Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[SH:11].C[O:13][C:14](=[O:17])[CH:15]=[CH2:16]>CO.C(OCC)C>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][CH2:16][CH2:15][C:14]([OH:17])=[O:13]
Reactant: COc1ccccc1S
Reactant: C=CC(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: COc1ccccc1SCCC(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
1.5 ml of a solution of 1N sodium hydroxide in methanol are added to a solution of 20.2 g of 2-methoxybenzenethiol in 20 ml of methanol and 20 ml of diethyl ether followed by cooling to 0° C. 13.9 ml of methylacrylate was then dropwise added to this solution. After completion of dropping, the reaction mixture was warmed to room temperature and stirred overnight. After concentrating the reaction mixture by a rotary evaporator, 8.7 g of sodium hydroxide, 100 ml of water and 35 ml of methanol was added followed by stirring vigorously overnight. The reaction mixture was acidified with concentrated hydrochloric acid while cooling and the resulting solution was extracted with chloroform. The chloroform layer was dried with magnesium sulfate, the solvent was distilled off and the resulting crystal was recrystallized from chloroform-hexane to obtain 25.4 g of the target 2-(2-methoxyphenylthio) ethanecarboxylic acid (yield: 83%, m.p.: 91°-91.5° C.).
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][S:5]([N:8]([CH3:11])[O:9][CH3:10])(=[O:7])=[O:6].Cl[S:13]([NH:16][C:17](=[O:25])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:15])=[O:14].Cl>CCCCCC.C1COCC1>[CH3:11][N:8]([O:9][CH3:10])[S:5]([N:4]([S:13]([NH:16][C:17](=[O:25])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:14])=[O:15])[CH3:3])(=[O:7])=[O:6]
Reactant: CNS(=O)(=O)N(C)OC
Reactant: O=C(NS(=O)(=O)Cl)Oc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CON(C)S(=O)(=O)N(C)S(=O)(=O)NC(=O)Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93.6 %

Procedure:
1.15 g (28.8 mmol) of 60% sodium hydride was washed with n-hexane, and dry THF was added, and the mixture was cooled with ice. To this mixture, a THF solution containing 2 g (13 mmol) of N,N'-dimethyl-N'-methoxysulfamide was dropwise added. After stirring the mixture for 10 minutes, a dry THF solution containing 3.21 g (13.6 mmol) of phenyl N-chlorosulfonylcarbamate was dropwise added thereto. The mixture was stirred at room temperature for 7 hours. The reaction mixture was poured into 500 ml of ice water containing 3.5 g of 35% hydrochloric acid and extracted three times with diethyl ether. The diethyl ether layer was washed sequentially with water and a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 4.3 g of phenyl N-[(N-(N-methyl N-methoxyaminosulfonyl)-N-methylamino)sulfonyl]carbamate as slightly yellow oil.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.[CH:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:7]([N:4]1[CH2:5][CH2:6][C@H:2]([OH:1])[CH2:3]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O[C@H]1CCNC1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: O[C@H]1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73 %

Procedure:
A solution of (3S)-3-hydroxypyrrolidine (2.0 g, 25 mmol) 50 mL CH2Cl2, under a nitrogen atmosphere, was cooled to 0° C. and benzaldehyde (2.92 g, 27.5 mmol was added, followed by 1 g of powdered 4A molecular sieves. Sodium triacetoxyborohydride (7.4 gm, 35 mmol)was added in several portions over 30 min, and the reaction was allowed to stir at room temperature for 18 h. The reaction was again cooled to 0° C. and quenched by addition of 10 mL methanol, followed by 5 mL of 1N HCl. The molecular sieve solids were removed by filtration through a glass fiber paper, and the filtrate was extracted with 20 mL diethyl ether. The organic phase was discarded, and the aqueous phase was first basified by addition of conc. ammonium hydroxide, and then extracted with EtOAc (3×20 mL). The combined extracts were washed with 20 mL brine, dried (MgSO4), filtered, and concentrated in vacuo to furnish 3.2 g (73%) of clear yellow oil, which required no further purification. 1H-NMR (400 MHz, CDCl3) δ7.2-7.4 (m, 5H), 4.33 (, 11H), 3.63, (s, 2H), 2.83-3.89 (m, 1H), 2.67 (d, J=9.9 Hz, 1H), 2.53-2.55 (m, 1H), 2.23-2.34 (m, 1H), 2.14-2.20 (m, 2H), 1.70-1.77 (n, 11H).
Reaction SMILES: [OH:1][C:2]1[C:9]([CH:10]=O)=[CH:8][C:7]([CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH:20](C(OCC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C=O)C>[CH2:24]([O:23][C:21]([C:20]1[O:1][C:2]2[C:3]([CH:4]=[O:5])=[CH:6][C:7]([CH3:12])=[CH:8][C:9]=2[CH:10]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: Cc1cc(C=O)c(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C)cc(C=O)c2o1
Temperature: 100 °C
Yield: 94.7 %

