Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:11]([OH:13])=[O:12].[H][H]>C(O)C.[OH-].[Pd+2].[OH-]>[CH3:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:11]([OH:13])=[O:12]
Reactant: [H][H]
Reactant: Cc1c(C(=O)O)ccc2ccoc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(=O)O)ccc2c1OCC2
Yield: 98.2 %

Procedure:
7-Methyl-1-benzofuran-6-carboxylic acid (synthesized in reagent preparation 15) (0.050 g, 0.28 mmol) was solubilized in anhydrous ethanol (2.0 mL) and 0.050 g of palladium (II) hydroxide (20%) was added. This mixture was shaken for 3 hours under 35 psi hydrogen gas using a Parr hydrogenator apparatus. The mixture was filtered through celite and concentrated in vacuo to give crude 7-methyl-2,3-dihydro-1-benzofuran-6-carboxylic acid (0.049 g, 97% yield) which was used without further purification. 1H NMR (400 MHz, d6-DMSO): 12.67 (broad s, 1H), 7.33 (d, 1H), 7.11 (d, 1H), 4.55 (t, 2H), 3.23 (t, 2H), 2.32 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[O:8][CH2:7][C:6]([CH:13]=[CH:14][C:15]1[CH:24]=[C:23]3[C:18]([CH2:19][CH:20]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:21][O:22]3)=[CH:17][C:16]=1[F:30])=[CH:5]2>C1COCC1.[Pd]>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[O:8][CH2:7][C:6]([CH2:13][CH2:14][C:15]1[CH:24]=[C:23]3[C:18]([CH2:19][CH:20]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:21][O:22]3)=[CH:17][C:16]=1[F:30])=[CH:5]2
Reactant: CCCCCC1COc2cc(C=CC3=Cc4cc(F)cc(F)c4OC3)c(F)cc2C1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCC1COc2cc(CCC3=Cc4cc(F)cc(F)c4OC3)c(F)cc2C1

Procedure:
6,8-Difluoro-3-[2-(6-fluoro-3-pentylchroman-7-yl)vinyl]-2H-chromene is dissolved in THF and hydrogenated to completion on a palladium/active carbon catalyst. The catalyst is filtered off, the solution is evaporated, the residue is filtered through silica gel with toluene/heptane (3:2), and the crude product is recrystallised from n-heptane at −25° C., giving colourless crystals of m.p. 84° C.
Reaction SMILES: [OH-].[Na+].[CH:3](/[C:16]1[CH:17]=[C:18]([C:21]([O:23]C)=[O:22])[NH:19][CH:20]=1)=[CH:4]/[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].S(=O)(=O)(O)O>C(O)C>[CH:3](/[C:16]1[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[NH:19][CH:20]=1)=[CH:4]/[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCC/C=C\c1c[nH]c(C(=O)OC)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCC/C=C\c1c[nH]c(C(=O)O)c1
Yield: 44.7 %

Procedure:
An aqueous solution (25 ml) containing 860 mg (20.4 mmol) of 95% sodium hydroxide was added to an ethanol solution (50 ml) of 3.10 g (10.2 mmol) of methyl 4-(1-cis-tridecenyl)pyrrole-2-carboxylate prepared in Example 46, and the whole was heated under reflux for 1 hour. The reaction mixture was acidified with 6N sulfuric acid and extracted with ethyl acetate. The extract was washed with an aqueous saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and treated with activated carbon. After removing the solvent under reduced pressure, the residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 1.33 g (45% yield) of 4-(1-cis-tridecenyl)pyrrole-2-carboxylic acid, m.p. 157°-158° C.
Reaction SMILES: C([O:8][CH2:9][CH:10]1[CH2:23][O:22][C:13]2=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=[C:12]2[O:11]1)C1C=CC=CC=1>C(O)C.[Pd]>[F:21][C:18]([F:19])([F:20])[C:15]1[N:14]=[C:13]2[O:22][CH2:23][CH:10]([CH2:9][OH:8])[O:11][C:12]2=[CH:17][CH:16]=1
Reactant: FC(F)(F)c1ccc2c(n1)OCC(COCc1ccccc1)O2
Agent: [Pd]
Solvent: CCO
Product: OCC1COc2nc(C(F)(F)F)ccc2O1
Reaction time: 3 h
Yield: 81.8 %

