Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:12])[CH2:9][C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.[C:13]1([CH2:19][CH:20]=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH4-].[Na+]>CO>[OH:12][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH2:20][CH2:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1)[CH2:9][C:10]#[N:11]
Reactant: O=CCc1ccccc1
Reactant: N#CCC(O)c1cccc(N)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#CCC(O)c1cccc(NCCc2ccccc2)c1
Reaction time: 18 h

Procedure:
Hydrogenation of aniline 12 and 2-phenylacetaldehyde gives 3-hydroxy-3-(3-(phenethylamino)phenyl)propanenitrile. A mixture of aniline 12 (1.00 g, 6.17 mmol), 2-phenylacetaldehyde (0.66 g, 5.55 mmol) and Å-3 molecular sieves in MeOH was stirred for 18 h and then NaBH4 (1.16 g, 30.8 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was filtered through Celite, concentrated under reduced pressure. Purification by column chromatography (100-200 silica mesh, 20% EtOAc—hexane) gave 3-hydroxy-3-(3-(phenethylamino)phenyl)propanenitrile as a yellow liquid. Yield (0.432 g, 27%); 1H NMR (400 MHz, DMSO-d6) δ 7.32-7.26 (m, 4H), 7.20 (t, J=6.4 Hz, 1H), 7.04 (t, J=7.6 Hz, 1H), 6.64 (s, 1H), 6.55 (d, J=7.2 Hz, 1H), 6.50 (d, J=8.4 Hz, 1H), 5.77 (d, J=4.4 Hz, 1H), 5.68 (t, J=5.6 Hz, 1H), 4.76-4.72 (m, 1H), 3.26-3.21 (m, 2H), 2.85-2.81 (m, 3H), 2.79-2.72 (m, 1H).
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:3].[Br:12]Br>CO>[CH:4]1([C:2]([CH2:1][Br:12])=[O:3])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: BrBr
Reactant: CC(=O)C1CCCCCCC1
Solvent: CO
Product: O=C(CBr)C1CCCCCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 217.9 %

Procedure:
An ice cold solution of 5.5 g of cyclooctyl methyl ketone in 50 ml of methyl alcohol was treated dropwise with 1.95 g of bromine. After 5 min, the ice bath was removed and the reaction mixture was allowed to warm to room temperature. The reaction mixture was then diluted with 200 ml of water and extracted with ethyl ether (3×60 ml). The combined extracts were washed with saturated sodium bicarbonate, brine, dried (MgSO4) and condensed in vacuo to yield 6.2 g of bromomethyl cyclooctyl ketone as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH2:28][NH:29][CH2:30]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[NH2:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH2:28][N:29]([C:15]1[C:16]([F:18])=[C:17]3[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:13][C:14]=1[F:20])[CH2:30]2
Reactant: Nc1cccc2c1CNC2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1cccc2c1CN(c1c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4)c3c1F)C2
Yield: 43.1 %

Procedure:
170 mg of 1-(4-fluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 81 mg of 4-amino isoindoline, 137 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 98 mg of the target compound.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[F:15][C:16]([F:34])([F:33])[CH:17]1[CH:32]=[CH:31][C:20]2[S:21][C:22]3[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=3[C:24](=O)[NH:25][C:19]=2[CH2:18]1.O>N1C=CC=CC=1>[F:15][C:16]([F:34])([F:33])[C:17]1[CH:32]=[CH:31][C:20]2[S:21][C:22]3[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=3[C:24](=[S:2])[NH:25][C:19]=2[CH:18]=1
Reactant: O=C1NC2=C(C=CC(C(F)(F)F)C2)Sc2ccccc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: O
Solvent: c1ccncc1
Product: FC(F)(F)c1ccc2c(c1)NC(=S)c1ccccc1S2
Yield: 70.7 %

