Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@@H:12]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C@H:13]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:14](=O)[CH2:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:10]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:41][CH2:42][CH2:43][CH2:44][NH2:45].[BH3-]C#N.[Na+]>CO>[CH2:26]([O:25][C@H:13]1[C@H:12]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C@@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:10][N:45]([CH2:44][CH2:43][CH2:42][Cl:41])[C@@H:14]1[CH2:15][O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)C(=O)COCc1ccccc1
Reactant: NCCCCl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: ClCCCN1C[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 35.9 %

Procedure:
To a stirred suspension of crude (2R,3R,4S)-2,3,4,6-tetrakis(benzyloxy)-5-oxohexanal 3 (20 g, 37.13 mmol) in MeOH (400 mL) were added 3-chloro propylamine (47 g, 743 mmol) at 0° C. and activated molecular sieves (100 g) and the reaction mixture was stirred at room temperature for 20 min. Then the reaction mixture was cooled to 0° C. and solid NaBH3CN (9.33 g, 148.5 mmol) was added to the reaction mixture and stirred at same temperature for 1 h. Then the reaction mixture was stirred at room temperature for 20 h. After removal of the molecular sieves through celite pad, the filtrate was concentrated under reduced pressure. The crude mass was dissolved in ethyl acetate (250 mL) and organic part was washed with saturated solution of NaHCO3 (100 mL), dried over Na2SO4 and concentrated under reduced pressure to get crude which was purified by column chromatography using 100-200 mesh silica gel and eluting with 8% EtOAc/hexane to afford (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-[(benzyloxy)methyl]-1-(3-chloropropyl)piperidine 4 (8.0 g, 36%) as white solid.
Reaction SMILES: C1CO[C:3]2([CH2:7][CH2:6][CH:5]([CH2:8][CH:9]=[O:10])[CH:4]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[O:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCOC1.C1COC2C(C(C)(CCCCC)C(=O)C2)O1>O.O1CCOCC1>[CH:9]([CH2:8][CH:5]1[CH2:6][CH2:7][C:3](=[O:2])[CH:4]1[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10]
Reactant: CCCCCC1C(CC=O)CCC12OCCO2
Agent: CCCCCC1(C)C(=O)CC2OCCOC21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: C1COCO1
Solvent: O
Product: CCCCCC1C(=O)CCC1CC=O
Yield: 56.1 %

