)n2)cc1
Temperature: 40 °C
Reaction time: 36 h

Procedure:
324 mg of (RS)-5-bromo-2-[4-(methylsulfinyl)phenylamino]pyrimidin-4-ol and 128 mg of sodium azide are suspended in 6 ml of methylene chloride and mixed drop by drop with 0.3 ml of concentrated sulfuric acid while being cooled with ice. The mixture is stirred for 36 hours at 40° C. The organic phase is decanted off, and the residue is stirred with ice water. The solid is suctioned off, washed twice with water and once with ethanol and dried. 266 mg (78.2% of theory) of the product with a melting point of 230° C. (decomposition) is obtained.
Reaction SMILES: C([O:5][C:6](=[O:60])[CH2:7][CH:8]1[O:13]C(C)(C)[O:11][CH:10]([CH2:16][CH2:17][NH:18][C:19]([C@:21]23[CH2:56][CH2:55][C@@H:54]([C:57]([CH3:59])=[CH2:58])[C@@H:22]2[C@@H:23]2[C@@:36]([CH3:39])([CH2:37][CH2:38]3)[C@@:35]3([CH3:40])[C@@H:26]([C@:27]4([CH3:53])[C@@H:32]([CH2:33][CH2:34]3)[C:31]([CH3:42])([CH3:41])[C@@H:30]([O:43][C:44](=[O:52])[CH2:45][C:46]([CH3:51])([CH3:50])[C:47]([OH:49])=[O:48])[CH2:29][CH2:28]4)[CH2:25][CH2:24]2)=[O:20])[CH2:9]1)(C)(C)C.Cl>CO>[C:47]([C:46]([CH3:51])([CH3:50])[CH2:45][C:44]([O:43][C@H:30]1[CH2:29][CH2:28][C@@:27]2([CH3:53])[C@@H:32]([CH2:33][CH2:34][C@:35]3([CH3:40])[C@@H:26]2[CH2:25][CH2:24][C@H:23]2[C@@:36]3([CH3:39])[CH2:37][CH2:38][C@@:21]3([C:19]([NH:18][CH2:17][CH2:16][CH:10]([OH:11])[CH2:9][CH:8]([OH:13])[CH2:7][C:6]([OH:60])=[O:5])=[O:20])[CH2:56][CH2:55][C@@H:54]([C:57]([CH3:59])=[CH2:58])[C@@H:22]32)[C:31]1([CH3:42])[CH3:41])=[O:52])([OH:49])=[O:48]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCC3CC(CC(=O)OC(C)(C)C)OC(C)(C)O3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCC(O)CC(O)CC(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 0 °C
Reaction time: 6 h
Yield: 30.1 %

Procedure:
4-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-(2-(6-(carboxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)ethylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yloxy)-2,2-dimethyl-4-oxobutanoic acid (Example 80, 0.3 g) was taken in MeOH (3 ml) and cooled the contents to 0° C. then Aq HCl (0.5 ml) was added and the contents were stirred for 6 hours at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was evaporated under reduced pressure. The residue was taken in water and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (0.08 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.57-0.97 (m, 19H); 1.18-1.21 (m, 8H); 1.25-1.41 (m, 12H); 1.49-1.62 (m, 8H); 1.65-1.82 (m, 10H); 1.85-1.98 (m, 4H); 2.56-2.69 (m, 2H); 2.88-3.06 (m, 3H); 3.29-3.38 (m, 1H); 3.89-3.90 (m, 1H); 4.44-4.47 (m, 1H); 4.56 (s, 1H); 4.71 (s, 1H); Mass: 744 [M+1].
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][C:6](=[O:34])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C@@H:17](/[CH:18]=[CH:19]/[C:20](=[O:30])[C:21]2[O:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=2)[CH2:16][C:15]([CH3:32])([CH3:31])[C:14]1=[O:33])[CH3:4]>CO>[CH2:3]([O:5][C:6](=[O:34])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C@@H:17](/[CH:18]=[CH:19]/[CH:20]([OH:30])[C:21]2[O:22][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:24][CH:25]=2)[CH2:16][C:15]([CH3:31])([CH3:32])[C:14]1=[O:33])[CH3:4]
Reactant: CCOC(=O)CCCCCCN1C(=O)C(C)(C)C[C@@H]1/C=C/C(=O)c1ccc(C(F)(F)F)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)CCCCCCN1C(=O)C(C)(C)C[C@@H]1/C=C/C(O)c1ccc(C(F)(F)F)o1
Reaction time: 0.75 h
Yield: 32.1 %