Procedure:
To a stirred solution of 2-benzyloxymethyl-6-trifluoromethyl-2,3-dihydro[1,4]dioxino[2,3-b]pyridine (420 mg, 1.3 mmol) in ethanol (50 mL) was added 10% palladium on carbon (10 mg, cat.). The reaction mixture was evacuated and purged with hydrogen six times, then stirred for 3 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite, washing with EtOH (60 mL), and the filtrate evaporated to dryness. Trituration using DCM/hexanes gave the title compound (250 mg, 78%) as a solid. m/z=236.2 (M+1), r.t.=2.46 mins. 1H NMR (400 MHz; CDCl3) δ7.38-7.28 (2H, m), 4.50-4.46 (1H, m), 4.41 (1H, dd), 4.20 (1H, dd), 4.04 (1H, dd), 3.90 (1H, dd).
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][OH:13])[CH:6]=[CH:5][N:4]=1.[SH:14][C:15]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:17]=2[N:16]=1.[OH-].[Na+]>C(O)C>[OH:13][CH2:12][CH2:11][O:10][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][S:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:17]=3[N:16]=2)[C:8]=1[CH3:9]
Reactant: COc1ccc2[nH]c(S)nc2c1
Reactant: Cc1c(OCCO)ccnc1CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2[nH]c(SCc3nccc(OCCO)c3C)nc2c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
60 ml of ethanol was added to a mixture comprising 0.7 g of 2-chloromethyl-4-(2-hydroxyethoxy)-3-methylpyridine, 0.63 g of 2-mercapto-5-methoxy-1H-benzimidazole and 0.16 g of sodium hydroxide to obtain a mixture. This mixture was stirred at 60° C. for one hour, concentrated and purified by silica gel column chromatography to obtain 1.08 g of the title compound.
Reaction SMILES: [OH:1][CH:2]([CH2:18][N:19]1[C:32]2[CH:31]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:29]=[CH:28][C:27]=2[S:26][C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:3][N:4]1[CH2:17][C:6]2([CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]2)[CH2:5]1.Cl>C(Cl)Cl>[CH2:5]1[C:6]2([CH2:7][NH:8][CH2:9]2)[CH2:17][N:4]1[CH2:3][CH:2]([OH:1])[CH2:18][N:19]1[C:32]2[CH:31]=[C:30]([C:33]([F:35])([F:34])[F:36])[CH:29]=[CH:28][C:27]=2[S:26][C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2
Reactant: CC(C)(C)OC(=O)N1CC2(CN(CC(O)CN3c4ccccc4Sc4ccc(C(F)(F)F)cc43)C2)C1
Agent: Cl
Solvent: ClCCl
Product: OC(CN1CC2(CNC2)C1)CN1c2ccccc2Sc2ccc(C(F)(F)F)cc21
Reaction time: 12 h

Procedure:
A solution of (±)-tert-butyl 6-(2-hydroxy-3-(2-(trifluoromethyl)-10H-phenothiazin-10-yl)propyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate and CH2Cl2 was reacted with HCl (0.13 mL, 0.52 mmol, 4.0N solution in dioxane). The reaction mixture was stirred for 12 h. Once no starting material was observed by analytical LCMS, the reaction mixture was concentrated. The residue was purified by flash chromatography on silica gel (0-100% EtOAc in hexanes) to afford the title compound. LCMS m/z 422 (M+H)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([CH2:18][Br:19])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cccc2c(-c3ccc(Br)cc3)nccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc2c(-c3ccc(Br)cc3)nccc12
Reaction time: 0.5 h

