Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.CCN(CC)CC>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([N:13]1[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]1)(=[O:7])=[O:6]
Reactant: CN1CCNCC1
Reactant: O=S(=O)(Cl)CCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(S(=O)(=O)CCCCl)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
3-Chloropropanesulfonyl chloride (1.0 g, 5.6 mmol) dissolved in CH2Cl2 (20 mL) and cooled to ˜0° C. was treated dropwise with a solution of 1-methylpiperazine (566 mg, 5.6 mmol) and Et3N (572 mg, 5.6 mmol) in CH2Cl2 (10 mL). Following complete addition, the mixture was allowed to warm to rt and stir an additional 2 h. The solvent was evaporated under reduced pressure, the residue triturated with EtOAc (30 mL), vacuum filtered and the solid washed well with EtOAc. The filtrate was concentrated under reduced pressure and the oil residue dried under high vacuum to give the title compound (1.27 g, 93%): 1H NMR (CDCl3) δ: 2.17-2.26 (2H, m), 2.49 (3H, s), 2.75-2.77 (4H, m), 3.02-3.07 (2H, m), 3.46-3.49 (4H, m), 3.60 (2H, t).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:28])(=O)C.[NH:29]1[CH:33]=[C:32]([C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[N:31]=[CH:30]1>>[NH:29]1[CH:33]=[C:32]([C:34]2[CH:40]=[CH:39][C:37]([NH:38]/[C:18](=[C:6]3\[C:5](=[O:28])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=4)/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:36][CH:35]=2)[N:31]=[CH:30]1
Reactant: Nc1ccc(-c2c[nH]cn2)cc1
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(OCC)c1ccccc1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(-c2c[nH]cn2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone and 4-(imidazol-4-yl)-aniline Rf value: 0.5 (silica gel, methylene chloride/ethanol/ammonia=10:1:0.01) C27H22N4O3
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:29])=[C:4]([NH:10][C@H:11]([C@@H:26]([OH:28])[CH3:27])[C:12]([NH:14][NH:15][C:16](=O)[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:29])=[C:4]([NH:10][C@@H:11]([C:12]2[O:13][C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)=[N:15][N:14]=2)[C@@H:26]([OH:28])[CH3:27])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: COc1cccc(C(=O)NNC(=O)[C@H](Nc2ccc(C#N)c(Cl)c2C)[C@H](C)O)c1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Product: COc1cccc(-c2nnc([C@H](Nc3ccc(C#N)c(Cl)c3C)[C@H](C)O)o2)c1
Temperature: 25 °C
Yield: 52.9 %

