Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[CH3:8].[O:10]=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:20])[N:12]1[CH2:21]C(O)=O>>[CH3:8][C:7]1[C:6]([CH2:21][N:12]2[C:13](=[O:20])[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]2=[O:10])=[CH:5][N:4]=[N:3][CH:2]=1
Reactant: Cc1cc(Cl)nnc1Cl
Reactant: O=C(O)CN1C(=O)c2ccccc2C1=O
Product: Cc1cnncc1CN1C(=O)c2ccccc2C1=O

Procedure:
Synthesis was carried out in the same manner as in Reference Synthetic Example 54 by using 3,6-dichloro-4-methylpyridazine and 2-(1,3-dioxoisoindolin-2-yl)acetic acid. The obtained crude product was used for the next reaction.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[C:9]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH:27]([CH3:29])[CH3:28]>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:26]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:18])[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:4][CH:5]([CH3:8])[CH3:6])=[CH:13][CH:12]=2)=[O:10])=[CH:6][CH:7]=1)[CH:27]([CH3:29])[CH3:28]
Reactant: O=C(C(=O)c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CC(C)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CN(C)C=O
Product: CC(C)COc1ccc(C(=O)C(=O)c2ccc(OCC(C)C)cc2)cc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 212.9 %

Procedure:
1,2-Bis(4-hydroxyphenyl)ethane-1,2-dione (0.77 g, 3.18 mmol) was dissolved in 20 mL of DMF. Potassium carbonate (1.3 g, 9.4 mmol), tetrabutylammonium bromide (0.5 g, 1.55 mmol) and 1-bromo-2-methylpropane (0.86 mL, 7.91 mmol) were added, then the reaction was stirred at 130° C. overnight. The mixture was extracted with ethyl acetate and the organic phase was washed with water, dried over sodium sulfate. Concentration under vacuum gave the title compound as oil (1.2 g, quantitative).
Reaction SMILES: [CH:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].S(=O)(=O)(O)O.[CH2:20](O)[CH3:21]>>[CH2:20]([O:11][C:10](=[O:12])[CH:9]=[CH:8][C:7]1[CH:13]=[CH:14][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)[CH3:21]
Reactant: CCO
Reactant: CC(C)c1ccc(C=CC(=O)O)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C=Cc1ccc(C(C)C)cc1
Yield: 97 %

Procedure:
4-Isopropylcinnamic acid (5.0 g), conc. sulfuric acid (0.5 ml) and ethanol (50 ml) were subjected to reaction and post-treatment in a similar manner to that described in Reference example 10(a) to obtain the title compound (5.5 g, 97%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>O>[CH3:18][N:17]([CH3:19])[CH:16]=[C:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:12])[F:13])=[CH:8][CH:7]=1)[C:10]#[N:11]
Reactant: N#CCc1ccc(C(F)(F)F)cc1
Reactant: COC(OC)N(C)C
Solvent: O
Product: CN(C)C=C(C#N)c1ccc(C(F)(F)F)cc1

Procedure:
4-(Trifluoromethyl)phenylacetonitrile (6.0 g.) in 5 ml. dimethylformamide-dimethylacetal was refluxed for 2 hours. Water was added and the final product was filtered, dried, and identified by NMR analysis.
Reaction SMILES: CN(C)C(=O)C.Br[C:8]1[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:10]([N+:21]([O-:23])=[O:22])[CH:9]=1.[CH:24]([C:26]1[CH:35]=[CH:34][C:29]2[O:30][CH2:31][CH2:32][O:33][C:28]=2[CH:27]=1)=[CH2:25].C1(CNCC2CCCCC2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(OCC)(=O)C>[O:30]1[C:29]2[CH:34]=[CH:35][C:26](/[CH:24]=[CH:25]/[C:8]3[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:10]([N+:21]([O-:23])=[O:22])[CH:9]=3)=[CH:27][C:28]=2[O:33][CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: C=Cc1ccc2c(c1)OCCO2
Agent: [Pd+2]
Agent: C1CCC(CNCC2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)c1ccc(/C=C/c2ccc3c(c2)OCCO3)cc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 3 h
Yield: 39.4 %

