Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[Cl:13][C:14]1[CH:40]=[CH:39][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[C:20]2[C:28]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]([OH:38])=O)[CH2:32][CH2:31]2)=[O:29])=[CH:16][CH:15]=1.N1(O)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[CH3:60][N:61]1[CH:65]=[C:64]([CH2:66][NH2:67])[N:63]=[CH:62]1>C(Cl)Cl.O.C(OCC)(=O)C>[Cl:13][C:14]1[CH:40]=[CH:39][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[C:20]2[C:28]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]([NH:67][CH2:66][C:64]3[N:63]=[CH:62][N:61]([CH3:60])[CH:65]=3)=[O:38])[CH2:32][CH2:31]2)=[O:29])=[CH:16][CH:15]=1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Reactant: Cn1cnc(CN)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: Cn1cnc(CNC(=O)C2CCN(C(=O)c3cc4ccccc4n3Cc3ccc(Cl)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (259 mg, 1.350 mmol), 1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (428 mg, 1.080 mmol), and 1H-benzo[d][1,2,3]triazol-1-ol (182 mg, 1.350 mmol) were dissolved in 4.0 mL of DCM. The reaction was stirred at room temperature for ten minutes before Hunig's Base (0.236 ml, 1.350 mmol) and (1-methyl-1H-imidazol-4-yl)methanamine (100 mg, 0.900 mmol) as a 1.0 mL DCM solution was added. The reaction was allowed to stir at room temperature overnight. The reaction was diluted with water and ethyl acetate. The organic phase was washed with water, saturated sodium bicarbonate (twice), and saturated sodium chloride. The organic phase was dried over magnesium sulfate, filtered and concentrated. The crude material was triturated with ether and ethyl acetate and filtered to obtain white solid as a product. 1H-NMR (400 MHz, DMSO-d6) 8.07, 7.62, 7.53, 7.46, 7.34, 7.21, 7.14-7.08, 6.87, 6.72, 5.49, 4.40, 4.09, 3.93, 3.59, 2.91, 2.47-2.37, 1.68, 1.43
Reaction SMILES: [CH3:1][N:2]([CH3:44])[CH2:3][CH2:4][NH:5][C:6]([NH:35][C:36]1[C:41]([CH3:42])=[CH:40][CH:39]=[CH:38][C:37]=1[CH3:43])=[N:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH2:21][CH:22]3[CH2:27][O:26][CH2:25][CH2:24][N:23]3CC3C=CC=CC=3)=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[CH:10][N:9]=1.FC(F)(F)C(O)=O.C(O)C.[H][H]>[Pd].C(Cl)Cl>[CH3:44][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:6]([NH:35][C:36]1[C:37]([CH3:43])=[CH:38][CH:39]=[CH:40][C:41]=1[CH3:42])=[N:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH2:21][CH:22]3[CH2:27][O:26][CH2:25][CH2:24][NH:23]3)=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[CH:10][N:9]=1
Reactant: COc1cc2c(N=C(NCCN(C)C)Nc3c(C)cccc3C)ncnc2cc1OCC1COCCN1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(N=C(NCCN(C)C)Nc3c(C)cccc3C)ncnc2cc1OCC1COCCN1
Yield: 81.3 %

Procedure:
A mixture of N-(2-dimethylaminoethyl)-N′-(2,6-dimethylphenyl)-N″-[7-(N-benzylmorpholin-3-ylmethoxy)-6-methoxyquinazolin-4-yl]guanidine (0.1 g), trifluoroacetic acid (0.091 ml), 10% palladium on carbon catalyst (0.03 g) and ethanol (12 ml) was stirred under an atmosphere pressure of hydrogen for 18 hours. The reaction was filtered and the filtrate was evaporated. The resulting gum was triturated under diethyl ether to give a solid which was dissolved in methylene chloride. The solution was washed with cooled 1N aqueous sodium hydroxide solution and with water. The organic solution was dried over magnesium sulphate and evaporated. There was thus obtained the title compound (0.069 g): NMR Spectrum: (CDCl3) 2.1 (s, 6H), 2.26 (s, 6H), 2.39 (m, 2H), 2.9 (m, 2H), 3.36 (m, 2H), 3.55 (m, 3H), 3.78 (d, 2H), 3.80–4.08 (m, 5H), 4.79 (s, 1H), 7.1 (s, 4H), 7.85 (s, 1H), 8.47 (s, 1H), 12.5 (s, 1H); Mass Spectrum: M+H+ 508.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].CS[C:7](SC)=[CH:8][N+:9]([O-:11])=[O:10]>C1(C)C=CC=CC=1>[OH:4][CH2:3][CH2:2][NH:1][C:7]([NH:1][CH2:2][CH2:3][OH:4])=[CH:8][N+:9]([O-:11])=[O:10]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCO
Solvent: Cc1ccccc1
Product: O=[N+]([O-])C=C(NCCO)NCCO
Temperature: 25 °C
Yield: 98.2 %

