Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]C1C=CC=CC=1C=O.[CH2:10]([OH:13])[CH2:11][OH:12].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17](S(O)(=O)=O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C1(C)C=CC=CC=1>[Br:1][C:17]1[CH:18]=[CH:19][C:14]([CH:24]2[O:13][CH2:10][CH2:11][O:12]2)=[CH:15][CH:16]=1
Reactant: OCCO
Reactant: O=Cc1ccccc1Br
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1ccc(C2OCCO2)cc1

Procedure:
40 g (216 mmol) of bromobenzaldehyde, 39 ml (700 mmol) of ethylene glycol, 1.6 g (9.3 mmol) of p-toluene sulphonic acid and 670 ml of toluene are introduced into a 2 l three-necked flask equipped with a Dean-Stark apparatus under nitrogen. The reaction mixture is taken to reflux whilst eliminating the water formed. After 24 hours of reflux, the reaction mixture is hydrolized with a saturated solution of sodium carbonate (240 ml). The organic phase is recovered and washed twice with a saturated solution of sodium chloride (2×160 ml), then concentrated under vacuum. The crude product obtained is distilled under 40 mm/Hg (150-156° C.).
Reaction SMILES: [CH:1]1([CH2:4][CH:5]([C:8]2[CH:9]=[N:10][CH:11]=[N:12][CH:13]=2)[C:6]#[N:7])[CH2:3][CH2:2]1.CI.[CH3:16]C([O-])(C)C.[K+]>O1CCOCC1>[CH:1]1([CH2:4][C:5]([CH3:16])([C:8]2[CH:9]=[N:10][CH:11]=[N:12][CH:13]=2)[C:6]#[N:7])[CH2:3][CH2:2]1
Reactant: N#CC(CC1CC1)c1cncnc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1COCCO1
Product: CC(C#N)(CC1CC1)c1cncnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
To a solution of 3-cyclopropyl-2-(pyrimidin-5-yl)propanenitrile (1.5 g, 8.67 mmol) and MeI (1.45 g, 13.0 mmol) in 1,4-dioxane (20 ml) was added t-BuOK (9.57 ml, 9.57 mmol) dropwise at room temperature under N2. The mixture was stirred for 1 h at room temperature then quenched by sat.aq NH4Cl (20 ml) and extracted with EtOAc (3×30 ml). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give 3-cyclopropyl-2-methyl-2-(pyrimidin-5-yl)propanenitrile (1.5 g), which was used directly for next step.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:16](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][N:8]([C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:5]2=[N:6][CH:7]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1c[nH]c2ncc(Br)nc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-bromo-7-nitro-5H-pyrrolo[2,3-b]pyrazine (5 g, 20.57 mmol) was dissolved in DMF (100 mL) under N2. Solution was cooled in an ice bath and sodium hydride (867.1 mg, 22.63 mmol) added portionwise. After 30 minutes (effervescence completed) trityl chloride (6.022 g, 21.60 mmol) was added in one portion and the mixture allowed to warm to ambient temperature (Precipitate observed after around 15 mins). Reaction mixture was poured into water and mixture stirred for 1 hour then filtered. Solid was washed with copious water then dried in a vacuum oven over 48 hours at 80° C. Taken on to the next step as is. (9.7 g, 97.3%) 1H NMR (400.0 MHz, DMSO) δ 8.46 (s, 1H), 8.40 (s, 1H), 7.38-7.36 (m, H), 7.23-7.20 (m, 8H) and 3.32 (s, 7H) ppm
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:38])([CH3:37])[O:6][C@@H:7]1[C@H:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[O:9][C@H:8]1[N:29]1[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]1=[O:31])([CH3:4])[CH3:3].[CH3:39][C:40]([C:43]1[CH:50]=[CH:49][C:46]([CH:47]=[O:48])=[CH:45][CH:44]=1)([CH3:42])[CH3:41]>>[CH3:42][C:40]([C:43]1[CH:44]=[CH:45][C:46]([CH:47]([OH:48])[C:35]2[C:33](=[O:34])[NH:32][C:30](=[O:31])[N:29]([CH:36]=2)[C@@H:8]2[O:9][C@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24])[C@@H:11]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[C@H:7]2[O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:38])[CH3:37])=[CH:49][CH:50]=1)([CH3:39])[CH3:41]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Product: CC(C)(C)c1ccc(C(O)c2cn([C@@H]3O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c(=O)[nH]c2=O)cc1