Procedure:
To N,N-dimethylacetamide 24 mL solution of tert-butyl 4-bromo-2-nitrobenzoate 3.0 g were added 2,3-dihydro-6-vinylbenzo[1,4]dioxin 2.4 g, N,N-dicyclohexylmethylamine 4.0 mL and palladium acetate 0.11 g at room temperature, and it was stirred under nitrogen atmosphere at 120° C. for 3 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added to it, and insoluble matter was filtrated. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with 10% citric acid aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; hexane:ethyl acetate=10:1] to give tert-butyl 4-((E)-2-(2,3-dihydrobenzo[1,4]dioxin-6-yl)vinyl)-2-nitrobenzoate 1.5 g of yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH:12]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH2:13][CH2:14]S(C)(=O)=O)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:27][C:28]1[CH:50]=[CH:49][C:31]([CH2:32][N:33]2[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[N:35]=[C:34]2[C:42]2([OH:48])[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[CH:30][CH:29]=1>>[CH3:1][N:2]([CH2:11][CH:12]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH2:13][CH2:14][N:45]1[CH2:46][CH2:47][C:42]([C:34]2[N:33]([CH2:32][C:31]3[CH:49]=[CH:50][C:28]([F:27])=[CH:29][CH:30]=3)[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[N:35]=2)([OH:48])[CH2:43][CH2:44]1)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccc(C(CCS(C)(=O)=O)CN(C)C(=O)c2ccccc2)cc1
Reactant: OC1(c2nc3ccccc3n2Cc2ccc(F)cc2)CCNCC1
Product: COc1ccc(C(CCN2CCC(O)(c3nc4ccccc4n3Cc3ccc(F)cc3)CC2)CN(C)C(=O)c2ccccc2)cc1

Procedure:
Prepare by the method of Example 1.7 using N-methyl-N-(2-(4-methoxyphenyl)-4-methanesulfonylbutyl)benzamide and 4-(1-(4-fluorobenzyl)-1H-benzoimidazol-2-yl)-4-hydroxypiperidine to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH:6]=[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[O:8]1.C([O-])=O.[NH4+].C(N(CC)CC)C.CCCCCC>C1COCC1.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]([OH:16])=[O:8])[CH:17]=[CH:18][CH:19]=1
Reactant: COc1cccc(C=C2OC(=O)c3ccccc32)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc(CCc2ccccc2C(=O)O)c1
Temperature: 70 °C
Yield: 50.3 %

Procedure:
A solution of 15.6 g of 1 (62 mmol) in 300 ml of THF was added 30 g of 10% Pd-C, 40 g of ammonium formate and 17.2 ml of triethyl amine. The reaction mixture was heated at 70° C. for 6 hours and filtered. The filtrate was concentrated and redissolved in 500 ml of ethyl acetate and washed with 2×150 ml of 3% aqueous HCl and 2×100 ml of brine. The organic layer was concentrated and triturated with 1:1 ethyl acetate:hexane to give 8 g (31.2 mmol, 51%) of 2.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[S:15]1[CH:19]=[C:18]([C:20]2[C:29]3[N:28]=[CH:27][CH:26]=[N:25][C:24]=3[C:23]([C:30](O)=[O:31])=[CH:22][CH:21]=2)[C:17]2[CH:33]=[CH:34][CH:35]=[CH:36][C:16]1=2>C(Cl)Cl.CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:30]([C:23]3[C:24]4[N:25]=[CH:26][CH:27]=[N:28][C:29]=4[C:20]([C:18]4[C:17]5[CH:33]=[CH:34][CH:35]=[CH:36][C:16]=5[S:15][CH:19]=4)=[CH:21][CH:22]=3)=[O:31])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc(N)cn2)CC1
Reactant: O=C(O)c1ccc(-c2csc3ccccc23)c2nccnc12
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(c2ccc(NC(=O)c3ccc(-c4csc5ccccc45)c4nccnc34)cn2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but stirring the reaction mixture for 20 h at rt, using 6-(4-methylpiperazin-1-yl)-pyridin-3-ylamine (prepared as described in Example 33 but using N-methyl-piperazine in Step 33.2) and 8-benzo[b]thiophen-3-yl-quinoxaline-5-carboxylic acid (Example 59). Title compound: ESI-MS: 481.0 [M+H]+; tR=3.81 min (System 1); TLC: Rf=0.40 (DCM/MeOH, 9:1).
Reaction SMILES: Cl[Sn]Cl.O.[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:18][N:17]=[N:16][CH:15]=2)=[CH:10][CH:9]=1)([O-])=O.C([O-])(O)=O.[Na+]>CCO>[S:18]1[C:14]([C:11]2[CH:10]=[CH:9][C:8]([NH2:5])=[CH:13][CH:12]=2)=[CH:15][N:16]=[N:17]1
Reactant: O=[N+]([O-])c1ccc(-c2cnns2)cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(-c2cnns2)cc1
Temperature: 70 °C
Yield: 94.7 %

