Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[O:17][CH2:18][CH2:19][CH2:20][CH3:21])CCC>[Li+].[OH-]>[CH2:18]([O:17][C:8]1[CH:9]=[C:10]([C:13]([F:14])([F:15])[F:16])[CH:11]=[CH:12][C:7]=1[C:6]([OH:22])=[O:5])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCOC(=O)c1ccc(C(F)(F)F)cc1OCCCC
Agent: [Li+]
Agent: [OH-]
Product: CCCCOc1cc(C(F)(F)F)ccc1C(=O)O

Procedure:
2-Butoxy-4-trifluoromethyl-benzoic acid butyl ester was reacted with 1N LiOH (10 ml) as described above to yield title compound (687 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([NH2:16])[CH:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:32])[CH2:26][O:27][CH2:28][C:29](O)=[O:30])=[C:20]([C:33]([O:35]C)=[O:34])[CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:32])[CH2:26][O:27][CH2:28][C:29](=[O:30])[NH:16][C:11]2[CH:10]=[C:9]([C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=3)[CH:14]=[CH:13][C:12]=2[CH3:15])=[C:20]([CH:19]=1)[C:33]([OH:35])=[O:34]
Reactant: Cc1cc(C)cc(-c2ccc(C)c(N)c2)c1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Product: Cc1cc(C)cc(-c2ccc(C)c(NC(=O)COCC(=O)Nc3ccc(Cl)cc3C(=O)O)c2)c1

Procedure:
Using the same method as in Example 1-(ii), 3′,4,5′-trimethylbiphenyl-3-amine was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-[((2-oxo-2-[(3′,4,5′-trimethylbiphenyl-3-yl)amino]ethoxy)acetyl)amino]benzoic acid.methyl ester (yield: 91%).
Reaction SMILES: [SH:1][CH2:2][C:3]#[N:4].[CH3:5][O:6][C:7]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:8]=1[CH2:9][N:10]1[C@@:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])([CH3:19])[C@@H:17]2[C@@H:13]([CH2:14][O:15][CH2:16]2)OS1(=O)=O.CN(C)C(N(C)C)=N.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:5][O:6][C:7]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:8]=1[CH2:9][NH:10][C@@:18]([C@H:17]1[CH2:16][O:15][CH2:14][C@@H:13]1[S:1][CH2:2][C:3]#[N:4])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26])[CH3:19]
Reactant: COc1ccc(CN2[C@](C)(c3ccccc3F)[C@H]3COC[C@H]3OS2(=O)=O)c(OC)c1
Reactant: N#CCS
Agent: CN(C)C(=N)N(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Product: COc1ccc(CN[C@](C)(c2ccccc2F)[C@H]2COC[C@@H]2SCC#N)c(OC)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 97.2 %

Procedure:
2-Mercaptoacetonitrile (1.03 g, 14.1 mmol) was added dropwise to a solution of (3aS,7S,7aS)-rel-6-(2,4-dimethoxy-benzyl)-7-(2-fluoro-phenyl)-7-methyl-hexahydro-2,4-dioxa-5-thia-6-aza-indene 5,5-dioxide (4.1 g, 9.37 mmol) and 1,1,3,3-tetramethylguanidine (1.62 g, 14.1 mmol) in N,N-dimethylformamide (55 ml) at room temperature. The reaction mixture was then stirred at 60° C. for 12 hours. For the workup, the solvent was evaporated at reduced pressure, and the residue was dissolved in dichloromethane (50 ml). After addition of sulfuric acid (20%; 50 ml, 185 mmol) and stirring overnight, the mixture was poured onto a saturated solution of sodium hydrogencarbonate followed by the extraction (2×) with dichloromethane. The combined organic layers were dried over sodium sulphate and evaporated. The residue was purified by flash chromatography on silica gel using a gradient of heptane and ethyl acetate=100:0 to 0:100 as the eluent. The {rel-(3R,4S)-4-[(S)-1-(2,4-dimethoxy-benzylamino)-1-(2-fluoro-phenyl)-ethyl]-tetrahydro-furan-3-ylsulfanyl}-acetonitrile (3.92 g, 97% yield) was obtained as a light brown oil. MS (ISP): m/z=431.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)Cl)=[CH:4][N:3]=1.C(=O)([O-])[OH:12].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:12])=[CH:4][N:3]=1
Reactant: Clc1ccc(C(Cl)Cl)cn1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=Cc1ccc(Cl)nc1
Reaction time: 2 h
Yield: 95 %

