Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[CH2:12]=[C:13]1[O:17][C:15](=[O:16])[CH2:14]1.S(=O)(=O)(O)O>CC(=O)CC.O>[C:15]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5])(=[O:16])[CH2:14][C:13]([CH3:12])=[O:17]
Reactant: C=C1CC(=O)O1
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCC(C)=O
Product: CC(=O)CC(=O)N[C@@H](CC(=O)O)C(=O)O
Temperature: -6 °C

Procedure:
L-aspartic acid, 133.1 parts, was slurried with 375 parts by volume of water and 81.5 parts 98.2% sodium hydroxide were added with cooling and stirring, the temperature being kept below 35° C. After all solid had dissolved, 50 parts by volume of 2-butanone were added and the mixture was cooled to -6° C. Diketene, 88 parts, was then added gradually over a period of 30-40 minutes with good stirring, with the temperature being maintained at from about -6° to -4° C. The mixture was then stirred for an additional 30-45 minutes without cooling. The pH of the reaction mixture initially was about pH 11.5 but fell to about pH 9 or less at the end of the reaction period. To the reaction mixture was then added 61 parts by volume of concentrated sulfuric acid with constant stirring but without cooling. The resulting mixture having a pH from about 1.9-2.0 was then warmed further to 40°-45° C. Additional 2-butanone, 250 parts by volume, was added and the liquid layers were well mixed. The organic layer was then separated and the aqueous layer was extracted at 40°-45° C. three times with 125 parts by volume portions of 2-butanone to which 12.5 parts by volume of water had been added. The aqueous layer was given a final extraction with 125 parts by volume of 2-butanone and the combined organic extracts were shaken with a little sodium sulfate to remove suspended water droplets. The extract was filtered and 2-butanone was distilled at 25-30 mm pressure to leave a residual solution of N-acetoacetyl-L-aspartic acid in water. The temperature of the solution was increased to 80°-90° C. in order to distill much of the water resulting in the formation of a thick syrup. The warm syrup was immediately mixed with 250 parts by volume of acetone and the mixture was stirred well. N-acetoacetyl-L-aspartic acid soon crystallized and the resulting slurry was cooled to about 10° C. The solid was collected on a funnel, rinsed with acetone, and then dried at 65° C. Acetone and some water were removed from the filtrate by distillation and the residual syrup was stirred with 70 parts by volume of acetone to afford a second crop of N-acetoacetyl-L-aspartic acid. A small third crop was obtained by reworking the filtrate from the second crop. The yield of crystalline N-acetoacetyl-L-aspartic acid in three crops averaged 193.3 parts.
Reaction SMILES: [CH3:1][C:2]1([CH2:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[NH:7][CH2:6][CH2:5][NH:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[C:25]1([CH:31](Br)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC(C)=O>[C:25]1([CH:31]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:4]2[CH2:5][CH2:6][NH:7][C:2]([CH3:1])([CH2:8][C:9]3[CH:14]=[CH:13][C:12]4[O:15][CH2:16][CH2:17][O:18][C:11]=4[CH:10]=3)[CH2:3]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: CC1(Cc2ccc3c(c2)OCCO3)CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(Cc2ccc3c(c2)OCCO3)CN(C(c2ccccc2)c2ccccc2)CCN1
Yield: 91.8 %

