Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:15]([F:18])([F:17])[F:16])([CH2:5][C:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[CH:3]=O.[NH2:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[N:23][NH:24]2.[Cl-].[Na+]>C1(C)C=CC=CC=1.[Ti]>[F:16][C:15]([F:18])([F:17])[C:2]([CH:3]=[N:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[N:23][NH:24]2)([OH:1])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:14])[CH3:7]
Reactant: Nc1cccc2[nH]ncc12
Reactant: CC(C)(CC(O)(C=O)C(F)(F)F)c1ccccc1
Agent: [Ti]
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(CC(O)(C=Nc1cccc2[nH]ncc12)C(F)(F)F)c1ccccc1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 101.2 %

Procedure:
130 mg (0.50 mmol) of 2-hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)-pentanal is dissolved in 15 ml of toluene and mixed with 73 mg (0.55 mmol) of 4-amino-indazole and with 0.22 ml of titanium tetraethylate and stirred at 100° C. for 2.5 hours under argon. For working-up, the reaction solution is mixed with 1 ml of saturated sodium chloride solution, and it is stirred for 30 minutes. The suspension is then suctioned off over Celite and washed with 200 ml of ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation in a vacuum: 246 mg. Column chromatography on silica gel with pentane-ethyl acetate yields 190 mg of the product.
Reaction SMILES: Br[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22].C([Li])CCC.[CH2:33]([S:40]C#N)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CCCCCC.O1CCCC1>[CH2:33]([S:40][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: N#CSCc1ccccc1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(Br)c1S(=O)(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(SCc2ccccc2)c1S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.7 %

Procedure:
A solution of 5-bromo-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulphonylpyrazole (3.0 g) in dry tetrahydrcfuran (32 ml , stirred under nitrogen at -78° C., was treated with a solution of n-butyllithium in hexane (2.8 ml of a 2.5M solution) over a period of 5 minutes. After 1 hour at -78° C., a solution of benzyl thiocyanate (0.95 g) in tetrahydrofuran (2 ml) was added. The stirred mixture was allowed to warm slowly to room temperature during 16 hours, then poured onto ice/water 50 ml) and extracted with ether (3×50 ml). The combined extracts were dried over anhydrous magnesium sulphate, evaporated in vacuo, and purified by chromatography, eluting with ethyl acetate/hexane (2:98). The product was triturated with hexane to give 5-benzylthio-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulphonylpyrazole (0.25 g), as a white solid, m.p. 117°-119° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][C:13](=[O:15])[CH3:14].[CH3:16][Mg+].[Br-].[NH4+].[Cl-]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][C:13]([CH3:16])([OH:15])[CH3:14]
Reactant: C[Mg+]
Reactant: CC(=O)CCc1c[nH]c2ccc(F)cc12
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(O)CCc1c[nH]c2ccc(F)cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 25.6 %

Procedure:
A solution of 4-(5-fluoro-1H-indol-3-yl)-butan-2-one (11.1 g, 54.1 mmol) in THF (200 mL) at 0° C. is treated with MeMgBr (54.1 mL, 3 M in THF, 162.3 mmol) and stirred at 0° C. for 2 h, and warmed to rt overnight. The mixture is then poured over ice, treated with solid NH4Cl (3 g), and extracted with EtOAc (3×120 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 10%-60% EtOAc in heptane to afford 4-(5-fluoro-1H-indol-3-yl)-2-methyl-butan-2-ol (3.07 g, 26%). MS: 222 (M+H); 1H NMR (300 MHz, CDCl3): δ 7.94 (s, NH, 1H), 7.22 (m, 2H), 7.03 (s, 1H), 6.93 (m, 1H), 2.81 (m, 2H), 1.90 (m, 2H), 1.33 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH2:15])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].CN(C(ON1N=N[C:26]2[CH:27]=[CH:28][CH:29]=N[C:25]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN([CH:46]([CH3:48])[CH3:47])C(C)C>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:1](=[O:3])[CH:2]([CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[C:47]2[CH:46]=[CH:48][CH:7]=[CH:6][CH:4]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCN(C(C)C)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)C(c2ccccc2)C2CCCC2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 161.4 %

Procedure:
To a solution of α-phenylcyclopenteacetic acid (2.04 g, 10 mmol), 2-Amino-indan-2-carboxylic acid ethyl ester (2.05 g, 10 mmol), HATU (7.60 g, 20 mmol) in anhydrous DMF (50 mL) is added DIPEA (3.30 mL, 20 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (100 mL) and washed with saturated NaHCO3 (1×100 mL), water (1×100 mL) and brine (1×100 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 0%-20% EtOAc in heptane) to give a pure product (268) as a solid (3.16 g, 82%).
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[C:9]([NH:10]C(OC)=O)=[CH:8][C:7]([O:15][CH3:16])=[CH:6][C:5]=1[CH2:17][CH3:18].CO.[OH-].[Li+]>O.C1COCC1>[NH2:10][C:9]1[CH:8]=[C:7]([O:15][CH3:16])[CH:6]=[C:5]([CH2:17][CH3:18])[C:4]=1[C:3]([OH:19])=[O:2]
Reactant: CCc1cc(OC)cc(NC(=O)OC)c1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCc1cc(OC)cc(N)c1C(=O)O
Yield: 98.1 %

Procedure:
Compound O (21.9 g, 82.0 mmol) in H2O, THF, and MeOH (3:1:1, 255 mL) was treated with lithium hydroxide (9.80 g, 410 mmol) at 100° C. for 2 hours under N2. The reaction mixture was partially concentrated and the remaining aqueous phase was washed with dichloromethane (50 mL). The aqueous phase was acidified to pH 4-5 with 3 N HCl and then extracted with ethyl acetate (3×400 mL). The combined organic solutions were washed with saturated NaCl solution and dried over anhydrous Na2SO4. Filtration and concentration by rotary evaporation provided compound R (15.71 g, 98%) as an off-white powder. 1H NMR (CDCl3, 400 MHz) δ: 6.18 (d, 1H, J=2.0 Hz), 6.01 (d, 1H, J=2.0 Hz), 3.79 (s, 3H), 2.93 (q, 2H, J=7.0 Hz), 1.23 (t, 3H, J=7.5 Hz). ESMS m/z: 196.0 [M+H]+, 178.0 [M−OH]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH:16]([F:18])[F:17])=[N:8][N:9]([CH3:15])[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])C.[OH-].[Na+]>C(O)C>[CH3:15][N:9]1[C:10]([C:11]([F:12])([F:13])[F:14])=[C:6]([C:4]([OH:5])=[O:3])[C:7]([CH:16]([F:18])[F:17])=[N:8]1
Reactant: CCOC(=O)c1c(C(F)F)nn(C)c1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1nc(C(F)F)c(C(=O)O)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
N-Methyl-5-trifluoromethyl-3-difluoromethyl-4-pyrazolecarboxylic acid ethyl ester (0.5 g, 1.84 mmol) in ethanol (3 ml) was admixed gradually with an 8N aqueous sodium hydroxide solution (0.7 ml) and stirred at room temperature for 3 h. The solvent was removed by rotary evaporation; the residue was taken up in water (10 ml) and extracted with diethyl ether (10 Acidification to pH 1 with 1M HCl was followed by extraction with ethyl acetate (3×10 ml). The combined organic phases were dried over sodium sulphate and filtered, and the solvent was removed by rotary evaporation. N-Methyl-3-difluoromethyl-5-trifluoromethyl-4-pyrazolecarboxylic acid (0.44 g, 1.80 mmol, 98%) was isolated as a yellowish solid.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[CH:14]1[C:23]2[O:22][C:21]3[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=3[O:19][C:18]=2[CH:17]=[CH:16][C:15]=1[CH2:28][NH2:29].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Cl:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:29]([CH2:28][C:15]1[CH:16]=[CH:17][C:18]3[O:19][C:20]4[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=4[O:22][C:23]=3[CH:14]=1)[CH2:11]2
Reactant: COC(=O)c1c(Cl)cccc1CBr
Reactant: NCc1ccc2c(c1)Oc1ccccc1O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1c2c(Cl)cccc2CN1Cc1ccc2c(c1)Oc1ccccc1O2
Temperature: 100 °C
Reaction time: 2 h
Yield: 10.5 %

Procedure:
A mixture of 2-bromomethyl-6-chloro-benzoic acid methyl ester (0.148 g, 0.6 mmol), C-dibenzo[1,4]dioxin-2-yl-methylamine (0.213 g, 1.0 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-Chloro-2-dibenzo[1,4]dioxin-2-ylmethyl-2,3-dihydro-isoindol-1-one (0.023 g, 13%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.34 (s, 2H), 4.65 (s, 2H), 6.85 (m, 8H), 7.40 (t, 2H). GC-MS: m/z 363 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)=S)=[CH:4][CH:3]=1.C1([N:39]=[C:40]=[N:41]C2CCCCC2)CCCCC1.C(N(C(C)C)CC)(C)C.N#CN>C(Cl)Cl.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)=[N:41][C:40]#[N:39])=[CH:4][CH:3]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=S)Nc4ccc(F)cc4)cc3)c2cc1OC
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N#CN
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2nccc(Oc3ccc(NC(=NC#N)Nc4ccc(F)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.2 %

Procedure:
N-(4-Fluorophenyl)-N'-(4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl)thiourea (33 mg) obtained in Example 165, dicyclohexylcarbodiimide (31 mg) and a catalytic amount of diisopropylethyl amine were dissolved in methylene chloride (10 ml). To this solution, a solution of cyanamide (16 mg) in THF (1 ml) was added, and the admixture was stirred at room temperature overnight. After removing the solvent by distillation, the resulting residue was purified by column chromatography on silica gel eluting with chloroform/methanol (100/1) to obtain 34 mg of the title compound (yield: 99%).
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][O:5][C:6]([C:8]1[CH:16]=[C:15]2[C:11]([C:12]([CH:17]=O)=[CH:13][NH:14]2)=[CH:10][CH:9]=1)=[O:7].[CH3:19][OH:20]>>[CH3:4][O:5][C:6]([C:8]1[CH:16]=[C:15]2[C:11]([C:12]([CH:17]=[C:1]3[C:19](=[O:20])[NH:14][C:15]4[CH:16]=[CH:8][CH:9]=[CH:10][C:11]=4[O:2]3)=[CH:13][NH:14]2)=[CH:10][CH:9]=1)=[O:7]
Reactant: COC(=O)c1ccc2c(C=O)c[nH]c2c1
Reactant: CO
Reactant: C[O-]
Agent: [Na+]
Product: COC(=O)c1ccc2c(C=C3Oc4ccccc4NC3=O)c[nH]c2c1
Temperature: 25 °C

Procedure:
Sodium methoxide (1 g, 0.018 mol) was added in one portion to a mixture of 2-diethylphosphonyl-2H-1,4-benzoxazin-3(4H)-one (3.42 g, 0.012 mol) and 6-methoxycarbonylindol-3-carboxaldehyde (2.55 g, 0.012 mol) in methanol (60 ml). The reaction mixture was refluxed for 21 h, then cooled at room temperature and the precipitated solid was collected by filtration, washed with methanol and dried. Yield 2.78 g (87%) as a mixture of isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:11]=2[C:12]([OH:14])=[O:13])=[O:9])=[CH:4][CH:3]=1.[N+:21]([O-])([OH:23])=[O:22].S(=O)(=O)(O)O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:11]=2[C:12]([OH:14])=[O:13])=[O:9])=[CH:6][C:7]=1[N+:21]([O-:23])=[O:22]
Reactant: O=C(O)c1c(F)ccc(F)c1C(=O)c1ccc(Cl)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1c(F)ccc(F)c1C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
2-[(4-chlorophenyl)carbonyl]-3,6-difluorobenzoic acid (3.20 g, 11.00 mmol) was dissolved while heating in concentrated.sulfuric acid (15 ml) and it was cooled to 0° C. A solution of fuming nitric acid (0.5 ml, 11.00 mmol) in concentrated.sulfuric acid (3.0 mL) was added dropwise and the reaction mixture was stirred at 0° C. for 60 minutes. It was poured into crushed ice. The product was precipitated. It was collected by filtration then it was dissolved in ethyl acetate (100 mL); it was washed with water (2×40 mL), brine (40 mL) and dried over anhydrous sodium sulfate. Filtration and concentration resulted in a crude product, which was triturated with hexane. The crystalline product was collected by filtration to give 2-[(4-chloro-3-nitrophenyl)carbonyl]-3,6-difluorobenzoic acid (2.73 g, 74% yield). 1H NMR (400 MHz, CD3OD): 8.28 (s, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.53-7.42 (m, 2H); MS (EI) for C14H7ClF2NO5: 341 (M−).
Reaction SMILES: Cl[C:2]1C=CC=C(C(OO)=O)C=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([C:22]3[O:23][C:24](SC)=[N:25][N:26]=3)=[CH:20][N:21]=2)[CH:18]=1.ClCCl.[S:32]([O-:36])([O-])(=[O:34])=S.[Na+].[Na+]>C(OCC)(=O)C>[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([C:22]3[O:23][C:24]([S:32]([CH3:2])(=[O:36])=[O:34])=[N:25][N:26]=3)=[CH:20][N:21]=2)[CH:18]=1
Reactant: CSc1nnc(-c2cnc3ccc(Br)cn23)o1
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1nnc(-c2cnc3ccc(Br)cn23)o1
Reaction time: 8 h

Procedure:
1.16 g of m-chloroperbenzoic acid was added to a mixture of 981 mg 6-bromo-3-(5-methylsulfanyl[1,3,4]oxadiazol-2-yl)imidazo[1,2-a]pyridine (compound in Production Example 279) and 30 mL dichloromethane under ice-coolingd water, then retuned to room temperature and stirred overnight. Ethyl acetate and an aqueous saturated sodium thiosulfate solution were added to the reaction solution, and the mixture was stirred. The organic layer was separated, washed twice with an aqueous saturated sodium bicarbonate solution and then with brine and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was evaporated. 995 mg crude product of a mixture of 6-bromo-3-(5-methanesulfinyl[1,3,4]oxadiazol-2-yl)imidazo[1,2-a]pyridine and 6-bromo-3-(5-methylsulfonyl[1,3,4]oxadiazol-2-yl)imidazo[1,2-a]pyridine was obtained as pale brown crystals. A mixture of 150 mg of this mixture, 90 μL methylamine (30% methanol solution) and 10 mL methanol was stirred at room temperature for 10 minutes. Ethyl acetate, tetrahydrofuran and water were added to the reaction solution, and the organic layer was separated. The aqueous layer was saturated with common salt and then extracted with ethyl acetate. The combined organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was evaporated. The resulting residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 121 mg of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[OH:13].[F:14][C:15]([F:25])([F:24])[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][N:17]=1.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O.C(O)(C)C>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([OH:12])[C:6]([CH2:20][C:19]1[CH:18]=[N:17][C:16]([C:15]([F:25])([F:14])[F:24])=[CH:23][CH:22]=1)=[C:5]2[OH:13]
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Reactant: O=c1cc(O)c2cc(Br)ccc2[nH]1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Solvent: CC(C)O
Solvent: c1ccncc1
Product: Oc1nc2ccc(Br)cc2c(O)c1Cc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 6-bromo-4-hydroxyquinolin-2(1H)-one (3.2 g, 18.3 mmol, Intermediate 45: step a), 6-(trifluoromethyl)nicotinaldehyde (4.0 g, 16.7 mmol) and diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (4.2 g, 16.7 mmol) in pyridine (34 mL) was heated to 105° C. for 3 hours. The solution was allowed to cool to ambient temperature, resulting in the formation of solid. Minimal isopropanol was added to the mixture and the slurry was stirred for 1 hour, sonicated, and filtered. The filtered solids were rinsed with isopropanol and dried under continuous air flow to provide the title compound as an off-white solid. Additional product was recrystallized from the filtrate, filtered, and rinsed with isopropanol.
Reaction SMILES: [C:1]([C:4]1[C:16]([OH:17])=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])=[C:6]([CH2:18][CH:19]=[CH2:20])[CH:5]=1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)Cl>[C:1]([C:4]1[C:16]([OH:17])=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])=[C:6]([CH2:18][CH:19]([OH:29])[CH3:20])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: C=CCc1cc(C(C)=O)c(O)cc1OCCCCC#N
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)c1cc(CC(C)O)c(OCCCCC#N)cc1O
Reaction time: 5 h
Yield: 70.1 %

Procedure:
To a solution of 5.46 g of 5-[4-acetyl-5-hydroxy-2-allylphenoxy]pentanenitrile in 100 ml of methylene chloride were added 6.1 g of 85% meta-chloroperbenzoic acid. After stirring for 5 hours, the reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and a cold sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo to approximately 35 ml. The solution was placed in a freezer overnight providing 4.08 g of the crystalline title product which were recovered by filtration, m.p. 86°-87° C.
Reaction SMILES: C1(N(C2CCCC2)[C:7]([NH:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[O:8])CCCC1.[CH:20]1([NH:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(N1C=CN=C1)(N1C=CN=C1)=O.NC1SC=C([CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])N=1>>[CH2:55]([O:54][C:52](=[O:53])[CH2:51][C:13]1[N:14]=[C:10]([NH:9][C:7]([N:26]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)=[O:8])[S:11][CH:12]=1)[CH3:56]
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=C(Nc1nccs1)N(C1CCCC1)C1CCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CCOC(=O)Cc1csc(NC(=O)N(C2CCCCC2)C2CCCCC2)n1

Procedure:
[2-(3,3-Dicyclohexyl-ureido)-thiazol-4-yl]-acetic acid ethyl ester was prepared in an similar manner to the synthesis of 1,1-dicyclopentyl-3-thiazol-2-yl-urea, using dicyclohexylamine, carbonyldiimidazole and ethyl 2-amino-4-thiazole acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH2:9])[S:8][C:4]=2[CH:3]=1.[CH2:12]([N:14]=[C:15]=[O:16])[CH3:13].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH:9][C:15]([NH:14][CH2:12][CH3:13])=[O:16])[S:8][C:4]=2[CH:3]=1
Reactant: Nc1nc2ccc(Cl)cc2s1
Reactant: CCN=C=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2ccc(Cl)cc2s1

Procedure:
Three grams of 6-chloro-1,3-benzothiazol-2-amine was dissolved in about 50 mL DMF. Next, about 2.5 mL of EtNCO was added followed by about 3.2 mL of triethylamine. The solution was allowed to react at about 80° C. for about 8 hours. The reaction solvent was then removed in vacuo and the crude oil was taken up in ether. The solids were isolated by filtration and washed with ether. The product was then dried in vacuo. 1H NMR 1.09 (t, 3H, J=7.2 Hz), 3.19 (m, 2H), 6.74 (br s, 1H), 7.37 (d, 1H, J=8.58 Hz), 7.60 (d, 1H, J=8.59 Hz), 8.01 (s, 1H), 10.8 (br s, 1H). LCMS: R.T. 2.3 min, MH-254 m/z.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[NH2:16][C@H:17]([C:26]([NH:28][C@H:29]([C:37]([O:39][CH3:40])=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22]C=1.Cl.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1>>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:16][C@H:17]([C:26]([NH:28][C@H:29]([C:37]([O:39][CH3:40])=[O:38])[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:27])[CH2:18][C:19]1[CH:20]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CCc1ccccc1
Agent: Cl
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 67 %

Procedure:
Condensation of ZPheOH (29.2 g.) and HPheOMe (21.6 g.) by the mixed anhydride method using isobutyl chloroformate gave ZPhe-PHeOMe in 57% yield. Debenzyloxycarbonylation of ZPhe-PHeOMe (26.4 g.) by hydrogenation in acidified methanol with palladium catalyst gave HPhe-PheOMe in 86% yield. Condensation of BocProOH (6.46 g.) and HPhe-PheOMe hydrochloride (10.9 g.) by the mixed anhydride method using diphenylphosphinyl chloride gave BocPro-Phe-PheOMe in 67% yield. Hydrazinolysis of BocPro-Phe-PheOMe (9.57 g.) gave BocPro-Phe-Phe-NHNH2 in 92% yield.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[CH2:20]([O:8][C:7]1[CH:9]=[CH:10][C:2]([C:1]([O:12][CH3:13])=[O:11])=[CH:3][C:4]=1[O:5][CH3:6])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccccc2)c(OC)c1
Temperature: 100 °C
Yield: 99.3 %

Procedure:
To a solution of methyl vanillate (7.29 g, 40 mmol) in dimethylformamide (25 mL), potassium carbonate (8.29 g, 60 mmol) and benzyl bromide (5.26 mL, 44 mmol) were added. The mixture was heated to 100° C. for 3 h. After cooling to r.t., water was added and the product was extracted several times with ethyl acetate. The combined organic phases were washed with water and brine. After drying over Na2SO4, the solvent was removed to yield methyl 4-benzyloxy-3-methoxybenzoate (10.8 g, 39.7 mmol, 99%) as a grey solid which was used without further purification. LC/ESI-MS: m/z=273 [M+H]+; Rt=3.82 min.
Reaction SMILES: C1(O[C:8](=[O:19])[NH:9][C:10]2[S:14][N:13]=[C:12]([SH:15])[C:11]=2[C:16](=[O:18])[NH2:17])C=CC=CC=1.[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1.O1CCCC1.[Cl:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][C:42]=1[F:43])[CH2:38][NH2:39]>CN(C=O)C.Cl>[Cl:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][C:42]=1[F:43])[CH2:38][NH:39][C:8](=[O:19])[NH:9][C:10]1[S:14][N:13]=[C:12]([S:15][CH2:20][C:21]2[CH:28]=[CH:27][C:24]([CH3:25])=[CH:23][CH:22]=2)[C:11]=1[C:16]([NH2:17])=[O:18]
Reactant: Cc1ccc(CCl)cc1
Reactant: NCc1ccc(F)c(Cl)c1
Reactant: NC(=O)c1c(S)nsc1NC(=O)Oc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(CSc2nsc(NC(=O)NCc3ccc(F)c(Cl)c3)c2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.4 %

Procedure:
To a mixture of (4-carbamoyl-3-mercapto-isothiazol-5-yl)-carbamic acid phenyl ester (0.075 g, 0.25 mmol) in 0.5 mL of DMF was added 4-methylbenzylchloride (0.036 g, 0.25 mmol), followed by N,N-disopropylethylamine (0.033 g, 0.25 mmol). After stirring for 18 hours at ambient temperature, tetrahydrofuran (1 mL) was added, followed by 3-chloro-4-fluorobenzylamine (0.051 g, 0.51 mmol). After stirring for 24 hours at 45° C., the mixture was diluted with 1M HCl, extracted 3× with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by radial chromatography on silica gel eluting with ethyl acetate-hexane, affording 26 mg of 5-[3-(3-chloro-4-fluoro-benzyl)-ureido]-3-(4-methyl-benzylsulfanyl)-isothiazole-4-carboxylic acid amide as a colorless solid. HPLC ret. time: 4.9 minutes. 1H NMR (400 MHz, acetone-d6) δ 7.95 (bs, 1H), 7.54 (dd, 1H, J=2, 7.2 Hz), 7.39 (m, 1H), 7.31-7.25 (m, 3H), 7.11 (d, 2H, J=8.0 Hz), 7.01 (bs, 2H), 4.48 (m, 4H), 2.28 (s, 3H) ppm; MS (APCI, m/z): 465 [M+H]+.