Procedure:
Phosphorus pentasulphide (0.6 g, 2.5 mmol) was added to a stirred solution of 8-trifluoromethyl-9,10-dihydrodibenzo [b,f][1,4]thiazepin-11-one (0.295 g, 1 mmol) in pyridine (10 ml). The mixture was heated under reflux for 6 hr and then at room temperature overnight. A further 0.3 g of phosphorous pentasulphide was added and the reaction mixture refluxed for 6 hr and then left at room temperature overnight before hot water (40 ml) added. Filtration and recrystallisation from toluene then ethanol gave he title compound as fine yellow needles (0.22 g, m.p. 232°-233° C. Rf 0.76, petrol/EtOAc 2:1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])[CH:9]=[CH:10][CH:11]=1)[CH3:2].[C:21](=O)([O:25]CC)[O:22][CH2:23][CH3:24].[H-].[Na+]>>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])[CH:9]=[CH:10][CH:11]=1)[C:21]([O:22][CH2:23][CH3:24])=[O:25])[CH3:2]
Reactant: CCOC(=O)Cc1cccc(-c2cccc(Cl)c2Cl)c1
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C(=O)OCC)c1cccc(-c2cccc(Cl)c2Cl)c1
Reaction time: 8 h

Procedure:
To a solution of 2′,3′-dichloro-[1,1′-biphenyl]-3-acetic acid ethyl ester (i.e. the product of Step A, 0.45 g, 1.45 mmol) and diethyl carbonate (5 mL) was added sodium hydride (60% dispersion in oil, 0.23 g, 5.8 mmol). The reaction mixture was stiffed overnight at room temperature, and then quenched with saturated aqueous ammonium chloride solution. The reaction mixture was then extracted with ethyl acetate, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure to yield the title compound (0.50 g).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].CC(C)([O-])C.[Na+].Br[C:14]1[CH:15]=[CH:16][C:17]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[C:18]([CH:22]=1)[C:19]([OH:21])=[O:20].Cl>O.CN(C=O)C>[F:26][C:25]([F:28])([F:27])[CH2:24][O:23][C:17]1[CH:16]=[CH:15][C:14]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]
Reactant: O=C(O)c1cc(Br)ccc1OCC(F)(F)F
Reactant: OCC(F)(F)F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Temperature: 100 °C
Reaction time: 10 h
Yield: 75.3 %

Procedure:
To a solution of 2,2,2-trifluoroethanol (14.7 g) and DMF (125 ml) was added sodium tert-butoxide (12.8 g) at 0° C. The solution was stirred at 20 to 25° C. for 1 hour at which point 5-bromo-2-(2,2,2-trifluoroethoxy)benzoic acid (20 g) was added followed by cupric bromide (2.0 g). The mixture was stirred at 100° C. for 10 hours, cooled to 10° C., and water (30 ml) was added followed by 20% HCl solution (90 ml). The solution was extracted with dichloromethane (3×80 ml), and the combined organic layers were washed with water (3×60 ml). The solution was concentrated to one-third of the original volume and hexane (200 ml) was added. The resulting suspension was stirred at room temperature for 2 hours, filtered and the damp cake was rinsed with hexane (2×40 ml). The damp cake was dried in vacuo at 40° C. for 5 hours to give the product as a white solid (16.02 g, yield 75.3%).
Reaction SMILES: CN1CCOCC1.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([OH:16])=O.ClC(OCC(C)C)=O.Cl.[CH3:26][NH:27][O:28][CH3:29]>ClCCl>[CH3:29][O:28][N:27]([CH3:26])[C:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][N:8]=1)=[O:16]
Reactant: CNOC
Reactant: O=C(O)c1ccccn1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccccn1
Temperature: -15 °C
Reaction time: 15 h
Yield: 80 %