Procedure:
To a 100 mL round bottom flask was added N′-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)-3-methoxybenzohydrazide (Intermediate 6a) (441 mg, 1.1 mmol) was added THF (90 mL) and stirred at room temperature. PS-BEMP (1.45 g, 3.2 mmol base) was added to the solution followed by slow addition of p-TSCl (208 mg, 1.1 mmol). The reaction mixture was stirred for 2 h and the progress of the reaction was monitored by TLC. After the completion of the reaction, the BEMP reagent was filtered off, washed with methanol (100 mL), and the resulting solution was concentrated to obtain the crude material. The crude material was chromatographed on silica gel with hexanes:EtOAc (2:8) to get the purified product (232 mg, 55%). 1H NMR (400 MHz, d6-acetone, δ in ppm) 7.42 (m, 1H), 7.33 (m, 3H), 7.01 (m, 1H), 6.50 (d, J=8.7 Hz, 1H), 5.37 (d, J=8.5 Hz, 1H), 4.72 (m, 1H), 4.62 (m, 1H), 3.94 (br s, 1H), 3.80 (s, 3H), 2.37 (s, 3H), 1.43 (d, J=6.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:24][C:25]4[CH2:26][NH:27][CH:28]([CH3:32])[CH2:29][C:30]=4[N:31]=3)=[O:22])[CH:17]([C:33](=[O:42])[NH:34][O:35]C3CCCCO3)[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:24][C:25]4[CH2:26][NH:27][CH:28]([CH3:32])[CH2:29][C:30]=4[N:31]=3)=[O:22])[CH:17]([C:33]([NH:34][OH:35])=[O:42])[CH2:16]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: CC1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3C(=O)NOC3CCCCO3)sc2CN1
Agent: Cl
Solvent: CO
Product: CC1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3C(=O)NO)sc2CN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In methanol (10 ml), 4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-2-[[N-(tetrahydropyran-2-yloxy)]carbamoyl]piperazine (297 mg) was dissolved, followed by the addition of 1N hydrochloric acid (10 ml). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by “HP-20” (Φ1.7×20.0 cm, acetonitrile:water=1:5), whereby the title compound (65 mg) was obtained as a pale yellow foam.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].[C:10]([Cu])#[N:11].N.C(OCC)C>CN(C=O)C>[F:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[C:10]#[N:11]
Reactant: N#C[Cu]
Reactant: Cc1ccc(Br)c(F)c1
Agent: N
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1ccc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
A mixture of 1-bromo-2-fluoro-4-methylbenzene (70 g, 370 mmol) and CuCN (50 g, 555 mmol) in DMF (300 mL) was heated at reflux for 24 h. After cooling to RT, concentrated aqueous ammonia (300 mL) and diethyl ether (200 mL) were added and the mixture stirred for 1 h. The mixture was extracted with diethyl ether (3×200 mL). The combined organic layers were washed with brine (3×200 mL) and dried over sodium sulfate. Solvent was removed in vacuo to give the product (44 g, 88%) as pale yellow solid. MS (M+H)+ 136.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][C:8]#[N:9])=[CH:5][CH:4]=1.[CH3:12][N:13]([CH3:17])[C:14](Cl)=[S:15].[OH-].[K+]>CO>[CH3:12][N:13]([CH3:17])[C:14]([O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][C:8]#[N:9])=[CH:5][CH:4]=1)=[S:15]
Reactant: N#CCc1ccc(O)cc1
Reactant: CN(C)C(=S)Cl
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: CO
Product: CN(C)C(=S)Oc1ccc(CC#N)cc1
Reaction time: 2 h
Yield: 49.2 %

Procedure:
Metallic sodium (1.15 g, 50 mg-atom) was dissolved in methanol (100 ml) and 4-hydroxybenzylcyanide (6.7 g, 50 mmol) was added. The obtained solution was concentrated and acetonitrile (2×10 ml) was evaporated from the residue. The obtained salt was dissolved in anhydrous dimethylformamide (200 ml) and about 25 ml of the solvent was removed under reduced pressure. To the obtained solution N,N-dimethylthiocarbamoyl chloride (9.9 g, 80 mmol) was added and the reaction mixture was stirred at 80°-85° C. for 2 hours. Thereafter additional N,N-dimethylthiocarbamoyl chloride (2.5 g, 20 mmol) was added and stirring at 80° C. was continued for further one hour. After cooling the mixture was poured into aqueous 1% KOH (500 ml) and extracted with ether (3×200 ml). The organic extracts were washed with water until neutral, dried over MgSO4 and concentrated. The solid residue was triturated with water and after drying also with isopropyl ether to give the title compound (5.42 g), mp. 120°-124° C., yield: 52.7%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([N:6]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH2:5].[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][NH:33][C:32](=[O:36])[CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:1][O:2][C:3](=[O:21])[CH:4]([N:6]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][N:33]1[CH:34]=[CH:35][C:30]([O:29][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:31][C:32]1=[O:36]
Reactant: C=C(C(=O)OC)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)C(Cn1ccc(OCc2ccccc2)cc1=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
To a solution of 2-(di-tert-butoxycarbonylamino)-acrylic acid methyl ester (900 mg, 3.0 mmol), and 4-benzyloxy-1H-pyridin-2-one (630 mg, 1.03 equiv) in acetonitrile (2.5 mL) was added cesium carbonate (100 mg, 0.10 equiv). The resulting suspension was heated to 80° C. via microwave for 2 h. The reaction was concentrated, dissolved in water, and extracted with methylene chloride (3×). The combined organic phases were washed with brine, dried over magnesium sulfate, and concentrated to give 1.47 g (97%) which was used without purification. Mass spec.: 503.56 (MH)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:10])[CH:8]=2)[CH:3]=[N:2]1.[Cl:11][C:12]1[N:17]=[C:16]([NH2:18])[N:15]=[C:14](NC2C=CC(Cl)=CC=2)[CH:13]=1>>[Cl:11][C:12]1[N:17]=[C:16]([NH2:18])[N:15]=[C:14]([NH:10][C:7]2[CH:8]=[C:9]3[C:4]([CH:3]=[N:2][NH:1]3)=[CH:5][CH:6]=2)[CH:13]=1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: Nc1nc(Cl)cc(Nc2ccc(Cl)cc2)n1
Product: Nc1nc(Cl)cc(Nc2ccc3cn[nH]c3c2)n1
Yield: 42 %

