Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[C:20]([Cl:27])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:18]C)=[C:9]([S:11]([CH2:14][CH:15]2[CH2:17][CH2:16]2)(=[O:13])=[O:12])[CH:10]=1.B(Br)(Br)Br.O>C(Cl)Cl>[CH:15]1([CH2:14][S:11]([C:9]2[CH:10]=[C:5]([O:4][C:3]3[C:2]([Cl:1])=[CH:23][C:22]([N+:24]([O-:26])=[O:25])=[CH:21][C:20]=3[Cl:27])[CH:6]=[CH:7][C:8]=2[OH:18])(=[O:12])=[O:13])[CH2:16][CH2:17]1
Reactant: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1S(=O)(=O)CC1CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)c(Oc2ccc(O)c(S(=O)(=O)CC3CC3)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.1 %

Procedure:
To a solution of 5-(2,6-dichloro-4-nitro-phenoxy)-2-methoxy-(cyclopropyl-methane-sulfonyl)-benzene (160 mg, 0.37 mmol) in CH2Cl2 (3 mL) was added boron tribromide (1M in CH2Cl2, 0.74 mL, 0.74 mmol). The resulting mixture was stirred at room temperature for 2 h and water (15 mL) was added. After stirring at room temperature for 1 h, the solution was extracted with EtOAc (3×20 mL). The combined organic extracts were dried and concentrated. The residue was purified by preparative TLC (100% CH2Cl2) to afford the title compound of Step D (76 mg). MS (APCl−) Calc.: 417.0. Found: 416.2 (M−1).
Reaction SMILES: [CH3:1][C:2]1([CH3:48])[CH2:10][C:9]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=[C:6]([C:19]3[N:20]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[C:23]([N:28](C)[C:29](=O)OCC3C=CC=CC=3)[CH:22]=4)[C:5]=2[CH2:4][CH2:3]1.C([O-])=O.[NH4+]>C(O)C.[C].[Pd]>[CH3:1][C:2]1([CH3:48])[CH2:10][C:9]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:16])([CH3:17])[CH3:18])[N:7]=[C:6]([C:19]3[N:20]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:46])([CH3:45])[CH3:47])[C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[C:23]([NH:28][CH3:29])[CH:22]=4)[C:5]=2[CH2:4][CH2:3]1
Reactant: CN(C(=O)OCc1ccccc1)c1ccc2cc(-c3nn(COCC[Si](C)(C)C)c4c3CCC(C)(C)C4)n(COCC[Si](C)(C)C)c2c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CNc1ccc2cc(-c3nn(COCC[Si](C)(C)C)c4c3CCC(C)(C)C4)n(COCC[Si](C)(C)C)c2c1
Yield: 81.4 %

Procedure:
A solution of benzyl N-(2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methylcarbamate (2.2 g, 3.1 mmol), 10% palladium-carbon (216 mg) and ammonium formate (989 mg, 16 mmol) in ethanol (30 ml) was heated under reflux for 2.5 hr. After cooling, the reaction mixture was filtered through celite, and the filtrate was concentrated. The residue was purified by silica gel chromatography to give the title compound (1.4 g, yield 79%).
Reaction SMILES: C1(CBr)CC1.CC1C=CC(S(O[CH2:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)(=O)=O)=CC=1.[CH3:22][C:23]1[N:24]=[C:25]([N:33]2[CH2:37][CH2:36][NH:35][C:34]2=[O:38])[S:26][C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH:19]1([CH2:18][CH2:17][N:35]2[CH2:36][CH2:37][N:33]([C:25]3[S:26][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:23]([CH3:22])[N:24]=3)[C:34]2=[O:38])[CH2:20][CH2:21]1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: Cc1ccc(S(=O)(=O)OCCC2CC2)cc1
Agent: BrCC1CC1
Product: CCOC(=O)c1sc(N2CCN(CCC3CC3)C2=O)nc1C
Yield: 60 %