Procedure:
78 ml of 2-aminoethanol (1.3 moles) were added slowly over half an hour to a solution of 95 g of 1,1-bis(methylthio)-2-nitroethene (0.57 mole) in 500 ml of toluene at 80° C. After the addition, the mixture was held at 80° C. for half an hour, was cooled to room temperature and the solid formed was filtered off, washed with chloroform (2×100 ml portions) and was dried to give 107 g N,N'-bis(2-hydroxyethyl)-2-nitro-1,1-ethenediamine (97-98% yield) in yellowish crystal form. m.p. 145°-146° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:27])[CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[S:9][CH:10]=1)C.S(=O)(=O)(O)O>CO>[CH3:1][O:3][C:4](=[O:28])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:27])[CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)[S:9][CH:10]=1
Reactant: CCOC(=O)Cc1csc(NC(=O)C(CC2CCCC2)c2cccc(Cl)c2)n1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)Cc1csc(NC(=O)C(CC2CCCC2)c2cccc(Cl)c2)n1
Yield: 61.1 %

Procedure:
A solution of {2-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-acetic acid ethyl ester (prepared as in Example 28A, 177.2 mg, 0.42 mmol) in methanol (15 mL) was treated with a catalytic amount of sulfuric acid. The reaction mixture was heated under reflux for 40 h. The reaction was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 70/30 hexanes/ethyl acetate) afforded {2-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-acetic acid methyl ester (104.4 mg, 60.9%) as a clear oil: EI-HRMS m/e calcd for C20H23ClN2O3S (M+) 406.1117, found 406.1118.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:25][CH:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1)[C:11]1[CH:12]=[C:13]([C:18]#[C:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[CH:14]=[CH:15][C:16]=1[F:17].C([O-])(=O)C([O-])=O.[CH3:39][CH:40]1[CH2:44][CH2:43][C:42](=O)[C:41]1=[O:46]>C(O)C.O.[OH-].[Na+]>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:25][CH:26]1[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]1)[C:11]1[CH:12]=[C:13]([C:18]#[C:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]=[C:42]2[C:41]([OH:46])=[C:40]([CH3:39])[CH2:44][CH2:43]2)[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: CN1CCC(OC(c2nc3ccccc3[nH]2)c2cc(C#CCCCCN)ccc2F)CC1
Reactant: CC1CCC(=O)C1=O
Agent: O=C([O-])C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1=C(O)C(=NCCCCC#Cc2ccc(F)c(C(OC3CCN(C)CC3)c3nc4ccccc4[nH]3)c2)CC1

Procedure:
A mixture of 6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylamine, oxalate (example 557, 50 mg), 3-methyl-1,2-cyclopentanedione (11.8 mg) in ethanol (2 mL) is refluxed for 2 h. The mixture is then cooled, diluted with water and 1N sodium hydroxide and extracted with ethyl acetate. Pooled extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane/methanol/ammonia from 100/0/0.5 to 95/5/0.5) to afford 5-(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylimino)-2-methylcyclopent-1-enol. TLC (Eluent: CH2Cl2/MeOH/NH4OH 95/5/0.5) Rf=0.30.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:4][N:3]=1.Br[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][C:2]1[N:3]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:4]=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: BrCCc1ccccc1
Reactant: COC(=O)c1c[nH]nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cnn(CCc2ccccc2)c1C
Temperature: 20 °C
Reaction time: 12 h
Yield: 36.2 %