Procedure:
Using 1H-indazol-6-yl-amine in place of 4-chloro-phenylamine in the method described in Example 2 for the synthesis of 6-chloro-N*4*-(4-chloro-phenyl)-pyrimidine-2,4-diamine provided 6-chloro-N*4*-(1H-indazol-6-yl)-pyrimidine-2,4-diamine (42% yield).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[C:12](=O)[CH3:13].[NH2:15][C:16]([NH2:18])=[S:17]>>[NH2:18][C:16]1[S:17][CH:13]=[C:12]([C:3]2[C:2]([F:1])=[C:7]([F:8])[C:6]([F:9])=[C:5]([F:10])[C:4]=2[F:11])[N:15]=1
Reactant: CC(=O)c1c(F)c(F)c(F)c(F)c1F
Reactant: NC(N)=S
Product: Nc1nc(-c2c(F)c(F)c(F)c(F)c2F)cs1
Yield: 86.7 %

Procedure:
Using 2′,3′,4′,5′,6′-pentafluoroacetophenone and thiourea as the raw materials, the same operation as the Example 395(1) gave the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:23])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20](=O)[CH3:21])[CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:24])[C:5]([C:25]([OH:27])=[O:26])=[CH:4]1)[CH3:2].Cl.[NH2:29][OH:30].C(=O)(O)[O-].[Na+].C(Cl)Cl>CO.O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:23])=[C:10]([N:13]3[CH2:14][CH2:15][N:16]([CH2:19][C:20](=[N:29][OH:30])[CH3:21])[CH2:17][CH2:18]3)[CH:11]=2)[C:6](=[O:24])[C:5]([C:25]([OH:27])=[O:26])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC(C)=O)CC3)cc21
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC(C)=NO)CC3)cc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.7 %