Procedure:
Following the procedure as described in Example 10, making variations as required to replace cyclopropylmethyl bromide with 2-cyclopropylethyl 4-methylbenzenesulfonate to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 60% yield: 1H NMR (300 MHz, CDCl3) δ 4.13 (q, J=7.2 Hz, 2H), 3.65 (t, J=7.4 Hz, 2H), 3.43 (t, J=7.8 Hz, 2H), 3.22 (t, J=7.8 Hz, 2H), 2.34 (s, 3H), 1.44-1.15 (m, 5H), 0.57-0.51 (m, 1H), 0.32-0.22 (m, 2H), −0.07-0.11 (m, 2H); MS (ES+) m/z 324.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:14]([OH:15])=[C:13]([CH3:16])[C:12]([CH3:17])=[C:11]2[C:3]=1[CH:4](O)[CH2:5][C:6]1([O:10]2)[CH2:9][CH2:8][CH2:7]1.[CH3:19][CH:20]([SH:22])[CH3:21].O.C(=O)(O)[O-].[Na+]>O.Cl.C(OCC)(=O)C>[CH:20]([S:22][CH:4]1[C:3]2[C:11](=[C:12]([CH3:17])[C:13]([CH3:16])=[C:14]([OH:15])[C:2]=2[CH3:1])[O:10][C:6]2([CH2:9][CH2:8][CH2:7]2)[CH2:5]1)([CH3:21])[CH3:19]
Reactant: CC(C)S
Reactant: Cc1c(C)c2c(c(C)c1O)C(O)CC1(CCC1)O2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1O)C(SC(C)C)CC1(CCC1)O2
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of 5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutane]-4,6-diol (290 mg) in acetonitrle (2 mL) was added 2-propanethiol (0.5 mL) and concentrated HCl water solution (5 drops). The solution was stirred at room temperature for 7 hours. The solution was neutralized using sodium bicarbonate water solution to pH about 7. Ethyl acetate was added, washed with water and brine. Evaporation and chromatography (silica gel, hexane-ethyl acetate 0 to 4%) gave 140 mg of 4-(isopropylthio)-5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-ol
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:10]=1[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-:19].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.O>CN(C=O)C>[Br:19][C:15]1[C:14]([CH3:18])=[C:10]([C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12]
Reactant: Cc1cccc(NC(=O)OC(C)(C)C)c1C(=O)O
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Br)ccc(NC(=O)OC(C)(C)C)c1C(=O)O
Reaction time: 18 h
Yield: 88.6 %

Procedure:
A solution of Example 104A (10 g, 40 mmol) and tetrabutylammonium tribromide (19.2 g, 40 mmol) in DMF (250 mL) was treated slowly with water (250 mL). The resulting suspension was stirred for 18 hours and partitioned between water (1.2 L) and ethyl acetate (500 mL). The organic layer was washed with water (2×1 L), dried (Na2SO4), filtered, and concentrated. The residue was dissolved in dichloromethane (900 mL), washed with water (5×1 L) and brine, dried (Na2SO4), filtered, and concentrated to provide the desired product (11.7 g). MS (ESI(−)) m/e 328, 330 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 13.60 (br s, 1H), 9.68 (s, 1H), 7.63 (d, 1H), 7.39 (d, 1H), 2.37 (s, 3H), 1.44 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1ccc(Cl)c(CO)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
30 g of 2-chloro-5-nitrobenzaldehyde was dissolved in 500 ml of methanol and cooled to 0° C. A solution of 10 g of sodium borohydride in 100 ml of water was then added dropwise over 90 minutes while maintaining the temperature below 10° C. The resultant reaction mixture was then stirred for one hour, then acidified with 2N HCl and left stirring overnight. The solids were then, washed with water and dried, to produce 27 g of 2-chloro-5-nitrobenzyl alcohol as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[H-].[Na+].Br[CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].O>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C:4](=[O:8])[CH:3]=1
Reactant: Nc1cc[nH]c(=O)c1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCn1ccc(N)cc1=O
Temperature: 78 °C
Yield: 41 %