Procedure:
SnCl2.H2O (3.21 g, 5 eq) was added to a slurry of (5-(4-Nitrophenyl)-1,2,3-thiadiazole (Lancaster Synthesis) (0.59 g, 2.8 mmol) in absolute EtOH (50 mL) and the reaction heated to 70° C. for 2 h. The reaction was allowed to cool to room temperature and pour into saturated NaHCO3 and ice. The product was extracted with EtOAc (2×) the solution dried (MgSO4) and evaporated to dryness in vacuo to yield 0.47 g of a light yellow solid mp 126-128° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]1([CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:18][CH2:19]O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.[Cl-].[Na+].C(OP([CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])(OCC)=O)C.[H-].[Na+]>ClCCl.C(OCC)(=O)C.C1COCC1>[C:11]1([CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:18][CH:19]=[CH:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: OCCC(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C=CCC(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
2.37 g (18.7 mmol) of oxalyl chloride and 2.92 g (37.3 mmol) of DMSO were dissolved in 10 ml of dichloromethane at −78° C. After stirring for one hour, 2.00 g (9.33 mmol) of 3,3-diphenyl-1-propanol was added to the obtained solution at that temperature, and they were stirred for additional 2 hours. 5.66 g (56.0 mmol) of triethylamine was added to the obtained mixture and they were stirred for one hour while the temperature was returned to room temperature. After the dilution with dichloromethane followed by the washing with saturated aqueous sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue thus obtained was added to a THF solution obtained by stirring 2.67 g (11.9 mmol) of ethyl diethylphosphonoacetate and 596 mg (14.9 mmol) of sodium hydride (60% oily) under cooling with ice for one hour. They were stirred at room temperature for 2 hours. After the dilution with ethyl acetate followed by the washing with saturated aqueous sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue thus obtained was purified by the silica gel chromatography (hexane/ethyl acetate=5/1 to 3/1) to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][Si](C)(C)C)=[CH:10][C:9]=1[N+:20]([O-:22])=[O:21])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.C1COCC1>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[CH:15])=[CH:10][C:9]=1[N+:20]([O-:22])=[O:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#C[Si](C)(C)C)cc1[N+](=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
To a solution of (2-nitro-4-trimethylsilanylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example F1) (3.54 g, 10.6 mmol) in MeOH (10 mL) and THF (20 mL) at 0° C. was added 1N NaOH (13 mL) and stirring was continued at 23° C. for 30 min. Poured into cold 5% citric acid, extracted with EtOAc (300 mL), washed with sat. NaHCO3-sol. and brine, dried over MgSO4. Removal of the solvent in vacuum left a dark brown oil, which was purified by silica gel column chromatography with hexane/EtOAc 19:1. Obtained as a yellow solid (2.4 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4](O)([C:19]([F:22])([F:21])[F:20])[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[NH:7][C:6]=1[CH3:18].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:24])[C:4](=[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[N:7]=[C:6]1[CH3:18])[C:19]([F:21])([F:20])[F:22]
Reactant: COC(=O)C(O)(c1c(C)[nH]n(-c2cccc(Cl)c2)c1=O)C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)C(=C1C(=O)N(c2cccc(Cl)c2)N=C1C)C(F)(F)F