Procedure:
To a suspension of the 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-[4-(2-oxopropyl)-1-piperazinyl]-quinoline-3-carboxylic acid [H. Kondo et. al., J. Med. Chem., 29, 2020 (1986)] (0.38 g, 1 mmol) in absolute methanol (20 ml) was added a solution of hydroxylamine hydrochloride (0.14 g, 2 mmol) and sodium bicarbonate (0.17 g, 2 mmol) in water (2 ml). The mixture was stirred for 20 hr at room temperature, then CH2Cl2 (50 ml) was added, and the layers were separated. The organic phase was washed successively with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to give a solid which was purified by flash column chromatography (silica gel, with CH2Cl2/methanol (10:1) as the eluant) and crystillization from CH2Cl2/methanol 5:1 to give 1-ethyl-6-fluoro-7-[4-(2-hydroxyiminopropyl)-1-piperazinyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid as an off-white amorphous solid (0.28 g, 72%). Mp: 218° C. (dec). 1H NMR (DMSO-d6) δ1.41 (t, 3H, J=7.2), 1.81 (s, 3H), 2.54 (m, 4H), 3.03 (s, 2H2), 3.33 (m, 4H), 4.57 (q, 2H, J=7.2), 7.17 (d, H, J=7.2), 7.90 (d, 1H, J=13.6), 8.92 (s, 1H), 10,61 (s, 1H), 15.27 (br s, 1H). Anal. Calcd. for C19H23FN4O4•0.5 H2O: C, 57.14; H. 6.06; N, 14.03. Found: C, 57.43; H, 5.87; N, 13.83.
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:10].C1C(=O)N([Br:18])C(=O)C1.O>CN(C=O)C>[Br:18][C:7]1[CH:8]=[C:9]2[O:1][C:2](=[O:10])[NH:3][C:4]2=[N:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1[nH]c2ncccc2o1
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c2ncc(Br)cc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5.07 g oxazolo[4,5-b]pyridin-2(3H)-one dissolved in 85 ml of DMF under nitrogen is added 7.46 g NBS in 50 ml of DMF. This is allowed to stir at room temperature overnight. To this is added 35 ml of water and chilled. The solid material which separates is filtered and washed with 3×100 ml H2O. This is then dried in a vac oven at 70° C. and then used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:10](=[O:11])[O:9][CH2:8]2.COC1C=C(C=CC=1)C=O.C1(P(=CC(OC)=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)(Cl)Cl>[OH:11][CH:10]1[C:12]2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=2[CH2:8][O:9]1
Reactant: COc1cccc2c1C(=O)OC2
Agent: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: COc1cccc(C=O)c1
Solvent: ClC(Cl)Cl
Product: COc1cccc2c1C(O)OC2
Temperature: 50 °C
Reaction time: 0.67 h

Procedure:
1Hydroxy-7-methoxy-1,3-dihydrobenzo[c]furan (1.08 g), which was prepared with using 7-methoxyphthalide which was synthesized with using 3-methoxybenzaldehyde by the method described in Journal of Organic Chemistry, 1980, 45, 1835-1838, was dissolved in Chloroform (20 ml). Methyl (Triphenylphosphoranylidene)acetate (2.68 g) was added to the solution. The mixture was stirred for 40 min. at 50° C. A temperature of the reaction mixture was down to room temperature. The reaction solution was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1) to give the title compound (1.25 g) having the following physical data.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)=[O:2].[BH4-].[Na+].O.C(OCC)(=O)C>CO>[OH:2][CH2:1][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2
Reactant: CC(C)(C)OC(=O)N1Cc2cccc(C=O)c2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1Cc2cccc(CO)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
To a solution of 350 mg of tert-butyl 4-formyl-1,3-dihydro-2H-isoindole-2-carboxylate in 11 mL of methanol was added 134 mg of sodium borohydride under ice-cooling, followed by stirring at room temperature overnight. To the reaction mixture were added water and ethyl acetate and the aqueous layer was separated. The obtained organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 213 mg of tert-butyl 4-(hydroxymethyl)-1,3-dihydro-2H-isoindole-2-carboxylate as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:17][CH:18]=2)[CH3:12])=[O:9])[CH:3]=1.[C:25](Cl)(=[O:28])[CH2:26][CH3:27]>>[C:25]([NH:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH2:20][C:21]([F:23])([F:22])[F:24])=[CH:17][CH:18]=2)[CH3:12])=[O:9])[CH:3]=1)(=[O:28])[CH2:26][CH3:27]
Reactant: CCC(=O)Cl
Reactant: CC(NC(=O)c1cc(N)ncn1)c1ccc(OCC(F)(F)F)nc1
Product: CCC(=O)Nc1cc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)ncn1