Procedure:
To a solution of 4-aminopyridin-2(1H)-one (Molbridge) (0.9 g, 8.17 mmol) in DMF (30 mL) was added NaH (60%, 490 mg, 12.3 mmol). The mixture was stirred at room temperature for 30 min before (2-bromoethoxy)(tert-butyl)dimethylsilane (2.15 g, 8.99 mmol) was added. The reaction mixture was heated at 78° C. for 15 h. The mixture was cooled and poured into H2O (100 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with H2O (5×50 mL), brine (50 mL), dried over MgSO4 and concentrated. The residue was purified by flash chromatography (silica gel, 40+S, 0% to 10% MeOH in EtOAc) to give 4-amino-1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyridin-2-one as a white solid (0.9 g, 41%).
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([CH:11]([CH3:25])[C:12]([OH:24])([C:17]2[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=2)[C:13]([F:16])([F:15])[F:14])[CH:5]=1.[OH-].[Na+]>CO>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:26])=[O:2])=[CH:5][C:6]=1[CH:11]([CH3:25])[C:12]([OH:24])([C:17]1[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=1)[C:13]([F:16])([F:14])[F:15]
Reactant: COC(=O)c1ccc(Cl)c(C(C)C(O)(c2cncc(C)n2)C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cncc(C(O)(C(C)c2cc(C(=O)O)ccc2Cl)C(F)(F)F)n1
Temperature: 40 °C
Reaction time: 12 h

Procedure:
To a solution of 4-chloro-3-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(6-methyl-pyrazin-2-yl)-propyl]-benzoic acid methyl ester (50 mg) in methanol (1 mL) was added an aqueous solution of 1N NaOH (0.257 mL) and the mixture was allowed to stir at 40° C. for 12 hours. Methanol was removed by evaporation and the residue was diluted with water. The solution was extracted with ethyl acetate and the organic layer was washed with water. The aqueous layers were combined and aqueous HCl (1N, 0.257 mL) was added. The solution was extracted with ethyl acetate twice and the organic layers were washed with brine, dried over MgSO4 and evaporated. The residue was evaporated once from heptane to give, after drying, the title compound as a white solid (47 mg). MS (m/e, ISP neg. ion): 373.1 (M−H+)−.
Reaction SMILES: [CH3:1][C:2]1[C:22]([O:23]C)=[C:21]([CH3:25])[C:20]([CH3:26])=[C:19]([O:27]C)[C:3]=1[O:4][C:5]1[CH:18]=[CH:17][C:8]([CH2:9][CH:10]2[S:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:7][CH:6]=1>O.C(#N)C>[CH3:1][C:2]1[C:22](=[O:23])[C:21]([CH3:25])=[C:20]([CH3:26])[C:19](=[O:27])[C:3]=1[O:4][C:5]1[CH:18]=[CH:17][C:8]([CH2:9][CH:10]2[S:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:7][CH:6]=1
Reactant: COc1c(C)c(C)c(OC)c(Oc2ccc(CC3SC(=O)NC3=O)cc2)c1C
Solvent: CC#N
Solvent: O
Product: CC1=C(C)C(=O)C(Oc2ccc(CC3SC(=O)NC3=O)cc2)=C(C)C1=O
Reaction time: 1 h
Yield: 70.3 %

Procedure:
A solution of 2.1 g of ceric ammonium nitrate in a mixture of 2 ml of water and 2 ml of acetonitrile was added dropwise at 0° C. to a solution of 0.4 g of 5-[4-(2,4,5-trimethyl-3,6-dimethoxyphenoxy)benzyl]thiazolidine-2,4-dione (prepared as described in Preparation 2) in 3 ml of acetonitrile, and the resulting mixture was stirred at the same temperature for 1 hour. At the end of this time, the reaction mixture was poured into water, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was then removed from the extract by distillation under reduced pressure, and the residue thus obtained was purified by column chromatography through silica gel, using a 4:1 by volume mixture of benzene and ethyl acetate as the eluent, to give 260 mg of the title compound, melting at 153°-156° C. (with decomposition).
Reaction SMILES: [OH:1][C:2]1[CH:13]=[C:12]2[O:14][CH2:15][O:16][C:11]2=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][OH:9])=[O:5].[CH3:17]OC(OC)OC.C(O)=O>C(Cl)(Cl)Cl.C(OCC)(=O)C>[O:16]1[C:11]2[C:12](=[CH:13][C:2]3[O:1][CH:17]4[O:9][CH:8]=[CH:7][N:6]4[C:4](=[O:5])[C:3]=3[CH:10]=2)[O:14][CH2:15]1
Reactant: COC(OC)OC
Reactant: O=C(NCCO)c1cc2c(cc1O)OCO2
Solvent: O=CO
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: O=C1c2cc3c(cc2OC2OC=CN12)OCO3

