Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C1COCC1>[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[O:28][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Oc1cccc(OCc2ccccc2)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(OCc2ccccc2)c1

Procedure:
43.459 ml tert-butyl-chloro-dimethyl-silane were added at rt to a solution of 17 g imidazole and 25 g 3-benzyloxy-phenol in 400 ml THF. After 3 hours water was added to the reaction mixture and the mixture was then extracted with methylene chloride. The organic phase was extracted three times with water, dried over sodium sulfate and concentrated in vacuo. The residue was solved in methylene chloride and filtered over Alox (neutral) and concentrated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:34])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([O:37]CC)=[O:36].[OH-].[Na+].C1COCC1.Cl>C(OCC)(=O)C.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:34])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29][C:30]([F:31])([F:33])[F:32])=[CH:25][CH:24]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([OH:37])=[O:36]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(SC(F)(F)F)cc4)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(NCCc1ccc(SC(F)(F)F)cc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Yield: 84.1 %

Procedure:
ethyl 6-chloro-7-(4-(4-(trifluoromethylthio)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate (73.3 mg, 0.126 mmol) was reacted with 1.0 molar sodium hydroxide (506 μL, 0.506 mmol) in a 3:1 THF:Ethanol solution (0.05 M). After 2 hours the reaction was diluted with ethyl acetate, neutralized with 1.0 molar hydrochloric acid (531 μL, 0.531 mmol) and partitioned between saturated aqueous sodium chloride. The organic layer was dried with sodium sulfate, filtered, concentrated, and dried under high vacuum to provide the title compound (58.7 mg, 0.106 mmol, 84.2% yield) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[N+:16]([C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1[O:28]N)([O-:18])=[O:17]>CC#N>[NH2:16][N+:4]1[CH:5]=[CH:6][C:7]([NH:8][C:9]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:15])=[C:2]([F:1])[CH:3]=1.[N+:16]([C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1[O-:28])([O-:18])=[O:17]
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)Nc1ccncc1F
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1cc[n+](N)cc1F
Product: O=[N+]([O-])c1ccc([O-])c([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl (3-fluoropyridin-4-yl)carbamate (25.0 g, 125 mmol) in MeCN (200 ml), was added O-(2,4-dinitrophenyl)hydroxylamine (26.64 g, 125 mmol) in MeCN (200 ml), drop wise over 30 min at RT, reaction mass was stirred at 40° C. for 12 hrs, reaction mass was concentrated at temperature below 40° C. under reduced pressure to afford Int-11 (50 g) which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]([CH2:14][C:15]#N)[CH2:9][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:27][CH3:28])(=[O:26])[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=C.C(#N)C>C(Cl)(Cl)Cl.[Ag]F>[C:20]1([C:18]2([C:17]([O:27][CH3:28])=[O:26])[CH2:15][CH2:14][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C=C(C(=O)OC)c1ccccc1
Reactant: C[Si](C)(C)CN(CC#N)Cc1ccccc1
Agent: F[Ag]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: COC(=O)C1(c2ccccc2)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
A suspension of 53.4 g (0.23 mol) of N-benzyl-N-(cyanomethyl)-N-[(trimethylsilyl)methyl]amine (J. Org. Chem., 50, 4006 (1985)), 41.2 g (0.25 mol) of methyl atropate, 32.2 g (0.25 mol) of silver fluoride and 1 l of acetonitrile was stirred overnight at room temperature in the dark. The mixture was diluted with chloroform and filtered through celite. Concentration of the filtrate gave an oil which was chromatographed on silica gel, eluting with an 80:20 chloroform:ethyl acetate mixture, to give 27.9 g of methyl 3-phenyl-1-(phenylmethyl)-3-pyrrolidinecarboxylate.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[C:11]3[S:15][C:14](=[S:16])[NH:13][C:12]3=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:18]CN(C(C)C)C(C)C.CI.CCOC(C)=O>CN1C(=O)CCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[C:11]3[S:15][C:14]([S:16][CH3:18])=[N:13][C:12]3=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C1NC(=S)SC1=Cc1ccc2c(c1)OCO2
Reactant: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CI
Product: CSC1=NC(=O)C(=Cc2ccc3c(c2)OCO3)S1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2 g (7.54 mmol) of 5-Benzo[1,3]dioxol-5-ylmethylene-2-thioxo-thiazolidin-4-one and 1.5 ml (1.15 eq.) of DIEA were dissolved in 80 ml NMP. To this solution was added dropwise a freshly prepared solution of 2.43 ml (5 eq.) of Methyliodide in 10 ml NMP. The reaction mixture was stirred for two hours at RT. EtOAc was added and the organic layer was washed 5 times with brine and twice with water. The organic layer was reduced to 50% of volume, where upon 5-Benzo[1,3]dioxol-5-ylmethylene-2-methylsulfanyl-thiazol-4-one started to crystallize. Crystals were filtered off and washed with cold EtOAc.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[SH:13][CH2:14][C:15]1[S:19][C:18]([CH2:20][CH2:21][C:22]2[N:23]=[C:24]([NH:27][C:28](=[O:30])[CH3:29])[S:25][CH:26]=2)=[CH:17][CH:16]=1.[C:31]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:34])[NH:32][NH2:33]>O1CCCC1>[C:28]([NH:27][C:24]1[S:25][CH:26]=[C:22]([CH2:21][CH2:20][C:18]2[S:19][C:15]([CH2:14][S:13][C:1]([NH:33][NH:32][C:31]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:2])=[CH:16][CH:17]=2)[N:23]=1)(=[O:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(=O)Nc1nc(CCc2ccc(CS)s2)cs1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CCc2ccc(CSC(=O)NNC(=O)OC(C)(C)C)s2)cs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.8 %

