Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl.O>[C:17]1([C:16]([NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)=[O:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1cccc(OCc2ccccc2)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1cccc(OCc2ccccc2)c1)c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 3-benzyloxyaniline 23 (1.0 g, 5.0 mmol) and TEA (0.74 mL, 5.3 mmol) in CH2Cl2 was added benzoyl chloride (0.61 mL, 5.26 mmol) dropwise and the mixture was allowed to stir overnight. The reaction mixture was diluted with water and the resulting solid was collected by vacuum filtration. The solid was allowed to air dry, to yield compound 25 as a white solid. Synthesis of phenyl{[(3-phenylmethoxy)phenyl]amino}methane-1-thione (26):
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7](Cl)[S:8][C:4]=2[CH:3]=1.CCN(CC)CC.[CH:19]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:21][CH2:20]1>CCO>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([N:25]3[CH2:26][CH2:27][N:22]([CH:19]4[CH2:21][CH2:20]4)[CH2:23][CH2:24]3)[S:8][C:4]=2[CH:3]=1
Reactant: Clc1nc2ccc(Br)cc2s1
Reactant: C1CN(C2CC2)CCN1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Brc1ccc2nc(N3CCN(C4CC4)CC3)sc2c1
Yield: 31 %

Procedure:
To a solution of 6-bromo-2-chlorobenzothiazole (8.2 g, 33 mmol) in EtOH (115 mL) was added Et3N (16.7 g, 165 mmol), followed by 1-cyclopropylpiperazine (5 g, 39.6 mmol). The mixture was heated at reflux for 12 h. Then the mixture was evaporated to remove EtOH. Water (120 mL) was added to the residue and the mixture was extracted with CH2Cl2 (3×50 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated to give a residue, which was purified by column chromatography on silica gel eluting with a mixture of EtOAc/petroleum ether (1:10 with 0.1% NH4OH added) to give 3.46 g (31%) 6-bromo-2-(4-cyclopropylpiperazin-1-yl)benzothiazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[CH2:6][CH2:7][NH:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C.Cl[C:25]([O:27][CH3:28])=[O:26]>C(OCC)C>[CH:9]1([N:8]([CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:25](=[O:26])[O:27][CH3:28])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)Cl
Reactant: COc1cccc(CCNC2CCCC2)c1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)N(CCc1cccc(OC)c1)C1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
To a solution of N-(3-methoxyphenethyl)cyclopentanamine (1.31 g, 6 mmol) in diethyl ether (50 mL) was added triethylamine (1.3 mL, 9 mmol) and methyl chloroformate (0.7 mL, 9 mmol) at 0° C. The reaction mixture was gradually warmed to room temperature and stirred for 30 min. Filtration and removal of solvent under reduced pressure followed by silica gel column chromatography using hexanes/ethyl acetate afforded methyl cyclopentyl(3-methoxyphenethyl)-carbamate as a pale yellow liquid (1.41 g, 84%). 1H NMR (400 MHz, CDCl3): δ 7.19 (t, 1H, J=7.6 Hz), 6.78-6.73 (overlapping doublets and singlet, 3H), 4.27-4.24 (m, 1H), 3.78 (s, 3H), 3.70 (s, 3H), 3.28 (t, 2H, J=7.9 Hz), 2.80 (t, 2H, J=7.9 Hz), 1.68-1.67 (m, 2H), 1.53-1.50 (m, 6H). LC-MS (ESI) Calcd for C16H23NO3 [M+H]+: 278.17. Found: 278.00.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)CC)C.[CH2:22]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([C:37](Cl)=[O:38])=[CH:33][CH:32]=2)=[CH:27][CH:26]=1)[CH2:23][CH3:24]>C(Cl)Cl>[CH2:22]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([N:7]3[C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=4[CH2:10][N:4]4[CH:3]=[CH:2][CH:1]=[C:5]4[CH2:6]3)=[O:38])=[CH:33][CH:32]=2)=[CH:27][CH:26]=1)[CH2:23][CH3:24]
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: CCCc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1ccc(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 2.0 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 30 ml of methylene chloride, under nitrogen, while cooling to 0° C. is added dropwise 30 ml of triethylamine followed by a solution of 4'-(propyl) [1,1'-biphenyl]-4-carbonyl chloride in 10 ml of methylene dichloride. The reactants are stirred at room temperature for 16 hours. The reaction mixture is poured in ice water and extracted with methylene chloride (3×50 ml) The organic layer is, washed with water, 2N citric acid, saturated aqueous NaHCO3, water and dried(MgSO4) and evaporated in vacuo to give a residue which is purified by column chromatography on silica gel with ethyl acetate-hexane to give 1.4 g of the desired product as a crystalline solid, m.p. 118°-120° C. MS(M+H=407.3; M+Na=429.3)
Reaction SMILES: [NH2:1][C@@H:2]([C@@H:38]([C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[C:47]([Cl:53])[CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:3]([NH:5][C:6]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:7]=1[CH2:8][CH2:9][C@H:10]1[O:15][CH2:14][C@@H:13]([CH2:16][O:17][C:18](=[O:25])[NH:19][CH2:20][C:21]([F:24])([F:23])[F:22])[N:12]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:11]1)=[O:4].C(N(CC)CC)C.Cl[C:62]([O:64][CH3:65])=[O:63]>ClCCl>[Cl:53][C:47]1[CH:46]=[C:45]([C@@H:38]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C@H:2]([NH:1][C:62]([O:64][CH3:65])=[O:63])[C:3]([NH:5][C:6]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:7]=2[CH2:8][CH2:9][C@H:10]2[O:15][CH2:14][C@@H:13]([CH2:16][O:17][C:18](=[O:25])[NH:19][CH2:20][C:21]([F:24])([F:23])[F:22])[N:12]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH2:11]2)=[O:4])[CH:50]=[CH:49][C:48]=1[O:51][CH3:52]
Reactant: COc1ccc([C@@H](c2ccccc2)[C@H](N)C(=O)Nc2cccc(F)c2CC[C@@H]2CN(C(=O)OC(C)(C)C)[C@H](COC(=O)NCC(F)(F)F)CO2)cc1Cl
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N[C@H](C(=O)Nc1cccc(F)c1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](COC(=O)NCC(F)(F)F)CO1)[C@H](c1ccccc1)c1ccc(OC)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of the product from step 3 (80 mg, 0.1 mmol) in dichloromethane (2 mL) was added triethylamine (0.02 mL, 0.16 mmol) and methyl chloroformate (0.01 mL, 0.12 mmol). The mixture was stirred at ambient temperature for 6 h, then diluted with dichloromethane (10 mL) and washed with aqueous NaHCO3 and brine. The organic phase was dried (MgSO4), filtered, and the solvents were removed in vacuo. The residue was chromatographed on a 12 g SiO2 column using a gradient elution of 0-100% EtOc in hexanes. Fractions containing product were combined and the solvents were removed in vacuo to give the title compound as a gum. (M+H)+=825.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.ClC(OC)=O.[N:32]1([CH2:37][C:38]2[CH:39]=[C:40]([CH:42]=[CH:43][CH:44]=2)[NH2:41])[CH:36]=[CH:35][N:34]=[CH:33]1>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:41][C:40]3[CH:42]=[CH:43][CH:44]=[C:38]([CH2:37][N:32]4[CH:36]=[CH:35][N:34]=[CH:33]4)[CH:39]=3)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Reactant: Nc1cccc(Cn2ccnc2)c1
Agent: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2cccc(Cn3ccnc3)c2)ncn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) solution of 6-(cyclopropylmethyl(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 112 mg; 0.45 mmol) in DCM was treated with diisopropylethylamine (78.4 mL; 0.52 mmol) and methyl chloroformate (36.2 mL; 0.47 mmol). After stirring at 0° C. for 15 minutes, 3-(1H-imidazol-1-ylmethyl)aniline (Maybridge, 117 mg; 0.67 mmol) was added and the mixture stirred for 72 hours. The solvent was evaporated and the compound purified by preparative HPLC to give the title compound as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[CH3:28])[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)[CH3:13])[CH2:9]1)=O)(C)(C)C.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]>C(Cl)Cl>[F:34][C:33]([F:36])([F:35])[C:31]([OH:37])=[O:32].[NH:8]1[CH2:9][CH:10]([N:12]([CH3:13])[C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[CH3:28])[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)[CH2:11]1
Reactant: Cc1cc2c(cc1N(C)C1CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)C1C)CO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1N(C)C1CNC1)N1C(=NNC(=O)C1C)CO2
Yield: 56 %

Procedure:
A solution of 3-[(4,7-dimethyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-methyl-amino]-azetidine-1-carboxylic acid tert-butyl ester (0.018 g, 0.043 mmol) in TFA (0.5 mL) and DCM (3 mL) was stirred at 25° C. for 2 h. The solvent was removed in vacuo to give 6-(azetidin-3-yl-methyl-amino)-4,7-dimethyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid (0.010 g, 56%). LC/MS (Table 1, Method 5) Rt=1.994 min.; MS m/z: 316 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]2[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=2)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N:4][CH:5]=[CH:6][CH:7]=1.[OH:21]O>ClCCl.C[Re](=O)(=O)=O>[C:14]([O:13][C:11]([C:10]1[CH:9]=[C:8]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N+:4]=2[O-:21])[CH:20]=[CH:19][CH:18]=1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: OO
Reactant: Cc1cccnc1-c1cccc(C(=O)OC(C)(C)C)c1
Agent: C[Re](=O)(=O)=O
Solvent: ClCCl
Product: Cc1ccc[n+]([O-])c1-c1cccc(C(=O)OC(C)(C)C)c1
Reaction time: 16 h
Yield: 57 %

Procedure:
tert-Butyl 3-(3-methylpyridin-2-yl)benzoate (49.6 g, 184 mmol) was dissolved in a mixture of 75 mL of dichloromethane and 40 mL of 30% hydrogen peroxide. Methyltrioxorhenium (VII) (2.35 g, 9.44 mmol) was added and the reaction mixture was stirred vigorously for 16 hours. The layers were then separated and the organic layer was treated with sodium sulfite and then dried over sodium sulfate. The crude product was then poured onto a pad of silica gel and washed with ethyl acetate. The product was then eluted from the silica gel pad with a mixture of 10% (v/v) methanol in ethyl acetate to yield 2-(3-(tert-butoxycarbonyl)phenyl)-3-methylpyridine 1-oxide (29.8 g, 57%) as a white solid. ESI-MS m/z calc. 285.1. found 286.1 (M+1)+. Retention time 1.22 minutes.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH3:6][O:7][C:8]1[CH:38]=[CH:37][CH:36]=[CH:35][C:9]=1[CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH3:31])=[CH:24][CH:23]=3)=[CH:21][C:16]=2[CH:15]=[C:14]([C:32]([OH:34])=O)[CH2:13][CH2:12]1.S(Cl)(Cl)=O>O1CCCC1>[CH3:6][O:7][C:8]1[CH:38]=[CH:37][CH:36]=[CH:35][C:9]=1[CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][CH3:31])=[CH:26][CH:27]=3)=[CH:21][C:16]=2[CH:15]=[C:14]([C:32]([NH:11][C:17]2[CH:18]=[CH:19][C:20]([CH2:4][N:2]([CH3:1])[CH:3]3[CH2:30][CH2:29][O:28][CH2:25][CH2:24]3)=[CH:21][CH:16]=2)=[O:34])[CH2:13][CH2:12]1
Reactant: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccccc2OC)cc1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2ccccc2OC)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 1-(2-methoxybenzyl)-7-(4-propoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (340 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (267 mg) was added thereto at 0° C., the temperature was returned to room temperature, and the mixture was stirred for 1 hour under nitrogen atmosphere. The solvent and excess thionyl chloride were evaporated under reduced pressure, and the resulting residue was suspended in tetrahydrofuran (30 ml), which was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (197 mg) and triethylamine (906 mg) in tetrahydrofuran (10 ml) at 0° C. The mixture was stirred at room temperature for 1 hour under nitrogen atmosphere, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8), which was recrystallized from hexane-ethyl acetate to give 1-(2-methoxybenzyl)-N-[4-[[N-methyl N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-(4-propoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxamide (337 mg) as yellow crystals.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9]C)[C:4]=1[CH2:11][CH2:12][CH3:13].Br.[C:15](O)(=[O:17])[CH3:16]>O>[CH2:11]([C:4]1[C:5]([OH:9])=[C:6]([C:15](=[O:17])[CH3:16])[CH:7]=[CH:8][C:3]=1[OH:2])[CH2:12][CH3:13]
Reactant: CCCc1c(OC)cccc1OC
Reactant: CC(=O)O
Agent: Br
Solvent: O
Product: CCCc1c(O)ccc(C(C)=O)c1O
Temperature: 25 °C
Yield: 41 %

Procedure:
1,3-Dimethoxy-2-(n-propyl)benzene (0.90 g, 5.0 mmol), 48% aqueous hydrobromic acid (30 ml, 265 mmol), and glacial acetic acid (150 ml) were combined and stirred at reflux temperature for 72 hours. The reaction mixture was cooled to room temperature then added to water (250 ml). The aqueous mixture was extracted with ether (500 ml, 2×). The organic phases were combined, washed with brine (100 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was flash chromatographed over Kieselgel 60 (230-400 mesh, 4 cm diameter×16 cm length) eluted with 1% ethyl acetate in hexane, followed by a step gradient (2%, 3%, 4%) of ethyl acetate in hexane to give 0.4 g, 41% of the title product.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([C:5]([F:8])([F:7])[F:6])=[O:4].[CH3:11][C:12]([CH3:25])([CH3:24])[CH2:13][CH2:14][NH:15][C@H:16]([C:21](O)=[O:22])[CH2:17][C:18]([OH:20])=[O:19]>O1CCOCC1>[CH3:11][C:12]([CH3:25])([CH3:24])[CH2:13][CH2:14][N:15]1[C@@H:16]([CH2:17][C:18]([OH:20])=[O:19])[C:21](=[O:22])[O:4][C:3]1([C:5]([F:8])([F:7])[F:6])[C:2]([F:10])([F:9])[F:1]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)CCN[C@@H](CC(=O)O)C(=O)O
Solvent: C1COCCO1
Product: CC(C)(C)CCN1[C@@H](CC(=O)O)C(=O)OC1(C(F)(F)F)C(F)(F)F

Procedure:
A gas flow of hexafluoroacetone is blown at a moderate rate at room temperature onto an intensely stirred suspension of 10 mmol of N-(3,3-dimethylbutyl)-L-aspartic acid in 20 ml 1,4-dioxane. A clear solution is formed overnight. The solvent was removed in vacuo, and the oily residue was confirmed to be an almost quantitative amount of 2-[(4S)-3-(3,3-dimethylbutyl)-5-oxo-2,2-bis(trifluoromethyl)-1,3-oxazolan-4-yl]acetic acid by NMR.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[CH2:13](Br)[C:14]#[CH:15]>CC(C)=O>[N:7]1([CH2:15][C:14]#[CH:13])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: C1COCCN1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C#CCN1CCOCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of cesium carbonate (1.6 g) and morpholine (0.437 ml) in acetone (10 ml) was added propargyl bromide (557 μl of 80% wt. in toluene) dropwise. The mixture was stirred at room temperature for 18 hours. The insoluble material was removed by filtration and the filtrate concentrated. The residue dissolved in ethyl acetate, washed with saturated NaHCO3 solution, dried (magnesium sulfate) and concentrated to yield 3-(4-morpholinyl)-1-propyne as a brown oil (494 mg); NMR Spectrum: (DMSOd6) 2.19 (t, 1H), 2.50 (m, 4H), 3.22 (d, 2H), 3.67 m, 4H).
Reaction SMILES: [C:1](/[C:3](=[C:9](/[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)\SC)/[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C(N(CC)C(C)C)(C)C.Cl.[CH:32]([NH2:34])=[NH:33]>C(O)C>[NH2:34]/[CH:32]=[N:33]/[C:9](/[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[C:3](\[C:1]#[N:2])/[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: N=CN
Reactant: CCOC(=O)/C(C#N)=C(\NCc1ccc(OC)cc1)SC
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C(C#N)=C(/N=C/N)NCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 25 %

Procedure:
(E)-Ethyl 2-cyano-3-((4-methoxybenzyl)amino)-3-(methylthio)acrylate was dissolved in 65 mL ethanol. N,N-Diisopropylethylamine (13 mL, 74.44 mmol) and formamidine hydrochloride (2.12 g, 26.33 mmol) were added and the reaction mixture was stirred at room temperature for 48 h. The solvent was concentrated and the residue was directly purified using SP1® Purification System (0% to 10%, dichloromethane-methanol) to give 0.96 g (25% yield) of the title compound as a yellow oil. Purity 85%.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[O:7])=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[CH2:45]([O:47][C:48](=[O:52])[CH2:49][NH:50][CH3:51])[CH3:46]>C(N(CC)CC)C.C1COCC1>[CH2:45]([O:47][C:48](=[O:52])[CH2:49][N:50]([C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=1[C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:18][CH:17]=1)[CH3:51])[CH3:46]
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(F)cc1
Reactant: CCOC(=O)CNC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(C)C(=O)c1ccccc1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(4-fluorobenzoyl)benzoic acid (3.00 g), 1-hydroxybenzotriazole (2.07 g), 1,3-dicyclohexylcarbodiimide (3.00 g) and anhydrous THF (50 ml) was stirred at room temperature for 1 hour. To this mixture were added N-methylglycine ethyl ester hydrochloride (2.84 g) and triethylamine (2.58 ml), followed by stirring at room temperature for 16 hours and with heating and refluxing for 4 hours. After the solvent was distilled off, ethyl acetate was added to the residue, and the insoluble crystals were separated by filtration. The filtrate was washed successively with water, aqueous sodium hydrogen carbonate, water, dilute hydrochloric acid and water and then dried, after which the solvent was distilled off, to yield N-[2-(4-fluorobenzoyl)benzoyl]-N-methylglycine ethyl ester as a colorless oily substance (4.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[C:21]3[C:16](=[C:17]([CH2:23][S:24][CH3:25])[C:18]([F:22])=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:9][CH2:10][C:11]#[N:12])=[CH:4][CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:37])C=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:13]2[C:21]3[C:16](=[C:17]([CH2:23][S:24]([CH3:25])=[O:37])[C:18]([F:22])=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:9][CH2:10][C:11]#[N:12])=[CH:6][CH:7]=1
Reactant: CSCc1c(F)ccc2c(C(CCC#N)c3ccc(Cl)cc3)c[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: CS(=O)Cc1c(F)ccc2c(C(CCC#N)c3ccc(Cl)cc3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
300 mg (0.80 mmol) of the compound from Example 50 were introduced into 55 ml of dichloromethane at 0° C., 198 mg (0.80 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 2 h. 2 ml of methanol were added, and the mixture was extracted with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The phases were separated, and the solvents were removed from the organic phase in vacuo. The crude product was purified initially by preparative HPLC (mobile phase: acetonitrile/water gradient) and then by flash chromatography of the resulting, slightly impure product on silica gel (mobile phase: ethyl acetate). 197 mg (63% of theory) of the title compound were obtained as mixture of diastereomers.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:15][CH:10]([O:11]C(=O)C)[C@H:9]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:8]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:7]1[Cl:34])(=[O:3])[CH3:2].C(O)(=O)C.NN>CN(C=O)C>[C:1]([O:4][CH2:5][C@H:6]1[O:15][CH:10]([OH:11])[C@H:9]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:8]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:7]1[Cl:34])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1Cl
Agent: NN
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1OC(O)[C@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1Cl
Yield: 95.3 %

Procedure:
A solution of acetyl 6-O-acetyl-2,3-di-O-benzoyl-4-chloro-4-deoxy-D-galactopyranoside (68) (8.53 g, 17.4 mmol) and hydrazine acetate (2.4 g, 26.0 mmol, 1.5 eq) in 70 mL of DMF was stirred for 1 hour at room temperature. The reaction mixture was then evaporated, washed with water (5 times) and evaporated. The residue was chromatographed on a silica gel, eluting with hexane-ethyl acetate (2:1), to provide 6-O-acetyl-2,3-di-O-benzoyl-4-chloro-4-deoxy-D-galactopyranose (7.44 g, 95.3%). This material was dissolved in dichloromethane (50 mL) and the resulting solution was cooled to 0° C. Trichloroacetonitrile (8.3 mL, 82.9 mmol) was added and the mixture was stirred for 2 hours. The solvent was then evaporated and the residue was chromatographed on a silica gel column, eluting with hexane-ethyl acetate (3:1), to give imidate 69 (6.3 g, 64%).
Reaction SMILES: [CH2:1]([C@@H:8]1[C@@H:16]([O:17][CH2:18][CH2:19][CH2:20][OH:21])[C@H:15]([CH3:22])[O:14][C:13](=[O:23])[C@@H:12]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:11][O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32]N(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.F[B-](F)(F)F.C[O+](C)C>C(Cl)Cl>[CH2:1]([C@@H:8]1[C@@H:16]([O:17][CH2:18][CH2:19][CH2:20][O:21][CH3:32])[C@H:15]([CH3:22])[O:14][C:13](=[O:23])[C@@H:12]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:11][O:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Reactant: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC[C@H](Cc2ccccc2)[C@H]1OCCCO
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COCCCO[C@@H]1[C@@H](Cc2ccccc2)COC[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
To a solution of tert-butyl ((3S,7S,8R,9S)-7-benzyl-8-(3-hydroxypropoxy)-9-methyl-2-oxo-1,5-dioxonan-3-yl)carbamate (118 mg, 0.270 mmol, 1.00 equiv) in CH2Cl2 (2.7 mL, 0.1 M) were added Proton Sponge™ (87 mg, 0.41 mmol, 1.5 equiv) and trimethyloxonium tetrafluoroborate (44 mg, 0.30 mmol, 1.1 equiv). A white precipitate quickly formed. The resulting mixture was stirred at room temperature for 16 h, quenched with 1 N HCl (2 mL), diluted with H2O (20 mL), and extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to provide a white solid. Purification by automated silica gel column chromatography (4-30% acetone in hexanes) provided tert-butyl ((3S,7S,8R,9S)-7-benzyl-8-(3-methoxypropoxy)-9-methyl-2-oxo-1,5-dioxonan-3-yl)carbamate (118 mg, 72%) as a colorless oil: IR (ATR) 3347, 2978, 2928, 2875, 1750, 1710, 1496, 1354, 1367, 1385, 1327, 1163, 1088, 910, 855, 731 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.28 (dd, J=8.6, 6.9 Hz, 2H), 7.24-7.14 (m, 3H), 5.13 (d, J=8.1 Hz, 1H), 4.94 (dq, J=9.3, 6.4 Hz, 1H), 4.60 (dd, J=14.9, 7.3 Hz, 1H), 3.88 (dd, J=11.5, 7.3 Hz, 1H), 3.76 (dt, J=12.7, 6.3 Hz, 1H), 3.63 (dt, J=8.7, 6.3 Hz, 1H), 3.53-3.42 (m, 3H), 3.41-3.33 (m, 1H), 3.30 (s, 4H), 3.28-3.22 (m, 1H), 3.18-3.05 (m, 2H), 2.29 (t, J=12.7