Procedure:
12.4 g of 3-methyl-3-(3,4-ethylenedioxybenzyl)-piperazine (1a) are dissolved in 200 ml of dry acetone, combined with 20.7 g of potassium carbonate and 14.8 g of diphenylmethyl bromide, and heated for four hours with stirring under reflux. The inorganic salts are filtered off and the filtrate is evaporated to dryness is vacuum. The residue is taken up in 300 ml of diethyl ether and washed with water until the wash water no longer contains halogen. After drying with magnesium sulfate, hydrogen chloride is introduced into the organic phase. The precipitated hydrochloric is filtered off and washed with a little ether. Thereafter, it it suspended in a little water, combined with 20% ammonium hydroxide solution until alkaline, and extracted three times with 50 ml of diethyl ether. The organic phases are dried over magnesium sulfate and reduced to dryness. 19 g (91.6%) of 1-diphenylmethyl-3-methyl-3-(3,4-ethylenedioxybenzyl)-piperazine (3a) are obtained.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30](=[O:34])[CH2:31][CH2:32][CH3:33])[C@H:14]2[CH3:35])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Br:38]Br>C(Cl)(Cl)Cl>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][C:21]=3[C:30](=[O:34])[CH:31]([Br:38])[CH2:32][CH3:33])[C@H:14]2[CH3:35])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: CCCC(=O)c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCC(Br)C(=O)c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-butyryl-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (300 mg, 0.554 mmol) in CHCl3 (3 mL) at 0° C. under N2, was added dropwise a solution of bromine (0.030 mL, 0.582 mmol) in CHCl3 (2 mL). The reaction was stirred at 0° C. for 1 h. The reaction mixture was evaporated in vacuo. The residue was purified by flash chromatography on silica gel to give (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(2-bromobutanoyl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one as a white solid. LCMS calc.=622.0; found=621.7 (M+1)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers) δ 7.91 (s, 1 H); 7.85 (d, J=5.1 Hz, 1 H); 7.83-7.77 (m, 2.5 H); 7.74-7.69 (m, 1.5 H); 5.79 (d, J=7.8 Hz, 0.5 H); 5.74 (d, J=7.9 Hz, 0.5 H); 5.06-4.92 (m, 2 H); 4.57 (d, J=16.4 Hz, 0.5 H); 4.47 (d, J=16.0 Hz, 0.5H); 4.24-4.16 (m, 1 H); 2.35-2.25 (m, 1 H); 2.19-2.09 (m, 1 H); 1.18-1.16 (m, 3 H); 0.80 (d, J=6.6 Hz, 1.5 H); 0.78 (d, J=6.6 Hz, 1.5 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][NH:6][C:7](=[O:24])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19](Br)=[CH:18][C:17]=2[CH3:23])=[CH:10][CH:9]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][NH:6][C:7](=[O:24])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:18][C:17]=2[CH3:23])=[CH:10][CH:9]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)CCNC(=O)c1ccc(OCc2ccc(Br)cc2C)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: Cc1ccccc1
Solvent: O
Product: COC(=O)CCNC(=O)c1ccc(OCc2ccc(-c3ccccc3)cc2C)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 101.2 %

Procedure:
A mixture of 3-[4-(4-bromo-2-methyl-benzyloxy)-benzoylamino]-propionic acid methyl ester (0.20 g, 0.49 mmol), phenyl boronic acid (0.09 g, 0.78 mmol), and Na2CO3 (0.11 g, 1.08 mmol) in toluene/water (3 mL: 1 mL) is degassed (2×). Pd(PPh3)4 (0.05 g, 0.04 mmol) is added, and the mixture is stirred at 100° C. for 12 h. The mixture is filtered through Celite. Water is added, and the mixture is extracted with EtOAc. The organics are dried with MgSO4 and concentrated. The crude material is purified by flash chromatography to yield 0.20 g (100%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].[C:11]([N:19]=[C:20]=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCOCC1>[C:7]([C:6]1[C:5]([CH3:9])=[C:4]([CH3:10])[S:3][C:2]=1[NH:1][C:20]([NH:19][C:11](=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[S:21])#[N:8]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Cc1sc(N)c(C#N)c1C
Solvent: C1COCCO1
Product: Cc1sc(NC(=S)NC(=O)c2ccccc2)c(C#N)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-amino-4,5-dimethylthiophene-3-carbonitrile (1.52 g, 10.0 mmol) in 1.4-dioxane (20 mL) was added benzoylisothiocyanate (1.63 g, 10.0 mmol). The reaction mixture was then stirred at room temperature under nitrogen overnight. The precipitation was collected by filtration, washed with EtOAc/Hexanes (1:4), and dried under vacuum overnight to give N-(3-Cyano-4,5-dimethylthiophen-2-ylcarbamothioyl)benzamide as a white solid. 1H NMR (400 MHz, CDCl3) δ2.23 (s, 3H), 2.31 (s, 3H), 7.58-7.54 (m, 2H), 7.68-7.66 (m, 1H), 7.94 (d, J=7.2 Hz, 2H), 9.13 (bs, 1H). MS 316 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH:9]1[CH:15]([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:21][C:22]1[N:23]([CH3:48])[C:24]2[C:29]([N:30]=1)=[C:28]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[N:27]=[C:26]([N:37]1[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=3[N:39]=[C:38]1[CH2:46][CH3:47])[N:25]=2>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:21][C:22]2[N:23]([CH3:48])[C:24]3[C:29]([N:30]=2)=[C:28]([N:31]2[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)[N:27]=[C:26]([N:37]2[C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=4[N:39]=[C:38]2[CH2:46][CH3:47])[N:25]=3)[C:10](=[O:14])[CH:9]1[CH:15]([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C1C(=O)NCCN1C(=O)OC(C)(C)C
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(=O)OC(C)(C)C)C(C(C)C)C3=O)n(C)c2n1
Reaction time: 19 h
Yield: 76.5 %