Procedure:
To a solution of 1,1′-carbonyldiimidazole (326.0 mg, 2.010 mmol) in anhydrous tetrahydrofuran (8 ml), a solution of N-(4-{2-[5-(sulfanylmethyl)thiophen-2-yl]ethyl}-1,3-thiazol-2-yl)acetamide (400.0 mg, 1.340 mmol) in anhydrous tetrahydrofuran (10 ml) was added dropwise at 0° C. The mixture was stirred at 0° C. for 15 min and at room temperature for 1 hr. tert-Butyl carbazate (351.4 mg, 4.021 mmol) was added, and the mixture was stirred at room temperature for 16 hr. The mixture was concentrated, and residue was added water (40 ml) and extracted 3 times with ethyl acetate. The combined organic layer was washed with ice-cooled 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. BW-300SP 100 g, ethyl acetate:hexane=1:1) to give tert-butyl 2-({[(5-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}thiophen-2-yl)methyl]sulfanyl}carbonyl)hydrazinecarboxylate (316.7 mg, 0.694 mmol, yield 51.8%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:34]([CH2:35][CH3:36])[C:6]2[N:7]=[C:8]([NH:11][C:12]3[C:17]([O:18][CH3:19])=[CH:16][C:15]([N:20]4[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]4)=[CH:14][C:13]=3[F:33])[N:9]=[CH:10][C:5]=2[C:4](=[O:37])[C:3]=1[C:38](=[O:40])[NH2:39].[ClH:41].CCOCC>CO.O1CCOCC1>[ClH:41].[NH2:1][C:2]1[N:34]([CH2:35][CH3:36])[C:6]2[N:7]=[C:8]([NH:11][C:12]3[C:17]([O:18][CH3:19])=[CH:16][C:15]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:14][C:13]=3[F:33])[N:9]=[CH:10][C:5]=2[C:4](=[O:37])[C:3]=1[C:38]([NH2:39])=[O:40]
Reactant: CCn1c(N)c(C(N)=O)c(=O)c2cnc(Nc3c(F)cc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3OC)nc21
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCn1c(N)c(C(N)=O)c(=O)c2cnc(Nc3c(F)cc(N4CCNCC4)cc3OC)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.14 g (0.23 mmol) of the product prepared in step 10.4 is suspended in 4 mL of methanol, and 1.15 mL (4.61 mmol) of a 4N solution of hydrogen chloride in dioxane are added. The mixture is stirred at room temperature overnight, and ether is added. The solid is drained by suction, rinsed with pentane and dried in an oven. 0.10 g of the expected product is obtained in the form of a grey powder, which is used as obtained in the following step. Yield (dihydrochloride)=95%.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][N:7]([CH2:11][C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[C:6](=[O:17])[C:5]=2[NH:4][N:3]=1.[C:18](=[O:21])([O-])[O-].[K+].[K+].ClC[CH2:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1)=O>>[NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][N:7]([CH2:11][C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[C:6](=[O:17])[C:5]=2[N:4]([C:18](=[O:21])[CH2:26][CH2:27][N:29]2[CH2:30][CH2:31][N:32]([C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)[CH2:33][CH2:34]2)[N:3]=1
Reactant: Nc1n[nH]c2c1CCN(Cc1ccco1)C2=O
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(N2CCN(C(=O)CCCl)CC2)cc1
Agent: [K+]
Product: COc1ccc(N2CCN(CCC(=O)n3nc(N)c4c3C(=O)N(Cc3ccco3)CC4)CC2)cc1

Procedure:
A target compound (191.5 mg, 0.400 mmol, 93.1%) was yielded as solid in the same manner as Example 1 by reacting 3-amino-6-N-((furan-2-yl)methyl)-5,6-dihydro-1H-pyrazolo[3,4-c]pyridin-7(4H)-one (100 mg, 0.430 mmol) with potassium carbonate (89.1 mg, 0.645 mmol) and 3-chloro-1-{4-(4-methoxyphenyl)piperazin-1-yl}propan-1-one (133.7 mg, 0.473 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7](Cl)[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[CH3:13][O-:14].[Na+]>COCCOCCOC.C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([O:14][CH3:13])[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: Clc1cc2ccc(Br)cc2cn1
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: COCCOCCOC
Product: COc1cc2ccc(Br)cc2cn1
Temperature: 150 °C
Yield: 87.2 %

Procedure:
A mixture of 7-bromo-3-chloroisoquinoline (100 mg, 0.4 mmol) and sodium methoxide (113 mg, 2.1 mmol) in diglyme (1 mL) was heated to 150° C. for 1 hour. The reaction was cooled to room temperature and diluted with toluene and water. The layers were separated and the aqueous layer was extracted with toluene (3×). The combined organics were washed with water and brine, dried over sodium sulfate, filtered, and concentrated to an oil. The oil was dried under vacuum overnight to give the title compound (83 mg, 85%) as a yellow solid. +ESI (M+H+1) 240.1; 1H NMR (400 MHz, CDCl3, δ): 8.87 (s, 1H), 8.01-8.05 (m, 1H), 7.58-7.64 (m, 1H), 7.53-7.58 (m, 1H), 6.97 (s, 1H), 4.02 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][CH:11]([OH:13])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>O>[CH3:24][S:25]([O:13][CH:11]1[CH2:12][CH:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:10]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CC(OCc2ccccc2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OC1CC(OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
A 100-mL round-bottom flask was charged with 3-(benzyloxy)cyclobutanol (1.83 g, 10.3 mmol), dichloromethane (20 mL) and triethylamine (2.15 mL, 15.4 mmol), and the solution was cooled to 0° C. Methanesulfonyl chloride (1.20 mL, 1.77 g, 15.4 mmol) was added dropwise, and the resulting solution stirred for 30 min at 0° C. The reaction mixture was poured into water (30 mL) and extracted with dichloromethane (2×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to afford 3-(benzyloxy)cyclobutyl methanesulfonate (2.60 g, 99%) as a light yellow solid. MS (ESI, pos. ion) m/z 257 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([O:12][CH2:13][CH2:14][O:15][CH3:16])[C:3]=1C(O)=O.C([N:19](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(O)C>O1CCOCC1.C(OCC)(=O)C>[F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([O:12][CH2:13][CH2:14][O:15][CH3:16])[C:3]=1[NH2:19]
Reactant: CCN(CC)CC
Reactant: COCCOc1ccc(F)c(F)c1C(=O)O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COCCOc1ccc(F)c(F)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 3,4-difluorophenol (1.43 g) and cesium carbonate (4.89 g) in N,N-dimethylformamide (10 mL) was added 2-methoxyethyl bromide (0.94 mL), and the mixture was stirred at room temperature for 4 days. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with 1 mol/L aqueous sodium hydroxide solution, water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (39 mL). To the solution was added n-butyllithium (2.64 mol/L n-hexane solution, 3.25 mL) at −78° C., and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added dryice (10 g), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was acidified by addition of 2 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 2,3-difluoro-6-(2-methoxyethoxy)benzoic acid (1.48 g). The obtained 2,3-difluoro-6-(2-methoxyethoxy)benzoic acid (0.5 g) was dissolved in 1,4-dioxane (10 mL). To the solution were added triethylamine (0.45 mL) and diphenylphosphoryl azide (0.61 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added ethanol (0.99 g), and the mixture was heated for reflux for 5 hours. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with 1 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. To a suspension of the residue in ethanol (10 mL) was added 5 mol/L aqueous sodium hydroxide solution (4.3 mL), and the mixture was heated for reflux for 2 hours. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with water twice and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1) to give the title compound (75 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5](O)=[O:6]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]([CH2:5][OH:6])[CH:8]=[C:9]([CH3:11])[CH:10]=1
Reactant: Cc1cc(Br)c(C)c(C(=O)O)c1
Solvent: C1CCOC1
Product: Cc1cc(Br)c(C)c(CO)c1
Temperature: 25 °C

Procedure:
To a solution of 3-bromo-2,5-dimethylbenzoic acid (3.5 g, 15 mmol) in anhydrous THF was added borane THF complex (1.0 M, 25 mL, 25 mmol) at 0° C., then the reaction was warmed to ambient temperature overnight. The reaction was quenched with MeOH and concentrated to afford (3-bromo-2,5-dimethylphenyl)methanol.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][O-:16].[Na+].[C:18](OCC)(=[O:24])[C:19]([O:21][CH2:22]C)=[O:20]>CO>[CH3:22][O:21][C:19](=[O:20])[C:18](=[O:24])[CH2:8][C:6]1[CH:7]=[C:2]([O:16][CH3:15])[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: C[O-]
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(=O)Cc1cc(OC)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 32 h

Procedure:
To a suspension of 1-fluoro-5-methyl-2,4-dinitro-benzene (about 100.0 g, 0.5 mol) in methanol (about 1.5 L), sodium methoxide (about 108 g, 1.9 mol) and diethyl oxalate (about 136 mL, 1.0 mol) are added at a temperature of about −10° C. The resulting orange color suspension is slowly allowed to reach a temperature of about 15-20° C. in about 2 hours and continuous stirring is carried out at a temperature of about 15-20° C. over a period of about 32 hours. The reaction mixture is quenched with 1.5 N HCl (about 200 mL), the precipitated solid obtained is filtered and dried under vacuum to obtain the product [3-(5-methoxy-2,4-dinitro-phenyl)-2-oxo-propionic acid methyl ester] as pale yellow solid (about 125 g, 85%). 1H NMR (DMSO-d6, 300 MHz): 3.84 & 3.87 (2s, 3H), 4.02 & 4.04 (2s, 3H), 8.63 & 10.93 (s & bs, 2H), 7.56 & 8.07 (2s, 1H), 8.63 & 8.75 (2s, 1H); LC-MS (ESI): 297.0 (M-H).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[N-:15]=[C:16]=[S:17].[NH4+].Br[C:20]1[CH:21]=[C:22]2[C:27](=[C:28](Br)[CH:29]=1)[NH:26][CH2:25][CH2:24][CH2:23]2>CC(C)=O.CN(C=O)C>[OH2:5].[N:26]1([C:16]2[S:17][C:2]3[N:10]=[CH:9][CH:8]=[CH:7][C:3]=3[C:4](=[O:6])[N:15]=2)[C:27]2[C:22](=[CH:21][CH:20]=[CH:29][CH:28]=2)[CH2:23][CH2:24][CH2:25]1
Reactant: Brc1cc(Br)c2c(c1)CCCN2
Reactant: [N-]=C=S
Reactant: O=C(O)c1cccnc1Cl
Agent: [NH4+]
Solvent: O=S(Cl)Cl
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: O
Product: O=c1nc(N2CCCc3ccccc32)sc2ncccc12
Yield: 84.3 %