Procedure:
Sodium borohydride (37 mg, 0.98 mmol) was slowly added to a solution of 7-{(R)-3,3-dimethyl-2-oxo-5-[(E)-3-oxo-3-(5-trifluoromethyl-furan-2-yl)-propenyl]-pyrrolidin-1-yl}-heptanoic acid ethyl ester (280 mg, 0.61 mmol) in methanol (4 mL) at −20° C. The reaction flask was kept at −10° C. for 45 minutes. When the addition was complete the reaction vessel was kept at −10 C for 40 min. When the reaction was done, it was quenched with acetone and concentrated to dryness. The residue was dissolved in ethyl acetate, washed with brine and dried. After concentration, the crude mixture was purified on a silica gel column using hexane:ethyl acetate 1:1 as the solvent, giving 90 mg of 7-{(R)-5-[(E)-3-hydroxy-3-(5-trifluoromethyl-furan-2-yl)-propenyl]-3,3-dimethyl-2-oxo-pyrrolidin-1-yl}-heptanoic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.Cl[C:10](=[O:15])[C:11]([O:13][CH3:14])=[O:12]>>[CH3:14][O:13][C:11](=[O:12])[C:10]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1)=[O:15]
Reactant: COC(=O)C(=O)Cl
Reactant: Nc1ccc(Br)cn1
Product: COC(=O)C(=O)Nc1ccc(Br)cn1

Procedure:
In a manner similar to that employed in Referential Example 242, the title compound was prepared from 2-amino-5-bromopyridine and methyl chlorooxoacetate.
Reaction SMILES: [BH4-].[Na+].[F:3][CH:4]([F:25])[C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C:19]2=[O:23])[C@H:15]2[C@H:6]1[C@@H:7]1[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:24])[CH2:9][CH2:8]1.[BH4-].C(O)(=O)C>C1COCC1.O>[F:3][CH:4]([F:25])[C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C@@H:19]2[OH:23])[C@H:15]2[C@H:6]1[C@@H:7]1[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:24])[CH2:9][CH2:8]1
Reactant: C[C@]12C[C@H](C(F)F)[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: C[C@]12C[C@H](C(F)F)[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O

Procedure:
A sodium borohydride solution (100 mg in 50 ml absolute ethanol, 4 ml) is added to a solution of 11β-difluoromethyl-estr-4-ene-3,17-dione (II, Example 2, 20 mg) in THF (4 ml) with cooling. After 1 hr another 1 ml of the borohydride solution is added. After 15 minutes acetic acid in water (5%, 10 ml) is added. Most of the solvent is removed under reduced pressure and the product extracted with diethyl ether. The product is chromatographed thru silica gel eluting with ethyl acetate/hexane (60/40). The appropriate fractions are pooled and concentrated to give the title compound, NMR (CDCl3) 0.81, 3.63, 5.84, 6.05 and 55.5 δ.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([O:21]C)=[O:20])[C:13]=3[C:12]([CH2:23][CH2:24][NH:25][C@H:26]3[CH:31]4[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]4)[CH2:27]3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+:36]>O1CCCC1.O>[C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([O-:21])=[O:20])[C:13]=3[C:12]([CH2:23][CH2:24][NH:25][C@H:26]3[CH:31]4[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]4)[CH2:27]3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+:36]
Reactant: COC(=O)c1cccc2c1c(CCN[C@@H]1CN3CCC1CC3)cn2S(=O)(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C([O-])c1cccc2c1c(CCN[C@@H]1CN3CCC1CC3)cn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-methyl 1-(phenylsulfonyl)-3-(2-(quinuclidin-3-ylamino)ethyl)-1H-indole-4-carboxylate (480 mg, 1.02 mmol) from Step D above in tetrahydrofuran (10 mL) was added lithium hydroxide monohydrate (129 mg, 3.07 mmol) in water (3 mL). The mixture was stirred at ambient temperature overnight and then concentrated under reduced pressure. The residue was dried overnight under vacuum to afford crude lithium (S)-1-(phenylsulfonyl)-3-(2-(quinuclidin-3-ylamino)ethyl)-1H-indole-4-carboxylate, which was used in the next step without further purification: MS (ESI+) m/z 454 (M+H).