Procedure:
A solution of 2-hydroxy-5-methylisophtalaldehyde (1 g) in DMF (10 ml) was treated under an Argon atmorphere with potassium carbonate (1.01 g) and diethyl bromomalonate (1.60 g). The reaction mixture was heated to 100° C. for 20 hrs, then cooled to r.t., quenched with water and extracted with EtOAc. The organics were dried over MgSO4, filtrated and concentrated to obtain 7-formyl-5-methyl-benzofuran-2-carboxylic acid ethyl ester (1.34 g) as off-white solid. MS (ISP): 233.1 ((M+H)+.). The crude product was used in the next reaction step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[N:18]=3)[CH2:9]2)[N:5]=[C:4]([NH2:27])[N:3]=1.[F:28][C:29]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[CH:33][C:30]=1[C:31]#[N:32].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:27][C:4]1[N:3]=[C:2]([C:35]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[C:29]([F:28])[CH:36]=2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[N:18]=3)[CH2:9]2)[N:5]=1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
Reactant: COc1ccc(-c2c[nH]c(C3CN(c4cc(Cl)nc(N)n4)CCO3)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2c[nH]c(C3CN(c4cc(-c5ccc(C#N)c(F)c5)nc(N)n4)CCO3)n2)cc1
Temperature: 140 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
A mixture of 4-chloro-6-(2-{4-[4-(methyloxy)phenyl]-1H-imidazol-2-yl}-4-morpholinyl)-2-pyrimidinamine (1.0 g, 2.59 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (0.83 g, 3.36 mmol), Na2CO3 (0.685 g, 6.46 mmol) and Pd(PPh3)4 (0.30 g, 0.26 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was heated at 140° C. under microwave conditions with stirring for 1 hour. The reaction mixture was filtered, washed by ethyl acetate (100 mL), and concentrated. The resulting residue was purified by silica gel chromatography using EtOAc/petroleum ether (3:1) to afford the title compound (675 mg) as a yellow solid. LC-MS (ES) m/z=472 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26]>>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:5]2[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][CH:30]=[C:22]([F:21])[CH:23]=3)[N:3]=[CH:4]2)=[CH:12][CH:13]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: CC(C)(C)c1ccc(Cn2cnc(N)c2C(N)=O)cc1
Product: CC(C)(C)c1ccc(Cn2cnc(NC(=O)c3cccc(F)c3)c2C(N)=O)cc1
Yield: 70 %

Procedure:
An amidation reaction and post-treatment were carried out under the same conditions as in Example 1, using 1.54 g (5.65 mmol) of 4-amino-1-(4-t-butylbenzyl)-5-imidazole carboxamide which was prepared in the same manner as in Example 57 and 3-fluorobenzoyl chloride instead of benzoyl chloride to obtain 1.57 g of 1-(4-t-butylbenzyl)-4-(3-fluorobenzoylamino)-5-imidazolecarboxamide (yield 70%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[N:7]([CH2:23][CH2:24][CH2:25][CH2:26][N:27]([CH2:31][CH2:32][CH3:33])[CH2:28][CH2:29][CH3:30])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][CH2:17][C:18]2[NH:19][CH:20]=[CH:21][N:22]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([BH3-])#N.[Na+].C(O)(=O)C.[CH3:43][N:44]1[CH:48]=[CH:47][N:46]=[C:45]1[CH:49]=O>CO>[C:1]([O:5][C:6](=[O:34])[N:7]([CH2:23][CH2:24][CH2:25][CH2:26][N:27]([CH2:28][CH2:29][CH3:30])[CH2:31][CH2:32][CH3:33])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]([CH2:17][C:18]2[NH:19][CH:20]=[CH:21][N:22]=2)[CH2:49][C:45]2[N:44]([CH3:43])[CH:48]=[CH:47][N:46]=2)=[CH:13][CH:14]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCN(CCC)CCCCN(Cc1ccc(CNCc2ncc[nH]2)cc1)C(=O)OC(C)(C)C
Reactant: Cn1ccnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCN(Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 144 h
Yield: 71.1 %

