Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][C:32](=[O:35])[N:31]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:30]=3[CH:41]=2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>O1CCOCC1>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][C:32](=[O:35])[N:31]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:30]=3[CH:41]=2)=[CH:7][CH:6]=1)([OH:4])=[O:2]
Reactant: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(C(=O)OC)cc3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(C(=O)O)cc3)cc21
Temperature: 80 °C

Procedure:
A solution of 1.200 g of tert-butyl 4-(4-methoxycarbonylphenyl)-3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate in 20 ml of dioxane is admixed with 10 ml of 2N NaOH. The reaction mixture is heated to 80° C. over 1 hour and subsequently cooled to room temperature. The phases are separated and the aqueous phase is adjusted to pH 2 with 2N HCl (9.5 ml) and extracted with tert-butyl methyl ether (2×40 ml). The organic phases are combined, washed with 50 ml of water, dried over sodium sulphate, filtered and concentrated by evaporation. The residue is recrystallized from 1:1 ethyl acetate/heptane (20 ml). The title compound is obtained as a colourless solid. Rt=4.48.
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)(O)[CH:8]=[CH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[OH:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([O:25][CH3:26])=[O:24]>ClCCl.CN(C)C=O>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][CH2:9][O:19][C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=2)[C:23]([O:25][CH3:26])=[O:24])[CH:12]=1
Reactant: C=CC(O)(c1ccccc1)c1cccnc1
Reactant: COC(=O)c1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cccc(OCC=C(c2ccccc2)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
Phorphorus pentachloride (3.0 g, 14.2 mmoles) was suspended in dichloromethane (4 ml). To the suspension was added dropwise a solution of 1-phenyl-1-(3-pyridyl)-2-propen-1-ol (2.0 g, 9.5 mmoles) in dichloromethane (20 ml) at 0° C., then the mixture was stirred for one hour at room temperature, followed by washing with water, saturated aqueous solution of sodium hydrogen carbonate in the order. The organic layer is dried (magnesium sulfate), and concentrated to about 20 ml at a temperature not exceeding 30° C. The solution was further dried with molecular sieves 4A. This solution was named as (a) solution. Separately, sodium hydride (400 mg, 10 mmoles) is suspended in dimethylformamide (5 ml). To the suspension was added dropwise methyl metahydroxybenzoate (1.37 g, 9.0 mmoles) dissolved in dimethylformamide (5 ml). The mixture was stirred for 30 minutes at 0° C., to which was added dropwise the (a) solution, followed by stirring at room temperature for 1.5 hours. The reaction mixture was poured in ice-water, which is subjected to extraction with ethyl acetate, washed with water and dried (magnesium sulfate), followed by removing the solvent by evaporation under reduced pressure. The residue was subjected to silica-gel column chromatography, using ether-ethyl acetate (7:3) as eluant to yield methyl 3-[3-(3-pyridyl)-3-phenyl-2-propenyloxy]benzoate (If-56) (3.0 g, 92%).
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[NH:12][C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.C([Li])CCC.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>C1COCC1.CCCCCC>[CH2:29]([O:28][C:26]([N:12]1[C:11](=[O:13])[CH2:10][CH2:9][C@H:8]1[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:6][CH:5]=1)=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C1CC[C@@H](Cc2ccc(-c3ccccc3)cc2)N1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1CC[C@@H](Cc2ccc(-c3ccccc3)cc2)N1C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1 g (4 mmol) (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (1-a, R1=H) is dissolved in 10 ml dry THF and cooled to −78° C. After the addition of 2.76 ml butyl lithium in hexane (1.59 M), the yellow solution is stirred at −78° C. for 30 min. Subsequently, 676 l (820 mg, 4.8 mmol) benzyl chloroformate (Cbz-Cl) is added and stirring is continued at −78° C. for 2 h. The reaction is then quenched by addition of 12 ml saturated NH4Cl solution followed by 10 ml water and then extracted with 2×40 ml isopropyl acetate. The layers are separated and the organic layer is dried over MgSO4, filtered and evaporated. The resulting residue (1.73 g) is purified on column chromatography (dichloromethane:methanol=99.5:0.5) to give (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid benzyl ester (1-a, R1=Cbz) as off-white solid. NMR (400 MHz, DMSO-d6, /ppm): 7.66 (m, 2H); 7.60 (m, 2H); 7.51-7.34 (m, 8H); 7.26 (d, J=8.2, 2 H); 5.28 (s, 2H); 4.37 (m, 1H); 3.05 (dd, J=3.3, 13.1, 1 H); 2.88 (dd, J=9.0, 13.1, 1 H); 2.45 (m, 1H); 2.28 (m, 1H); 2.01 (m, 1H); 1.77 (m, 1H). MS (ESI, m/e) 386 [M+H]+, 788 [2M+NH4+]. IR (solution in CH2Cl2, /cm−1): 3092; 2957; 1756; 1705; 1488; 1396; 1304; 1287; 1231; 1139; 1043; 952; 750.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][NH:4][C:3]1=[O:9].[H-].[Na+].[I:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH:21]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[CH:22]([CH2:30][CH2:31]OS(C)(=O)=O)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:15][CH:14]=1>CN(C)C=O>[I:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH:21]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=2)[CH:22]([CH2:30][CH2:31][N:4]2[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[C:3]2=[O:9])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:17][CH:18]=1
Reactant: COc1ccc(COC(CCc2ccc(I)cc2)C(CCOS(C)(=O)=O)C(=O)OC(C)(C)C)cc1
Reactant: Cn1c(=O)cc[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COC(CCc2ccc(I)cc2)C(CCn2ccc(=O)n(C)c2=O)C(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 27.4 %

Procedure:
3-Methyl-2,4(1H,3H)-pyrimidinedione (0.28 g, 2.2 mmol) was added in one portion to a stirred suspension of sodium hydride (60% suspension in mineral oil; 80 mg, 2.0 mmol) in dimethylformamide (3 mL) at room temperature under nitrogen. The resulting suspension was stirred for 5 min then a solution of 1,1-dimethylethyl 5-(4-iodophenyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)-2-{2-[(methylsulfonyl)oxy]ethyl}pentanoate (1.15 g, 1.86 mmol) in dimethylformamide (3 mL) was added in one portion. The resulting solution was heated at 80° C. for 1 h 45 min then cooled to room temperature. The volatiles were evaporated and the residue partitioned between dichloromethane (50 mL) and water (50 mL). The layers were separated and the organic phase evaporated to dryness. The residue was chromatographed on silica gel (10% methanol: dichloromethane) to give the title compound (0.33 g, 27%) as a yellow oil which was a mixture of diastereomers. LC/MS: 3.87 min; z/e 649, calcd (M+1) 649. 1H NMR (400 MHz: CDCl3): 7.55 (2H), 7.25 (2H), 7.10 (1H), 6.90-6.75 (4H), 5.70 (1H), 4.40 (2H), 3.85-3.60 (6H), 3.75-2.45 (3H), 2.00-1.70 (4H), 1.40 (9H).
Reaction SMILES: C(OC([N:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=4)=[CH:28][CH:27]=3)[O:23][N:22]=2)=[CH:17][CH:16]=1)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:38][C:35]1[CH:34]=[CH:33][C:32]([C:29]2[CH:28]=[CH:27][C:26]([C:24]3[O:23][N:22]=[C:21]([C:18]4[CH:19]=[CH:20][C:15]([CH2:14][NH:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:16][CH:17]=4)[N:25]=3)=[CH:31][CH:30]=2)=[CH:37][CH:36]=1
Reactant: COC(=O)CN(Cc1ccc(-c2noc(-c3ccc(-c4ccc(C)cc4)cc3)n2)cc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CNCc1ccc(-c2noc(-c3ccc(-c4ccc(C)cc4)cc3)n2)cc1
Yield: 65 %

Procedure:
Prepared using General Procedure 8. To a stirring solution of methyl 2-((tert-butoxycarbonyl)(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)amino)acetate INT-76 (518 mg, 1.01 mmol) in DCM (10 mL) was added TFA (1 mL) at room temperature. After 2 h the reaction mixture was evaporated to dryness. The crude product was purified by chromatography, eluting with 0.7 M ammonia in MeOH/DCM. The mixture was concentrated in vacuo to afford 272 mg (65%) of methyl 2-((4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)amino)acetate INT-77 as a white solid. LCMS-ESI (m/z) calculated for C25H23N3O3: 413; found 414 [M+H]+, tR=1.89 min (Method 10). Compound 495 was prepared from INT-77 and INT-23 using General Procedures 6 then 9. Compound 498 was prepared from INT-77 and INT-15 using General Procedures 6 then 9.
Reaction SMILES: [CH:1]([N:3]([CH2:5][C:6](O)=O)C)=O.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[C:10]#[CH:11].C(OC(=O)C)(=O)C>>[CH3:1][N:3]1[CH:5]=[CH:6][C:10]([C:9]([O:13][CH2:14][CH3:15])=[O:12])=[CH:11]1
Reactant: C#CC(=O)OCC
Reactant: CN(C=O)CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1ccn(C)c1
Yield: 71.3 %

Procedure:
A mixture of 117.1 g (1 mole) of N-formylsarcosine prepared in the Reference Example 1, 98.10 g (1 mole) of ethyl propiolate, and 638 ml of acetic anhydride was stirred using a magnetic stirrer over an oil bath at 130° C. for 22 hours. The reaction mixture was concentrated under vacuum. 100 ml of toluene was added to the residue and the mixture was evaporated under reduced pressure. This procedure was repeated to obtain a brown oily substance. This oily substance was distilled under vacuum to obtain 109.19 g (yield 71.3%) of a colorless or light-yellow oil of the title compound as fractions with a boiling point of 103°-104° C. at 4 mmHg.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:17])[CH2:4][CH2:5][O:6][C:7]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10].[CH2:18]([OH:20])[CH3:19]>>[ClH:1].[CH3:2][N:3]([CH3:17])[CH2:4][CH2:5][O:6][C:7]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:8]=1[C:9](=[NH:10])[O:20][CH2:18][CH3:19]
Reactant: CCO
Reactant: COc1ccc(C#N)c(OCCN(C)C)c1
Agent: Cl
Product: CCOC(=N)c1ccc(OC)cc1OCCN(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 96 %

Procedure:
Hydrogen chloride gas was passed through a solution of 2-(2-dimethylamino-ethoxy)-4-methoxy-benzonitrile (200 mg, 0.908 mmol) in anhydrous ethanol (10 mL) at 0° C. After 45 min, hydrogen chloride gas was stopped and the reaction vessel was sealed with a septum. After stirring at room temperature for 3 d, the reaction vessel was cooled to 0° C. and the septum was removed. The solvent was removed in vacuo to afford ethyl 2-(2-dimethylamino-ethoxy)-4-methoxy-benzimidate hydrochloride as a pale-yellow foam (310 mg, 96%). It was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:35][CH2:36][CH2:37][CH3:38])[N:14]([CH2:15][CH2:16][NH:17][C:18](=[O:34])[C:19]3[CH:24]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:22]([OH:29])=[C:21]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:20]=3)[C:10]=2[C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1>FC(F)(F)C(O)=O.[Pt]=O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:35][CH2:36][CH2:37][CH3:38])[N:14]([CH2:15][CH2:16][NH:17][C:18](=[O:34])[C:19]3[CH:24]=[C:23]([C:25]([CH3:27])([CH3:28])[CH3:26])[C:22]([OH:29])=[C:21]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:20]=3)[C:10]=2[C:9]2[NH:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCNC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: O=[Pt]
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(N)nc3c(c2n1CCNC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)NCCC3
Yield: 50.5 %

Procedure:
A solution of N1-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-3,5-di-(1,1-dimethylethyl)-4-hydroxybenzamide (0.1 g, 0.19 mmol) in trifluoroacetic acid (15 mL) and platinum oxide (0.1 g) were combined and hydrogenated overnight on a Parr apparatus. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under vacuum. The residue was dissolved in dichloromethane. The dichloromethane solution was washed twice with 10% sodium hydroxide and with brine, dried and then concentrated under vacuum to provide crude product. This material was purified by chromatography eluting with 10% methanol in dichloromethane. The resulting oil was triturated with acetonitrile to provide 0.05 g of N1-[2-(4-amino-2-butyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-3,5-di-(1,1-dimethylethyl)-4-hydroxybenzamide as a white powder, m.p. 208-210° C. Analysis: Calculated for C30H44N6O2+0.1CF3CO2H: % C, 68.17; % H, 8.35; ON, 15.79; Found: % C, 68.48; % H, 8.29; % N, 16.08.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:13][CH2:12][S:11][N:10]([CH:14]([CH3:16])[CH3:15])[C@@H:9]2[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH:5]=[CH:6][CH:7]=1.IC.[CH3:26][Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:13][C@@H:12]([CH3:26])[S:11][N:10]([CH:14]([CH3:16])[CH3:15])[C@@H:9]2[C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)N1SCC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)N1S[C@H](C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a degassed solution of 239.9 mg (0.602 mmol) of (3S,4R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-2-(2-propanyl)-1,2-thiazinan (Example 117, Step D) in THF (2.0 mL) was added iodomethane (60.0 μl, 0.960 mmol), followed by dropwise addition of a 1 M solution of lithium bis(trimethylsilyl)-amide in THF (640.0 μl, 0.640 mmol). After stirring at room temperature for 17 hours, the reaction was quenched with MeOH (3 mL), then concentrated under reduced pressure. Purification by flash chromatography on silica gel (0 to 70% DCM in hexanes gradient) provided the title compound as a white solid. The 1H NMR showed 6% of the 6S epimer was also isolated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[CH3:12])[CH2:8][CH:7]=[C:6]2[C:13]#[N:14].[H][H]>[Pd].[Pt].C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9]([CH2:8][CH2:7][CH:6]2[C:13]#[N:14])=[CH:10][C:11]=1[CH3:12]
Reactant: COc1cc2c(cc1C)CC=C2C#N
Reactant: [H][H]
Agent: [Pd]
Agent: [Pt]
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1C)CCC2C#N
Reaction time: 0.75 h
Yield: 91.6 %