Procedure:
To a solution of methyl 3-methyl-1H-pyrazole-4-carboxylate (280 mg, 2 mmol) in N,N-dimethylformamide (30 mL) was added (bromoethyl)benzene (0.37 g, 2 mmol) and potassium carbonate (0.55 g, 4 mmol). The mixture was stirred at 20° C. for 12 hours. The solvent was evaporated in vacuo and the residue was purified by CXTH (Column: Dsisol, 10 μM, C18, 250 mm*50 mm; Mobile: acetonitrile (0.1% formic acid)—water (0.1% formic acid), acetonitrile from 30% to 70% in 80 minutes; oven: 20° C.; flow rate: 50 mL/minute, wavelength: 214 nm) to give crude methyl 5-methyl-1-phenethyl-1H-pyrazole-4-carboxylate (177 mg, 36%). The product was used for the next step directly. LRMS (M+H+) m/z: calcd. 244.12. found 244.
Reaction SMILES: C(OCC)(=O)C(C)C.O.NN.C(S[C:15]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)=[N:16][C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:24])C.[C:32]([NH:37][NH2:38])(=O)[CH:33]([CH3:35])[CH3:34]>C(O)CCC>[CH3:23][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:24])[C:17]=1[N:16]1[C:32]([CH:33]([CH3:35])[CH3:34])=[N:37][N:38]=[C:15]1[C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1
Reactant: CCSC(=Nc1c(C)cccc1C)c1ccc(F)cc1
Reactant: CC(C)C(=O)NN
Agent: CCOC(=O)C(C)C
Agent: NN
Solvent: CCCCO
Solvent: O
Product: Cc1cccc(C)c1-n1c(-c2ccc(F)cc2)nnc1C(C)C
Temperature: 80 °C
Reaction time: 5 h
Yield: 11 %

Procedure:
First, 2.40 g of ethyl isobutyrate, 10 mL of 1-butanol, and 1.05 g of hydrazine monohydrate (NH2NH2.H2O) were put in a 100 nil, three-neck flask, and heated and stirred at 80° C. for 5 hours to be reacted. Then, 5.0 g of N-[(ethylsulfanyl)(4-fluorophenyl)methylidene]-2,6-dimethylaniline was added to this mixed solution, and heated and stirred at 130° C. for 22 hours to be reacted. Further, 0.96 g of isobutyric acid hydrazide was added to this mixed solution, and heated and stirred at 130° C. for 15 hours to be reacted. After the reaction, 1-butanol was distilled off under a reduced pressure. The resulting residue was purified by silica gel column chromatography. Ethyl acetate was used as a developing solvent. The resulting fraction was concentrated to give a solid. This solid was recrystallized from a mixed solvent of toluene and hexane, so that 4-(2,6-dimethyl-phenyl)-3-(4-fluorophenyl)-5-isopropyl-4H-1,2,4-triazole (abbreviation: HiPrFptz-dmp) was prepared (a white solid, yield: 11%). The synthetic scheme of Step 1 is shown by (a-11).
Reaction SMILES: [ClH:1].Cl.[CH3:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1N.[C:12]([NH:14][C:15]([NH2:17])=[NH:16])#[N:13].[OH-].[Na+]>O>[ClH:1].[ClH:1].[NH:14]([C:12]1[N:4]([CH3:3])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:13]=1)[C:15]([NH2:17])=[NH:16]
Reactant: CNc1ccccc1N
Reactant: N#CNC(=N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1c(NC(=N)N)nc2ccccc21
Yield: 42 %