Procedure:
1-(4-Bromophenyl)-5-methylisoquinoline (26 g) was dissolved in 200 ml of carbon tetrachloride, and 17.6 g of N-bromosuccinimide was added. Under irradiation of light, the mixture was heated with stirring for 30 minutes. After the reaction, the insoluble matter was removed by filtration. The filtrate was washed in water, dried, and concentrated to remove the solvent. Thus, 1-(4-bromophenyl)-5-bromomethylisoquinoline was obtained. The product was dissolved in 150 ml of acetic acid, and 30 g of anhydrous sodium acetate was added. The mixture was stirred at 140° to 150° C. for 3 hours. After the reaction, the acetic acid was distilled off. The residue was poured into water, and neutralized with an aqueous solution of sodium hydroxide. The resulting oily product was extracted with benzene to afford 30 g of 1-(4-bromophenyl)-5-acetoxymethylisoquinoline. The product was heated with stirring for 2 hours together with 350 ml of methanol and 60 ml of 5 N sodium hydroxide. After the reaction, the reaction mixture was concentrated to remove the solvent. Water was added, and the crystals precipitated were collected by filtration. Recrystallization from benzene-tetrahydrofuran afforded 21 g of 1-(4-bromophenyl)-5-hydroxymethylisoquinoline having a melting point of 225.5° to 226.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[F:12].C(Cl)(=O)C(Cl)=O.[NH2:19][C:20](=[N:26]O)[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(N(CC)C(C)C)(C)C>ClCCl.N1C=CC=CC=1.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[O:11][N:26]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:19]=2)=[CH:4][C:3]=1[F:12]
Reactant: CCOC(=O)C(N)=NO
Reactant: O=C(O)Cc1ccc(Cl)c(F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1noc(Cc2ccc(Cl)c(F)c2)n1
Yield: 23.4 %

Procedure:
This compound was prepared according to general method 2 with (step I) 2-(4-chloro-3-fluorophenyl)acetic acid (0.714 g; 3.78 mmol) and oxalyl chloride (0.352 mL; 4.16 mmol) in dichloromethane (8 mL) with few drops of DMF and (step II) ethyl 2-amino-2-(hydroxyimino)acetate (0.500 g; 3.78 mmol) and N,N diisopropylethylamine (1.05 mL; 6.06 mmol) in dichloromethane (10 mL) and (step III) pyridine (18 mL). The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.252 g (23%) of ethyl 5-(4-chloro-3-fluorobenzyl)-1,2,4-oxadiazole-3-carboxylate as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:19])[CH:16]([CH3:18])[CH3:17])=[C:10]([N+:20]([O-])=O)[CH:9]=1)=[O:7]>C(O)C>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:19])[CH:16]([CH3:17])[CH3:18])=[C:10]([NH2:20])[CH:9]=1)=[O:7]
Reactant: COC(=O)CCC(=O)c1ccc(NC(=O)C(C)C)c([N+](=O)[O-])c1
Solvent: CCO
Product: COC(=O)CCC(=O)c1ccc(NC(=O)C(C)C)c(N)c1

Procedure:
15.5 gm of 4-(3'-nitro-4'-isobutyrylamino-phenyl)-4-oxo-butyric acid methylester were hydrogenated with 4 gm of palladized coal in 480 ml of ethanol at room temperature and 5 atmospheres pressure. The mixture was then suction-filtered, the filter cake was taken up in hot ethanol, the mixturewas filtered, and the reaction product was allowed to crystallize out of the filtrate; m.p. 178° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][CH:9]2[CH2:14][CH:13]3[N:15](C(OC(C)(C)C)=O)[CH:10]2[CH2:11][CH2:12]3)[N:2]=1.[ClH:23]>O1CCOCC1.CC(O)C>[ClH:23].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][CH:9]2[CH2:14][CH:13]3[NH:15][CH:10]2[CH2:11][CH2:12]3)[N:2]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1C(COc1cccnn1)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: c1cnnc(OCC2CC3CCC2N3)c1
Temperature: 70 °C

Procedure:
To the title compound from step A (300 mg, 1 mmol) in 1,4-dioxane (3 mL) was added 6N HCl in iPrOH (1 mL). The reaction was heated to 70° C. for 3 h, cooled to rt and concentrated to give the title compound that was used without further purification. MS (ESI) mass calcd. for C11H15N3O, 205.1; m/z found 206.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:11]([C:22]([F:25])([F:24])[F:23])=[CH:10][C:9]=1[N+:26]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:11]([C:22]([F:24])([F:25])[F:23])=[CH:10][C:9]=1[NH2:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(COC2CCCCO2)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc(COC2CCCCO2)c(C(F)(F)F)cc1N