Procedure:
5-((4-(1,1-Dimethylethyl)phenyl)hydroxymethyl)-2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine was prepared from 2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine according to the method of Example 1 step (i) (using 4-(1,1-dimethylethyl)benzaldehyde instead of benzophenone) as a colourless foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][C:21]([F:24])=[CH:22][CH:23]=3)[N:16]=[C:15]([C:25]([OH:27])=O)[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(N3CC(=O)NC3)=O)C=2)C=C(F)C=1.[S:55]1[CH2:59][CH2:58][NH:57][CH2:56]1>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][C:21]([F:24])=[CH:22][CH:23]=3)[N:16]=[C:15]([C:25]([N:57]3[CH2:58][CH2:59][S:55][CH2:56]3)=[O:27])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:10])[F:11])[CH:7]=1
Reactant: C1CSCN1
Reactant: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2ccc(F)nc2)n1
Agent: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Product: O=C(c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2ccc(F)nc2)n1)N1CCSC1

Procedure:
113 mg (0.25 mmol) of the compound of Example 42A is reacted analogously to the synthesis of the compound of Example 1 with 25 mg (0.28 mmol) of thiazolidine. 91 mg (70% of theory) of the title compound is obtained.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:23][C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)=[C:16]([CH:22]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN1CCCC1=O.C(=O)([O-])O.[Na+]>[Cl:30][C:28]1[CH:29]=[C:24]([CH:25]=[C:26]([Cl:31])[CH:27]=1)[O:23][C:15]1[CH:14]=[CH:13][C:12]([NH:11][C:2]2[C:3]3[NH:10][CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:22][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1cc(N)ccc1Oc1cc(Cl)cc(Cl)c1
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1cc(Nc2ncnc3cc[nH]c23)ccc1Oc1cc(Cl)cc(Cl)c1
Temperature: 140 °C
Reaction time: 2.5 h
Yield: 84.6 %

Procedure:
To a solution of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (61 mg) in 1-methyl-2-pyrrolidone (0.8 mL), was added ethyl 5-amino-2-(3,5-dichlorophenoxy)benzoate (186 mg), and the mixture was heated to 140° C. and stirred for 2.5 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (20 mL), and extracted with a mixed solvent (25 mL×3) of ethyl acetate/tetrahydrofuran (1/1). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluent:hexane/ethyl acetate=8/2→0/10). The object fraction was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the resultant precipitate was collected by filtration and dried under reduced pressure to give the title compound (149 mg) as pale-yellow powder crystals.
Reaction SMILES: [CH3:1][NH:2][CH3:3].CS(O[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[C:14]([O:48][CH3:49])=[N:15][C:16](/[C:19](/[C:38]2[CH:43]=[CH:42][C:41]([C:44]([CH3:47])([CH3:46])[CH3:45])=[CH:40][CH:39]=2)=[CH:20]/[C@H:21]2[CH2:25][CH2:24][C:23](=[O:26])[N:22]2[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=2[O:36][CH3:37])=[CH:17][CH:18]=1)(=O)=O>>[C:44]([C:41]1[CH:40]=[CH:39][C:38](/[C:19](/[C:16]2[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][N:2]([CH3:3])[CH3:1])=[C:14]([O:48][CH3:49])[N:15]=2)=[CH:20]\[C@@H:21]2[N:22]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=3[O:36][CH3:37])[C:23](=[O:26])[CH2:24][CH2:25]2)=[CH:43][CH:42]=1)([CH3:47])([CH3:46])[CH3:45]
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(CCCCOS(C)(=O)=O)c(OC)n2)c(OC)c1
Reactant: CNC
Product: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(CCCCN(C)C)c(OC)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Triethylamine (50 μL) and methanesulfonyl chloride (25 μL) were added to a solution of (5R)-5-{(E)-2-(4-tert-butylphenyl)-2-[5-(4-hydroxybutyl)-6-methoxypyridin-2-yl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (144 mg) in chloroform (2 mL), and the mixture was stirred at room temperature for three hours. Triethylamine (50 μL) and methanesulfonyl chloride (25 μL) were further added thereto and the mixture was stirred at room temperature for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 4-(6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-methoxypyridin-3-yl)butyl methanesulfonate as a crude product. 2 M dimethylamine (solution in methanol) (3 mL) was added to 4-(6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-methoxypyridin-3-yl)butyl methanesulfonate, and the mixture was stirred at room temperature for 17 hours. The solvent was evaporated from the reaction solution and then water was added, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:0→4:1) to give (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-{5-[4-(dimethylamino)butyl]-6-methoxypyridin-2-yl}ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a colorless oil.
Reaction SMILES: C1(S([CH2:10][C:11]2[N:15]=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[NH:13][N:12]=2)(=O)=O)C=CC=CC=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]=[CH:29][C:30]#[N:31])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:29]=[C:30]([NH2:31])[N:12]3[N:13]=[C:14]([C:16]4[O:17][CH:18]=[CH:19][CH:20]=4)[N:15]=[C:11]3[CH:10]=2)=[CH:26][CH:27]=1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccco2)n1)c1ccccc1
Reactant: N#CC=Cc1ccc(F)cc1
Product: Nc1cc(-c2ccc(F)cc2)cc2nc(-c3ccco3)nn12

Procedure:
The title compound, MS m/e (%): 295 (M+H+, 100), was prepared in accordance with the general method of example 1 from 3-benzenesulfonylmethyl-5-furan-2-yl-1H-[1,2,4]triazole and 3-(4-fluoro-phenyl)-acrylonitrile.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]([F:18])=[C:16]([F:19])[C:15]([F:20])=[CH:14][C:10]=2[C:11]([OH:13])=O)=[C:4]([CH3:21])[CH:3]=1.[CH:22]([O:24][CH2:25][CH2:26][O:27][NH2:28])=[CH2:23].C(N(C(C)C)CC)(C)C.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>ClCCl.CCOCC>[I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]([F:18])=[C:16]([F:19])[C:15]([F:20])=[CH:14][C:10]=2[C:11]([NH:28][O:27][CH2:26][CH2:25][O:24][CH:22]=[CH2:23])=[O:13])=[C:4]([CH3:21])[CH:3]=1
Reactant: C=COCCON
Reactant: Cc1cc(I)ccc1Nc1c(C(=O)O)cc(F)c(F)c1F
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOCC
Product: C=COCCONC(=O)c1cc(F)c(F)c(F)c1Nc1ccc(I)cc1C
Yield: 72.9 %

Procedure:
To a solution comprised of 2-(4-iodo-2-methyl-phenylamino)-3,4,5-trifluoro-benzoic acid (3.60 g, 8.84 mmol), O-(2-vinyloxyethyl)hydroxylamine (1.09 g, 10.5 mol) and diisopropylethylamine (2.80 mL, 16.0 mmol) in dichloromethane (50 mL) was added benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium-hexafluorophosphate (5.26 g, 10.1 mmol). The resultant solution was stirred 90 min at ambient temperature. The reaction mixture was diluted with ether (100 mL) and washed with water (3×50 mL) and saturated brine (50 mL). The organics were dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography to afford 2-(4-iodo-2-methyl-phenylamino)-3,4,5-trifluoro-N-(2-vinyloxyethoxy)benzamide (3.17 g, 73%) as a pale-yellow foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[CH:21]=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[C:25]([F:28])([F:27])[F:26]>[F-].[Cs+].Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[C@@H:21]([OH:22])[C:25]([F:28])([F:27])[F:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C=O
Reactant: C[Si](C)(C)C(F)(F)F
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Product: CC(C)(C)OC(=O)N1CC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1[C@@H](O)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.7 %