Procedure:
The compound (231 mg) obtained in Example 1-6 was dissolved in anhydrous methanol (5.0 ml) The solution was added with sodium cyanoborohydride (61.6 mg), acetic acid (2.00 ml), and 1-methyl-2-imidazole carboxaldehyde (80.9 mg) and the whole was stirred at room temperature for 6 days under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off. The resultant was then dissolved in chloroform and added with a saturated aqueous sodium hydrogen carbonate solution and the whole was stirred for a while. The solution was subjected to extraction with chloroform and the extract was then washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. Subsequently, the solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining the subject compound (197 mg) as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH2:23])[O:5][C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][CH:11]=1.[N:24]#[C:25]Br>O1CCCC1.C(OCC)(=O)C>[NH2:24][C:25]1[NH:1][C:2]2[CH:3]=[C:4]([O:5][C:6]3[CH:7]=[C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][CH:11]=3)[CH:20]=[CH:21][C:22]=2[N:23]=1
Reactant: N#CBr
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc(N)c(N)c2)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc3nc(N)[nH]c3c2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 135 %

Procedure:
To a solution of tert-butyl [3-(3,4-diaminophenoxy)phenyl]carbamate (3.00 g, 9.51 mmol) in tetrahydrofuran (150 mL) was added cyanogen bromide (2.93 g, 27.7 mmol), and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate (300 mL), washed with saturated aqueous sodium hydrogencarbonate solution (100 mL×2) and saturated brine (100 mL), successively, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated to give the title compound (4.37 g) as a brown solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH3:7].[CH3:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[CH:14]=O.C(OC(=O)C)(=O)C>C(O)(C)C>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]=[CH:14][C:10]1[S:11][CH:12]=[CH:13][C:9]=1[CH3:8]
Reactant: Cc1nccn1C
Reactant: Cc1ccsc1C=O
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)O
Product: Cc1ccsc1C=Cc1nccn1C
Yield: 41.2 %

Procedure:
A mixture was prepared by admixing together in a 1.0 liter-3-necked round bottomed flask 144.0 grams (1.5 moles) of 1,2-dimethylimidazole, 189.3 grams (1.5 moles) of 3-methyl-2-thiophenecarboxaldehyde and 450 cubic centimeters (cc) of acetic anhydride. The flask was equipped with a stirrer, thermometer and a 12 foot distillation column. The mixture was stirred and heated at ~150° C. for ~2 hours. The temperature increased to ~160° C. At this time 250 cc of the distillate (mostly acetic acid by-product and acetic anhydride) had been collected. An additional 250 cc of acetic anhydride was added to the reaction flash and the heating continued until the temperature again rose to ~160° C. At this time about 320 cc of the distillate had been collected. The reaction mixture in the flask was thereafter concentrated under vacuum giving a residue of 427.0 grams. This residue was mixed with 500 cc of isopropyl alcohol and the resulting dark colored solution concentrated under vacuum giving a residue of 410 grams. This residue was distilled under reduced pressure. The first fraction (124 grams, boiling at 72°-76° C/0.2-0.4 millimeters of mercury (mm)) consisted mainly of starting material. The main fraction, which was the free base of the desired compound was collected in a yield of 155 grams and boiled at 172°-174° C/0.6 mm. The thick tarry pot residue weighed 115 grams. The main fraction was mixed with 150 cc of ethanol and 150 cc of concentrated hydrochloric acid. The insoluble yellow crystals which formed were filtered, washed with ~1.0 liter of ethanol and dried to give 126.3 grams of 1-methyl-2-(2-(3-methyl-2-thienyl)ethenyl)1H-imidazole:monohydrochloride, (Compound I) melting at 287°-288° C. The product was recovered in a yield of 34.9 percent of theoretical.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22](=[O:33])[C:23]3[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=3[Cl:32])=[N:17][CH:18]=[C:19]([CH3:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:34]([F:37])([F:36])[F:35].O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22](=[O:33])[C:23]3[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=3[Cl:32])=[N:17][CH:18]=[C:19]([CH3:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:34]([F:37])([F:35])[F:36]
Reactant: COCN(c1cc(C)cnc1C(=O)c1cc([N+](=O)[O-])ccc1Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1cnc(C(=O)c2cc([N+](=O)[O-])ccc2Cl)c(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Temperature: 25 °C
Yield: 64 %