Procedure:
A mixture of 7.0 g (0.0356 mol) of 2-chloro-5-dichloromethyl-pyridine and 100 ml of water is heated to reflux. The pH is kept between 4 and 7 by adding a saturated sodium hydrogencarbonate solution dropwise. After 2 hours, the mixture is cooled, extracted using ethyl acetate and the solvent is carefully removed from the organic phase by distillation in a water jet vacuum. 4.6 g (95% of theory) of 6-chloro-nicotinaldehyde of melting point 70° C. are obtained.
Reaction SMILES: I[C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)=[C:12]([O:26][CH3:27])[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[CH2:30]1[C:33]2([CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)[CH2:32][NH:31]1.C(=O)([O-])[O-].[K+].[K+].N1CCC[C@H]1C(O)=O>CS(C)=O.[OH-].[NH4+].[Cu]I>[CH3:27][O:26][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[O:16][CH2:17][C:18]1[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[CH2:9][N:6]1[C:5]2[CH:28]=[CH:29][C:2]([N:31]3[CH2:30][C:33]4([CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:37][CH2:38]4)[CH2:32]3)=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC2
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(I)ccc43)cc2OC)cn1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: COc1ccc(COc2ccc(Cn3cnc4cc(N5CC6(CCN(C(=O)OC(C)(C)C)CC6)C5)ccc43)cc2OC)cn1
Temperature: 120 °C
Reaction time: 16 h
Yield: 72.4 %

Procedure:
To a stirred suspension of 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole (0.61 g, 1.22 mmol) in dimethyl sulfoxide (4 mL) was added tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (0.30 g, 1.34 mmol), copper(I) iodide (0.028 g, 0.15 mmol), potassium carbonate (0.41 g, 2.94 mmol), and L-proline (0.034 g, 0.29 mmol). The light yellow reaction mixture was heated to 120° C. After 16 h, the reaction mixture was allowed to cool to room temperature and was diluted with 3 N ammonium hydroxide solution (20 mL). The mixture was extracted with dichloromethane, resulting in a thick emulsion. The elmusion was filtered through Celite to remove any insoluble material. The organic phase was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated. Chromatographic purification (CombiFlash, 40 g SiO2 column, 1-5% methanol/dichloromethane elute) afforded 0.53 g (72%) of tert-butyl 2-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate.
Reaction SMILES: [N:1]1([C:7]2[S:8][C:9](=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[C:10](=[O:12])[N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:27][CH2:28][C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=1)[OH:30]>>[Cl:37][C:33]1[CH:32]=[C:31]([C@@H:29]([OH:30])[CH2:28][NH:27][CH:23]2[CH2:22][CH2:21][N:20]([C:17]3[CH:16]=[CH:15][C:14]([CH:13]=[C:9]4[S:8][C:7]([N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)=[N:11][C:10]4=[O:12])=[CH:19][CH:18]=3)[CH2:25][CH2:24]2)[CH:36]=[CH:35][CH:34]=1
Reactant: O=C1CCN(c2ccc(C=C3SC(N4CCOCC4)=NC3=O)cc2)CC1
Reactant: NC[C@H](O)c1cccc(Cl)c1
Product: O=C1N=C(N2CCOCC2)SC1=Cc1ccc(N2CCC(NC[C@H](O)c3cccc(Cl)c3)CC2)cc1

Procedure:
The title compound was prepared from 1-[4-(2-morpholin-4-yl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one(which was obtained in Intermediate 28) and (1R)-2-amino-1-(3-chloro-phenyl)-ethanol(which was obtained in Intermediate 1) according to the procedure of Example 1 as a yellowish solid; mp >70° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2 H), 1.70-1.95 (m, 2 H), 2.60-2.90 (m, 7H), 3.50-4.00(m, 8H), 4.55-4.65(m, 1 H), 5.46 (brs, 1 H), 7.02 (d, J=9.0 Hz, 2 H), 7.25-7.45 (m, 7H), 7.54 (s, 1 H); MS (ES) m/z: 527.1(MH+, 100%); HRMS Calcd. for C27H32ClN4O3S (MH+): 527.1884. Found: 527.1863.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5]1.Cl[C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:18]([Cl:24])=[CH:17][N:16]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1>[Cl:24][C:18]1[CH:19]=[C:20]([N+:21]([O-:23])=[O:22])[C:15]([O:3][C:4]2([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5]2)=[N:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)C1(O)CC1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C1(Oc2ncc(Cl)cc2[N+](=O)[O-])CC1
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
Under ice cooling, to a toluene suspension (60 ml) of 63% sodium hydride (2.81 g) was added dropwise a toluene solution (30 ml) of tert-butyl 1-hydroxycyclopropanecarboxylate (11.65 g) over 15 minutes, followed by stirring as it stood for 30 minutes, and further at room temperature for 2 hours. After cooling again using an ice bath, a toluene solution (30 ml) of 2,5-dichloro-3-nitropyridine (7.13 g) was added, and the temperature was brought back to room temperature, followed by stirring for 3 hours. After a 10% aqueous citric acid solution was added, the separated organic layer was washed with saturated sodium chloride solution, and the aqueous layer was extracted with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford tert-butyl 1-[(5-chloro-3-nitropyridin-2-yl)oxy]cyclopropanecarboxylate (9.61 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[C:6]([CH3:10])=[CH:5][N:4]=1.[CH3:11][NH2:12].C(Cl)Cl.CO>C(O)C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:12][CH3:11])[C:6]([CH3:10])=[CH:5][N:4]=1
Reactant: CN
Reactant: CSc1ncc(C)c(Cl)n1
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: CNc1nc(SC)ncc1C

Procedure:
Prepared from 2-methylsulphenyl-4-chloro-5-methyl-pyrimidine by reacting with methylamine in ethanol at 100° C., melting point: 134° C., Rf value: 0.35 (silica gel; methylene chloride/methanol=40:1)
Reaction SMILES: Br[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[N:7]=1.[OH:12][C:13]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:14]=1[CH:15]=[O:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:8]([C:6]1[N:7]=[C:3]([CH2:2][O:12][C:13]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:14]=2[CH:15]=[O:16])[S:4][CH:5]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1csc(CBr)n1
Reactant: COc1ccc(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(OCc2nc(C(C)(C)C)cs2)c(C=O)c1
Yield: 72.8 %

Procedure:
A mixture of 2-bromomethyl-4-tert-butylthiazole (3.4 g), 2-hydroxy-5-methoxybenzaldehyde (2.21 g) and potassium carbonate (2.0 g) in acetone (25 ml) was stirred under reflux for 7 hours. After being filtered, the filtrate was concentrated under reduced pressure to give a crude residue. The residue was subjected to column chromatography on silica gel and eluted with a mixture of toluene and ethyl acetate. The fractions containing object compound were combined and concentrated under reduced pressure to give a syrup. The syrup was crystallized from n-hexane and filtered to give 4-tert-butyl-2-(2-formyl-4-methoxyphenoxymethyl)thiazole (3.23 g).
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][C@H:11]2[C:16]([OH:18])=[O:17])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:20]1([CH:26](O)[CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:20]1([CH:26]([O:17][C:16]([C@@H:11]2[CH2:12][S:13][CH2:14][CH2:15][N:10]2[S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=2)(=[O:9])=[O:8])=[O:18])[CH2:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)O)cc1
Reactant: OC(CCc1ccccc1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)OC(CCc2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.3 %

