Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8](C)=[CH:9][CH:10]=2)[C:5]([CH3:14])([CH3:13])[CH:4]([CH3:15])[CH2:3]1.[Al+3].[Cl-].[Cl-].[Cl-].Cl[CH2:22]Cl>>[CH3:13][C:5]1([CH3:14])[C:6]2[C:11](=[CH:10][C:9]([CH3:22])=[CH:8][CH:7]=2)[C:2]([CH3:16])([CH3:1])[CH2:3][CH:4]1[CH3:15]
Reactant: Cc1ccc2c(c1)C(C)(C)C(C)CC2(C)C
Reactant: ClCCl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc2c(c1)C(C)(C)CC(C)C2(C)C
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
The starting material 1,1,2,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene is prepared as follows. A 100 ml four-necked round bottom flask is charged with 1,1,3,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene (HMT) (20 g) and dichloromethane (32.6 g) and cooled to 0° C. with a dry ice/isopropanol bath. To the flask is then added, with stirring, anhydrous AlCl3 (2.507 g). The temperature of the flask is maintained between about 0° C. and 10° C. while the reaction is allowed to proceed for about 2.5 hrs. The reaction is then quenched with ice water (25 ml), and the resultant product washed with deionized water. The aqueous layer is extracted twice with ether, the organics are combined, dried over K2CO3 and rotoevaporated to yield a crude product (18.26 g) containing 37.22 weight percent of a mixture of 1,1,2,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene, HMT, 1,1,3,5-tetramethyl-3-isopropylindane and 1,3,3,5-tetramethyl-1-isopropylindane. The indanes are removed from the mixture by preparative gas chromatography. The desired compound, 1,1,2,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene, is then separated from HMT using a vacuum spinning band fractional distillation apparatus.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19]Br)[CH:6]=1.[CH3:22][C@@H:23]1[C@H:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:26][C:25](=[O:34])[NH:24]1>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][N:24]2[C@H:23]([CH3:22])[C@H:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:26][C:25]2=[O:34])[CH:6]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CBr)c1
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN2C(=O)O[C@@H](c3ccccc3)[C@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 6, Step 5, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-phenyl]-acetic acid methyl ester and (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23](OC)=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=O>O1CCCC1>[OH:8][CH2:9][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][CH:18]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc(-c2ccc(C(=O)OC)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(-c2ccc(CO)cc2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
789 mg (20.8 mmoles) of LiAlH4 in 150 ml of anhydrous THF (tetrahydrofuran) are placed in a 2-liter flask which has a mechanical agitator, cooler, filler funnel and heating bath. A solution, heated to 50° C., of 7.5 g (27.7 mmoles) of 4,4'-bis (methoxycarbonyl)biphenyl in 500 ml of anhydrous THF is added dropwise, over a period of 1 hour, to the mixture, heated in an inert atmosphere to 50° C. under agitation. After a further 30 minutes of agitation in a heating bath, the mixture is cooled to ambient temperature and the excess LiAlH4 is destroyed by the careful addition of 15 ml of a THF/H2O (80:20) mixture. The reaction mixture is filtered on Septum G2, washing the precipitate with anydrous ethanol (3×100 ml). The combined filtrate and washings are evaporated to dryness under vacuum with the heating bath at 40° C. The residue is then redissolved with 100 ml of hot acetone (50° C.), eliminating the insoluble residue by filtration, dried on anhydrous Na2SO4 and evaporated to dryness. 5.74 g of 4,4'-bis (hydroxymethyl) biphenyl are obtained with a molar yield of 96.6%.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[CH:13]=[CH:14]/[C:15]([O:17]C)=[O:16])=[CH:7][C:6]=1[O:19][CH3:20])(=O)C.[OH-].[Na+].O.Cl>CO>[OH:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])=[CH:7][C:6]=1[O:19][CH3:20]
Reactant: COC(=O)/C=C/C=C/c1ccc(OC(C)=O)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(/C=C/C=C/C(=O)O)ccc1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Methyl 5-(4-Acetoxy-3-methoxyphenyl)-penta-2E,4E-dienoate (400 mg, 1.45 mmol) [Example 1] was dissolved in 60 mL MeOH, 20 mL of 5% NaOH and 40 mL of water were added, and the mixture was stirred for 24 h at room temperature. The mixture was acidified to pH 2 with 5% HCl, methanol was evaporated and the compound was extracted with ethyl acetate. The organic layer was dried with Na2SO4 and evaporated.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([S:12]([N:15]([CH2:26][CH2:27][S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:30])=[O:29])[CH2:16][CH2:17][NH:18]C(OC(C)(C)C)=O)(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[ClH:37].CO>C(OCC)C>[ClH:37].[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([S:12]([N:15]([CH2:26][CH2:27][S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:30])=[O:29])[CH2:16][CH2:17][NH2:18])(=[O:13])=[O:14])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)NCCN(CCS(=O)(=O)c1ccccc1)S(=O)(=O)c1cccc2c(N)nccc12
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: NCCN(CCS(=O)(=O)c1ccccc1)S(=O)(=O)c1cccc2c(N)nccc12
Temperature: 25 °C

Procedure:
According to the method of Example 1, Step C, deprotection was performed (50° C., 2 hours) by using Intermediate 17 (134 mg) and 10% hydrogen chloride/methanol solution (2.5 ml). The reaction mixture was cooled to room temperature and then added with diethyl ether (2.5 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (100 mg) as white powdery solid.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[CH:17]=[C:16]([CH2:18][CH3:19])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[OH:20])=[N+]=[N-].[H][H]>O.CO.[Pd]>[NH2:1][CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[CH:17]=[C:16]([CH2:18][CH3:19])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[OH:20]
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CN=[N+]=[N-])O2)c(=O)[nH]c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CN)O2)c(=O)[nH]c1=O

Procedure:
5'-Azido-5-ethyl-2',5'-dideoxyuridine (300 mg) is dissolved in a mixture of water-methanol (1:1, 25 ml) and then hydrogen gas is introduced with 10% Pd/C at room temperature under 1 atmosphere for 2 hr, after which the mixture is filtered and the filtrate is evaporated to a foam (160 mg, 50%).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9]([O-:12])(=[O:11])=[O:10])[CH:4]=1.[Na+].[CH:14](OC)(OC)OC>>[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9]([O:12][CH3:14])(=[O:11])=[O:10])[CH:4]=1
Reactant: COC(OC)OC
Reactant: C=Cc1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Product: C=Cc1cccc(S(=O)(=O)OC)c1

Procedure:
Next, the desalted product of sodium m-styrenesulfonate was subjected to methyl esterification with trimethyl orthoformate by following the same procedure as in Example Y-1, whereby methyl m-styrenesulfonate was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][NH:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[Cl:8].BrBr.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:12]([NH:29][CH2:28][C:27]3[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=3)=[N:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=c1[nH]cc(-c2ccccc2)n1-c1ccc(Cl)c(Cl)c1
Reactant: NCc1ccc(F)cc1
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: O=C1N=C(NCc2ccc(F)cc2)C(c2ccccc2)N1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.6 %

Procedure:
To a stirred solution of 1-(3,4-dichloro-phenyl)-5-phenyl-1,3-dihydro-imidazol-2-one (1 equiv., 0.33 mmol, 100 mg) in chloroform (5 mL) was added dropwise Br2 (1.1 equiv., 0.36 mmol, 19 μL) in chloroform (2 mL) at 0° C. under nitrogen. After 10 min, 4-fluorobenzylamine (10 equiv., 3.28 mmol, 372 μL) was added in situ at 0° C. The reaction mixture was allowed to warm up to room temperature and heated at reflux overnight. After evaporation of solvent, the residue was purified by column chromatography (SiO2, n-heptane/ethyl acetate: 0-100%) affording the title compound as a white solid (32 mg, 23%). δH NMR (DMSO, 300 MHz) 8.83 (1H, br, s, NH), 7.91 (1H, d, J=2.4 Hz, H arom), 7.46-7.08 (11H, m, H arom), 6.16 (1H, s, C5H), 4.44 (2H, s, CH2Ph); m/z (EI) 431.0 (12%), 430.0 (74), 429.1 (26), 428.0 (100, M+H+).
Reaction SMILES: [Br-].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)([OH:23])[C:10]2[CH:15]=[CH:14][N+:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.CO.[BH4-].[Na+]>O>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)([C:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH:11]=2)[OH:23])=[CH:5][CH:4]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)c1cc[n+](Cc2ccccc2)cc1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC(C1=CCN(Cc2ccccc2)CC1)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
To a stirred solution of 140.5 parts of 4-[bis(4-fluorophenyl)hydroxymethyl]-1-(phenylmethyl)pyridinium bromide in 640 parts of methanol were added portionwise, during a 2 hours-period, 15.1 parts of sodium borohydride at room temperature (cooling in ice-water was necessary). Upon completion, the whole was stirred and refluxed for 30 minutes. After cooling to room temperature, 800 parts of water were added. The whole was allowed to stand overnight. The reaction mixture was evaporated till all traces of methanol were removed. 1040 Parts of dichloromethane were added. The layers were separated. The organic layer was washed with 200 parts of water, dried, filtered and evaporated. The residue was taken up in dry methylbenzene and the whole was evaporated, yielding 111 parts (94.5%) of α,α-bis(4-fluorophenyl)-1,2,3,6-tetrahydro-1-(phenylmethyl)-4-pyridinemethanol as an oily residue (intermediate 28).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].F[B-](F)(F)F.[CH3:18][O+](C)C>ClCCl>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7](=[NH:9])[O:8][CH3:18]
Reactant: COc1ncc(Br)cc1C(N)=O
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=N)c1cc(Br)cnc1OC
Reaction time: 12 h
Yield: 124.5 %

Procedure:
To a solution of 5-bromo-2-methoxynicotinamide (4.7 g, 0.02 mol) in dichloromethane (100 mL) was added Trimethyl-oxonium tetrafluoro borate (4.6 g, 0.02 mol) at room temperature. The mixture was stirred at room for 12 hours. The solvent was moved off and the resulting residue was washed with dichloromethane (50 mL*2), then dry to provide methyl 5-bromo-2-methoxynicotinimidate (6.1 g, yield 91%). 1HNMR (400 MHz, D2O) δ 8.46 (m, 2H), 4.22 (s, 3H), 4.02 (s, 3H), 1.93 (s, 2H). MS (M+H)+: 333/335.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:39]([CH3:41])[CH3:40])[C:30]3[CH:35]=[CH:34][C:33]4[O:36][CH2:37][O:38][C:32]=4[CH:31]=3)=[O:28])[C:22]3[CH:42]=[CH:43][CH:44]=[CH:45][C:21]=3[N:20]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:19]2=[O:52])=[N:9]1)=O)(C)(C)C.Cl.C(OCC)C>O1CCOCC1>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:39]([CH3:41])[CH3:40])[C:30]3[CH:35]=[CH:34][C:33]4[O:36][CH2:37][O:38][C:32]=4[CH:31]=3)=[O:28])[C:22]3[CH:42]=[CH:43][CH:44]=[CH:45][C:21]=3[N:20]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:19]2=[O:52])=[N:9]1
Reactant: CC(C)N(C(=O)CN1C(=O)C(Cc2nn(C(=O)OC(C)(C)C)c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21)c1ccc2c(c1)OCO2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)N(C(=O)CN1C(=O)C(Cc2n[nH]c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-[3-(1-Tert-butoxycarbonyl-1H-indazol-3-ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(3,4-methylenedioxy-phenyl) acetamide, prepared as in Intermediate 72, (123 mg, 0.175 mmol) and 4N HCl in dioxane (1 mL) is stirred at RT for 3 h. Diethyl ether (20 mL) is added and the resultant mixture stirred vigorously for 20 min. The solids were allowed to settle and the solvent is decanted. This procedure is repeated three times and the final solid dried by concentration in vacuo to afford the titled product (106 mg) as a white solid: 1H NMR (300 MHz, CDCl3) δ7.95 (d, 1H, J=8.3), 7.68 (d, 1H, J=8.5), 7.59 (t, 1H, J=6.8), 7.2-7.5 (m, 11H), 7.12 (t, 1H, J=8.5), 6.94 (d, 1H, J=8.2), 6.84 (dd, 1H, J=15.8, 8.3), 6.03 (s, 2H), 5.00 (m, 1H, J=6.9), 4.40 (m, 1H), 4.24 (t, 2H, J=6.1), 3.92 (dd, 1H, J=16.5, 7.7), 3.83 (dd, 1H, J=16.5, 5.8), 1.08 (m, 6H); Low resolution MS (FAB) m/e 602 (M+); Tr =23.06 min (RP-HPLC, 70% A to 70% C, 30 min).