Procedure:
The reaction procedure of Example 57 was followed except that 1.339 g (8.5 mmol) of 2-chloronicotinic acid, 13 ml of thionyl chloride, two droplets of DMF, 680 mg of ammonium isothiocyanate, 13 ml of acetone, 2.473 g of 6,8-dibromo-1,2,3,4-tetrahydroquinoline and 8 ml of acetone were used. The product was then recrystallized from a mixture of ethanol and hexane to obtain 2.244 g of 2-(1,2,3,4-tetrahydroquinolin-1-yl)-4H-pyrido[3,2-e]-1,3-thiazin-4-one monohydrate.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][CH:17]([CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:22]=1)=[O:19]>>[CH3:16][CH:17]([CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2[CH2:32][CH2:31][N:30]([CH2:12][C:11]3[CH:14]=[CH:15][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:9][CH:10]=3)[CH2:29][CH2:28]2)[CH:22]=1)=[O:19]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(Oc4ccccc4)cc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 4-phenoxybenzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 429.2 (M+H)+.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10]1)=O)(C)(C)C.[ClH:22].CCOCC>CO>[ClH:21].[ClH:22].[NH2:8][CH:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2ccc(Cl)cc2)C1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: NC1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.9 %

Procedure:
A solution of 3-(tert-butoxycarbonyl)amino-1-(4-chlorobenzyl)pyrrolidine (6.38 g, 20.5 mmol) in CH3OH (80 mL) was treated with 1 N HCl-Et2O (100 mL) and was stirred at 25° C. for 15 h. The solvent was removed under reduced pressure to afford a solid which was purified by recrystallization (1:2 CH3OH—CH3CN, 150 mL) to give 3-amino-1-(4-chlorobenzyl)pyrrolidine dihydrochloride as a white powder (4.939 g, 84.9%): 1H NMR (d6-DMSO, 300 MHz) δ3.15 (br, 1 H), 3.3-3.75 (br-m, 4 H), 3.9 (br, 1 H), 4.05 (br, 1 H), 4.44 (br, 1 H), 4.54 (br, 1 H), 7.5-7.7 (m, 4 H), 8.45 (br, 1 H), 8.60 (br, 1 H); The purity was determined by RPLC/MS (>99%); ESI/MS m/e 211.0 (M++H, C11H16ClN2).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[S:5]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20]OS(C1C=CC(C)=CC=1)(=O)=O)([C:8]1[CH:14]=[CH:13][C:11]([CH3:12])=[CH:10][CH:9]=1)(=[O:7])=[O:6].O>CN(C=O)C>[C:11]1([CH3:12])[CH:10]=[CH:9][C:8]([S:5]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][N:1]=[N+:2]=[N-:3])(=[O:6])=[O:7])=[CH:14][CH:13]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCOCCN=[N+]=[N-])cc1
Temperature: 110 °C
Yield: 16.5 %