Procedure:
The title compound is prepared from 6-amino-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carboxamide (30 mg, 0.09 mmol, Step-1, single enantiomer) and propionyl chloride (12 mg, 0.13 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:10]([C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1)=[O:24])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([OH:22])[CH2:20][OH:21])[CH:14]=1)=[O:12].[C:32]([O-])([O-])([O:34][CH3:35])[CH3:33].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1COCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:10]([C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]2[CH2:20][O:21][C:32]([O:34][CH3:35])([CH3:33])[O:22]2)[CH:14]=1)=[O:12])[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1)=[O:24]
Reactant: O=C(C(C(=O)c1cccc(C(O)CO)c1)=C1Nc2ccccc2N1)c1cccc(F)c1
Reactant: COC(C)([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: COC1(C)OCC(c2cccc(C(=O)C(C(=O)c3cccc(F)c3)=C3Nc4ccccc4N3)c2)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A 6 ml portion of THF solution containing 0.21 g of 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-[3-(1,2-dihydroxyethyl)phenyl]-3-(3-fluorophenyl)propane-1,3-dione and 0.3 g of methyl orthoacetate was mixed with 63 mg of pyridinium p-toluenesulfonate and then stirred at room temperature for about 30 minutes. After evaporation of the solvent, the residue was mixed with an appropriate amount of sodium bicarbonate aqueous solution, extracted several times with ethyl acetate, dried with anhydrous magnesium sulfate and concentrated. The thus formed residue was purified by a silica gel column chromatography to obtain 162 mg (68%) of 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-(3-fluorophenyl)-3-[3-(2-methoxy-2-methyl-1,3-dioxolan-4-yl)phenyl]propane-1,3-dione (Example 3-1) as a pale yellow foam from an ethyl acetate-hexane (1:2) eluate.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([OH:17])([C:13]([O:15][CH3:16])=[O:14])[CH2:6][C:7]=1[C:8](=[O:12])[CH2:9][CH2:10][CH3:11].O.C1(C)C=CC(S(O)(=O)=[O:26])=CC=1>O.O1CCCC1>[C:8]([CH:7]1[CH2:6][C:5]([OH:17])([C:13]([O:15][CH3:16])=[O:14])[CH:4]=[CH:3][C:2]1=[O:26])(=[O:12])[CH2:9][CH2:10][CH3:11]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCC(=O)C1=C(N)C=CC(O)(C(=O)OC)C1
Solvent: C1CCOC1
Solvent: O
Product: CCCC(=O)C1CC(O)(C(=O)OC)C=CC1=O
Reaction time: 18 h

Procedure:
To a stirred solution of methyl 4-amino-5-butyryl-1-hydroxycyclohexa-2,4-diene-1-carboxylate (1.25 g, 5.2 mmol) in a 1:1 mixture of water/tetrahydrofuran (10 mL) was added p-toluenesulfonic acid monohydrate (1.1 g, 5.8 mmol). The reaction mixture was stirred for 18 h and then partitioned between dichloromethane and water. The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure to afford methyl 5-butyryl-1-hydroxy-4-oxocyclohex-2-ene-1-carboxylate which was used without further purification or characterization.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=O)=O.[NH2:16][C:17]1[CH:25]=[C:21]([C:22]([OH:24])=[O:23])[C:20]([OH:26])=[CH:19][CH:18]=1>C(O)C>[C:22]([C:21]1[CH:25]=[C:17]([N:16]2[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=3[CH:8]=[C:6]2[C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH:18]=[CH:19][C:20]=1[OH:26])([OH:24])=[O:23]
Reactant: O=C(CC1CCCCC1=O)c1cccs1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Solvent: CCO
Product: O=C(O)c1cc(-n2c(-c3cccs3)cc3c2CCCC3)ccc1O

Procedure:
A mixture of 2.22 g. (0.01 mole) of 2-(2-thienoylmethyl)cyclohexanone, (1.53 g. (0.01 mole) of 5-aminosalicylic acid, and 25 ml. of ethanol was heated uder reflux under nitrogen for 4 hours and filtered. The filtrate was concentrated to an oil which solidified when triturated with petroleum ether. Recrystallization from acetonitrile gave 1.0 g. (29%) of yellow crystals, m.p. 211°-213°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:12][N:11]([C:13](Cl)=[O:14])[CH2:10]2)=[CH:4][CH:3]=1.[CH2:16]([NH2:19])[CH:17]=[CH2:18]>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:12][N:11]([C:13]([NH:19][CH2:16][CH:17]=[CH2:18])=[O:14])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CC(Sc2ccc(Cl)cc2)C1
Reactant: C=CCN
Solvent: C1CCOC1
Solvent: O
Product: C=CCNC(=O)N1CC(Sc2ccc(Cl)cc2)C1
Reaction time: 3 h