Procedure:
To a toluene solution (5 ml) of 1-(3-chlorophenyl)-2,5-dihydro-α-hydroxy-3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester (182 mg, 0.5 mmol), thionyl chloride (0.365 ml, 5.0 mmol) was added and the mixture was stirred under reflux for 3 hours. After concentrating the liquid reaction mixture under reduced pressure, the title compound was obtained as a reddish brown solid (173 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([CH3:18])=[C:12]([CH3:17])[CH:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=1>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([CH3:18])=[C:12]([CH3:17])[CH:13]=2)[N:8]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: Cc1cccc(CBr)n1
Reactant: CCOC(=O)c1c[nH]c2nc(C)c(C)cc2c1=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2cccc(C)n2)c2nc(C)c(C)cc2c1=O
Yield: 37.6 %

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 60 were used with 3 g (12.17 mmol) of 6,7-Dimethyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester, 2.49 g (13.39 mmol) of 2-Bromomethyl-6-methyl-pyridine, 0.54 g (13.39 mmol, 60% dispersion in oil), and 60 mL of N,N-dimethylformamide to give 1.61 g of 6,7-Dimethyl-1-(6-methyl-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester.
Reaction SMILES: Cl[CH:2]([CH2:6][CH2:7][Cl:8])[C:3](=[O:5])[CH3:4].[C:9]([SH:11])#[N:10].N>CC(CC)=O>[S:11]([CH:2]([CH2:6][CH2:7][Cl:8])[C:3](=[O:5])[CH3:4])[C:9]#[N:10]
Reactant: CC(=O)C(Cl)CCCl
Reactant: N#CS
Agent: N
Solvent: CCC(C)=O
Product: CC(=O)C(CCCl)SC#N
Reaction time: 1 h
Yield: 95.7 %

Procedure:
A suspension of 7.8 g (0.05 moles) of 3,5-dichloro-2-pentanone with 3.9 g (0.051 moles) of ammonium rhodanide in 50 cm3 of methyl-ethyl-ketone is boiled for 1 hour under stirring. Then the procedure described in Example 1 is followed. 8.5 g (95.5%) of 3-thiocyanato-5-chloro-2-pentanone are obtained, which after distillation is identical in all respect with the product of Example 1.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH:3]([C:6]2[CH:7]=[CH:8][C:9]([C:12]([F:15])([F:14])[F:13])=[N:10][CH:11]=2)[CH2:2]1.[N:16]#[C:17][NH2:18].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>CC#N>[F:14][C:12]([F:15])([F:13])[C:9]1[N:10]=[CH:11][C:6]([CH:3]2[CH2:4][CH2:5][S:1](=[N:18][C:17]#[N:16])[CH2:2]2)=[CH:7][CH:8]=1
Reactant: N#CN
Reactant: FC(F)(F)c1ccc(C2CCSC2)cn1
Agent: N#C/N=S1\CCC(c2ccc(C(F)(F)F)nc2)C1
Solvent: CC#N
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Product: N#CN=S1CCC(c2ccc(C(F)(F)F)nc2)C1
Temperature: 25 °C

Procedure:
5-(Tetrahydrothiophen-3-yl)-2-trifluoromethylpyridine (1.082 g, 4.64 mmol) was dissolved in 9 mL anhydrous CH3CN under nitrogen. The solution was cooled in an ice bath. Solid cyanamide (0.195 g, 4.64 mmol) was added followed by iodobenzene diacetate (1.496 g, 4.64 mmol). The reaction mixture was allowed to slowly warm to room temperature overnight. The solution was extracted with hexane (6×30 mL). The acetonitrile layer was concentrated by rotary evaporation, and the residue was triturated with ether. The resulting solid was collected and washed with ether to yield (1E)-3-[6-(trifluoromethyl)pyridin-3-yl]tetrahydro-1H-1λ4-thien-1-ylidenecyanamide (1.12 g; 88.4% yield) as an off-white powder. The 1H NMR spectrum of this solid exhibited resonances for a 1:1 mixture of diastereomers. 1H NMR (acetone-d6) δ 8.85 (d, J=2.2 Hz, 1H, pyridine H6), 8.83 (d, J=2.2 Hz, 1H, pyridine H6), 8.26 (dd, J=2.2, 8.3 Hz, 1H, pyridine H4), 8.15 (dd, J=2.2, 8.3 Hz, 1H, pyridine H4), 7.90 (d, J=8.3 Hz, 1H, pyridine H3), 7.86 (d, J=8.3 Hz, 1H, pyridine H3), 4.38 (dd, J=8.7, 14 Hz, 1H), 4.23 (tt, J=6, 12 Hz, 1H), 4.16 (ddd, J=2.6, 8.3, 11.2 Hz, 1H), 3.83 (td, J=8.7, 18 Hz, 1H), 3.68-3.48 (m, 3H), 3.29-3.17 (m, 2H), 2.95 (m, 1H), 2.85-2.79 (m, 3H), 2.33 (m, 1H). LC-MS (ELSD): 273 [m]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]1[C:17](O)=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:22]=1[NH2:23].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]1[C:17](=[O:18])[NH:23][C:22]1[C:21]([F:20])=[CH:27][CH:26]=[CH:25][C:24]=1[F:28])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2[C@H]1C(=O)O
Reactant: Nc1c(F)cccc1F
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1Cc2ccccc2[C@H]1C(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
To the solution of (S)-2-(tert-butoxycarbonyl)isoindoline-1-carboxylic acid (300 mg, 1.14 mmol, Eq: 1.00) and 2,6-difluoroaniline (177 mg, 1.37 mmol, Eq: 1.2) in pyridine (3.00 mL) at 0° C. was added POCl3 (262 mg, 159 μL, 1.71 mmol, Eq: 1.5). The mixture was warmed to RT and stirred for 2 h. The mixture was evaporated, water was added and the mixture extracted with EtOAc. The combined organics were washed with water, brine, dried with MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography to give (S)-1-(2,6-difluoro-phenylcarbamoyl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (298 mg) as a light yellow foam.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:23]([NH:25][C:26]2[S:27][CH:28]=[CH:29][N:30]=2)=[O:24])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:50]N1C(=O)CCC1=O>O1CCCC1>[Cl:50][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:23]([NH:25][C:26]2[S:27][CH:28]=[CH:29][N:30]=2)=[O:24])=[CH:5][CH:4]=1
Reactant: O=C(Nc1nccs1)c1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1-c1ccc(CO)cc1
Reactant: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(Nc1nccs1)c1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1-c1ccc(CCl)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93.3 %

Procedure:
5-(4-Hydroxymethylphenyl)-2-(4-nitrophenyl)-N-(2-thiazolyl)imidazole-4-carboxamide (2.67 g) obtained in Example 93 was dissolved in tetrahydrofuran (300 ml) and triphenylphosphine (3.33 g) and N-chlorosuccinimide (1.70 g) were added. The mixture was stirred for 15 min and triphenylphosphine (3.33 g) and N-chlorosuccinimide (1.70 g) were added. The mixture was stirred for 30 min. The reaction mixture was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and, after drying, concentrated. The obtained residue was recrystallized from ethyl acetate to give 5-(4-chloromethylphenyl)-2-(4-nitrophenyl)-N-(2-thiazolyl)imidazole-4-carboxamide (2.60 g), melting point 280° C. or above.
Reaction SMILES: CO[C:3]([C:5]1[C:6](=[O:25])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[C:12]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[CH:11]=[CH:10][CH:9]=2)=[O:4].[NH2:26][C@H:27]([C:29]([OH:31])=[O:30])[CH3:28].C[O-].[Na+]>COCCO>[F:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][O:16][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:13]=2[C:14]([OH:15])=[C:5]([C:3]([NH:26][C@@H:27]([CH3:28])[C:29]([OH:31])=[O:30])=[O:4])[C:6](=[O:25])[O:7]3)=[CH:23][CH:22]=1
Reactant: C[C@H](N)C(=O)O
Reactant: COC(=O)c1c(O)c2c(OCc3ccc(F)cc3)cccc2oc1=O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: C[C@H](NC(=O)c1c(O)c2c(OCc3ccc(F)cc3)cccc2oc1=O)C(=O)O
Yield: 60.8 %