Procedure:
To aldehyde 51C (2.10 g, 6.38 mmol) was added trimethyl(trifluoromethyl)silane (800 μL, 6.57 mmol) and cesium fluoride (dried under high vacuum at 130° C. for 12 h) (10.0 mg, 0.0658 mmol). The reaction was stirred at rt for 24 h then heated to 50° C. for 5 h. After cooling to rt, 4 N HCl (ca. 10 mL) was added and the reaction was stirred overnight. The brown aqueous solution was decanted and the waxy yellow solid was dried under high vacuum overnight then recrystallized from hexane to provide (2R,3R)-3-(tert-butyl-dimethyl-silanyloxy)-2-[(1R)-(2,2,2-trifluoro-1-hydroxy-ethyl)]-pyrrolidine-1-carboxylic acid tert-butyl ester (66A) (1.19 g) as a white solid. The mother liquor was concentrated and purified via flash chromatography eluting with 5-20% ethyl acetate/hexane to provide (2R,3R)-3-(tert-butyl-dimethyl-silanyloxy)-2-[(1S)-(2,2,2-trifluoro-1-hydroxy-ethyl)]-pyrrolidine-1-carboxylic acid tert-butyl ester (66B) (192 mg) as an oil and a mixture of 66A and starting material 51C (306 mg). The latter mixture was recrystallized from hexane to provide additional 66A (100 mg).
Reaction SMILES: C(OC(=O)C)(=O)C.[CH2:8]([O:15][C@H:16]1[C@H:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:20]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@H:19]([CH3:38])[O:18][CH:17]1[OH:39])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCOC(C)=O>CS(C)=O>[CH2:8]([O:15][C@H:16]1[C@H:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:20]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C@H:19]([CH3:38])[O:18][C:17]1=[O:39])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C[C@@H]1OC(O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C[C@@H]1OC(=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reaction time: 24 h
Yield: 62.7 %

Procedure:
Acetic anhydride (7.40 mL, 78 mmol, commercially available from Sigma Aldrich) was added to a solution of (3S,4R,5R,6S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-ol (1.70 g, 3.91 mmol) in DMSO (12 mL), and the resulting mixture was stirred for 24 h at P. EtOAc was added, and the mixture was washed with water (3×), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give an oil. The oil was purified by silica gel chromatography (0 to 40% EtOAc/hexanes gradient) to give (3S,4R,5R,6S)-3,4,5-tris(benzyloxy)-6-methyltetrahydro-2H-pyran-2-one as a colorless oil (1.06 g, 62.6% yield). ESI (M+H) 433.1; calc for C27H28O5 432.2.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[CH2:10]([O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)[CH2:11][CH3:12]>>[F:9][C:4]1[CH:3]=[C:2]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([O:13][CH2:10][CH2:11][CH3:12])[CH:19]=2)[CH:8]=[CH:7][C:5]=1[NH2:6]
Reactant: Nc1ccc(Br)cc1F
Reactant: CCCOc1cccc(B(O)O)c1
Product: CCCOc1cccc(-c2ccc(N)c(F)c2)c1
Yield: 71.3 %

Procedure:
The title compound (280 mg) was prepared from 4-bromo-2-fluoroaniline (390 mg, 1.6 mmol) and 3-propoxyphenylboronic acid (369 mg, 2 mmol) as a colourless liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=2)[CH:9]1[C:20](O)=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:23][C:24]1[CH:25]=[C:26]([CH:28]=[C:29]([F:37])[C:30]=1[C:31]([CH3:36])([CH3:35])[CH2:32][O:33][CH3:34])[NH2:27].CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O>[F:23][C:24]1[CH:25]=[C:26]([NH:27][C:20]([CH:9]2[C:10]3[C:15](=[CH:14][C:13]([O:18][CH3:19])=[CH:12][CH:11]=3)[CH2:16][CH2:17][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:21])[CH:28]=[C:29]([F:37])[C:30]=1[C:31]([CH3:35])([CH3:36])[CH2:32][O:33][CH3:34]
Reactant: COc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2C(=O)O
Reactant: COCC(C)(C)c1c(F)cc(N)cc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COCC(C)(C)c1c(F)cc(NC(=O)C2c3ccc(OC)cc3CCN2C(=O)OC(C)(C)C)cc1F
Temperature: 60 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To a solution of 2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (671 mg, 2.18 mmol), 3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)aniline (470 mg, 2.18 mmol), DIEA (1.907 mL, 10.92 mmol) and DMAP (267 mg, 2.18 mmol) in ethyl acetate (30 mL) was added T3P (3.85 mL, 6.55 mmol) at room temperature, and the mixture was stirred overnight at 60° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5→60% ethyl acetate/hexane), and then silica gel column chromatography (NH, solvent gradient; 5→60% ethyl acetate/hexane), and the precipitate was washed with ethyl acetate/hexane to give tert-butyl 1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (440 mg, 0.872 mmol, 39.9%) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7](OC)=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1.[CH3:12][N:13]([CH3:21])[CH2:14][C:15]#[C:16][CH2:17][CH2:18][CH2:19][NH2:20]>>[CH3:1][O:2][C:3]1[C:7]([NH:20][CH2:19][CH2:18][CH2:17][C:16]#[C:15][CH2:14][N:13]([CH3:21])[CH3:12])=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1
Reactant: COC1=NS(=O)(=O)N=C1OC
Reactant: CN(C)CC#CCCCN
Product: COC1=NS(=O)(=O)N=C1NCCCC#CCN(C)C