Procedure:
A mixture of N-methyl-o-phenylenediamine dihydrochloride (10.80g. 0.005 mol) and cyanoguanidine (9.30g, 0.11 mol) was heated under reflux in water (80 ml) for 21/2 hours. The reaction mixture was cooled, basified with excess 40% sodium hydroxide, and the resulting precipitate filtered, washed with water and dried in vacuo. (7.19g; m.p. 142°-146°C). This was dissolved in excess dilute hydrochloric acid and evaporated in vacuo. The crude hydrochloride was recrystallised from ethanol/ether to yield 2-guanidino-1-methylbenzimidazole dihydrochloride (600g; 42%) as off-white micro-crystals m.p. 228°-238°C.
Reaction SMILES: [H-].[Na+].O1CCOCC1.[Br:9][C:10]1[C:11]([NH2:16])=[N:12][CH:13]=[CH:14][CH:15]=1.[N:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[C:18]=[S:19]>[Cl-].[NH4+]>[Br:9][C:10]1[C:11]([NH:16][C:18]([NH:17][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[S:19])=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: COc1ccc(N=C=S)cc1
Reactant: Nc1ncccc1Br
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: COc1ccc(NC(=S)Nc2ncccc2Br)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a suspension of sodium hydride, 60% disp. in mineral oil (3:2, sodium hydride: mineral oil, 1.0 g, 25 mmol) in 1,4-dioxane (50 mL, 600 mmol) was added 3-bromo-pyridin-2-ylamine (2.68 g, 15.5 mmol). The mixture was stirred for 5 minutes at room temperature under an atmosphere of nitrogen. 1-Isothiocyanato-4-methoxy-benzene (2.35 mL, 17.0 mmol) was slowly added to the suspension. Slow gas evolution was noted and the suspension slowly thickened to a slurry. The mixture was stirred at room temperature for 18 hours and the volatiles were evaporated to a yield a tan solid. To the solid was added saturated aqueous ammonium chloride solution (100 mL). Gas evolution and exotherm noted. The mixture was stirred for 30 minutes and the waxy solid was filtered. The solid was triturated with ether (50 mL), filtered and rinsed with ether. 1-(3-Bromo-pyridin-2-yl)-3-(4-methoxy-phenyl)-thiourea was isolated as a yellow solid (4.96 g, 95%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 12.85 (s, 1H), 8.75 (s, 1H), 8.38 (dd, J=4.8, 1.2 HZ, 1H), 8.24 (dd, J=7.9, 1.3 Hz, 1H), 7.56-7.50 (m, 2H), 7.15 (dd, J=7.9, 4.9 Hz, 1H), 7.00-6.95 (m, 2H), 3.77 (s, 3H). MS=338, 340 (MH)+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH2:20][C:21]1[N:25](C(OC(C)(C)C)=O)[N:24]=[C:23]([CH2:33][CH2:34][C:35]2[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[C:37]([O:43][CH3:44])[CH:36]=2)[CH:22]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:11]=[CH:12][C:13]([C:14]([NH:20][C:21]3[CH:22]=[C:23]([CH2:33][CH2:34][C:35]4[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[C:37]([O:43][CH3:44])[CH:36]=4)[NH:24][N:25]=3)=[O:16])=[CH:18][CH:19]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(N2CCN(C(C)=O)CC2)cc1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCN(C(C)=O)CC4)cc3)n[nH]2)cc(OC)c1
Yield: 0.9 %

Procedure:
4-(4-acetylpiperazin-1-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide was prepared as for Example 94, but starting from methyl 4-(4-acetylpiperazin-1-yl)benzoate (221 mg, 0.84 mmol), tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (244 mg, 0.7 mmol) and 1M NaHMDS (1.13 ml, 1.13 mmol) in THF (5 ml). The crude product was purified by reverse phase prep. HPLC (basic) using a 31-51% gradient of acetonitrile in water, containing 1% 0.880 ammonia. The clean fractions were taken and evaporated to afford the title compound as a white solid (3 mg, 1.0%); 1H NMR (399.9 MHz, DMSO-d6) δ 2.06 (3H, s), 2.78 (4H, s), 3.28 (2H, s) 3.25 (2H, t), 3.49-3.56 (4H, m), 3.73 (6H, s), 6.33 (1H, t), 6.42 (2H, d), 6.45 (1H, s), 6.99 (2H, d), 7.92 (2H, d), 10.32 (1H, s), 12.08 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[C:15]([O:22][CH3:23])[C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)[N:11]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[C:19]3[C:14](=[C:15]([O:22][CH3:23])[C:16]([O:20][CH3:21])=[CH:17][CH:18]=3)[CH:13]=[C:12]([NH:24][C:25]3[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1OC
Reactant: Oc1ccc(F)cc1
Product: COc1ccc2c(Oc3ccc(F)cc3)nc(Nc3cc(C)[nH]n3)cc2c1OC

Procedure:
Similar procedure as described in example 10 was used, starting from 4-fluoro-phenol and (1-chloro-5,6-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(4-fluoro-phenoxy)-5,6-dimethoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 395(MH+).
Reaction SMILES: [CH:1]([CH:4]1[O:9][CH2:8][CH:7]([CH2:10]O)[CH2:6][O:5]1)([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:32]>>[CH:1]([CH:4]1[O:9][CH2:8][CH:7]([CH2:10][Cl:32])[CH2:6][O:5]1)([CH3:3])[CH3:2]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(C)C1OCC(CO)CO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)C1OCC(CCl)CO1
Temperature: 70 °C

Procedure:
A solution of 217 g 2-isopropyl-5-hydroxymethyl-1,3-dioxane in 11 of carbon tetrachloride is added dropwise to a solution of 356 g triphenylphosphine in 1 l of carbon tetrachloride, heated to 70° C. The mixture is refluxed and after approx. 1 hour cooled down (ice-bath), filtrated and evaporated. The residue is repeatedly treated with diethylether and filtered. After evaporating the filtrate the residue is purified by distillation. The desired 2-isopropyl-5-chloromethyl-1,3-dioxane is obtained as a colorless liquid; b.p. 84°-94° C. mm Hg; cis-trans mixture; identification by NMR.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=1)[CH3:2].[CH2:10](N(CC)CC)C.C([Li])CCC.CI>CCCCCC.O1CCCC1>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[N:4]=1)[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCc1cccc(C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CI
Product: CCc1cccc(CC)n1
Temperature: -40 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
In a 250-ml 3-neck jacketed reactor flask, 4.3 g (40.2 mmol) of 2,6-dimethylpyridine and 4.06 g (40.2 mmol) of triethylamine were dissolved by addition of 50 ml of anhydrous tetrahydrofuran, and the solution was cooled to −40° C., after which 28.7 ml (46 mmol) of 1.6 M butyllithium in hexane was added dropwise thereto. At the same time, the solution changed to deep red. Next, the solution was stirred for 1 hour, and then warmed to 0° C., after which 5.7 g (40.2 mmol) of methyl iodide was added dropwise thereto, followed by stirring for 1 hour. Then, the reaction product was concentrated, and the concentrate was dissolved in ethyl acetate, washed with water and saline, dried with anhydrous magnesium sulfate, and then concentrated again, thereby obtaining crude 2-ethyl-6-methylpyridine. Subsequently, 3.2 g of the obtained 2-ethyl-6-methylpyridine was placed in a 250-ml 3-neck jacketed reactor flask and dissolved by addition of 4.06 g (40.2 mmol) of triethylamine and 50 ml of anhydrous tetrahydrofuran. The solution was cooled to −40° C., and 28.7 ml (46 mmol) of 1.6 M n-butyllithium in hexane was added dropwise. At this time, the solution changed to deep red. Next, the solution was stirred for 1 hour, and then cooled to 0° C., after which 6.0 g (42 mmol) of methyl iodide was added thereto dropwise. Then, the cooling bath was removed, and the solution was stirred at room temperature for 1 hour, and then concentrated. The concentrate was dissolved in ethyl acetate, washed with water and saline, dried with anhydrous magnesium sulfate, and then concentrated again. The concentrate was purified by column chromatography (stationary phase:silica gel; eluent:n-hexane/ethyl acetate (6/1), thereby obtaining 2 g of 2,6-diethyl pyridine as liquid. The obtained 2,6-diethyl pyridine was analyzed by NMR.
Reaction SMILES: C([O:8][C:9]1[C:10]([CH3:42])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C:14]([CH2:22][N:23]([CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]=[C:35]3[S:39][C:38](=[O:40])[NH:37][C:36]3=[O:41])=[CH:30][CH:29]=1)[CH3:24])([CH3:21])[CH2:13][CH2:12]2)C1C=CC=CC=1.Cl>C(O)(=O)C>[OH:8][C:9]1[C:10]([CH3:42])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C:14]([CH2:22][N:23]([CH2:25][CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([CH:34]=[C:35]3[S:39][C:38](=[O:40])[NH:37][C:36]3=[O:41])=[CH:32][CH:33]=1)[CH3:24])([CH3:21])[CH2:13][CH2:12]2
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(CN(C)CCOc1ccc(C=C3SC(=O)NC3=O)cc1)O2
Agent: Cl
Solvent: CC(=O)O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CN(C)CCOc1ccc(C=C3SC(=O)NC3=O)cc1)O2
Temperature: 60 °C
Yield: 92.6 %