Procedure:
N-Methylmorpholine (3.7 ml) is added to a solution of picolinic acid (2.05 g, 16.65 mmol) in anhydrous dichloromethane (50 mL) and cooled to −15° C. Isobutyl chloroformate (2.2 ml, 16.75 mmol) is added thereto, and the mixture is stirred for 15 hr, after which N,O-dimethylhydroxylamine hydrochloride (1.63 g, 16.71 mmol) is added. After 15 min, the cooling bath is removed and stirring is continued at room temperature for 4 hr. The reaction mixture is added to water (50 ml) and extracted with dichloromethane. The organic phases are washed with water and brine and dried over Na2SO4. The residue is chromatographed on silica gel to afford N-methoxy-N-methylpyridine-2-carboxamide as a colorless oil (2.2 g; 80% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[N+:24]([O-])=O.Cl>C(O)C.O.[Fe]>[NH2:24][C:3]1[CH:4]=[C:5]([CH:8]2[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(Cl)c([N+](=O)[O-])c1)N2
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(Cl)c(N)c1)N2
Temperature: 25 °C
Yield: 15.4 %

Procedure:
To a solution of methyl 2-(4-chloro-3-nitrophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (2.82 g, 7.53 mmol) in ethanol/water (30 mL/7.5 mL) was added 0.5 mL of concentrated hydrochloric acid solution and iron powder (4.21 g, 75.3 mmol). The resultant mixture was stirred and heated to reflux for 4 h. LC-MS showed the reaction was complete. The reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated and the residue was purified by column chromatography on silica gel to afford 400 mg of methyl 2-(3-amino-4-chlorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a solid. Yield: 15%.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[C:13]([OH:14])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[C:9]2[C:15]([O:17]C)=[O:16].Cl>O.CO>[F:3][C:4]1[C:13]([OH:14])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[C:9]2[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1cccc2c(F)c(O)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc2c(F)c(O)ccc12
Temperature: 80 °C

Procedure:
Sodium hydroxide (116 g, 2.9 mol) was dissolved in 100 mL water and added to a solution of methyl 5-fluoro-6-hydroxy-1-naphthoate (8.56 g, 38.9 mmol) in methanol (200 mL). The mixture was refluxed at 80° C. for 2 h. The mixture was allowed to cool to RT, then poured into 6N HCl in ice. The pH was adjusted to 3 to give a fine purple/pink solid. The title compound was isolated by centrifuge (with some salts).
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:15]2[NH:16][C:17](=[O:19])[O:18][C@H:14]2[CH2:13][C@H:12]([CH:20]=[O:21])[C@H:11]1[O:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](Cl)(=[O:33])[CH3:32].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:9][C@@H:10]1[C@H:15]2[N:16]([C:31](=[O:33])[CH3:32])[C:17](=[O:19])[O:18][C@H:14]2[CH2:13][C@H:12]([CH:20]=[O:21])[C@H:11]1[O:22][C:23](=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C[C@H]1C[C@@H]2OC(=O)N[C@@H]2[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1C(=O)O[C@H]2C[C@H](C=O)[C@@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@H]21
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
To a solution of (3aS,4R,5R,6S,7aS)-6-formyl-2-oxooctahydrobenzo[d]oxazole-4,5-diyl dibenzoate (580 mg, 1.42 mmol) in dry DCM (10 mL) at 0° C. under N2 was added a solution of acetyl chloride (223 mg, 2.84 mmol) in dry DCM (2.84 mL) followed by a solution of DIPEA (330 mg, 2.56 mmol) in dry DCM (2.56 mL) dropwise. The mixture was stirred at 0° C. for 2 h. The reaction was further diluted with DCM (20 mL), washed with 0.1 N HCl and brine. The solvent was evaporated to give the crude (3aS,4R,5R,6S,7aS)-3-acetyl-6-formyl-2-oxooctahydrobenzo[d]oxazole-4,5-diyl dibenzoate (614 mg, 96%) which was carried onto next reaction without further purification. 1H NMR (400 MHz, CDCl3) δ 9.89 (s, 1H), 7.93 (d, J=7.8 Hz, 2H), 7.90 (d, J=7.8 Hz, 2H), 7.54-7.59 (m, 2H), 7.40-7.44 (m, 4H), 5.79 (dd, J=5.7 Hz, 4.1 Hz, 1H), 5.68 (t, J=5.7 Hz, 1H), 5.01-5.04 (m, 1H), 4.82 (dd, J=7.7 Hz, 4.0 Hz, 1H), 3.13-3.19 (m, 1H), 2.54-2.60 (m, 1H), 2.50 (s, 3H), 2.26-2.34 (m, 1H).
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].CC(C)([O-])C.[Na+].[C:12]([O:16][C:17](=[O:41])[N:18]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[C:34](F)[CH:33]=2)=[CH:27][CH:26]=1)[CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])([CH3:15])([CH3:14])[CH3:13].CCOCC>CN(C=O)C>[C:12]([O:16][C:17](=[O:41])[N:18]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[C:34]([O:5][N:4]=[C:2]([CH3:3])[CH3:1])[CH:33]=2)=[CH:27][CH:26]=1)[CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])([CH3:14])([CH3:15])[CH3:13]
Reactant: CC(C)CCN(Cc1ccc(Oc2ccc(C#N)c(F)c2)cc1)C(=O)OC(C)(C)C
Reactant: CC(C)=NO
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)=NOc1cc(Oc2ccc(CN(CCC(C)C)C(=O)OC(C)(C)C)cc2)ccc1C#N
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 27 %