Procedure:
To a solution of 2-isopropyl-3-oxopiperazine-1-carboxylic acid tert-butyl ester (58 mg, 0.24 mmol) in DMF (1.5 mL) at 0° C. was added NaH (11 mg, 0.29 mmol, 60% dispersion in mineral oil) and the resulting mixture stirred at r.t. for 30 min before the addition of 8-bromomethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (100 mg, 0.22 mmol) in DMF (1.5 mL). The resulting mixture was allowed to stir for 19 h then partitioned between EtOAc and H2O. The organic phase was dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-10%) affording the title compound as a yellow oil (104 mg, 77%), LCMS (method H): RT 3.03 min [M+H]+ 618.4
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:20])[C:4]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8][C:7](=[CH:10][C:11]([OH:13])=O)[CH2:6][CH2:5]1.C1(N=[C:28]=[N:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)CCCCC1.[OH-].[Na+]>CN(C)C=O.O>[CH3:20][N:3]([CH3:2])[C:4]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:5][CH2:6][C:7](=[CH:10][C:11]([NH:3][CH2:4][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[C:31]3[C:30](=[CH:35][CH:34]=[CH:33][CH:32]=3)[NH:29][CH:28]=2)=[O:13])[CH2:8][CH2:9]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CN(C)C1(c2ccccc2)CCC(=CC(=O)O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C1(c2ccccc2)CCC(=CC(=O)NCCCCCCc2c[nH]c3ccccc23)CC1
Temperature: 0 °C
Reaction time: 264 h
Yield: 14.7 %

Procedure:
(4-dimethylamino-4-phenylcyclohexylidene)acetic acid hydrochloride (810 mg, 2.73 mmol) in dry dimethylformamide (10 ml) under argon. The solution was cooled to 0° C. and dicyclohexylcarbodiimide (1.13 g, 5.46 mmol) was added. The reaction mixture was stirred at RT for 11 d. Working up of the mixture was carried out by separating off the urea which had precipitated out and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO3 solution (10 ml). Still further urea thereby precipitated out and was separated off. The aqueous phase was diluted with water (300 ml), 5 M sodium hydroxide solution (7 ml, 35 mmol) was added and the mixture was stored at 5° C. for 16 h. The crude product thereby precipitated out as a beige-coloured solid in a yield of 16% (197 mg). After chromatography on silica gel (20 g) with EA/methanol (4:1), the product was isolated as an oily compound (92 mg) in a yield of 8%.
Reaction SMILES: [F:1][C:2]1([CH3:19])[CH2:7][C:6]([F:9])([F:8])[C@:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])([CH3:10])[NH:4][C:3]1=[O:18].FC(F)(F)C(O)=O.OS(O)(=O)=O.[N+:32]([O-])([OH:34])=[O:33].[OH-].[Na+]>>[F:1][C:2]1([CH3:19])[CH2:7][C:6]([F:9])([F:8])[C@:5]([C:11]2[CH:16]=[C:15]([N+:32]([O-:34])=[O:33])[CH:14]=[CH:13][C:12]=2[F:17])([CH3:10])[NH:4][C:3]1=[O:18]
Reactant: O=[N+]([O-])O
Reactant: CC1(F)CC(F)(F)[C@@](C)(c2ccccc2F)NC1=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CC1(F)CC(F)(F)[C@@](C)(c2cc([N+](=O)[O-])ccc2F)NC1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.2 %

Procedure:
(6R)-3,5,5-Trifluoro-6-(2-fluorophenyl)-3,6-dimethylpiperidin-2-one (1.86 g, 6.76 mmol) (1:1.8 mixture of diastereomers) was suspended in trifluoroacteic acid (11.5 ml, 149 mmol). The mixture was cooled to 0° C. and concentrated H2SO4 (2.86 ml, 52.0 mmol, 97%) was added. Finally, fuming HNO3 (0.33 ml, 7.4 mmol) was added in a dropwise manner and the reaction was stirred at 0° C. for 10 min. The reaction mixture was poured onto 150 g ice and basified to pH>11 using 5 M NaOH. The resulting suspension was extracted with ethyl acetate (250 mL). The phases were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organics were washed with a solution of saturated aqueous NH4Cl (50 mL) and water (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to afford (6R)-3,5,5-trifluoro-6-(2-fluoro-5-nitrophenyl)-3,6-dimethylpiperidin-2-one (2.08 g, 6.50 mmol, 96% yield) (1:1.8 mixture of diastereomers) LC-MS (m/z) 321.1 (MH+) tR=0.62 minutes (Method B).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.[Cl:15][C:16]1[CH:21]=[C:20](Cl)[CH:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[Cl:15][C:16]1[CH:21]=[C:20]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]3)[CH:19]=[CH:18][N:17]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: O=C(O)c1cccc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cccc2cc(Oc3ccnc(Cl)c3)ccc12
Temperature: 90 °C