Procedure:
2-(2-Hydroxy-4,5-methylenedioxybenzamido)ethanol (8.9 g; 40 mmol) was suspended in 320 mL dry chloroform, to which trimethylorthoformate (32 mL, 290 mmol) and formic acid (7.8 mL, 170 mmol) were added. The suspension was heated to reflux for 2.5 hours and diluted with ethyl acetate. The diluted solution was washed with a sodium bicarbonate buffer (pH 10), followed by a saturated sodium chloride solution and finally, dried over anhydrous sodium sulfate. The solution was evaporated onto silica gel and purified by multiple flash chromatographic steps on silica gel (ethyl acetate/hexane=1:1 or diethyl ether/hexane=9:1). Subsequent isolation of intermediate byproducts and treatment with formic acid yielded a total of 4.78 g (51%; after recrystallization from methylene chloride/diethyl ether) of (R,S)-7,8-dihydro-5aH, 10H-1,3-dioxolo[4,5-g]oxazolo[2,3-b][1,3]benzoxazin-10-one with mp=152-153° C. IR (thin film): 2899, 1667, 1460, 1420, 1260, 1117, 1034, and 926 cm-1. 1HNMR (500 MHz; CDCl3): δ 7.27 (1H, s), 6.53 (1H, s), 6.18 (1H, s), 6.015 (2H, AB quartet), 4.30 (1H, td, J=7 & 1.2 Hz), 4.22-4.28 (1H, m), 4.20 (1H, ddd, J=10, 7 & 1.4 Hz), and 3.55-3.60 ppm (1H, m.
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[C:11]([C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:12]3[C:13](Br)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].[SnH4]>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]([C:11]2[C:12]3[C:13]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]3[CH2:8][CH2:7][CH:6]([CH2:2][C:3]([OH:5])=[O:4])[C:10]=23)=[O:28])=[CH:22][CH:23]=1
Reactant: CC(C(=O)[O-])C1CCn2c1c(C(=O)c1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Agent: [SnH4]
Product: O=C(O)CC1CCn2c1c(C(=O)c1ccc(Cl)cc1)c1c(-c3ccccc3)cc(F)cc12