Procedure:
0.301 g (1 mmol) of (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.318 g (1.5 mmol) of (1,3-diphenyl)-propanol, 0.088 g (0.33 mmol) of CAS, 0.227 g (1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP were dissolved in 15 mL of CH2Cl2. The mixture was stirred for 24 h at room temperature. The solid was filtrated and the solvent was evaporated. The residual was dissolved in a suitable amount of ethyl acetate (20 ml) and then the mixture was filtered to remove insoluble substance. The ethyl acetate was added to 60 ml and then the liquid was washed with 10% NaHCO3 solution, saturated NaCl solution and dried over Na2SO4. After the drying agent was removed and part of ethyl acetate was evaporated, the crude product was purified by flash column chromatography (eluent: ethyl acetate:cyclohexane=1:3) to obtain the product as a oil (0.15 g). 1H-NMR (400 MHz, CDCl3): δ 7.5040(d, 2H, J=8.32 Hz), 7.3751-7.0634 (m, 12H), 5.7186-5.6846 (m, 1H), 5.0645 (t, 1H, J=3.42 Hz), 4.0136-3.9800 (m, 1H), 3.4760-3.4052 (m, 1H), 3.1031-3.0773 (m, 2H), 2.8562-2.7914 (m, 1H), 2.6613-2.5414 (m, 2H), 2.4304-2.3855 (m, 1H), 2.3333 (s, 3H), 2.2283-2.2041 (m, 1H), 2.0565-2.0328 (m, 1H); MS (EI) m/z: 495.8, 449.8, 391.8, 339.8, 299.7, 255.7, 193.8, 154.8, 138.8, 116.9, 90.8, 64.9.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]2[O:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=O.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH2:17]([O:16][C:14]1[C:8]2[O:9][C:10]([CH3:12])([CH3:13])[O:11][C:7]=2[CH:6]=[C:5]([CH2:3][OH:2])[CH:15]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)c2c(c1)OC(C)(C)O2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC1(C)Oc2cc(CO)cc(OCc3ccccc3)c2O1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A −78° C. solution of 7-benzyloxy-2,2-dimethyl-benzo[1,3]dioxole-5-carboxylic acid methyl ester (0.62 g, 2.0 mmol) in toluene (17 mL) is treated with di-isobutylaluminum hydride (1.0 M solution I hexanes, 4.4 mL, 4.4 mmol), which is added dropwise over 15 minutes. After 5 minutes of stirring, the reaction is quenched by the addition of 10% aqueous hydrochloric acid solution. After warming to room temperature, the mixture is extracted 3× with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide (7-benzyloxy-2,2-dimethyl-benzo[1,3]dioxol-5-yl)-methanol in quantitative yield.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][C:20]=4[O:28][CH3:29])[CH2:11][CH2:10]3)=[N:7][S:8][C:4]=2[CH:3]=1.CO.C1COCC1.[BH4-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]4[CH:24]=[CH:23][C:22]([CH:25]([CH3:26])[OH:27])=[CH:21][C:20]=4[O:28][CH3:29])[CH2:11][CH2:10]3)=[N:7][S:8][C:4]=2[CH:3]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCN1CCC(c2nsc3cc(F)ccc23)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(C)O)ccc1OCCCN1CCC(c2nsc3cc(F)ccc23)CC1
Reaction time: 3.5 h
Yield: 91.9 %

Procedure:
To a starred solution of 1-[4-[3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propoxy]3-methoxyphenyl]ethanone (4.1g, 9.3 mmol) in 60 mi MeOH--THF (1:1) under N2 at ambient temperature, NaBH4 (0,386g, 10.2 mmol) was added portionwise. After complete addition, the reaction was stirred for 3.5 hours and was concentrated to yield a white gum. This was triturated with H2O (2×) and the aqueous fraction was decanted away. Residual water was removed under high vacuum to afford 5.0 of a white powder. The compound was taken up in boiling toluene and the insolubles were filtered away. Concentration of the toluene filtrate afforded 3.8g of a beige solid. Purification via preparative HPLC (Water's Associates prep LC/System 500, using 2 silica gel columns and 2% Et2NH--EtoAc) provided 2.7 g of a light beige solid. The product was recrystallized from EtoAc to afford 1.7g (42%) of a pure white powder, m.p.=113°-115° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:49]([O:53][CH2:54][CH3:55])(=[O:52])[C:50]#[CH:51]>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([C:8]1([N:13]([CH:51]=[CH:50][C:49]([O:53][CH2:54][CH3:55])=[O:52])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)(=[O:15])=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C#CC(=O)OCC
Reactant: CC(C)(C)OC(=O)C1(NS(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2)CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C=CN(C1(C(=O)OC(C)(C)C)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reaction time: 1 h
Yield: 77.4 %

Procedure:
To a mixture of 1-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-cyclopentanecarboxylic acid tert-butyl ester (1.0 g, 2.3 mmole) in 10 mL THF and 2.3 mL (2.3 mmole) 1M tetrabutylammonium fluoride in THF was added 0.23 mL (2.3 mmole) ethyl propiolate at ambient temperature. After stirring 1 hour the reaction was complete by HPLC and was stripped to dryness in vacuo. The residue was dissolved in 20 mL ethyl acetate and washed with 2×10 mL water and the organic solution stripped to an oil. This oil was chromatographed over silica gel, eluting with 10% ethyl acetate/hexane to yield 0.95 g (77% yield) 1-{(2-ethoxycarbonyl-vinyl)-[4-(4-fluoro-phenoxy)-benzenesulfonyl]-amino}-cyclopentanecarboxylic acid tert-butyl ester as a colorless oil. 1H NMR (CDCl3) indicated a 1.5:1 trans/cis ratio.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([CH:28]([CH3:30])[CH3:29])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@@:12]2([CH3:27])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@H:23]([OH:25])[CH2:24][C:19]4=[CH:18][CH:17]=[C:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH3:7]>C(O)C>[CH3:1][CH2:2][C@H:3]([CH:28]([CH3:29])[CH3:30])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@@:12]2([CH3:27])[CH2:13][CH2:14][CH2:15]/[C:16](=[CH:17]\[CH:18]=[C:19]3\[CH2:24][C@@H:23]([OH:25])[CH2:22][CH2:21][C:20]\3=[CH2:26])/[C@@H:11]2[CH2:10][CH2:9]1)[CH3:7]
Reactant: CC[C@H](CC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)C(C)C
Solvent: CCO
Product: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)CC[C@H](CC)C(C)C)CC[C@@H]12
Yield: 40.1 %