Procedure:
6-Hydroxynaphtoic acid (10.0 g, 53.1 mmol), 2,4-dichloropyridine (9.44 g, 63.8 mmol) and cesium carbonate (51.9 g, 159 mmol) were combined in DMSO (266 mL) and the reaction mixture was heated at 90° C. for 16 h. After cooling to RT, water was added and the aqueous layer was acidified to pH=4-5. The title compound was isolated by filtration and dried under vacuum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:23][C:11]3=[N:12][C:13]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[C:14](I)[CH:15]=[C:10]3[C:9]=2[C:24]([NH:26][CH3:27])=[O:25])=[CH:4][CH:3]=1.[C:28]([OH:34])(=[O:33])[CH2:29][CH2:30][C:31]#[CH:32].C(N(CC)CC)C>[Cu]I.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:23][C:11]3=[N:12][C:13]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([C:32]#[C:31][CH2:30][CH2:29][C:28]([OH:34])=[O:33])[CH:15]=[C:10]3[C:9]=2[C:24](=[O:25])[NH:26][CH3:27])=[CH:4][CH:3]=1
Reactant: C#CCCC(=O)O
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(C)S(C)(=O)=O)c(I)cc12
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(C)S(C)(=O)=O)c(C#CCCC(=O)O)cc12
Temperature: 80 °C

Procedure:
A mixture of 2-(4-fluorophenyl)-5-iodo-N-methyl-6-(N-methylmethylsulfonamido)furo[2,3-b]pyridine-3-carboxamide (52 mg), pent-4-ynoic acid (51 mg), triethylamine (0.43 ml), copper(I) iodide (0.79 mg), Pd(PPh3)Cl2 (5.8 mg) and THF (1.4 ml) was bubbled with nitrogen. Heated at 80° C. for 16 h. Cooled to rt and purified by preparative HPLC. (M+H)+=474.1; Retention time=1.22 min, Method A.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18](=[O:23])[CH2:19][C:20]([CH3:22])=[O:21])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][O:17][C:18](=[O:23])[CH2:19][C:20]([CH3:22])=[O:21])=[CH:13][CH:14]=1
Reactant: CC(=O)CC(=O)OCCc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)CC(=O)OCCc1ccc(O)cc1
Yield: 97.5 %

Procedure:
A solution of 6.2 g of 2-(4-benzyloxyphenyl)ethylacetoacetate in 100 mL of ethanol with 0.5 g of 10% palladium on carbon was hydrogenated at 50 psi for 18 h. The mixture was filtered and the filtrate evaporated to afford 4.3 g of 2-(4-hydroxyphenyl)ethylacetoacetate.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C([N:14]=C=NCCCN(C)C)C.[Cl-].[NH4+].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:14])=[O:5]
Reactant: Nc1c(Cl)cccc1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(Cl)c1N
Reaction time: 6 h
Yield: 50.4 %

Procedure:
To 2-amino-3-chlorobenzoic acid (1.72 g, 10 mmol) in DMF (5 mL) were added hydroxybenzatriazole (2.0 g, 13 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2.3 g, 12 mmol), ammonium chloride (2.3 g, 42 mmol), and DIEA (7.5 ml, 42 mmol). The mixture was purged with nitrogen and was stirred for 6 h. The mixture was then poured into water and extracted with EtOAc (3×50 mL). The combined extracts were washed with brine (2×20 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was treated with DCM (10 mL) resulting in a precipitate that was collected by filtration to afford 2-amino-3-chlorobenzamide (860 mg). LCMS (ESI) m/z 171 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:17]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[S:20]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:10][CH2:11][C@H:12]([O:15][C:17]2[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:18]=2[C:19]([O:21][CH3:22])=[S:20])[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=S)c1ccc(C)cc1O
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Product: COC(=S)c1ccc(C)cc1O[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)CC1