Procedure:
Under a nitrogen atmosphere, 0.1 gram (catalyst) of 10% palladium on carbon and 0.05 gram (catalyst) of 5% platinum on carbon were placed in a 250 mL Parr hydrogenation bottle, followed by a solution of 2.5 grams (0.014 mole) of 5-methoxy-6-methylinden-3-carbonitrile (iii) in 100 mL of ethyl acetate. The mixture was hydrogenated in a Parr hydrogenation apparatus for about 45 minutes, during which time the theoretical amount of hydrogen was taken up by the reaction. The reaction mixture was then washed through a pad of diatomaceous earth with methylene chloride. The methylene chloride wash was concentrated under reduced pressure, yielding 2.4 grams of subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCOCC>CO>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][O:16][CH2:15][CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOCc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Clc1ccc(COCCC2CCNCC2)cc1
Reaction time: 8 h
Yield: 445.2 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-[2-(4-chlorobenzyloxy)ethyl]piperidine (760 mg, 0.47 mmol) in MeOH (0.5 mL) was added 2N anhydrous HCl/ether (1.5 mL, 3.0 mmol). The reaction mixture was stirred overnight, then evaporated, and the residue was dissolved in deionized water. EtOAc was used to wash the aqueous layer before the pH was altered to approx. 9-10. The aqueous layer was extracted three times with CH2Cl2, and the combined organic phases were dried over Na2SO4. After evaporation, 4-[2-(4-chlorobenzyloxy)ethyl]piperidine (531 mg, 97%) was obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[C:23]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C(O)C>[C:23]([C:27]1[CH:28]=[CH:29][C:30]([CH2:31][N:10]2[C:11]3[C@@:12]4([CH3:22])[C:19]([CH3:21])([CH3:20])[C@H:15]([CH2:14][CH2:13]4)[C:16]=3[C:17](=[O:18])[N:9]2[C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:33][CH:34]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(C)c1ccc(Cn2c3c(c(=O)n2-c2ccc(F)cc2F)[C@H]2CC[C@]3(C)C2(C)C)cc1
Temperature: 80 °C
Yield: 68.4 %