Procedure:
7-Dehydrositosterol (7) (1.5 g, 3.63 mmol) in ethanol (200 mL) was heated at 60° C. for 4 h. The reaction was monitored by TLC. The solution was concentrated in vacuo and the crude vitamin D5 was purified on a silica gel column using 20% ethyl acetate in hexane to yield 600 mg (40%) of Vitamin D5 (9).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([Cl:29])[CH:23]=4)[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:71]=[CH:70][C:67]([C:68]#[N:69])=[CH:66][C:65]=1[O:72][CH3:73]>>[C:68]([C:67]1[CH:70]=[CH:71][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([Cl:29])[CH:23]=2)=[O:32])=[C:65]([O:72][CH3:73])[CH:66]=1)#[N:69]
Reactant: COc1cc(C#N)ccc1N
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cc(F)cc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C#N)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cc(F)cc(Cl)c1

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-5-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 87 (0.4 g, 0.71 mmol), was reacted with diisopropylethylamine (0.46 g, 3.6 mmol), diphenylphosphinic chloride (0.34 g, 1.4 mmol), then reacted with 4-amino-3-methoxy-benzonitrile prepared in Example 57 (0.32 g, 2.1 mmol) to give rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-5-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-methoxy-phenyl)-amide as a white solid (Yield, 0.15 g, 36%).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=O.[CH2:12]([O:14][CH2:15][C:16]1[N:17]([CH2:35][C:36]([OH:39])([CH3:38])[CH3:37])[C:18]2[C:27]3[CH:26]=[C:25]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:34]=1)[CH3:13].[OH-].[NH4+:41].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:41][C:20]1[C:19]2[N:34]=[C:16]([CH2:15][O:14][CH2:12][CH3:13])[N:17]([CH2:35][C:36]([OH:39])([CH3:37])[CH3:38])[C:18]=2[C:27]2[CH:26]=[C:25]([NH:28][C:29](=[O:33])[CH:30]([CH3:31])[CH3:32])[CH:24]=[CH:23][C:22]=2[N:21]=1
Reactant: CCOCc1nc2cnc3ccc(NC(=O)C(C)C)cc3c2n1CC(C)(C)O
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3ccc(NC(=O)C(C)C)cc3c2n1CC(C)(C)O
Reaction time: 1 h

Procedure:
3-Chloroperoxybenzoic acid (60% pure, 0.283 g, 1.0 mmol) was added to a solution of N-[2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-8-yl]-2-methylpropanamide (0.380 g, 1.0 mmol) in chloroform (10 mL) and the reaction was stirred for 1 hour. The mixture was cooled in an ice bath and ammonium hydroxide (3 mL) was added. After 15 minutes of stirring, p-toluenesulfonyl chloride (0.190 g, 1.0 mmol) was added and the reaction mixture was stirred for 72 hours. The fractions were separated and the aqueous fraction was extracted with chloroform. The combined organic fractions were washed with brine and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a linear gradient of 2-20% CMA in chloroform). Recrystallization from acetonitrile provided 0.231 g of N-[4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-8-yl]-2-methylpropanamide as an off-white solid, mp 259-261° C.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Si:25]([O:32][CH2:33][CH:34]1[CH:38]([CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:37][C:36](CO)=[CH:35]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>ClCCl>[Si:25]([O:32][CH2:33][CH:34]1[CH:38]([CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:42])[CH3:43])[CH2:37][C:36]([CH2:1][Br:5])=[CH:35]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)[Si](C)(C)OCC1C=C(CO)CC1CO[Si](C)(C)C(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC1C=C(CBr)CC1CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
A mixture of carbon tetrabromide (3.18 g, 9.6 mmol) and triphenyl phosphine (3.15 g, 12.9 mmol) were added to [3,4-di(t-butyldimethylsilyloxymethyl)cyclopent-1-en-1-yl]methyl alcohol (3.09 g, 8.0 mmol) in dichloromethane under ice bath and then, the reaction mixture was stirred for 30 min at 0° C. After overnight at room temperature, the reaction mixture was extracted with dichloromethane, dried with MgSO4, filtered, concentrated and separated by column chromatography to give a desirable product (2.43 g).