Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC1C=CN(CC(C2C=CC(C[Br:25])=CC=2C)=O)C(=O)C=1)C1C=CC=CC=1.O[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:55])[CH2:37][N:38]2[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][N:47]=3)=[CH:40][C:39]2=[O:54])=[C:32]([CH3:56])[CH:31]=1.C(OC1C=CN(CC(C2C=CC(CO)=CC=2C)=O)C(=O)C=1)C1C=CC=CC=1>COC(C)(C)C>[Br:25][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:55])[CH2:37][N:38]2[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][N:47]=3)=[CH:40][C:39]2=[O:54])=[C:32]([CH3:56])[CH:31]=1
Reactant: COc1ccc(COc2ccn(CC(=O)c3ccc(CO)cc3C)c(=O)c2)nc1
Reactant: Cc1cc(CBr)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Agent: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Solvent: COC(C)(C)C
Product: COc1ccc(COc2ccn(CC(=O)c3ccc(CBr)cc3C)c(=O)c2)nc1
Reaction time: 8 h
Yield: 80 %

Procedure:
1-[2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-methoxy-pyridin-2-ylmethoxy)-1H-pyridin-2-one is prepared following preparation 1d employing 1-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-methoxy-pyridin-2-ylmethoxy)-1H-pyridin-2-one (preparation 11c) instead of preparation 1c. The reaction mixture is stirred overnight. Tert-butyl methyl ether is added and the resulting precipitate is filtered off and dried.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:18][O:17][CH2:16][CH2:15][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([O:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:36][CH:35]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].B([O-])[O-]>COCCOC.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:18][O:17][CH2:16][CH2:15][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13]3)[N:9]=[C:10]([C:44]3[CH:45]=[CH:46][C:41]([O:40][C:37]4[CH:38]=[CH:39][CH:34]=[CH:35][CH:36]=4)=[CH:42][CH:43]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCOCC(n2nc(I)c3c(N)ncnc32)C1
Reactant: CC1(C)OB(c2ccc(Oc3ccccc3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [O-]B[O-]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 75 °C

Procedure:
tert-butyl 6-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1,4-oxazepane-4-carboxylate (1.18 mmol) is dissolved in ethylene glycol dimethylether (50 mL) and water (10 mL). 4,4,5,5-tetramethyl-2-(4-phenoxyphenyl)-1,3,2-dioxaborolane (1.47 mmol), palladium tetrakistriphenylphosphine (0.059 mmol) and sodium carbonate (2.95 mmol) are added and the reaction is heated for 12-20 hours. Additional boronate and palladium tetrakistriphenylphosphine are added and the reaction is heated at 60-90° C. for a further 20-24 hours. The reaction is concentrated under reduced pressure. The remaining residue was partitioned between dichloromethane and water. The organic layer is dried then concentrated under reduced pressure to yield the title compound.
Reaction SMILES: Cl.[C:2]([NH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([OH:17])[CH:11]=1)=[O:9])([CH3:5])([CH3:4])[CH3:3].C[O-].[Na+].[C:21]([Cl:31])(=[O:30])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>CN(C)C=O>[ClH:31].[C:2]([NH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:21](=[O:30])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[C:12]([OH:17])[CH:11]=1)=[O:9])([CH3:5])([CH3:3])[CH3:4]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)NCC(=O)c1ccc(O)c(O)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Oc2ccc(C(=O)CNC(C)(C)C)cc2O)cc1

Procedure:
Using a procedure similar to that described above in Example 58A, 26 g. of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride was reacted with 16 g. of sodium methoxide in 300 ml. of N,N-dimethylformamide under an atmosphere of nitrogen and then 17 g. of p-anisoyl chloride was added to produce 3-hydroxy-4-(p-anisoyloxy)phenyl tert-butylaminomethyl ketone hydrochloride. This salt was converted to the free base which was treated with acetic acid to yield 35 g. of the acetic salt, m.p. 170°-175° C. (dec.)(uncorr.). By treating this salt in (dec.) (uncorr.), with concentrated hydrochloric acid there was obtained 28 g. of the hydrochloride salt, m.p. >235° C. (dec.) (uncorr.). When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 30B, there is obtained 3-hydroxy-4-(p-anisoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [O:1]1[CH:5]([CH2:6][OH:7])[CH2:4][C:3]2[CH:8]=[CH:9][C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=3[C:2]1=2.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1.O>[CH3:26][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:7][CH2:6][CH:5]2[O:1][C:2]3[C:15]4[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=4[CH:9]=[CH:8][C:3]=3[CH2:4]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: OCC1Cc2ccc3c(c2O1)CCCC3
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2Cc3ccc4c(c3O2)CCCC4)cc1
Temperature: 40 °C
Reaction time: 12 h
Yield: 85.2 %