Procedure:
A mixture of (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 150 mg, 0.49 mmol), tetrabutylammonium iodide (181 mg, 0.49 mmol) and 4-tert-butylbenzyl bromide (360 μL, 1.96 mmol) in dimethylformamide (3 mL) was heated at 80° C. for 4 days. The solvent was evaporated, dichloromethane (50 mL) was added and the solution was washed with water (2×20 mL), saturated aqueous sodium thiosulfate (20 mL), and brine (20 mL). The solution was dried (magnesium sulfate), filtered, evaporated, and purified by column chromatography, eluting with 60-70% ethyl acetate/petroleum ether, and dried under high vacuum overnight to give a pale yellow foam. This was dissolved in ethanol and treated with charcoal. The mixture was filtered through Celite, and the filtrate was evaporated and dried under high vacuum to give (4S,7R)-1-(4-tert-butyl-benzyl)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (151 mg, 68%). APCI(+)-MS (M+H) 451.
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH2:23][CH2:24][CH3:25])[CH2:3][O:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[C:10]([O:20][CH3:21])[N:11]2C2CCCCO2)=[C:7]([NH2:22])[N:6]=1.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>CO>[F:30][C:29]([F:32])([F:31])[C:27]([OH:33])=[O:28].[CH3:1][C:2]([CH3:26])([CH2:23][CH2:24][CH3:25])[CH2:3][O:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[C:10]([O:20][CH3:21])[NH:11]2)=[C:7]([NH2:22])[N:6]=1
Reactant: CCCC(C)(C)COc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCCC(C)(C)COc1nc(N)c2nc(OC)[nH]c2n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2-[(2,2-dimethylpentyl)oxy]-8-methoxy-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (323 mg) in dry MeOH (3.23 mL) was added TFA (0.323 mL) and the reaction was stirred at room temperature for 48 h. The reaction was concentrated in vacuo to give a yellow residue. The residue was triturated with Et2O and was filtered to give the title compound as an off-white solid (252 mg).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14][NH2:15])[CH3:11]>>[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14][N:15]=[CH:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[F:1])[CH3:11]
Reactant: CCOC(CN)OCC
Reactant: O=Cc1ccccc1F
Product: CCOC(CN=Cc1ccccc1F)OCC
Temperature: 100 °C

Procedure:
2-Fluorobenzaldehyde (7.45 g), was added to aminoacetaldehyde diethylacetal (9.16 g) and the reaction heated to 100° C. for 3 h. After cooling, the mixture was transferred to a separating funnel and partitioned between diethyl ether and water. The ether layer was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure to leave an oil. Distillation at 0.6-0.8 mm collecting the fraction boiling at 102-106° C. afforded the title compound as a colourless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][O:9][C:10]([CH:12]2[N:16]3[C:17](=[O:22])[C@H:18]([C@H:19]([OH:21])[CH3:20])[C@H:15]3[C@@H:14]([CH3:23])[C:13]2=O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:27][N:28]1[CH2:32][C@@H:31]([SH:33])[CH2:30][C:29]1=[S:34]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([C:12]2[N:16]3[C:17](=[O:22])[C@H:18]([C@H:19]([OH:21])[CH3:20])[C@H:15]3[C@@H:14]([CH3:23])[C:13]=2[S:33][C@@H:31]2[CH2:32][N:28]([CH3:27])[C:29](=[S:34])[CH2:30]2)=[O:11])=[CH:25][CH:26]=1)([O-:3])=[O:2]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CN1C[C@@H](S)CC1=S
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3CC(=S)N(C)C3)[C@H](C)[C@H]12

Procedure:
In the same manner as described in Example 29-(1), (1R, 5R, 6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-carbapenam-3-carboxylic acid 4-nitrobenzyl ester is treated with (4S)-N-methyl-4-mercaptopyrrolidine-2-thione to give (1R, 5S, 6S)-2-[(4S)-N-methylpyrrolidine-2-thion-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid 4-nitrobenzyl ester as an amorphous powder.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:15]3[NH:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:16])[N:8]([CH2:17][O:18][CH3:19])[C:7]=2[CH:20]=1.S(Cl)(Cl)=O.C(=O)(O)[O-].[Na+].[C-:30]#[N:31].[Na+]>ClCCl>[CH3:19][O:18][CH2:17][N:8]1[C:7]2[CH:20]=[C:3]([CH2:2][C:30]#[N:31])[CH:4]=[CH:5][C:6]=2[C:15]2[NH:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9]1=[O:16]
Reactant: COCn1c(=O)c2c(c3ccc(CO)cc31)NCCC2
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COCn1c(=O)c2c(c3ccc(CC#N)cc31)NCCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.6 %

Procedure:
8-(hydroxymethyl)-6-(methoxymethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine-5-(6H)-one (100 mg, 0.36 mmol) prepared in step 5 of Example 41 was dissolved in dichloromethane (10 ml), added dropwise with thionylchloride (66 μl, 0.91 mmol) at 0° C. The resulting mixture was stirred at room temperature for 4 hours and poured into saturated sodium bicarbonate aqueous solution. The mixture was extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was then dissolved in N,N-dimethylformamide (5 ml) and sodium cyanide (55 mg, 1.09 mmol) was added. The resulting mixture was stirred at room temperature overnight and poured into ice water. The mixture was extracted with chloroform and the organic layer was washed with brine. The solution was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was then purified by flash column chromatography (chloroform:methanol=30:1) to obtain the title compound (70 mg, yield: 69%, white solid).