Procedure:
To a solution of acetone oxime (1.1 equiv) in DMF was added sodium tert-butoxide (1.1 equiv). The mixture was stirred at room temperature for 45 min followed by the addition of a solution of compound from Step 3 (1 equiv). The reaction was stirred at room temperature for 3 hours. It was poured on NH4Cl sat and ether. Washed with water and dry over magnesium sulphate, filtered and concentrate. It was purified by silica gel chromatography using hexane:ethyl acetate (15%) to afford the title compound as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([O:16][CH3:17])=[O:15]>N1C=CC=CC=1>[C:1]([NH:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([O:16][CH3:17])=[O:15])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: COC(=O)c1sccc1N
Reactant: CCCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCCC(=O)Nc1ccsc1C(=O)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3.8 ml of n-pentanoic acid chloride was added to 50 ml of an anhydrous pyridine solution containing 5.0 g of methyl 3-aminothiophene-2-carboxylate at 0° C. The mixture was stirred at 0° C. for 1 hour and further stirred at room temperature for 2 hours. The reaction mixture was concentrated, diluted with ethyl acetate and washed with 1N chloric acid, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution in this order. Ethyl acetate was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (elution with n-hexane:ethyl acetate=5:1) to provide 7.0 g of methyl 3-pentanoylaminothiophene-2-carboxylate as a colorless oily compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([C:17](=O)[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[CH:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)=[O:5])[CH3:2].CC[O-].[Na+].Cl.[NH2:33][C:34]1[N:38]2[CH2:39][CH2:40][CH2:41][N:37]2[C:36](=[O:42])[CH:35]=1>CCO>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[C:35]2[C:36](=[O:42])[N:37]3[CH2:41][CH2:40][CH2:39][N:38]3[C:34]=2[NH:33][C:17]=1[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[O:5])[CH3:2]
Reactant: Nc1cc(=O)n2n1CCC2
Reactant: CCOC(=O)C(=Cc1ccc(C(=O)O)cc1)C(=O)CCc1ccc(F)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C(CCc2ccc(F)cc2)Nc2c(c(=O)n3n2CCC3)C1c1ccc(C(=O)O)cc1
Temperature: 25 °C
Yield: 41 %