Procedure:
To a solution of (±)-2,3,6,7,8,9-hexahydronaphtho[1,2-b]furan-2-ylmethanol (1.37 g, 6.71 mmol) in dichloromethane (50 mL) was added p-toluenesulfonyl chloride (2.56 g, 13.41 mmol), 4-(dimethylamino)pyridine (0.164 g, 1.34 mmol), and triethylamine (1.70 g, 16.77 mmol) and the reaction mixture was allowed to stir at 40° C. for 12 h. The reaction mixture was diluted with water (250 mL) and the aqueous layer extracted with dichloromethane (2×150 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried (magnesium sulfate), and the solvent was removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:5) gave 2.05 g (85%) of (±)-2,3,6,7,8,9-hexahydronaphtho[1,2-b]furan-2-ylmethyl 4-methylbenzenesulfonate as a colorless oil. Rf=0.5 (silica, ethyl acetate:hexanes 1:4); Anal. calcd. for C20H22O4S: C, 67.01; H, 6.19. Found: C, 66.50; H, 6.27.
Reaction SMILES: [F:1][CH:2]([F:27])[C:3]1([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=2[CH3:26])[CH:9]2[CH:7]([CH2:8]2)[O:6][C:5]([NH:10]C(=O)C2C=CC=CC=2)=[N:4]1.N12CCCN=C1CCCCC2>CO>[F:27][CH:2]([F:1])[C:3]1([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=2[CH3:26])[CH:9]2[CH:7]([CH2:8]2)[O:6][C:5]([NH2:10])=[N:4]1
Reactant: Cc1c(F)cccc1C1(C(F)F)N=C(NC(=O)c2ccccc2)OC2CC21
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1c(F)cccc1C1(C(F)F)N=C(N)OC2CC21
Temperature: 40 °C
Reaction time: 18 h
Yield: 65.1 %

Procedure:
N-(5-(difluoromethyl)-5-(3-fluoro-2-methylphenyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-yl)benzamide (1.0 g, 2.67 mmol) was dissolved in methanol (50 mL) under nitrogen and 1,8-diazabicyclo-[5.4.0]undec-7-ene (0.798 ml, 5.34 mmol) was added. The reaction was heated to 40° C. After 18 hours, the reaction mixture was concentrated to dryness under reduced pressure and the residue partitioned between water and ethyl acetate. The organic layer was isolated and concentrated under reduced pressure. The crude residue was purified via silica gel flash chromatography eluting with 0-60% ethyl acetate in hexanes afforded the title compound 5-(difluoromethyl)-5-(3-fluoro-2-methylphenyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine (0.470 g, 1.739 mmol, 65.1% yield). LC/MS (ESI+) m/z=270.9 (M+H).
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[Si:9]([O:16][CH2:17][CH2:18][C@H:19]([OH:23])[C:20]([CH3:22])=[CH2:21])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1C=CN=C1.OS([O-])(=O)=O.[K+]>CN(C=O)C>[Si:9]([O:16][CH2:17][CH2:18][C@H:19]([O:23][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7])[C:20]([CH3:22])=[CH2:21])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: C=C(C)[C@@H](O)CCO[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=C(C)[C@H](CCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.9 %

Procedure:
946 mg (6.28 mmol, 1.3 equivalents) of tert-butyldimethylchlorosilane is added to a solution of 1.173 g (4.83 mmol) of (S)-1-[(tert-butyldimethylsilyloxy)]-4-methyl-4-penten-3-ol 10 and 855 mg (12.56 mmol, 2.6 equivalents) of imidazole in 15.0 ml of absolute DMF. The mixture is stirred for 16 hours at room temperature. It is mixed with 50 ml of an aqueous 1 M KHSO4 solution and extracted four times with 50 ml of Et2O each. The combined ether extracts are dried on MgSO4. After the solvent is distilled off in a vacuum, the residue is flash-chromatographed by a silica gel column with pentane/Et2O (20:1). As an alternative to this aqueous working-up, the reaction mixture can be chromatographed directly. By the two variations of working-up procedure, 1.643 g (4.73 mmol, 98%) of 11 is obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C=O)C>[Cl:15][C:12]([F:13])([F:14])[C:6]1[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:2]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Cl
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1N1CCCC1
Yield: 83.8 %

Procedure:
This compound was prepared as described in Example 37: 5.0 g (0.013 mol) of product of Example 28, 2.1 ml (0.026 mol) of pyrrolidine in 30 ml of DMF were reacted at room temperature for 16 hours affording 4.69 g of solid. Recrystallization in hot hexane-ether gave 4.36 g (77.9%) of product as a white solid; mp 72°-73.5° C.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:16])[C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10]CC)=O.[CH3:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].Cl>O1CCCC1>[CH3:16][N:4]([CH3:3])[C:5]1[CH:6]=[C:7]([C:8](=[O:10])[CH2:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1cccc(N(C)C)c1
Reactant: CC(=O)C(C)(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)c1cccc(C(=O)CC(=O)C(C)(C)C)c1
Reaction time: 3 h
Yield: 74.8 %

Procedure:
Into a 100 ml three-necked flask equipped with a stirrer, a dropping funnel, a reflux condenser, and a nitogen-inlet tube, were charged 2.08 gm (31 mmol) of 60% sodium hydride and 5.0 gm (26 mmol) of ethyl 3-dimethylaminobenzoate. The mixture was dispersed in 40 ml of tetrahydrofuran and heated under refluxing. To the mixture was dropwise added 3.0 gm (30 mmol) of pinacolone and the mixture was heated with stirring for 3 hours. After cooling, 50 ml of 1N hydrochloric acid was added to the reaction mixture, and the organic layer was extracted twice with chloroform. The extract was thoroughly washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation to obtain an yellow oil. The oily substance was submitted to the Kugelrohr distillation at 200° C., 1 mmHg, and crystallized from hexane to give 4.81 gm (yield: 75%) of yellow solid product.
Reaction SMILES: [OH:1][C@H:2]([CH3:34])[C@H:3]([NH:8][C:9](=[O:33])[C:10]1[CH:15]=[CH:14][C:13]([C:16]#[C:17]C#CC2C=CC(CN3CCOCC3)=CC=2)=[CH:12][CH:11]=1)[C:4](=[O:7])[NH:5][OH:6].C([CH:54]([NH2:67])[CH2:55][NH:56][C:57](=[O:66])[C:58]1[CH:63]=[CH:62][C:61]([C:64]#[CH:65])=[CH:60][CH:59]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCN(CC)CC>C(Cl)Cl.CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:1][C@H:2]([CH3:34])[C@H:3]([NH:8][C:9](=[O:33])[C:10]1[CH:11]=[CH:12][C:13]([C:16]#[C:17][C:65]#[C:64][C:61]2[CH:60]=[CH:59][C:58]([C:57](=[O:66])[NH:56][CH2:55][CH2:54][NH2:67])=[CH:63][CH:62]=2)=[CH:14][CH:15]=1)[C:4](=[O:7])[NH:5][OH:6]
Reactant: C[C@@H](O)[C@H](NC(=O)c1ccc(C#CC#Cc2ccc(CN3CCOCC3)cc2)cc1)C(=O)NO
Reactant: C#Cc1ccc(C(=O)NCC(N)C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](O)[C@H](NC(=O)c1ccc(C#CC#Cc2ccc(C(=O)NCCN)cc2)cc1)C(=O)NO
Reaction time: 0.08 h
Yield: 3.8 %

Procedure:
Resin 4 (150 mg, 0.116 mmol) was swelled in DCM (2 mL) for 1 h and drained. A solution of 4-ethynylbenzamide 3 (151 mg, 0.350 mmol) and Et3N (150 μL, 1.10 mmol) in DMF (2.0 mL) was added and the resin agitated for 5 min. A mixture of PdCl2(PPh3)2 (21 mg, 0.030 mmol) and CuI (28 mg, 0.147 mmol) was added and the resin was agitated for 60 h. The resin was drained, washed with DMF (3×2 mL), DCM (3×2 mL) and cleaved with 10% TFA/DCM (1.5 mL) for 20 min. The solution was collected and the resin was rinsed with additional 10% TFA/DCM (1.0 mL). The cleavage fractions were combined, treated with neat TFA (2.0 mL), stirred for 1 h at rt and concentrated by rotary evaporation to give a crude brown residue. Purification by RP-HPLC (C18 column, CH3CN gradient 5-65%, 0.1% TFA, UV analysis 300 nm, 26 min) and lyophilization of the collected fractions afforded 2.0 mg (4% yield) of (1S,2R)-N-(2-hydroxy-1-hydroxycarbamoyl-propyl)-4-{4-[4-(2-amino-ethylcarbamoyl)-phenyl]-buta-1,3-diynyl}-benzamide. LRMS (ES+) m/z 449.1 (C24H24N4O5+H requires 449.18); RP-HPLC (300 nm, 26 min run) 17.0 min.
Reaction SMILES: [C:1]1([P:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[C:1]1([P:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][N:10]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCP(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1
Solvent: CCO
Product: C(=NCCP(c1ccccc1)c1ccccc1)c1ccccc1
Yield: 98 %

Procedure:
Under argon, a solution of 2-diphenylphosphino-ethylamine (590.3 mg, 2.57 mmol) and benzaldehyde (275.0 mg, 2.59 mmol) in ethanol (15 mL) was heated at 65° C. (oil bath) for 4 h. Then, the solvent was removed in-vacuo to give the desired product (>98% by 1H-NMR) as a colourless oil which solidified on standing (733.9 mg, 2.31 mmol, 90%).
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:14][CH:13]=2)[N:9]=1)(=O)C.[OH-].[Na+]>CCO>[NH2:4][C:5]1[S:6][C:7]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)=[C:8]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:16][CH:17]=2)[N:9]=1
Reactant: CC(=O)Nc1nc(CCc2ccc(NC(=O)OC(C)(C)C)cc2)c(Cc2ccc(S(C)(=O)=O)cc2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccc(CCc2nc(N)sc2Cc2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Yield: 71.4 %

Procedure:
tert-Butyl [4-(2-{2-(acetylamino)-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-4-yl}ethyl)phenyl]carbamate (230 mg), 1N-NaOH (1.09 ml) and EtOH (5 ml) were combined, and the mixture was refluxed for 16 hours. After cooled to r.t., the organic solvent was removed in vacuo. The aqueous solution was neutrallized with 1N-HCl, and extracted with AcOEt. The organic layer was washed with water and brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by preparative silica gel chromatography with CHCl3/MeOH (30:1) as an eluent to give tert-butyl [4-(2-{2-amino-5-[4-(methylsulfonyl)benzyl]-1,3-thiazol-4-yl}ethyl)phenyl]carbamate (151.2 mg) as an off-white amorphous substance.
Reaction SMILES: [C:1]([O:4][C@H:5]([C@H:8]([C@@H:13]([C@@H:18]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:19][C:20](=O)C)[O:14][C:15](=[O:17])[CH3:16])[O:9][C:10](=[O:12])[CH3:11])C=O)(=[O:3])[CH3:2].[BrH:28]>C(O)(=O)C>[CH3:26][C:25]([O:24][CH2:23][C@H:18]1[O:19][C@H:20]([Br:28])[C@H:5]([O:4][C:1]([CH3:2])=[O:3])[C@@H:8]([O:9][C:10]([CH3:11])=[O:12])[C@@H:13]1[O:14][C:15]([CH3:16])=[O:17])=[O:27]
Reactant: Br
Reactant: CC(=O)OC[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H](C=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 69 h
Yield: 74 %