Procedure:
A mixture of 4-chloro-N-[2-(2-chloro-5-nitro-benzoyl)-5-methyl-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (230 mg, 0.398 mmol) in 4 M HCl in dioxane (4 mL) and water (1 mL) was 50° C. for overnight. Reaction mixture was cooled to room temperature, evaporated to dryness and treated slowly with saturated aqueous NaHCO3 solution until pH 7-8. The mixture was extracted with EtOAc (2×25 mL), dried (anhydrous Na2SO4) and concentrated. The obtained residue was purified by flash chromatography (SiO2, 50% EtOAc-hexanes) to afford 4-chloro-N-[2-(2-chloro-5-nitro-benzoyl)-5-methyl-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (136 mg) in 64% yield. ESMS m/z (relative intensity): 533.9 (M+H)+ (90), 555.9 (M+Na)+ (100).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH:7]2[O:11][CH2:12][CH2:13][CH2:14][CH:6]12.C([O-])([O-])=O.[K+].[K+].[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]2[C:39]3[C:34](=[CH:35][C:36]([O:41][CH3:42])=[C:37]([OH:40])[CH:38]=3)[N:33]=[CH:32][N:31]=2)[CH:25]=[CH:26][C:27]=1[F:28]>CN(C=O)C>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]2[C:39]3[C:34](=[CH:35][C:36]([O:41][CH3:42])=[C:37]([O:40][CH2:2][CH2:3][CH2:4][N:5]4[CH2:10][CH2:9][CH2:8][CH:7]5[O:11][CH2:12][CH2:13][CH2:14][CH:6]45)[CH:38]=3)[N:33]=[CH:32][N:31]=2)[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Reactant: ClCCCN1CCCC2OCCCC21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCCC2OCCCC21
Temperature: 80 °C
Reaction time: 7 h
Yield: 23.4 %

Procedure:
A mixture of 5-(3-chloropropyl)octahydro-2H-pyrano[3,2-b]pyridine (0.23 g), K2CO3 (0.26 g) and 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (0.30 g) in 20 mL of DMF was stirred at 80° C. for 7 h and cooled to rt. To this, 50 mL of ice-water was added and the mixture was extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column eluting agent: 20:1 (v/v) DCM/MeOH) to afford the title compound as a pale yellow solid (0.11 g, 25.00%), HPLC: 96.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 501.3 (M+1); 1H NMR (400 MHz, d6-DMSO) δ: 9.54 (s, 1H), 7.78 (d, J=4.0 Hz, 1H), 7.70 (t, J=8.0 Hz, 1H), 7.64 (s, 2H), 7.24 (d, J=4.2 Hz, 1H), 7.09 (t, J=8.0 Hz, 1H), 4.19 (m, 2H), 3.93 (s, 3H), 3.33-3.30 (m, 2H), 2.51-2.49 (m, 4H), 2.14-1.93 (m, 6H), 1.74-1.71 (m, 3H), 1.36-1.23 (m, 3H) ppm.
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].[N:6]#[C:7][NH2:8].[CH3:9][OH:10]>>[S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[CH3:9][O:10][C:7](=[NH:8])[NH2:6]
Reactant: N#CN
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=N)N

Procedure:
The filtrate from the second batch of crystals was mixed with methanol, sulfuric acid, and cyanamide as described above to produce a third batch of O-methyl-isourea hydrogen sulfate, and the procedure was repeated twice more to produce a total of 6,588 g O-methyl-isourea hydrogen sulfate (93% yield). The mixed product had a melting point of 109° to 112°C and had a nitrogen content of 16.06% compared with a value of 16.27% calculated for C2H8N2O5S.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].[N+:24]([CH3:27])([O-:26])=[O:25]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:27]/[N+:24]([O-:26])=[O:25])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1ccc(/C=C/[N+](=O)[O-])cc1OCc1ccccc1
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 80.6 %