Procedure:
Starting from (+/−)-methyl[8-bromo-9-(4-chlorobenzoyl)-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate (Example 61, Step 1, 100 mg, 0.22 mmol) and tributylephenyl)stannane (121 mg, 0.33 mmol), the title compound was synthesized following the procedures as described in Example 42 and Step 10 of Example 7.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:11]([O:13][CH3:14])=[O:12])[NH:4][N:3]=1.[CH3:19]C1C=C(C)C(B2OC(C)(C)C(C)(C)O2)=CC=1C(OC)=O.CC1C=CC(C(OC)=O)=CC=1B1OC(C)(C)C(C)(C)O1>>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[C:10]([CH:9]=2)[C:11]([O:13][CH3:14])=[O:12])[NH:4][N:3]=1
Reactant: COC(=O)c1ccc(C)c(-c2[nH]nc(C)c2C)c1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1C
Agent: COC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Product: COC(=O)c1cc(-c2[nH]nc(C)c2C)c(C)cc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 59.2, except methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1) was used in place of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4). m/z (ES+) 259 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]([CH3:12])[C:4](=[O:13])[C:3]=1[C:14]1[O:18][N:17]=[C:16]([CH3:19])[N:15]=1.N1C=CC=CC=1.[C:26](Cl)(=[O:30])[CH:27]([CH3:29])[CH3:28]>ClCCl>[CH3:12][N:5]1[C:6]2=[N:7][CH:8]=[CH:9][N:10]=[C:11]2[C:2]([O:1][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])=[C:3]([C:14]2[O:18][N:17]=[C:16]([CH3:19])[N:15]=2)[C:4]1=[O:13]
Reactant: Cc1noc(-c2c(O)c3nccnc3n(C)c2=O)n1
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1noc(-c2c(OC(=O)C(C)C)c3nccnc3n(C)c2=O)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 8-hydroxy-5-methyl-7-(3-methyl-1,2,4-oxadiazol-5-yl)-5H-pyrido[2,3-b]pyrazin-6-one (Example 7.4) (0.044 g) and pyridine (0.018 ml) in dichloromethane (1 ml) was added dropwise isobutyryl chloride (0.022 ml). The reaction mixture was stirred at ambient temperature for 4 hours and then stored at ambient temperature for 16 hours. The reaction mixture was diluted with more dichloromethane and the mixture was washed successively with aqueous sodium hydrogen carbonate (saturated), aqueous ammonium chloride (saturated) and brine. The organic fraction was dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 1:1) to give Compound No. B6 of Table 6 as a pale yellow solid (0.020 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14](=O)[CH:15]=[CH:16]N(C)C)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10].[F:21][C:22]([F:33])([F:32])[C:23]1[N:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](=[NH:27])[NH2:26].CC(C)([O-])C.[K+].O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]2[CH:15]=[CH:16][N:26]=[C:25]([C:24]3[C:23]([C:22]([F:32])([F:21])[F:33])=[N:31][CH:30]=[CH:29][CH:28]=3)[N:27]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10]
Reactant: N=C(N)c1cccnc1C(F)(F)F
Reactant: COc1cc(C(=O)C=CN(C)C)cc([N+](=O)[O-])c1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1cc(-c2ccnc(-c3cccnc3C(F)(F)F)n2)cc([N+](=O)[O-])c1OC
Temperature: 80 °C

Procedure:
A stirred suspension of 1-(3,4-dimethoxy-5-nitro-phenyl)-3-dimethylamino-propen-1-one (0.28 g, 1.0 mmol), 2-(trifluoromethyl)nicotinimidamide (0.283 g, 1.5 mmol) and potassium tert-butoxide (0.17 g, 1.5 mmol) in absolute ethanol (5 mL) was heated to 80° C. in a sealed tube for one hour and then allowed to cool to room temperature. The mixture was poured onto cold water (100 mL) and the resulting precipitate was filtered off, washed with water and dried to give 4-(3,4-dimethoxy-5-nitrophenyl)-2-(2-(trifluoromethyl)pyridin-3-yl)pyrimidine, 0.296 g (73%).
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2[C:16]2C=[C:18]([NH:22][S:23](C3C(F)=CC=CC=3F)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)C=CN=1.[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[N:43][C:42]=2[C:52]2[C:53]([F:59])=[C:54]([CH:56]=[CH:57][CH:58]=2)[NH2:55])[CH:38]=[CH:37][N:36]=1.N1(S(Cl)(=O)=O)CCCCC1>>[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([N:46]3[CH2:47][CH2:48][O:49][CH2:50][CH2:51]3)=[N:43][C:42]=2[C:52]2[C:53]([F:59])=[C:54]([NH:55][S:23]([N:22]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:16]3)(=[O:25])=[O:24])[CH:56]=[CH:57][CH:58]=2)[CH:38]=[CH:37][N:36]=1
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Reactant: Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Agent: O=S(=O)(Cl)N1CCCCC1
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)N1CCCCC1
Yield: 29 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-fluoroaniline (200 mg, 0.510 mmol) and 1-piperidinesulfonyl chloride (0.201 mL, 1.531 mmol) the title compound of Step A was obtained as a yellow foam (193 mg, 41% and 29% yield, repeated twice). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.72 (s, 1H), 8.15-8.44 (m, 1H), 7.45-7.67 (m, 1H), 7.22-7.42 (m, 2H), 6.61 (d, J=5.4 Hz, 1H), 3.68 (t, J=4.7 Hz, 4H), 3.52 (t, J=4.7 Hz, 4H), 3.03 (t, J=5.0 Hz, 4H), 1.24-1.66 (m, 6H).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][CH:24]=3)[CH:16]=2)[O:8][C@H:7]([O:32][CH3:33])[C@H:6]1[O:34]C(=O)C)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C@H:9]2[C@H:10]([OH:11])[C@@H:5]([OH:4])[C@H:6]([OH:34])[C@@H:7]([O:32][CH3:33])[O:8]2)=[CH:16][C:17]=1[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH3:31])=[CH:27][CH:28]=1
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](OC)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](OC)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Reaction time: 1 h
Yield: 95.5 %