Procedure:
The product from Step C (920 mg, 2.48 mmol) and NaOEt (170 mg, 2.50 mmol) were added portionwise to a stirred solution of 3-amino-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-1-one hydrochloride (refs. R. B. Greenwald, U.S. Pat. No. 4,128,425 and E. E. Boros, F. Bouvier, S. Randhawa and M. H. Rabinowitz, J. Heterocyclic Chem., 2001, 38, 613–616.) (440 mg, 2.51 mmol) in EtOH (6 mL). The reaction mixture was heated at reflux for 5.5 h and then allowed to cool to rt and filtered to remove NaCl. The filtrate was concentrated at reduced pressure and the remaining material was triturated with CH2Cl2 to yield D as an off-white solid (500 mg, 1.02 mmol, 41%): 1H NMR (400 MHz, DMSO-d6) δ 12.63 (br, 1H), 9.76 (s, 1H), 7.77 (d, 2H, J=8), 7.27 (dd, 2H, J=8, 6), 7.20 (d, 2H, J=8), 7.11 (t, 2H, J˜9), 4.76 (s, 1H), 3.87 (q, 2H, J=7), 3.42 (m, 2H), 3.27 (m, 2H), 2.98 (m, 2H), 2.85 (m, 2H), 2.26 (m, 2H), 0.96 (t, 3H, J=7) ppm; ESI-MS m/z 492 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[C:18]([NH2:19])=[CH:17][CH:16]=[C:15]([CH3:20])[N:14]=2)=[O:12])=[N:6]1.Cl[C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][N:23]=1>>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[C:18]([NH:19][C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][N:23]=3)=[CH:17][CH:16]=[C:15]([CH3:20])[N:14]=2)=[O:12])=[N:6]1
Reactant: Fc1ccnc(Cl)c1
Reactant: COCCn1ccc(NC(=O)c2nc(C)ccc2N)n1
Product: COCCn1ccc(NC(=O)c2nc(C)ccc2Nc2cc(F)ccn2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid [1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-amide in accordance with the general method of example) step using 2-Chloro-4-fluoropyridine instead of 3-bromopyridineto yield the final compound as a off-white solid, MS (ISP): m/e=371.4 (M+H+).
Reaction SMILES: [O-]CC.[Na+].[C:5]([C:10]1[O:11][C:12]([CH3:17])=[C:13]([OH:16])[C:14]=1[OH:15])(OCC)=O>CN(C)C=O.C1(C)C=CC=CC=1>[OH:15][C:14]1[C:13](=[O:16])[CH:12]([CH3:17])[O:11][C:10]=1[CH3:5]
Reactant: CCOC(=O)c1oc(C)c(O)c1O
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC1=C(O)C(=O)C(C)O1
Reaction time: 20 h
Yield: 64.8 %

Procedure:
In a 1 L three-necked flask fitted with a mechanical stirrer and a gas inlet tube is placed a suspension of 34 g of sodium ethoxide in a mixture of 100 ml of dimethylformamide and 300 ml of toluene. To the stirred suspension is added at room temperature, under nitrogen, 93 g of 2-carbethoxy-5-methyl-3,4-dihydroxy-furan. Gaseous methyl bromide is bubbled through the stirred reaction mixture at 30°-40° C. till the pH of the reaction mixture reaches 6.5-7.0. The solvents are removed under vacuum and the residue is dissolved in a solution of 80 g of sodium hydroxide in 350 ml of water. The reaction mixture is kept at room temperature under nitrogen for 20 hours, acidified with hydrochloric acid and continuously extracted with ether. The ether extract is dried and the solvent removed under vacuum, the residue is recrystallized from ether, yielding 41.5 g (65%) of 4-hydroxy-2,5-dimethyl-3-oxo-2H-furan, m.p. 81.5°-83.1° C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][NH2:15].O>O1CCOCC1>[Br:1][C:2]1[S:6][C:5]([S:7]([NH:15][CH2:14][CH2:13][N:12]([CH3:16])[CH3:11])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: CN(C)CCN
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Solvent: C1COCCO1
Solvent: O
Product: CN(C)CCNS(=O)(=O)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
A mixture of 5-bromothiophene-2-sulfonyl chloride (2.0 g, 7.6 mmol, 1.0 eq) and N,N-dimethyl ethane-1,2-diamine (1.0 g, 11.5 mmol, 1.5 eq) in dioxane (20 mL) was stirred at room temperature for 2 h. Water was added and the reaction was extracted with dichloromethane. The combined organic layers were dried (Na2SO4), filtered, evaporated and purified by silica gel chromatography to afford 5-bromo-N-(2-(dimethylamino)ethyl)thiophene-2-sulfonamide (1.35 g, 94%). LC-MS (m/z)=313.0, 315.0 [M+H]+.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[F:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[CH3:23][S:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH2:28]>>[CH3:23][S:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH:28][C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:16]([F:22])=[CH:17][CH:18]=[CH:19][C:20]=2[F:21])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5]
Reactant: CCOC(=O)c1nc(-c2c(F)cccc2F)n(C)c(=O)c1O
Reactant: CSc1ccccc1CN
Product: CSc1ccccc1CNC(=O)c1nc(-c2c(F)cccc2F)n(C)c(=O)c1O