Procedure:
The title compound was prepared from [2-nitro-5-(tetrahydro-pyran-2-yloxymethyl)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester [prepared from (5-hydroxymethyl-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example A30) (476 mg, 1.42 mmol) by treatment with 3,4-dihydro-2H-pyran (0.19 mL, 2.12 mmol) and p-TsOH (5 mg, 0.03 mmol) in DCM at 0° C., stirring at 0° C. for 15 min and at 23° C. for 18 h.] (0.58 g, 1.38 mmol) reduction with SnCl2.2H2O according to the general procedure J (method b). Obtained as an amorphous yellow substance (414 mg, 77%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:31])=[C:16]([O:21][CH2:22][CH:23]=[CH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:33])[CH3:32])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H][H]>C(O)C.[C].[Pd]>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[C:14]3[C:15]([CH3:31])=[C:16]([O:21][CH2:22][CH2:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:33])[CH3:32])=[CH:8][CH:9]=1)([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: Cc1c(C)c2c(c(C)c1OCC=Cc1ccccc1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Agent: [Pd]
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1OCCCc1ccccc1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 75.7 %

Procedure:
3-(4-Isopropylphenyl)-2,2,4,6,7-pentamethyl-5-(3-phenyl-2-propen-1-yl)oxy-2,3-dihydrobenzofuran (800 mg, 1.82 mmol) and 10% palladium-carbon (hydrate) (80 mg) were suspended in ethanol (20 mL), and the mixture was stirred for 3 hours in a hydrogen atmosphere at room temperature. The catalyst was removed through filtration, and the filtrate was concentrated under reduced pressure. The residue was crystallized from methanol to obtain the title compound (610 mg, yield 76%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1C(OCC)=O.[H-].[Na+].[CH2:18]([N:20]1[C:28]2[C:23](=[N:24][CH:25]=[CH:26][CH:27]=2)[N:22]([C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=2)[C:21]1=[O:36])[CH3:19].[Cl-].[Cl-].[Ca+2]>CN(C=O)C.CO>[CH2:18]([N:20]1[C:28]2[C:23](=[N:24][CH:25]=[CH:26][CH:27]=2)[N:22]([C:29]2[CH:30]=[CH:31][C:32]([O:35][C:2]3[N:3]=[C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][N:5]4[CH:10]=3)=[CH:33][CH:34]=2)[C:21]1=[O:36])[CH3:19]
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncccc21
Reactant: CCOC(=O)c1c(Cl)nc2ccccn12
Agent: [Ca+2]
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CO
Product: CCn1c(=O)n(-c2ccc(Oc3cn4ccccc4n3)cc2)c2ncccc21
Yield: 11 %

Procedure:
The mixture of ethyl 2-chloroimidazo[1,2-a]pyridine-3-carboxylate (220 mg), NaH (70 mg) and 1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (255 mg) in DMF (2 mL) was stirred at 100° C. under a dry atmosphere (CaCl2 tube) for 1 h. The mixture was diluted with MeOH and concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, eluted with 0%-30% EtOAc in hexane) to give 1-ethyl-3-[4-(imidazo[1,2-a]pyridin-2-yloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (40 mg) as white crystals.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[OH:11])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[NH2:1][CH:4]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[OH:11]
Reactant: [N-]=[N+]=NC1CCCCCC1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NC1CCCCCC1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 66.4 %