Procedure:
A mixture of 24 g of 1,1-ethylenedioxy-3-formylmethyl-2-n-pentyl-cyclopentane, 40 ml of dioxane, 32 ml of water and 0.18 g paratoluenesulphonic acid is refluxed for 3 hours. It is then cooled, 120 ml of water added and extracted three times with 100 ml of benzene. The benzene solutions are washed to neutrality and concentrated under reduced pressure. There are obtained 22 g of crude product which are rectified and which yield 15.5 g of product; b.p.1.0 = 110°-140°C. The distillate is a mixture of keto aldehyde and the dioxolane of the aldehyde function (3-ethylenedioxymethyl-2-n-pentyl-1-cyclopentanone) in the proportions of 75/25. By careful rectification of this mixture, there is obtained 11 g of pure 3-formylmethyl-2-n-pentyl-1-cyclopentanone exhibiting: b.p.0.5 = 90°C, nD15 = 1.4688.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[C@H:17]([O:18][CH3:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:20](=[O:22])[NH2:21])=[CH:13][CH:14]=2)[C:9]1([CH3:24])[CH3:23])(C)(C)C.[ClH:26].O1CCOCC1>C(Cl)Cl>[ClH:26].[NH2:7][CH:8]1[C:9]([CH3:24])([CH3:23])[C:10]2[CH:11]=[C:12]([C:20]([NH2:21])=[O:22])[CH:13]=[CH:14][C:15]=2[CH2:16][CH:17]1[O:18][CH3:19]
Reactant: CO[C@@H]1Cc2ccc(C(N)=O)cc2C(C)(C)[C@H]1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC1Cc2ccc(C(N)=O)cc2C(C)(C)C1N
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a slurry of trans-(7-carbamoyl-3-methoxy-1,1-dimethyl-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid tert-butyl ester (9.22 g, 26.4 mmol) in DCM (100 mL) was added 4 N HCl in dioxane (25 mL, 100 mmol) slowly. The reaction mixture was stirred at RT for 15 h, concentrated to dryness, triturated with DCM (25 mL) for 30 min, filtered, rinsed with DCM (3×15 mL), and dried under vacuum. Ethanol (100 mL) was added and the reaction mixture was concentrated under vacuum to give the HCl salt of the title compound (7.17 g) as a white powder. (m/z): [M+H]+ calcd for C14H20N2O2 249.16. found 249.1. 1H NMR (d6-DMSO, 400 mHz) δ (ppm): 8.18 (s, 3H), 8.00 (s, 1H), 7.92 (d, J=1.6 Hz, 1H), 7.66 (dd, J=8.0 Hz, 1.8 Hz, 1H), 7.32 (s, 1H), 7.17 (d, J=8.0 Hz, 1H), 3.70 (m, 1H), 3.44 (s, 3H), 3.43 (m, 1H), 3.22 (m, 1H), 2.67 (dd, J=16.4 Hz, 10.2 Hz), 1.50 (s, 3H), 1.24 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C([O-])(O)=O.[Na+].[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O.O1CCOCC1.CCOC(C)=O>[CH2:13]([O:20][C:21]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CNCCN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C1CN(C(=O)OCc2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
Piperazin-2-one (2.00 g, 20.0 mmol) was dissolved in H2O (10 ml)-1,4-dioxane (10 ml); and NaHCO3 (1.85 g, 22.0 mmol) and benzylchloroformate (3.42 g, 20.0 mmol) was added thereto. After stirring at room temperature for 13 h, the reaction mixture was diluted with H2O and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layer was washed with brine, dried over MgSO4. The desiccant was removed through filtration and the filtrate was concentrated under reduced pressure to obtain crude 3-Oxo-piperazine-1-carboxylic acid benzyl ester as pale brown oil. This oil was used for the next step without further purification. The crude 3-Oxo-piperazine-1-carboxylic acid benzyl ester was dissolved in DMF (40 ml) and NaH (55% in oil, 1.05 g, 24.0 mmol) and SEMCl (5.01 g, 30.0 mmol) was added thereto at room temperature. After stirring at 50° C. for 18 h, the reaction mixture was diluted with EtOAc. The mixture was washed with H2O and brine, dried over MgSO4. The desiccant was removed through filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc=8/2 to 5/5, to obtain the intended compound as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:21](Cl)(=[O:30])[C:22]1[C:23]([O:28][CH3:29])=[CH:24][CH:25]=[CH:26][CH:27]=1>C(#N)C>[CH3:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:21]([NH:13][S:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)(=[O:11])=[O:12])=[O:30]
Reactant: COc1ccccc1C(=O)Cl
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccccc1C(=O)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
30.0 g (0.15 mol) of 4-nitrobenzenesulfonamide are treated with 30.0 g (0.3 mol) of triethylamine in 300 ml of acetonitrile and, at 50° C., treated with 27.8 g (0.16 mol) of o-anisoyl chloride, dissolved in 20 ml of acetonitrile. After 3 hours at 50° C., the mixture is stirred into 80 ml of ice-water, and the precipitate is filtered off with suction and dried. More product can be obtained by acidifying the mother liquor;
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([CH2:18][CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:24])[N:7]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][N:10]=1)[CH2:18][CH2:19][S:20]([CH3:23])(=[O:21])=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCS(C)(=O)=O)Cc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCS(C)(=O)=O)Cc1ccc(N)cn1
Reaction time: 2 h

Procedure:
To a stirred solution of 34 (0.35 g 1.0 mmol) in MeOH (6 mL) was added 10% Pd/C and hydrogenated under balloon pressure at rt for 2 h. The reaction mixture was filtered through Celite and the filtrate was evaporated to give the desired amine A4-9 (0.25 g, 78%) as a liquid. Rf: 0.1 (10% MeOH/CHCl3); (m/z): 330 [M+1]+; 1H NMR (400 MHz, CDCl3): δ 8.01 (1H, s), 7.07-6.94 (2H, m), 4.44 (2H, br s), 3.74-3.72 (2H, m), 3.33-3.31 (2H, m), 2.95-2.86 (3H, m), 2.06-2.01 (2H, m), 1.39 (9H, m).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10]C)=[C:2]=[O:3].[CH2:12]([NH2:14])[CH3:13].B(Br)(Br)Br>ClCCl>[CH2:12]([NH:14][C:2]([NH:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])=[O:3])[CH3:13]
Reactant: COc1ccccc1N=C=O
Reactant: CCN
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCNC(=O)Nc1ccccc1O
Reaction time: 1 h