Procedure:
To a solution of 12.5 g of the product obtained in example 1, in 120 ml of acetic acid was added 40 ml of concentrated hydrochloric acid. The resulting mixture was heated at 60° C. for 1 h. At the end of this time, the solvent was removed under reduced pressure and the residue was diluted with acetone. The resulting white solid was filtered and washed with excess of acetone. The solid was suspended in methanol and the pH was adjusted to 7 by the addition of triethylamine. The solvent was removed under reduced pressure and the resulting residue was dissolved in ethyl acetate and washed with water followed by brine. The organic layer was dried over anhydrous sodium sulphate and the solvent was removed by distillation under reduced pressure. The crude product was purified by column chromatography on silicagel using 2 to 10% (gradient elution) of methanol in chloroform to afford 9.8 g of the title compound.
Reaction SMILES: C(O)(=O)C.[CH2:5]([NH:12][C:13]1[C:14]([CH3:24])=[C:15]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:16]=[CH:17][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N+:25]([C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1)([O-:27])=[O:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C.CC#N>[CH2:5]([N:12]([CH2:32][C:31]1[CH:34]=[CH:35][C:28]([N+:25]([O-:27])=[O:26])=[CH:29][CH:30]=1)[C:13]1[C:14]([CH3:24])=[C:15]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:16]=[CH:17][CH:18]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Cc1c(NCc2ccccc2)cccc1NS(C)(=O)=O
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: CC(Cl)Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 5 %

Procedure:
Glacial acetic acid (0.37 mL, 6.4 mmoles) was added to a solution of Example 8A (0.46 g, 1.6 mmoles) and 4-nitrobenzaldehyde (0.48 g, 3.2 mmoles) in dichloroethane (3.2 mL) and CH3CN (4.0 mL). The reaction was stirred for 4 hours at room temperature and was treated with sodium triacetoxyborohydride (0.68 g, 3.2 mmoles). The reaction mixture was stirred overnight at room temperature. The mixture was poured into saturated aqueous NaHCO3 (150 mL) and extracted with diethyl ether (150 mL). The organic phase was washed with brine (150 mL), dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (5:2→1:1 hexanes:ethyl acetate) to provide the title compound as a brown solid (0.034 g, 5% yield). 1H NMR (300 MHz, CDCl3) δ8.12 (d, J=8.9 Hz, 2H), 7.37 (d, J=8.9 Hz, 2H), 7.27 (m, 6H), 7.12 (t, J=7.8 Hz, 1H), 6.87 (d, J=8.1 Hz, 1H), 6.14 (s, 1H), 4.18 (s, 2H), 4.06 (s, 2H), 2.99 (s, 3H), 2.38 (s, 3H); MS (APCI+) m/z 426 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:12][C:13](N)=[O:14]>>[Cl:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:12][C:13](=[O:14])[NH:1]2)=[CH:7][CH:8]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: NC(N)=O
Product: O=c1[nH]c(=O)c2ccc(Cl)cc2[nH]1
Temperature: 200 °C

Procedure:
A mixture of 2-amino-4-chlorobenzoic acid (2.00 g, 11.6 mmol) and urea (2.80 g, 46.6 mmol) was heated to 200° C. for 1 h. The mixture was allowed to cool to room temperature and the resulting mass was triturated well with water. The product was collected by filtration (2.30 g, 100%). The MS and NMR data are in agreement with those that have been previously described: Organic Process Research & Development, 2003, 7, 700-706. 1H NMR (600 MHz, DMSO-d6): 12.00 (br s, 2H), 8.59-8.53 (m, 1H), 7.93-7.80 (m, 2H).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[N:24]=[N+:25]=[N-:26])(=O)C>CO>[C@@H:6]1([N:24]=[N+:25]=[N-:26])[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](N=[N+]=[N-])[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CO
Product: [N-]=[N+]=N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl azide (3, 5.6 g) in methanol (50 ml) 1M methanolic sodium methoxide (0.5 ml) was added and the solution was stirred overnight at 0° C., then it was neutralized with AG 50W-X8 (H+) ion-exchange resin. The resin was filtered off, the filtrate was evaporated and dried in vacuo to give the known β-D-glucopyranosyl azide (4).