Procedure:
To a stirred mixture of (±)-2-azidocycloheptanol (190 mg, 1.2 mmol) in THF (1 mL) and H2O (100 μL) was added PPh3 (321 mg, 1.2 mmol). The mixture was stirred at rt for 15 h, then concentrated under reduced pressure. The residue was purified via silica gel flash chromatography eluting with 100:15:1, CH2Cl2:MeOH:TEA to afford (±)-2-aminocycloheptanol (103 mg, 50%) as a white solid. LCMS (ELSD) (ESI) m/z 130 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[CH2:29][C@:28]3([CH3:43])[C@@H:30]([CH3:42])[CH2:31][CH2:32][C@H:33]4[C:34]([CH3:41])([CH3:40])[C@@H:35]([OH:39])[C@@H:36]([OH:38])[CH2:37][C@@:27]34[O:26][C:11]=2[C:12]2[CH2:13][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:15](=[O:18])[C:16]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[C:53](Cl)(=[O:55])[CH3:54].O>ClCCl>[C:53]([O:38][C@@H:36]1[C@H:35]([OH:39])[C:34]([CH3:41])([CH3:40])[C@H:33]2[C@@:27]3([O:26][C:11]4[C:12]5[CH2:13][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:15](=[O:18])[C:16]=5[CH:17]=[C:9]([O:8][CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[C:10]=4[CH2:29][C@:28]3([CH3:43])[C@@H:30]([CH3:42])[CH2:31][CH2:32]2)[CH2:37]1)(=[O:55])[CH3:54]
Reactant: CC(=O)Cl
Reactant: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)[C@@H](O)C[C@]23Oc2c(c(OCc4ccccc4)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: ClCCl
Product: CC(=O)O[C@H]1C[C@@]23Oc4c(c(OCc5ccccc5)cc5c4CN(C(=O)OC(C)(C)C)C5=O)C[C@]2(C)[C@@H](C)CC[C@H]3C(C)(C)[C@H]1O
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
To a solution of Compound (48a) (51 mg, 0.086 mmol) in 5.0 ml of dichloromethane were added 32 mg (0.26 mmol) of dimethylaminopyridine and 9.2 μl (0.13 mmol) of acetyl chloride under ice-cooling, and the mixture stirred for 30 min at the same temperature. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed sequentially with 1N HCl, water, an aqueous saturated hydrogen carbonate solution, and water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a column chromatography (Merck, Lobar column, size A; toluene:ethyl acetate=2:1) to give 49 mg (90%) of Compound (48b).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH3:8][C:9]1[CH:20]=[CH:19][C:12]2[O:13][CH:14]([CH2:17][NH2:18])[CH2:15][O:16][C:11]=2[CH:10]=1>>[CH2:6]([O:5][C:1](=[O:4])[CH2:2][CH2:3][NH:18][CH2:17][CH:14]1[O:13][C:12]2[CH:19]=[CH:20][C:9]([CH3:8])=[CH:10][C:11]=2[O:16][CH2:15]1)[CH3:7]
Reactant: Cc1ccc2c(c1)OCC(CN)O2
Reactant: C=CC(=O)OCC
Product: CCOC(=O)CCNCC1COc2cc(C)ccc2O1
Reaction time: 60 h

Procedure:
4.4 ml (0.04 mol) of ethyl acrylate are added to 7.2 g (0.04 mol) of 6-methylbenzo-1,4-dioxan-2-ylmethylamine and the reaction mixture is left to stand for 60 hours at room temperature, yielding crude 3-[N-(6-methylbenzo-1,4-dioxan-2-ylmethyl)amino]-propionic acid ethyl ester which can be used without further purification.
Reaction SMILES: O.[NH2:2]N.[CH2:4]([O:11][C:12]1[C:13]([CH:27]=O)=[C:14]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:15]([N:17](CC)CC)=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)(=O)C>[CH2:4]([O:11][C:12]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[C:14]2[C:13]=1[CH:27]=[N:2][NH:17][C:15]2=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCN(CC)C(=O)c1ccc(OC)c(OCc2ccccc2)c1C=O
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c(=O)[nH]ncc2c1OCc1ccccc1
Reaction time: 2 h
Yield: 95.8 %

Procedure:
Glacial acetic acid (285 ml) at 10-20° C. was dropwise added with hydrazine monohydrate (10.16 ml, 209 mmoles) and added with 3-benzyloxy-N,N-diethyl-2-formyl-4-methoxy-benzamide (14.27 g, 41.8 mmoles), prepared as described in example 56. The mixture was left to stand for 2 hours, then evaporated, dissolved in CH2Cl2, washed with water, anhydrified over Na2SO4, brought to dryness, and the crude was triturated in petrolatum/ethyl ether 2:1 (150 ml) and filtered to give 11.3 g of the title compound (yield: 96%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([N:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21](O)=[O:22])[C:12]3=[O:24])[CH:9]=[CH:10][C:2]1=2.CN(C)C=O.C(Cl)(=O)C([Cl:33])=O>ClCCl>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([N:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]([Cl:33])=[O:22])[C:12]3=[O:24])[CH:9]=[CH:10][C:2]1=2
Reactant: O=C(O)c1nc2ccccc2n(-c2ccc3c(c2)OCCO3)c1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1nc2ccccc2n(-c2ccc3c(c2)OCCO3)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9.9 g (31 mmol) of 1-(2,3-dihydrobenzo[b] 1,4-dioxin-6-yl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid was dissolved in dichloromethane (100 mL), and to this solution, N,N-dimethylformamide (0.5 mL) and 4.7 g (37 mmol) of oxalyl chloride were added sequentially. The mixture was stirred for one hour at room temperature. After confirming the completion of the reaction, the solvent was distilled off under reduced pressure to obtain 1-(2,3-dihydrobenzo[b]1,4-dioxin-6-yl)-2-oxo-1,2-dihydroquinoxaline-3-carbonyl chloride as yellow crystals (Compound No. of Production Intermediate: IX-75).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C:17]#[N:18])=[C:13]([NH2:16])[O:14][CH:15]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:19]([O:22][CH:23](OCC)OCC)(=O)[CH3:20]>C(O)(=O)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([C:17]#[N:18])=[C:13]([N:16]=[CH:23][O:22][CH2:19][CH3:20])[O:14][CH:15]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CCOC(OCC)OC(C)=O
Reactant: CC(=O)Nc1ccc(-c2coc(N)c2C#N)cc1
Solvent: CC(=O)O
Product: CCOC=Nc1occ(-c2ccc(NC(C)=O)cc2)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
At room temperature, to the mixture of 4-(4-acetamidophenyl)-2-amino-3-cyanofurane 5 (6.0 g, 25 mmol) in acetic acid (60 mL), diethoxymethyl acetate (41 mL, 25 mmol) was added dropwise. The mixture was stirred at room temperature for 30 min and then concentrated (below 40° C. in water bath). The residual paste was dried up with a pump. The dried solid material was triturated with ether then filtrated to afford 6 (3.93 g) as a solid. MS(ES) m/e 298 [M+H].
Reaction SMILES: [C:1]([CH:4]1[CH:9]2[CH:5]1[CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8]2)(=O)[NH2:2].N1C(Cl)=NC(Cl)=NC=1Cl>CN(C=O)C.O>[C:1]([CH:4]1[CH:5]2[CH:9]1[CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]2)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CC2C(C1)C2C(N)=O
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC2C(C#N)C2C1
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a solution of 2 (1.83 g, 8.09 mmol) in DMF (30 mL) was added cyanuric chloride (1.50 g, 8.09 mmol) and stirred for 2 h. The reaction was diluted with water (100 mL) and extracted with EtOAc (2×80 mL). The combined organic extracts were washed with water (2×100 mL), brine (120 mL), dried over MgSO4 and concentrated under vacuum to afford 3 (1.67 g, 99%) as a clear yellow oil; 1H-nmr (400 MHz, CDCl3) δ 3.80-3.58 (m, 2H), 3.40 (d, J=12.0 Hz, 2H), 2.16 (s, 2H), 1.43 (s, 9H), 1.25 (t, J=3.0 Hz, 1H).
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]2[C:10]([NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=[CH:7][N:6]2[C:18]=1[CH3:19].S(Cl)([Cl:22])=O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:22][CH2:2][C:3]1[N:4]=[C:5]2[C:10]([NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=[CH:7][N:6]2[C:18]=1[CH3:19]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(CO)nc2c(NC(=O)C(C)(C)C)cccn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(CCl)nc2c(NC(=O)C(C)(C)C)cccn12
Reaction time: 2 h
Yield: 91.3 %

Procedure:
To a stirred suspension of 13 g of 2-hydroxymethyl-3-methyl-8-pivaloylaminoimidazo[1,2-a]pyridine in 500 ml of dry dichloromethane is added dropwise a solution of 6.5 g thionyl chloride in 50 ml dry dichloromethane at 0–5° C. to give a clear yellow solution. After 2 h the reaction mixture is hydrolysed by adding 200 ml saturated sodium bicarbonate solution under cooling. The resulting mixture is transferred to a separatory funnel and shaken vigorously. The organic layer is separated, washed with water and dried over anhydrous sodium sulfate. The solvent is removed in vacuo to give 12.7 g (92%) of the title compound (m.p. 168° C.).