Procedure:
Recrystallized triacetate from step C (5.98 g, 11.2 mmol) was treated with K2CO3 (7.7 g, 56 mmol) in MeOH (112 ml) with vigorous stirring for 1 hour. The reaction was filtered through celite and concentrated under vacuum. The residue was dissolved in DCM, washed with H2O and brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was passed through a plug of silica gel with 5% MeOH:CH2Cl2, concentrated under vacuum, suspended in H2O, and lyophilized to give (2S,3R,4R,5S,6S)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-methoxy-tetrahydro-pyran-3,4,5-triol (4.37 g, 10.7 mmol, 96%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[C:7]([CH:14]=[CH2:15])[C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1.[C:23](=[O:30])([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[NH2:24]>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([NH:24][C:23](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:3][CH:4]=3)[O:9][C:8]([CH3:13])([CH3:12])[C:7]=2[CH:14]=[CH2:15])=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(N)=O
Reactant: C=CC1=C(c2ccc(F)cc2)c2ccc(Cl)cc2OC1(C)C
Product: C=CC1=C(c2ccc(F)cc2)c2ccc(NC(=O)OC(C)(C)C)cc2OC1(C)C

Procedure:
The compound obtained in (1) described above (155 mg) and tert-butyl carbamate (280 mg) were treated in the same manner as Reference Example 5(4) to give the titled compound (185 mg) as a yellow powder.
Reaction SMILES: N12CCCN=C1CCCCC2.[C:12]([OH:16])(=[O:15])[C:13]#[CH:14].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>C(Cl)Cl>[C:12]([O:16][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=1)(=[O:15])[C:13]#[CH:14]
Reactant: COc1ccc(CCl)cc1
Reactant: C#CC(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: C#CC(=O)OCc1ccc(OC)cc1
Reaction time: 2 h

Procedure:
64 ml (0.43 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene were added to a solution of 26.4 ml (0.43 mol) of propiolic acid in 400 ml of methylene chloride at 25°, where required while cooling with ice. The mixture was stirred at 25° for 2 hours, then 56 ml (415 mmol) of 4-methoxybenzyl chloride were added and the mixture was finally stirred at 25° for a further 2 days. The reaction mixture was washed in succession with 200 ml of saturated sodium hydrogen carbonate solution and twice with 200 ml of water each time. The organic phase was dried over sodium sulphate and concentrated. The residue was purified by flash chromatography on 1000 g of silica gel (elution agent hexane/ethyl acetate 9:1). There was obtained 4-methoxybenzyl propiolate as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[N:6]=[C:5]([C:14]([O:16]CC)=[O:15])[C:4]1=[O:19])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[N:6]=[C:5]([C:14]([OH:16])=[O:15])[C:4]1=[O:19])[CH3:2]
Reactant: CCOC(=O)c1nc2ccc(F)cc2n(CC)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCn1c(=O)c(C(=O)O)nc2ccc(F)cc21

Procedure:
4-Ethyl-6-fluoro-3,4-dihydro-3-oxo-2-quinoxalinecarboxylic acid, ethyl ester (8 g) and sodium carbonate (0.25 g) in methanol (20 ml) and water (10 ml) were heated under reflux for 2 hours. The methanol was distilled off and the aqueous solution was acidified with hydrochloric acid and the solid was collected. It had m.p. 162.5°-164° (39%).