Procedure:
Sodium azide (0.47 g, 7.24 mmol) added to a solution of diethyleneglycol ditosylate (3 g, 7.24 mmol) in DMF (30 mL) and the resulting mixture was heated to 110° C. for 5 hours. The reaction mixture was poured into chilled water (125 mL) and the product was extracted with ethyl acetate (3×100 mL), the collected organic extracts were washed with water (3×100 mL), brine and dried over MgSO4. The crude product was purified on SiO2 and DCM/MeOH 0-100% gradient as eluant to yield 0.34 g (16%) of 7 as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 2.45 (s, 3H), 3.16 (t, J=4.8 Hz, 2H), 3.60 (t, J=4.8 Hz, 2H), 3.70 (t, J=4.8 Hz, 2H), 4.17 (t, J=4.8 Hz, 2H), 7.35 (d, J=8 Hz, 2H), 7.81 (d, J=8 Hz, 2H); 13C NMR (100.6 MHz, CDCl3): δ 21.6, 50.6, 68.7, 69.1, 70.2, 128.0, 129.9, 133.0, 144.9; MS ESI (m/z): [M+H]+ calcd. for C11H15N3O4S, 286.08. found 286.1
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][C@H:4]([NH:8][S:9]([C:12]1[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:11])=[O:10])[C:5](=[O:7])[CH3:6].[C:20]([O:24][CH2:25][Li])([CH3:23])([CH3:22])[CH3:21].O>C1COCC1>[C:20]([O:24][CH2:25][C:5]([CH3:6])([OH:7])[CH:4]([NH:8][S:9]([C:12]1[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:11])=[O:10])[CH2:3][CH:2]([CH3:19])[CH3:1])([CH3:23])([CH3:22])[CH3:21]
Reactant: [Li]COC(C)(C)C
Reactant: CC(=O)[C@H](CC(C)C)NS(=O)(=O)c1ccccc1C
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1S(=O)(=O)NC(CC(C)C)C(C)(O)COC(C)(C)C
Temperature: 25 °C
Yield: 85 %

Procedure:
To a -78° C. solution of the resultant compound of Example 57 (1.0 g, 3.5 mmol) in dry THF (7 ml) was added 3 equivalent, of t-butoxymethyl lithium [E. J. Corey and T. M. Eckridge, Tetrahedron Letters, 3165 (1983)]. The mixture was warmed to room temperature for 4 hours and then poured into water. Acidification with 0.1M H3PO4, extraction into ether, washing with brine, drying, and evaporating gave 1.1 g, (85%) of the desired compound. Mass spectrum: M+ =371.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[C:7]([NH:10][C:11]1[S:12][C:13]([S:17](Cl)(=[O:19])=[O:18])=[C:14]([CH3:16])[N:15]=1)(=[O:9])[CH3:8].C(N(CC)CC)C.O>O1CCOCC1>[OH:4][CH2:3][C:2]([NH:1][S:17]([C:13]1[S:12][C:11]([NH:10][C:7](=[O:9])[CH3:8])=[N:15][C:14]=1[CH3:16])(=[O:18])=[O:19])([CH3:6])[CH3:5]
Reactant: CC(C)(N)CO
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)Nc1nc(C)c(S(=O)(=O)NC(C)(C)CO)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 31.2 %

Procedure:
To a stirred solution of 2-amino-2-methyl-1-propanol (1.14 g, 13 mmol) in dioxane (20 ml) was added at 0° C. (ice water bath) commercially available 2-acetamido-4-methylthiazole-5-sulfonyl chloride (2.95 g, 12 mmol) and triethylamine (1.78 ml, 13 mmol). The light yellow suspension was stirred at room temperature for 17 h, poured into water (100 ml) and extracted with dichloromethane (2×10 ml). The combined organic layers were washed with sat. NaHCO3 solution (2×70 ml) and brine (70 ml), dried (MgSO4) and evaporated. The crude product was further purified by column chromatography on silica gel (ethyl acetate/MeOH 9:1) and subsequent crystallization (ethyl acetate/MeOH/heptane) to yield 2-acetamido-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (1.15 g, 32%) as a light brown solid. MS (ISP) 306.1 [(M−H)−]; mp 194° C.