Procedure:
A stirred solution of 2.6 g (0.01 mole) of 3-[(4-chlorophenyl)thio]-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was cooled in a water bath and treated with 2.2 g (0.02 mole) of 2-propenylamine. After stirring for 3 hr, the reaction mixture was diluted with 200 ml of water and the product separated as a yellow oil. The oil slowly solidified to yield a dull orange-red waxy material. After decanting the water and allowing the residue to air dry, the residue was triturated 5 times with boiling isopropyl ether and the decanted solutions upon cooling yielded 5 solid fractions, from white to pale beige color. The fractions were all consistent with the expected product by mass spectral analysis and TLC showed only a single product. All five fractions were combined to give 1.7 g (60.3%), m.p. 88°-89° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]2[S:37][C:36]([CH3:38])=[N:35][C:34]=2[CH:39]=1>C(Cl)Cl.CO.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][CH:11]([C:14]([NH:29][C:30]3[CH:31]=[CH:32][C:33]4[S:37][C:36]([CH3:38])=[N:35][C:34]=4[CH:39]=3)=[O:16])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCC(c2ccc(Cl)cc2)CC1
Reactant: Cc1nc2cc(N)ccc2s1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: Cc1nc2cc(NC(=O)C3CCC(c4ccc(Cl)cc4)CC3)ccc2s1
Temperature: 45 °C
Reaction time: 2 h
Yield: 101.2 %

Procedure:
A suspension of 4-(4-chlorophenyl)-cyclohexane-1-carboxylic acid (100 mg, 0.42 mmol) in DCM (10 ml) was treated with catalytic DMF and oxalyl chloride (110 ul, 1.26 mmol) at 0° C. and the mixture was then stirred at room temp. for 1 h and at 45° C. for 2 h. The solvent and excess oxalyl chloride was removed in vacuo and the residue resuspended in DCM (5 ml). To this was added pyridine (35 ul, 0.42 mmol) and 5-amino-2-methylbenzothiazole (63 mg, 0.38 mmol) and the reaction stirred at room temp. overnight. MeOH (1 ml) was added and the mixture was washed with sat. aq. sodium bicarbonate solution and brine then dried (MgSO4) and concentrated to give the title compound as an off-white solid (148 mg). 1H NMR (400 MHz, DMSO) δ (ppm): 8.37 (d, 1H), 7.96 (d, 1H), 7.63 (dd, 1H), 7.40 (d, 2H), 7.38 (d, 2H), 2.83 (s, 3H), 2.49-2.63 (m, 2H), 2.04 (m, 2H), 1.94 (m, 2H), 1.69 (m, 2H), 1.53 (m, 2H). MS(ES): MH+ 385/387, M−H+ 383/385.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[H-].[Na+].[O:10]=[C:11]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[S:14][C:13]([C:21]2[N:26]=[C:25]([CH2:27]S([O-])(=O)=O)[CH:24]=[CH:23][CH:22]=2)=[N:12]1.C(OCC)(=O)C>CN(C=O)C.O>[N:5]1[CH:6]=[CH:7][C:2]([S:1][CH2:27][C:25]2[N:26]=[C:21]([C:13]3[S:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:11](=[O:10])[N:12]=3)[CH:22]=[CH:23][CH:24]=2)=[CH:3][CH:4]=1
Reactant: Sc1ccncc1
Reactant: O=c1nc(-c2cccc(CS(=O)(=O)[O-])n2)sc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1nc(-c2cccc(CSc3ccncc3)n2)sc2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.6 %

Procedure:
4-Mercaptopyridine (0.21 g, 1.89 mmol) and sodium hydride (60% in oil, 0.083 g, 2.06 mmol) were dissolved in DMF (30 ml), and 6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridylmethanesulfonate (0.60 g, 1.72 mmol) was added thereto. The reaction mixture was stirred at room temperature for 18 hrs and combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.11 g, 17%) as pale yellow crystals.