Procedure:
To a mixture of 5-(4-fluoro-benzyloxy)-4-hydroxy-2-oxo-2H-chromene-3-carboxylic acid methyl ester (86 mg, 0.25 mmol) and L-alanine (334 mg, 3.75 mmol) in 2-methoxyethanol was added sodium methoxide (176 mg, 3.25 mmol). Resulting mixture was refluxed overnight and concentrated. Residue was dissolved in water (100 mL) and acidified using 1 N HCl to pH=3-4. Precipitate was collected, rinsed with water and dried. Crude product was triturated with MeOH. Solid was collected and dried in vacuo to provide the title compound (61 mg). MS ESI(+) m/e: 402.13 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][NH:5][C:6](=C=S)[CH2:7][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:9].[BH4-].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3](=[O:19])[CH2:4][NH:5][CH2:6][CH2:7][N:8]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH3:9]
Reactant: COC(=O)CNC(=C=S)CN(C)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CNCCN(C)C(=O)OC(C)(C)C

Procedure:
To a suspension of the N-[(N-Boc)(N-methyl)(1-thiocarbonyl)-2-aminoethyl]-glycine methyl ester (2.67 g, 0.0097 mol) and NiCl26H2O (18.39 g, 0.077 mol) in THF:MeOH 1:1 (100 ml) at −20° C., NaBH4 (8.78 g, 0.23 mol) was slowly added so that the temperature did not exceed 0° C. After addition of the NaBH4, the reaction was allowed to go to room temperature. The reaction mixture was filtered several times through celite and evaporated to dryness. The product was isolated by column chromatography on silica gel with CH2CL2/MeOH 90:10 eluent. The yield of the title compound was 60%.
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[O-:16][N+:17]1[C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][C:21]=2[N:20]=[C:19]([NH:30][CH2:31][CH2:32][OH:33])[N:18]=1)[CH2:27][CH2:26][CH2:25]3.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[O-:16][N+:17]1[C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][C:21]=2[N+:20]([O-:4])=[C:19]([NH:30][CH2:31][CH2:32][OH:33])[N:18]=1)[CH2:27][CH2:26][CH2:25]3
Reactant: [O-][n+]1nc(NCCO)nc2cc3c(cc21)CCC3
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: [O-][n+]1nc(NCCO)[n+]([O-])c2cc3c(cc21)CCC3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 40.4 %

Procedure:
H2O2 (70%, 0.5 mL, ca. 10 mmol) was added dropwise to a stirred solution of TFAA (1.4 mL, 10 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 24 (246 mg, 1.0 mmol) and TFA (0.28 mL, 2.0 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 0° C. for 1 h and then at 20° C. for 30 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with DCM (5×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-4%) of MeOH/DCM, to give 1,4-dioxide 25 (106 mg, 40%) as a red solid: mp (MeOH/DCM) 187-188° C.; 1H NMR [(CD3)2SO] δ 7.99 (s, 1H, H-9), 7.92-7.98 (m, 2H, NH, H-5), 4.84 (t, J=6.0 Hz, 1H, OH)), 3.61 (q, J=6.0 Hz, 2H, CH2O), 3.46 (q, J=6.0 Hz, 2H, CH2N), 2.98-3.10 (m, 4H, H-6, H-8), 2.05-2.14 (m, 2H, H-7); 13C NMR [(CD3)2SO] δ 154.5, 149.4 144.9, 137.6, 129.0, 115.0, 110.9, 59.1, 43.1, 32.6, 31.7, 25.1. Anal. calcd for C12H14N4O3: C, 55.0; H, 5.4; N, 21.4. Found: C, 54.8; H, 5.4; N, 21.1%.