Procedure:
In a similar manner to Example 1, 3,4-dimethoxy-1,2,5-thiadiazole-1,1-dioxide (1.0 g) and 6-(dimethylamino)hex-4-ynylamine (0.79 g) were reacted to give a solution of 3-methoxy-4-[6-dimethylaminohex-4-ynylamino]-1,2,5-thiadiazole-1,1-dioxide. Reaction with ammonia and purification as in Example 1 gave the title compound (0.62 g), m.p. 183°-5° C. (recrystallisation from acetonitrile).
Reaction SMILES: [CH2:1]([CH:8]1[C:14](=[O:15])[N:13]2[CH:9]1[CH2:10][CH:11]([S:26][CH2:27][CH3:28])[CH:12]2[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:29].N1C=CC=CC=1.[Cl-:36].[Cl-].IC1C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:1]([CH:8]1[C:14](=[O:15])[N:13]2[CH:9]1[CH2:10][C:11]([Cl:36])([S:26]([CH2:27][CH3:28])=[O:29])[CH:12]2[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCSC1CC2C(Cc3ccccc3)C(=O)N2C1C(=O)OCc1ccccc1
Reactant: [Cl-]
Reactant: O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: Ic1ccccc1
Product: CCS(=O)C1(Cl)CC2C(Cc3ccccc3)C(=O)N2C1C(=O)OCc1ccccc1
Yield: 56.6 %

Procedure:
A solution of benzyl 6-benzyl-3-ethylthio-7-oxo-1-azabicyclo[3.2.0]heptane-2-carboxylate (98) (0.047 g) in chloroform (5 ml) was treated with water (0.005 g), pyridine (0.033 g) and iodobenzene dichloride (0.082 g) at 0° under argon. The solution was concentrated after 2 hours and then chromatographed on silica gel 60 (<230 mesh) eluting with ethyl acetate/60°-80° petroleum ether 7:3 to give benzyl 6-benzyl-3-ethylsulphinyl-7-oxo-1-azabicyclo[3.2.0]heptane-2-carboxylate (79) (0.030 g); m.p. 118°-123° (ethyl acetate/60°-80° petroleum ether); νmax (CHCl3) 2980, 1775 and 1745 cm-1 ; τ(CDCl3) 2.6-2.9 (10H, m, phenyls), 4.89 (2H, s, OCH2) 4.98 (1H, s, C2-H), 5.92 (1H, ddd J 8, 3 and 2 Hz, C5-H), 6.26 (1H, ddd J 9, 6 and 3 Hz, C6-H), 6.6-7.3 (5H, m, C4-H, C8-H2, SCH2), 7.72 (1H, dd J 15 and 2 Hz, C4-H) and 8.68 (3H, t J 71/2 Hz, CH3).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:29])([F:28])[F:27])[NH:15][C:16]3=[O:19])=[CH:11][CH:10]=2)[CH2:4]1.[C:30](Cl)(=[O:32])[CH3:31].Cl>N1C=CC=CC=1>[O:8]=[C:6]1[N:5]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:28])([F:27])[F:29])[NH:15][C:16]3=[O:19])=[CH:11][CH:10]=2)[CH2:4][CH:3]([CH2:2][NH:1][C:30](=[O:32])[CH3:31])[O:7]1
Reactant: NCC1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)NCC1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
The 7-(5-aminomethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (15.3 mg, 0.038 mmol) obtained in Example 1-31 was dissolved in pyridine (380 μl). Thereafter, acetyl chloride (3.2 μl) was added to the obtained solution, and the obtained mixture was stirred at a room temperature for 2 hours. Thereafter, 1 N hydrochloric acid was added to the reaction solution under cooling on ice, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=20:1), so as to obtain N-{2-oxo-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]oxazolidin-5-ylmethyl}acetamide (12.1 mg; yield: 71%) in the form of a colorless amorphous substance.