Procedure:
First, 14 g of glucose pentaacetate, from Sigma Chemical Company, was dissolved in 60 ml of 30% HBr in acetic acid and allowed to stand a 4° C. for 69 hours. The acetic acid was removed. The residue was dissolved in 100 ml of chloroform, washed twice with 100 ml of saturated NaHCO3, dried over MgSO4, concentrated, and crystallized from 95% ethanol to give 10.88 g (74%) of acetobromoglucose.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].[CH2:10](Br)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH-].[K+]>CS(C)=O>[CH2:10]([O:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C1CCCN1CCO
Reactant: CCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCCCCCCOCCN1CCCC1=O
Temperature: 25 °C
Yield: 92.9 %

Procedure:
1.29 g of 1-(2-hydroxyethyl)-2-pyrrolidone, 4.14 g of n-nonylbromide, 2.24 g of potassium hydroxide in a powder state and 30 ml of dimethyl sulfoxide were mixed together and agitated at room temperature for a whole day. The resulting reaction mixture was extracted with dichloromethane, after which the thus obtained extract was washed with water, dried, feed from the solvent by distillation off and then finally distilled to obtain 2.37 g of colorless 1-[2-(n-nonyloxy) ethyl] azacyclopentane-2-one having the following appearance, column temperature and analysis:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[N:11][C:10]2[O:9][CH:8](CCCl)[CH2:7][N:6]([CH3:16])[C:5](=[O:17])[C:4]=2[CH:3]=1.[CH2:18]([CH2:25][NH2:26])[C:19]1C=C[CH:22]=[CH:21][CH:20]=1.[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29]>C(O)C.C(O)(C)C>[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].[Cl:1][C:2]1[CH:12]=[N:11][C:10]2[O:9][CH:8]([NH:26][CH2:25][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:27]=3[CH3:28])[CH2:7][N:6]([CH3:16])[C:5](=[O:17])[C:4]=2[CH:3]=1
Reactant: NCCc1ccccc1
Reactant: CN1CC(CCCl)Oc2ncc(Cl)cc2C1=O
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: CC(C)O
Product: Cc1ccccc1CNC1CN(C)C(=O)c2cc(Cl)cnc2O1
Yield: 47.9 %

Procedure:
To a solution of 6.0 g (0.022 mole) of 7-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepine-5(4H)-one in 50 ml of absolute ethanol was added 5.3 g (0.044 mole) of benzylmethylamine and the mixture heated to reflux for three days. The solvent was removed by rotary evaporation, and the residue was taken up in 100 ml of methylene chloride, which was subsequently washed with 2×50 ml of dilute sodium hydroxide and 50 ml water, dried over sodium sulfate, filtered, and concentrated by rotary evaporation. Residual benzylmethylamine was removed at 95° C., 0.5 mm Hg. However, the mass spectrum now showed starting material; therefore, the residue was taken up in 50 ml of absolute ethanol. To the resulting solution was added 2.7 g (0.022 mole) of benzylmethylamine and the mixture heated to reflux for 24 hrs. The reaction mixture was subjected to the same work-up as mentioned before. The syrup was treated with oxalic acid in isopropyl alcohol. The resulting crystals were recrystallized from ethanol/isopropyl alcohol to give 4.7 g (47.9%) of white crystals, m.p. 176°-179° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8]Cl)=[C:4]([O:10][CH3:11])[CH:3]=1.[Cl:12][C:13]1[C:14]([F:25])=[C:15]([C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)[C:16]([F:19])=[CH:17][CH:18]=1.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][N:21]2[CH:22]=[CH:23][N:24]=[C:20]2[C:15]2[C:16]([F:19])=[CH:17][CH:18]=[C:13]([Cl:12])[C:14]=2[F:25])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: Fc1ccc(Cl)c(F)c1-c1ncc[nH]1
Reactant: COc1cc(Cl)nnc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Cl)nnc1Cn1ccnc1-c1c(F)ccc(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 6-chloro-3-chloromethyl-4-methoxy-pyridazine (58 mg, 0.3 mmol) and 2-(3-chloro-2,6-difluoro-phenyl)-imidazole (65 mg, 0.3 mmol) in DMF (6 mL) is added NaH (60% suspension in mineral oil, 14 mg). The mixture is stirred at room temperature overnight. The solvent is removed in vacuo and water (5 mL) and EtOAc (8 mL) is added. The layers are separated and the aqueous layer is extracted with EtOAc (8 mL). The combined extracts is washed with brine (8 mL) and dried (Na2SO4) and evaporated. Preparative TLC purification (5% MeOH in CH2Cl2) of the residue provides the title compound as a light yellow oil. H1 NMR δ (CDCl3) 7.48–7.56 (m, 1H), 7.15–7.20 (m, 2H), 7.02 (t, 1H, J=8.4 Hz), 6.87 (s, 1H), 5.27 (s, 2H), 3.764 (s, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH2:32]([N:39]([CH2:46][C@H:47]([OH:51])[CH2:48][O:49][CH3:50])[CH2:40][C@H:41](O)[CH2:42][O:43][CH3:44])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>O1CCCC1>[CH2:32]([N:39]1[CH2:40][C@H:41]([CH2:42][O:43][CH3:44])[O:51][C@H:47]([CH2:48][O:49][CH3:50])[CH2:46]1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COC[C@@H](O)CN(Cc1ccccc1)C[C@H](O)COC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC[C@@H]1CN(Cc2ccccc2)C[C@H](COC)O1
Temperature: 0 °C
Reaction time: 5 h
Yield: 38.6 %