Procedure:
Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 2-methylthiobenzylamine (77 mg, 0.5 mmol). The title product was obtained as an off-white solid (34.2 mg, 82% yield). 1HNMR (500 MHz, CDCl3) δ: 12.37 (1H, s), 7.92 (1H, br s), 7.55–7.44 (1H, m), 7.33–7.25 (2H, m), 7.17–7.14 (1H, m), 7.04 (2H, dd, J=8.24, 7.32 Hz), 4.67 (2H, d, J=6.10 Hz), 3.40 (3H, s), 2.44 (3H, s). HRMS (ESI) calcd for C20H16F2N3O3S (M−H): 416.0880; found: 416.0879.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:26])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[C:18]=2[CH3:25])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].CCO>O>[C:23]([C:19]1[C:18]([CH3:25])=[C:17]([CH:22]=[CH:21][CH:20]=1)[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:26])#[N:24]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C#N)c2C)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(C#N)cccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
The mixture of 2-(3-cyano-2-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (3) (310 mg, 0.89 mmol), KOH (50% aqueous solution, 2 g, 17.8 mmol), EtOH (10 mL) and water (1 mL) are stirred in a 20 mL vial at 50° C. for 30 min. After concentration in vacuo, the residue is dissolved in water (5 mL) and acidified with conc. HCl until no more white precipitate came out of the water. The filtration affords 2-(3-cyano-2-methyl-benzoylamino)-indan-2-carboxylic acid (238) as white solid (270 mg, 95%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]=[C:10]=[O:11])[N:3]=1.[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([NH2:23])(=[O:22])=[O:21])=[CH2:13]>C(#N)C>[Cl:8][C:6]1[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([NH:9][C:10]([NH:23][S:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH:12]=[CH2:13])(=[O:21])=[O:22])=[O:11])[N:5]=1
Reactant: C=Cc1ccccc1S(N)(=O)=O
Reactant: O=C=Nc1nc(Cl)nc(Cl)n1
Solvent: CC#N
Product: C=Cc1ccccc1S(=O)(=O)NC(=O)Nc1nc(Cl)nc(Cl)n1
Reaction time: 16 h

Procedure:
A solution of 4,6-dichloro-1,3,5-triazin-2-yl isocyanate (0.87 g, 4.5 mmol) in acetonitrile (9 ml) is contacted with 2-ethenylbenzenesulfonamide (0.83 g, 4.5 mmol) and stirred for 16 hours. The mixture is then evaporated under reduced pressure to yield the title compound which is used directly in subsequent reactions.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[N+:18]([C:21]1[CH:30]=[C:29]([C:31]([NH:33][NH2:34])=[O:32])[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24])([O-:20])=[O:19]>>[N+:18]([C:21]1[CH:30]=[C:29]([C:31]([NH:33][N:34]=[C:15]([C:12]2[C:13]([OH:14])=[C:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[S:10][CH:11]=2)[CH3:17])=[O:32])[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24])([O-:20])=[O:19]
Reactant: COC(=O)c1ccc(C(=O)NN)cc1[N+](=O)[O-]
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2csc(-c3ccc(Cl)c(Cl)c3)c2O)cc1[N+](=O)[O-]

Procedure:
Using 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (100 mg, 0.35 mmol) and methyl 2-nitro-4-hydrazinocarbonylbenzoate (93 mg, 0.39 mmol) as the starting materials, the desired product was obtained in the same manner as in Synthetic Example 65 as a yellow solid (147 mg, yield 83%).