Procedure:
Commercially available 3-benzyloxy-4-methoxybenzaldehyde (30 g, 124 mmol) was dissolved in acetic acid (100 mL), then ammonium acetate (10.8 g, 140 mmol) and nitromethane (16.8 mL, 310 mmol) were added under nitrogen atmosphere at room temperature, and the mixture was heated and stirred at 130° C. for 2 hours and 20 minutes. The mixture was cooled to room temperature, then the precipitate was collected by filteration and washed with ethanol to obtain the title compound (28.5 g, 81%).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[C:19](Cl)(=[O:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:19](=[O:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: O=C(Cl)CCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(CCc1ccccc1)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of (R)-(+)-4-benzyl-2-oxazolidinone (910 g, 5.14 mol) and 500 mg of 2,2'-dipyridyl as an indicator in tetrahydrofuran (9 L) at -78° C. was added over 30 minutes a 2.5M solution of BuLi in hexanes (2.03 L, 5.14 mol). The temperature of the reaction mixture was maintained at less than -55° C. during the addition. The reaction mixture was cooled to -75° C. and hydrocinnamoyl chloride (950 g, 5.63 mol) was added over 5 minutes. The reaction mixture was allowed to warm to 0° C., at which point the reaction mixture was judged to be complete by thin layer chromatography (hexanes/ethyl acetate, 2:1). The reaction was quenched by adding 10% aqueous sodium bicarbonate (3.6 L) and water (3.6 L). The aqueous phase was separated and extracted with ethyl acetate (3 L). The combined organic layers were washed with 5% aqueous sodium carbonate (3.6 L) and saturated aqueous sodium chloride (2 L), dried over magnesium sulfate, and concentrated in vacuo to approximately 2 L of a viscous yellow suspension. This slurry was dissolved in ethyl acetate (3 L), concentrated to a solid, and dissolved in ethyl acetate at 50° C. Hexanes (10.7 L) was added, and the mixture was slowly cooled to 10° C. resulting in the precipitation of solids which were stirred at 10° C. for 30 minutes. The solids were collected by filtration, washed with hexanes, and air-dried at ambient temperature yielding 1.4 kg (88%) of (R)-4-benzyl-3-(3-phenyl-propionyl)-oxazolidin-2-one as pale yellow needles: 1H NMR (300 MHz, CDCl3) δ 7.14-7.33 (m, 10H), 4.66 (m, 1H), 4.17 (t, J=3.4 Hz, 2H), 3.26 (m, 3H), 3.03 (t, J=7 Hz, 2H), 2.75 (dd, J=9.5, 13.4 Hz, 1H); IR 1787, 1761, 1699, 1390, 1375, 1308, 1208, 1203, 746, 699 cm-1 ; mp 102-104° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH:3]=1.[CH3:19][NH:20][C:21](=[O:28])[CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C1(O)C=CC=CC=1>O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:4]2[CH:3]=[C:2]([N:25]3[CH2:26][CH2:27][CH:22]([C:21]([NH:20][CH3:19])=[O:28])[CH2:23][CH2:24]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[CH:13][CH:14]=1
Reactant: CNC(=O)C1CCNCC1
Reactant: Clc1ccc(-c2cc(Cl)c3ccccc3n2)cc1
Solvent: Oc1ccccc1
Solvent: O
Product: CNC(=O)C1CCN(c2cc(-c3ccc(Cl)cc3)nc3ccccc23)CC1
Temperature: 160 °C
Yield: 57.7 %

Procedure:
A mixture of 5.1 g (21 mmole) of 4-chloro-2-(4-chlorophenyl)quinoline, prepared as in Example 1(a), 6.2 g (42 mmole) of N-methylisonipecotamide, and 10 g of phenol was stirred and heated in an oil bath at 160° C. for 3.5 hr. It was then cooled and diluted with 100 ml of water. Crystallization was induced by scratching, warming and the addition of a small amount of ethanol. The solid was collected and washed with ether to give 7.0 g of crude product. Recrystallization from 150 ml of butanol gave 4.6 g of product, mp 251°-255° dec.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[C:13]([O:17][C:18]([N:20]1[CH:25]2[CH2:26][CH2:27][CH:21]1[CH2:22][C:23](=[O:28])[CH2:24]2)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])O.[Na+]>C1COCC1.C(OCC)(=O)C>[C:13]([O:17][C:18]([N:20]1[CH:25]2[CH2:26][CH2:27][CH:21]1[CH2:22][C:23]([OH:28])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH2:24]2)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Reactant: Brc1ccccn1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C2CCC1CC(O)(c1ccccn1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.2 %

Procedure:
n-Butyl lithium (2.5 M, 2.4 mL, 6.0 mmol) was added dropwise to a solution of 2-bromopyridine (0.57 mL, 6.0 mmol) in THF (10 mL) at −78° C. under nitrogen and stirred for 30 minutes. A solution of 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.3 g, 5.78 mmol) in THF (10 mL) was added dropwise and the mixture stirred at −78° C. for 1 hour. The reaction mixture was warmed to room temperature then saturated aqueous sodium hydrogen carbonate and ethyl acetate were added, the organics separated, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 20-50% ethyl acetate/pentane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.62 g). LCMS m/z 305.3 [M+H]+. R.T.=2.50 min (Analytical Method 3).