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([C:30]([F:33])([F:32])[F:31])=[C:24]([CH2:26][C:27](O)=[O:28])[CH:25]=1.[Br:34]N1C(=O)CCC1=O>ClC1C=CC=CC=1.C(OCC)(=O)C.O1CCCC1>[Br:34][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:30]([F:33])([F:32])[F:31])=[C:24]([CH2:26][CH2:27][OH:28])[CH:25]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(F)(F)F)c(CC(=O)O)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Product: OCCc1cc(CBr)ccc1C(F)(F)F
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Benzoyl peroxide (0.085 g) was added to a suspension of 2-(5-methyl-2-(trifluoromethyl)phenyl)acetic acid (1.12 g) and N-bromosuccinimide (1.101 g) in chlorobenzene (18 mL), and the resulting mixture was heated at 100° C. under nitrogen for 80 minutes, then allowed to cool. The resulting mixture was diluted with ethyl acetate, washed three times with water, once with brine, then dried (MgSO4), filtered and concentrated in vacuo to give a yellow oil. The oil was dissolved in tetrahydrofuran (11 mL) and treated with a 2 molar solution of borane-methyl sulfide complex in THF (5.1 mL), portionwise over 2 minutes. The resulting mixture was stirred at room temperature overnight, then cooled in ice-water and quenched by the addition of methanol. The effervescing mixture was removed from the cooling bath, stirred at room temperature for 70 minutes, then concentrated in vacuo. The residue was purified by flash chromatography on silica eluted with 15% ethyl acetate in isohexane to afford the crude product as a yellow oil. Yield 0.919 g.
Reaction SMILES: N#N.CCN(CC)CC.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:22][CH2:23][C:24]([OH:26])=O)[CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19].[CH3:27][O:28][C:29]([C@H:31]1[CH2:36][CH2:35][C@@H:34]([NH2:37])[CH2:33][CH2:32]1)=[O:30]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:27][O:28][C:29]([CH:31]1[CH2:36][CH2:35][CH:34]([NH:37][C:24](=[O:26])[CH2:23][CH2:22][C:14]2[CH:15]=[C:16]([O:20][CH3:21])[C:17]([O:18][CH3:19])=[C:12]([O:11][CH3:10])[CH:13]=2)[CH2:33][CH2:32]1)=[O:30]
Reactant: COc1cc(CCC(=O)O)cc(OC)c1OC
Reactant: COC(=O)[C@H]1CC[C@@H](N)CC1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CCC(NC(=O)CCc2cc(OC)c(OC)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76.9 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Suspend EDCHCl (175 mg, 0.91 mmol) and Et3N (127 μL, 0.91 mmol) in anhydrous DCM (8.0 mL) and stir the resulting solution for 5 min at rt. Add 3-(3,4,5-Trimethoxy-phenyl)-propionic acid (219 mg, 0.91 mmol) and DMAP (22 mg, 0.18 mmol) and stir the resulting solution for 10 min. Add cis-4-Amino-cyclohexanecarboxylic acid methyl ester (74) (136 mg, 0.87 mmol) and stir the reaction solution 2d at rt Remove solvent and purify the crude product by flash chromatography (silica gel, EtOAc/CyH 3+1, later EtOAc) to obtain cis-{4-[3-(3,4,5-Trimethoxy-phenyl)-propionylamino]-cyclohexanecarboxylic acid methyl ester (75) (254 mg, 76%) as a colorless viscous oil. 1H NMR (400 MHz, CDCl3): 1.40-1.51 (m, 2 H); 1.59-1.70 (m, 4H); 1.70-1.82 (m, 2H); 2.40-2.48 (m, 3H); 2.88 (t, 2H, J=7.6 Hz); 3.65 (s, 3H); 3.79 (s, 3H); 3.82 (s, 6H); 3.86-3.95 (m, 1H); 5.33 (br.d, 1H, J=7.3 Hz); 6.40 (s, 2H).
Reaction SMILES: [C:1]([C:3]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1)#[N:2].CN(C)C=O.[Cl:38][CH2:39][C:40]#[N:41].C(N(CC)CC)C>O>[ClH:38].[C:1]([C:3]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:12]([O:14][CH2:39][C:40]#[N:41])=[O:13])[CH2:8][CH2:7]1)#[N:2]
Reactant: N#CC(CCN1CCC(C(=O)O)(c2ccccc2)CC1)(c1ccccc1)c1ccccc1
Reactant: N#CCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cl
Product: N#CCOC(=O)C1(c2ccccc2)CCN(CCC(C#N)(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.12 Grams of 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylic acid was dissolved in 60 ml. of redistilled N,N-dimethylformamide by warming to approximately 60° C. To the resultant solution was added .4 gram of chloracetonitrile, followed by .55 gram of triethylamine. The solution was stirred at room temperature under anhydrous conditions for about 24 hours, then diluted with water and extracted with ethyl acetate. The ethyl acetate extract was washed with water, acidified with concentrated hydrochloric acid in 2-propanol, diluted with ethyl ether and cooled. The precipitate which formed was recrystallized from a mixture of methanol and tetrahydrofuran, affording cyanomethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylate hydrochloride, melting at about 243.5°-245.5° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=O)C>O1CCCC1>[CH:18]1([C:12]2([CH2:10][OH:9])[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CCOC(=O)C1(C2CCCCC2)CCNCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1(C2CCCCC2)CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled (−5° C.) solution of lithium aluminum hydride (900 mL, 0.90 moles, 1.0M solution in THF) is added tetrahydrofuran (2000 mL) and 4-cyclohexyl-piperidine-4-carboxylic acid ethyl ester, 1, (59.5 g, 249 mmol). The resulting solution is stirred at between −5° C. and +3° C. for 1 hour and then allowed to warmed to room temperature and stir an additional sixty-six hours. The reaction is then re-cooled to 0° C. and carefully quenched with saturated ammonium chloride (100 mL). The reaction mixture is stirred for 10 minutes and then 87:10:3 ethyl acetate:methanol:triethylamine (500 mL) is added. The suspension is then stirred at room temperature for 20 minutes and filtered through a pad of Celite. The solids are re-suspended in 1:1 THF:EtOAc (2000 mL), stirred at room temperature for 1 hour and the suspension was again filtered through a pad of Celite. The filtrates are combined and concentrated in vacuo to afford 53.6 g of a mixture of the desired compound and 4-cyclohexyl-piperidine-4-carbaldehyde. The crude mixture is used directly in without further purification.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:6]1O[CH:8]=[CH:9][C:10](=[O:12])[CH:11]=1)([CH3:5])[CH3:4].[NH4+:15].[OH-]>>[F:1][C:2]([F:14])([F:13])[C:3]([C:6]1[NH:15][CH:8]=[CH:9][C:10](=[O:12])[CH:11]=1)([CH3:5])[CH3:4]
Reactant: [NH4+]
Reactant: CC(C)(c1cc(=O)cco1)C(F)(F)F
Agent: [OH-]
Product: CC(C)(c1cc(=O)cc[nH]1)C(F)(F)F
Temperature: 90 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
A mixture of 2-(1,1,1-trifluoro-2-methylpropan-2-yl)-4H-pyran-4-one (800 mg, 3.88 mmol) in NH4OH (8 mL, 205 mmol) was stirred at 90° C. for 1 h. Then the mixture was concentrated, triturated with MeOH (20 mL) and filtered. The filtrate was concentrated and purified by silica column chromatography (DCM/MeOH=9:1). All fractions found to contain product by TLC (DCM/MeOH=9:1, Rf=0.2) were combined and concentrated to yield a yellow oil of 2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4(1H)-one (700 mg, 2.90 mmol, 74.7% yield): 1H NMR (400 MHz, CD3OD): δ 7.87 (d, J=7.2 Hz, 1H), 6.70 (d, J=2.4 Hz, 1H), 6.54 (dd, J=2.4, 7.2 Hz, 1H), 1.60 (s, 6H). ES-LCMS m/z 206.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:20][CH:19]=3)[C:16]3[C:11](=[CH:12][C:13]([O:33]C)=[CH:14][CH:15]=3)[O:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1>>[OH:33][C:13]1[CH:12]=[C:11]2[C:16]([C@@H:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]4[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]4)=[CH:20][CH:19]=3)[C@H:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:9][O:10]2)=[CH:15][CH:14]=1
Reactant: COc1ccc2c(c1)OC[C@@H](c1ccc(F)cc1)[C@@H]2c1ccc(OCCN2CCCCC2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccc2c(c1)OC[C@@H](c1ccc(F)cc1)[C@@H]2c1ccc(OCCN2CCCCC2)cc1

Procedure:
The intermediate, (±)-trans-3-(4-fluorophenyl)-7-methoxy4-(4-(2-piperidinoethoxy)phenyl)-chromane (70 mg, 0.152 mmol) was de-methylated by heating with pyridine hydrochloride (0.176 g, 1.52 mmol) for 18 h; giving the title compound as a colourless foam after purification.
Reaction SMILES: C([O:4][CH:5]([CH:26]1[CH2:28][CH2:27]1)[C@H:6]1[O:10][C@@H:9]([N:11]2[C:15]3[N:16]=[C:17]([NH2:20])[N:18]=[CH:19][C:14]=3[S:13][C:12]2=[O:21])[C@@H:8](CC([O-])=O)[CH2:7]1)(=O)C.C(OC([C@H]1O[C@@H](N2C3N=C(N)N=CC=3SC2=O)[C@@H](CC([O-])=O)C1)CC)(=[O:31])C>>[NH2:20][C:17]1[N:18]=[CH:19][C:14]2[S:13][C:12](=[O:21])[N:11]([C@H:9]3[C@H:8]([OH:31])[CH2:7][C@@H:6]([CH:5]([CH:26]4[CH2:28][CH2:27]4)[OH:4])[O:10]3)[C:15]=2[N:16]=1
Reactant: CC(=O)OC(C1CC1)[C@@H]1C[C@H](CC(=O)[O-])[C@H](n2c(=O)sc3cnc(N)nc32)O1
Reactant: CCC(OC(C)=O)[C@@H]1C[C@H](CC(=O)[O-])[C@H](n2c(=O)sc3cnc(N)nc32)O1
Product: Nc1ncc2sc(=O)n([C@@H]3O[C@H](C(O)C4CC4)C[C@H]3O)c2n1

Procedure:
The title compound was prepared in analogy to Example 2, by using [(2R,3R,5S)-5-[acetoxy(cyclopropyl)methyl]-2-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-3-yl] acetate (compound 16a) instead of [(2R,3R,5S)-5-(1-acetoxypropyl)-2-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-3-yl]acetate (compound 2a). Example 17 was purified and separated by preparative HPLC to afford Example 17-A and Example 17-B as white solid.