Procedure:
A mixture of triphenylphosphine (10.2 g), diethyl azodicarboxylate (6.12 ml), and (2S)-1-[N-benzyl-N-[(2S)-2-hydroxy-3-methoxypropyl]amino]-3-methoxypropan-2-ol (7.34 g) in tetrahydrofuran (70 ml) was stirred at 0° C. for 5 hours. To the mixture was added successively triphenylphosphine (2.04 g) and diethyl azodicarboxylate (1.2 ml), and the mixture was stirred at 0° C. for 3 hours. The mixture was poured into water and extracted with dichloromethane (×3). The combined extracts were washed with brine, dried over sodium sulfate, and evaporated. Isopropyl ether (50 ml) was added to the residue and stirred at room temperature for 30 minutes. The insoluble precipitate was filtered off, and the solution was evaporated and purified twice with column chromatography (1st: silica gel 800 ml, ethyl acetate:isopropyl ether=2:8–3:7) (2nd: silica gel 300 ml, ethyl acetate:isopropyl ether 3:97–10.90) to give 4-benzyl-cis-2,6-dimethoxymethylmorpholine (2.65 g) as an oil.
Reaction SMILES: C([Li])CCC.[Cl-].[Cl:7][C:8]1[CH:33]=[CH:32][C:11]([CH2:12][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:10][CH:9]=1.[O:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]1[O:40][CH2:41][CH2:42][CH2:43][CH:44]=O>O1CCCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH:12]=[CH:44][CH2:43][CH2:42][CH2:41][O:40][CH:35]2[CH2:36][CH2:37][CH2:38][CH2:39][O:34]2)=[CH:32][CH:33]=1
Reactant: O=CCCCOC1CCCCO1
Reactant: Clc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Clc1ccc(C=CCCCOC2CCCCO2)cc1
Yield: 47.7 %

Procedure:
In an argon atmosphere, butyllithium (10%; 37 ml) was added dropwise to a suspension of (4-chlorobenzyl)triphenylphosphonium chloride (24 g) in tetrahydrofuran (70 ml) with ice-cooling and stirring. After stirring at the same temperature for 30 minutes, a solution of 4-tetrahydropyranyloxy-1-butanal (9 g) in tetrahydrofuran (30 ml) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The tetrahydrofuran was distilled off under reduced pressure and water was added to the residue, followed by extraction with petroleum ether. After washing with water and drying over magnesium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography, elution being carried out with chloroform to give 1-(4-chlorophenyl)-5-(2-tetrahydropyranyloxy)-1-pentene (7 g) as a light-yellow oil.