Procedure:
A solution of 1-isocyanato-2-methoxybenzene (0.32 g, 2.15 mmol) and ethylamine (1 mL) in dichloromethane (15 mL) was stirred at room temperature for 2 days. Then the volatiles were removed in vacuo. The residue was redissolved in dichloromethane (15 mL), and boron tribromide (BBr3) (1 M in dichloromethane (CH2Cl2), 6.5 ml, 6.5 mmol) was added dropwise via syringe under nitrogen. After stirring for 1 h the reaction mixture was diluted with dichloromethane and washed 3 times with water. The product was purified by HPLC (Kromasil column; eluant:acetonitrile+0.1% trifluoroacetic acid (TFA)/water+0.1% TFA) to give subtitle compound (167 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][C@H:12]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:13]([CH3:17])[C:14](O)=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[O:36][NH2:37]>C(Cl)Cl>[OH:36][NH:37][C:14](=[O:15])[C@@H:13]([CH3:17])[C@H:12]([S:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C[Si](C)(C)ON
Reactant: COc1ccc(S[C@H](CCCCc2ccccc2)[C@H](C)C(=O)O)cc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc(S[C@H](CCCCc2ccccc2)[C@H](C)C(=O)NO)cc1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
(2R,3R)-3-(3,4-Dimethoxyphenylsulfanyl)-2-methyl-7-phenylheptanoic acid (0.33 g, 0.85 mmol) is dissolved in CH2Cl2 (4 mL) and cooled to 0° C. and to this is added 2 M oxalyl chloride in CH2Cl2 (1.3 mL, 2.6 mmol) over 3 minutes. After 10 minutes the ice bath is removed and the reaction is stirred at room temperature for 2 hours. The reaction is concentrated in vacuo and azeotroped with chloroform twice. The residue is dissolved in CH2Cl2 (4 mL), cooled in ice and O-trimethylsilylhydroxylamine (0.32 mL, 2.6 mmol) is added over 2 minutes. After 10 minutes the reaction is concentrated in vacuo. The residue is dissolved in CH2Cl2 (50 mL) and washed with 1 N HCl (20 mL). The organic layer is dried over MgSO4 and the solvent removed in vacuo to give (+)-(2R,3R)-3-(3,4-Dimethoxyphenylsulfanyl)-2-methyl-7-phenylheptanoic acid hydroxyamide (0.27 g, 79%): [a]D23 +40° (c=1.0, CHCl3); 1H NMR (300 MHz, CD3OD) δ 7.25-7.20 (m, 2H), 7.13-7.11 (m, 3H), 7.00-6.96 (m, 2H), 6.88 (d, J=8.0 Hz, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 3.01-2.95 (m, 1H), 2.57-2.55 (m,1H), 2.23-2.15 (m, 1H), 1.71-1.41 (m, 6H), 1.34 (d, J=6.9 Hz, 3H); MS (FAB) m/e 404 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].Cl.[Cl:8][C:9]1[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=1)[O:12][C@@H:13]1[CH2:18][CH2:17][N:16](C)[CH2:15][C@H:14]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[Cl:8][C:9]1[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=1)[O:12][C@@H:13]1[CH2:18][CH2:17][N:16]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH2:15][C@H:14]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)Cl
Reactant: CN1CC[C@@H](Oc2cccc(Cl)c2)[C@H](c2ccccc2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCOC(=O)N1CC[C@@H](Oc2cccc(Cl)c2)[C@H](c2ccccc2)C1
Reaction time: 18 h

Procedure:
2.01 g of ethyl chloroformate are added to a mixture of 3.7 g of the free base of trans-4-(3-chlorophenoxy)-1-methyl-3-phenylpiperidine of Example 32, 2.56 g of anhydrous potassium carbonate, and 28 ml of dry benzene. The mixture is then refluxed for 18 hours under nitrogen. An additional 0.67 g of ethyl chloroformate is added, and, after 4 more hours of reflux, the mixture is cooled and partitioned between water and ether. The phases are separated and the aqueous phase is extracted with ether. The combined organic phases are washed with saturated aqueous NaCl solution, stirred for 18 hours with anhydrous MgSO4, filtered and concentrated in vacuo to an oil comprising trans-4-(3-chlorophenoxy)-1-ethoxycarbonyl-3-phenylpiperidine.
Reaction SMILES: [ClH:1].Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH2:15][CH2:16][CH2:17][N:18]([CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=4)[CH2:25][CH2:24]3)[CH3:19])OCC[O:11]2)=[CH:6][CH:5]=1.Cl.C(=O)(O)[O-].[Na+]>CO>[ClH:36].[ClH:1].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:11])[CH2:15][CH2:16][CH2:17][N:18]([CH2:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=3)[CH2:27][CH2:28]2)[CH3:19])=[CH:6][CH:5]=1
Reactant: CN(CCCN1CCC(Oc2cccc(Cl)c2)CC1)CCCC1(c2ccc(F)cc2)OCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CN(CCCC(=O)c1ccc(F)cc1)CCCN1CCC(Oc2cccc(Cl)c2)CC1
Temperature: 25 °C
Yield: 161.4 %

Procedure:
A solution prepared from 3.36 g (5.96 mmol) of 1-{3-{N-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-N-methylamino}propyl}-4-(3-chlorophenoxy)piperidine dihydrochloride, 90 ml of methanol and 40 ml of 3N HCl was heated at reflux under nitrogen for 3 hours. The solution was allowed to cool to room temperature, neutralized with saturated sodium bicarbonate and the methanol evaporated. The residue was made basic with sodium carbonate, extracted twice with ether and washed with saturated sodium chloride. The ether solution was dried over potassium carbonate. Filtration followed by evaporation of the solvent provided an oil. The dihydrochloride was recrystallized from ethanol/methanol to provide 2.50 g (74.4%) of the desired ketone.
Reaction SMILES: [N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.COC1C=CC(C[N:32]2[CH2:38][CH2:37][CH2:36][C:35]3[N:39]=[C:40]([CH2:42][O:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[S:41][C:34]=3[C:33]2=[O:50])=CC=1>O.C(#N)C>[O:43]([CH2:42][C:40]1[S:41][C:34]2[C:33](=[O:50])[NH:32][CH2:38][CH2:37][CH2:36][C:35]=2[N:39]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: COc1ccc(CN2CCCc3nc(COc4ccccc4)sc3C2=O)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: O=C1NCCCc2nc(COc3ccccc3)sc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.7 %

Procedure:
A solution of ammonium cerium (IV) nitrate (1.08 g, 1.97 mmol) in H2O (1.5 mL) was added to a stirred solution of 5,6,7,8-tetrahydro-5-[(4-methoxyphenyl)methyl]-2-(phenoxymethyl)-4H-thiazolo[5,4-c]azepin-4-one (0.22 g, 0.56 mmol) in ACN (5 mL). The mixture was stirred at room temperature for 16 hours and then diluted with H2O and extracted with AcOEt. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 100/0). The desired fractions were collected and the solvents evaporated in vacuo to yield 5,6,7,8-tetrahydro-2-(phenoxymethyl)-4H-thiazolo[5,4-c]azepin-4-one (0.081 g, 52%) as a white solid. C14H14N2O2S LCMS: Rt 1.59, m/z 275 [M+H]+ (using method, LC-MS Method 6).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:13]3([OH:19])[CH2:18]COCC3)[N:8]2[CH2:11][CH3:12])=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][C@@H:21]2[CH3:26])[N:3]=1.[O:27]1CC(=O)[CH2:28]1>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:13]3([OH:19])[CH2:18][O:27][CH2:28]3)[N:8]2[CH2:11][CH3:12])=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][C@@H:21]2[CH3:26])[N:3]=1
Reactant: CCn1c(C2(O)CCOCC2)nc2c(N3CCOC[C@@H]3C)nc(Cl)nc21
Reactant: O=C1COC1
Product: CCn1c(C2(O)COC2)nc2c(N3CCOC[C@@H]3C)nc(Cl)nc21

Procedure:
This compound (i-j) was prepared in an analogous fashion to (S)-4-(2-chloro-9-ethyl-6-(3-methylmorpholino)-9H-purin-8-yl)tetrahydro-2H-pyran-4-ol, using 3-oxetanone as the starting material. 1H NMR (CDCl3, 500 MHz) δ ppm 5.70 to 4.70 (broad s, 2H), 5.20 (dd, J=12.1 Hz, 7.2 Hz, 2H), 4.95 (d, J=7.2 Hz, 2H), 4.31 (q, J=7.1 Hz, 2H), 4.02 (dd, J=11.3, 3.2 Hz, 1H), 3.78 (dt, J=11.7 Hz, 7.2 Hz, 2H), 3.61 (td, J=11.9 Hz, 2.7 Hz, 1H), 3.47 (s, 2H), 1.46 (t, J=7.2 Hz, 3H), 1.41 (d, J=6.8 Hz, 3H); LC-MS m/z (method B2)=354/356 [M+H]+, RT=1.71 min.
Reaction SMILES: [C:1]12([O:11][C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[C:14]([F:21])[CH:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>C(OCC)(=O)C.[Pt]>[C:1]12([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:21])[CH:13]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: O=[N+]([O-])c1ccc(OC23CC4CC(CC(C4)C2)C3)cc1F
Agent: [Pt]
Solvent: CCOC(C)=O
Product: Nc1ccc(OC23CC4CC(CC(C4)C2)C3)cc1F
Yield: 135.5 %

Procedure:
13.4 g of 4-(1-adamantyloxy)-2-fluoronitrobenzene (approximately 80% pure; 0.037 mole) in ethyl acetate solution was hydrogenated for two hours over platinum (from 1.0 g of PtO2). The catalyst was filtered and the solvent was evaporated to give 13.1 g of white solid, which was purified by two recrystallizations from CH2Cl2 -Skellysolve B, affording a pink solid, m.p. 152.0-154.0. The NMR spectrum of this material was consistent with the assigned structure.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.[CH3:64][CH:65]1[CH2:70][CH2:69][CH2:68][CH2:67][NH:66]1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CC(O)=O.CC(O)=O.[Pd]>[CH2:1]([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=2)[CH:13]=[C:14]([N:66]2[CH2:67][CH2:68][CH2:69][CH2:70][CH:65]2[CH3:64])[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CC1CCCCN1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(N2CCCCC2C)c1
Temperature: 100 °C

Procedure:
To a solution of 4-methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester, 1g (63 mg, 0.12 mmol) in toluene (1 mL) in a sealed tube was added racemic-2-(di-t-butylphosphino)-1,1′-binaphthyl (48 mg, 0.12 mmol), Pd(O AC)2 (27 mg, 0.12 mmol), 2-methyl-piperidine (0.020 mL, 0.17 mmol). The system was flushed with nitrogen. To this was added NaOtBu (14 mg, 0.14 mmol) and heated to 100° C. for 10 minutes. The reaction was cooled to room temperature. To this was added another portion of Pd(OAC)2 (27 mg, 0.12 mmol), 2-methyl-piperidine (0. 020 mL, 0.17 mmol) and NaOtBu (14 mg, 0.14 mmol). The system was heated to 100° C. for 5 minutes, cooled to room temperature and quenched by slow addition of water. The mixture was extracted with EtOAc (3×20 mL). The organic phase was washed with saturated NaHCO3 solution and brine. The organic fraction was dried (MgSO4) and concentrated in vacuo. The crude mixture was purified by ISCO column chromatography to obtain 4-methyl-2-[5-(2-methyl-piperidin-1-yl)-4′-trifluoromethyl-biphenyl-3-yl]-pentanoic acid ethyl ester. Calcd for C27H34F3NO2 (M+H) 462.56, Found 462.3.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>C1C=CC=CC=1>[CH3:1][CH:2]1[CH2:7][CH2:6][C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][CH2:3]1
Reactant: CC1CCC(=O)CC1
Reactant: C1COCCN1
Solvent: c1ccccc1
Product: CC1CC=C(N2CCOCC2)CC1
Yield: 70.8 %

Procedure:
In a flask equipped with a dean stark, a solution of 4-methylcyclohexanone (20.1 g, 179.3 mmol, 22 mL) and morpholine (31.3 g, 359.0 mmol, 31.4 mL) were refluxed in benzene (55 mL) for 26 hours. The benzene was removed under vacuum and the crude product was purified by distillation under reduced pressure to afford 23 g (70%) of 4-(4-methyl-cyclohex-1-enyl)-morpholine (44) as an oil (b.p. 120° C. at 10 mmHg). The structure was confirmed by 1H NMR (300 MHz, CDCl3): δH 0.94 (3H, d, J=6.0 Hz, CH3), 1.15-1.35 (1H, m, CH2CH═CN), 1.50-1.80 (3H, m, CH2CH2CHCH3), 2.00-2.25 (4H, m, CH2CH═CN and CH2CH2CHCH3), 2.65-2.95 (4H, m, OCH2NCH2), 3.73 (4H, t, J=6.0 Hz, OCH2NCH2), and 4.60-4.65 (1H, m, CH2CH═CN).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH2:14]O)=[C:12]([CH:16]([CH3:18])[CH3:17])[N:11]=[C:10]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])[N:9]=2)=[CH:4][CH:3]=1.[BrH:25]>C(OCC)(=O)C.CCCCCC>[Br:25][CH2:14][C:13]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:9][C:10]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])=[N:11][C:12]=1[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CO
Reactant: Br
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CBr
Temperature: 80 °C
Reaction time: 15 h
Yield: 94 %

Procedure:
N-[4-(4-fluorophenyl)-5-hydroxymethyl-6-isopropyl-pyrimidin-2-yl]-N-methyl-methanesulfonamide (50.0 g) and 48% hydrogen bromide (130.0 mL) were added to a reactor. The reaction mixture was stirred at 80° C. for 15 hours. The reaction was monitored with thin layer chromatography (ethyl acetate/n-hexane=1:2). The reaction mixture was cooled to 20˜25° C., stirred for over 1 hour, and then filtered under reduced pressure. The resulting white solid was washed with water (500.0 mL) and then dried under reduced pressure to obtain N-[5-bromomethyl-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-2-yl]-N-methyl-methanesulfonamide as a white solid (55.3 g, yield 94%).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([O:8][C:9](=[O:35])[CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[N:25]=[C:24]3[N:19]([C:20](=O)[NH:21][C:22]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=4[Cl:33])=[CH:23]3)[N:18]=2)[CH2:13][CH2:12]1)[CH3:7]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH2:6]([O:8][C:9](=[O:35])[CH2:10][N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[N:25]=[C:24]3[N:19]([C:20]([Cl:3])=[N:21][C:22]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=4[Cl:33])=[CH:23]3)[N:18]=2)[CH2:15][CH2:16]1)[CH3:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)CN1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)[nH]c(=O)n3n2)CC1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Product: CCOC(=O)CN1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(Cl)n3n2)CC1
Temperature: 120 °C
Reaction time: 2.5 h

Procedure:
5 ml of phosphoryl chloride were added to 500 mg (1.11 mmol) of ethyl{4-[7-(2,4-dichlorophenyl)-5-oxo-5,6-dihydro [1,2,4]triazolo[1,5-c]-pyrimidin-2-yl]piperidin-1-yl}acetate (Example 54A), 1.01 g (4.44 mmol) of benzyltriethylammonium chloride were added and the reaction mixture was stirred at 120° C. for 2.5 h. The reaction mixture was concentrated and carefully, with vigorous stirring, added to saturated aqueous sodium bicarbonate solution. The pH was adjusted to pH=7 by addition of solid sodium bicarbonate. The aqueous phase was extracted three times with dichloromethane. The combined organic phases were washed once with water, dried with magnesium sulfate and then freed from the solvent. Without further purification, this gave 506 mg (88% of theory) of the product.