Procedure:
Using a procedure analogous to Example 1-D, trans-4-(t-butoxycarbonylamino)cyclohexanol and methyl 2-hydroxy-4-methylthiobenzoate gave the title compound as a white solid (16.0 g, 16%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](CC#N)=[C:4]([F:11])[C:3]=1[F:12].OS(O)(=O)=O.[CH3:18][C:19](=[O:23])[O:20]CC>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:18][C:19]([OH:20])=[O:23])=[C:4]([F:11])[C:3]=1[F:12]
Reactant: N#CCc1ccc(Br)c(F)c1F
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1ccc(Br)c(F)c1F
Temperature: 100 °C
Reaction time: 1 h
Yield: 41.6 %

Procedure:
Compound 2-(4-bromo-2,3-difluorophenyl)acetonitrile (200 mg, 0.690 mmol) was dissolved in H2O (1 mL) and H2SO4 (1 mL) at 20° C. in one charge. The reaction mixture was stirred at 100° C. for 1 h. Then the solution was distributed between EA and H2O. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The resulting 2-(4-bromo-2,3-difluorophenyl)acetic acid (180 mg, 0.287 mmol, 41.6% yield) was used in the next step without further purification. TLC (PE/EtOAc=2:1, Rf 0.6): 1H NMR (400 MHz, CDCl3) δ 7.27-7.20 (m, 1H), 6.92-6.85 (m, 1H), 3.65 (s, 2H); ES-LCMS m/z 250.0 (M+H).
Reaction SMILES: N12CCCN=C1CCCCC2.[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:27](Cl)=[C:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[S:25][C:24]=2[CH:34]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:35]1([SH:41])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:27]([S:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[S:25][C:24]=2[CH:34]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1sc2cc(OCc3ccccc3)ccc2c1Cl
Reactant: Sc1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1sc2cc(OCc3ccccc3)ccc2c1Sc1ccccc1
Temperature: 60 °C
Yield: 83.7 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU--0.39 ml, 2.5 mmol) was added to a mixture of ethyl 6-(benzyloxy)-3-chlorobenzo[b]thiophene-2-carboxylate (Preparation 8, 800 mg, 2.3 mmol) and thiophenol (0.47 ml, 4.6 mmol) in dimethylformamide (4 ml) under a nitrogen atmosphere. The solution was heated to 60° C. for 6 hours and then partitioned between diethyl ether and water. The organics were separated and washed with water, dried (magnesium sulfate) and evaporated under reduced pressure. The residue was flash chromatographed on silica gel using a mixture of 20% dichloromethane and 80% hexane, then 50% dichloromethane and 50% hexane as eluant. The isolated product was crystallised from diisopropyl ether and hexane to give the title compound as a colourless solid (810 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[O:24][C:13]2=[C:14]3[C:19](=[C:20](I)[CH:21]=[C:12]2[CH2:11]1)[NH:18][C:17](=[O:23])[CH:16]=[CH:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][N:26](C)C=O>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[O:24][C:13]2=[C:14]3[C:19](=[C:20]([C:25]#[N:26])[CH:21]=[C:12]2[CH2:11]1)[NH:18][C:17](=[O:23])[CH:16]=[CH:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC1Cc2cc(I)c3[nH]c(=O)ccc3c2O1
Reactant: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC1Cc2cc(C#N)c3[nH]c(=O)ccc3c2O1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
2-(t-Butoxycarbonyl)aminomethyl-5-iodo-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (610 mg) and cuprous cyanide (134 mg) were dissolved in dimethylformamide (30.5 ml), and stirred at 150° C. for 1 hour. After completion of the reaction, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent=chloroform:methanol=70:1). As a result, 347 mg of 2-(t-butoxycarbonyl)aminomethyl-5-cyano-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one was obtained (73.7%). This compound was recrystallized from a solvent mixture of chloroform-n-hexane to obtain pale yellow powdery crystals (mp.: 200°-202° C. (dec.)).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[CH3:16][C:17](=O)[CH2:18][CH2:19][CH2:20][CH3:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:18]([C:17]1([CH3:16])[NH:1][C:2]2[CH:6]=[C:5]([C:7]3[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=3)[S:4][C:3]=2[C:13](=[O:14])[NH:15]1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCC(C)=O
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCC1(C)NC(=O)c2sc(-c3ccncc3)cc2N1
Temperature: 80 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.108 g, 0.500 mmol), 2-hexanone (2.0 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (2.0 mL) was stirred for 3 h at 80° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (150 mL). Extraction with ethyl acetate (100 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. This oil was purified by column chromatography (Combiflash, 12 g silica gel, dichloromethane to 90:10 dichloromethane/methanol), then triturated with ethyl acetate, and the precipitate was collected by filtration to afford the title compound (0.0747 g, 50%) as a yellow solid: