Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11](O)=[O:12])=O)(C)(C)C.C(N(CC)CC)C.C(OC([Cl:28])=O)C(C)C.[C:29]([C:31]1[CH:36]=[CH:35][C:34]([C:37]2[O:50][C:40]([CH:41]=[N:42][N:43]3[CH2:49][C:47](=[O:48])[NH:46][C:44]3=[O:45])=[CH:39][CH:38]=2)=[CH:33][CH:32]=1)#[N:30].Cl>CN(C)C=O>[ClH:28].[NH2:8][CH2:9][CH2:10][C:11]([N:46]1[C:47](=[O:48])[CH2:49][N:43]([N:42]=[CH:41][C:40]2[O:50][C:37]([C:34]3[CH:33]=[CH:32][C:31]([C:29]#[N:30])=[CH:36][CH:35]=3)=[CH:38][CH:39]=2)[C:44]1=[O:45])=[O:12]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: N#Cc1ccc(-c2ccc(C=NN3CC(=O)NC3=O)o2)cc1
Reactant: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2ccc(C=NN3CC(=O)N(C(=O)CCN)C3=O)o2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
t-Butoxycarbonyl -β-alanine (16.1 g, 0.080 mole) in dimethylformamide (200 ml) was cooled to 0°, and triethylamine (23.8 ml, 0.17 mole) was rapidly added. The solution was kept at -5° to 0° while isobutylchloroformate (11.9 ml, 0.085 mole) was added dropwise. The solution was stirred 10 minutes and then 1-{[5-(4-cyanophenyl)furfurylidene]amino}hydantoin (recrystallized and predried at 100° overnight; 23.5 g, 0.080 mole) was rapidly added. The mixture was maintained at -5° to 0° for 0.5 hr and was then stirred 1 hour without cooling. The mixture was poured into a solution of ice water (1,400 ml) and concentrated hydrochloric acid (25 ml). The resulting solid was collected and air-dried. The product was dissolved in acetonitrile, filtered, and concentrated to a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[F:27][C:28]1[CH:29]=[C:30]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[C:31](=[N:33]O)[NH2:32].[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]3[O:20][N:33]=[C:31]([C:30]4[CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=[C:28]([F:27])[CH:29]=4)[N:32]=3)=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1OC
Reactant: NC(=NO)c1cc(F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1-c1nc(-c2cc(F)cc(C(F)(F)F)c2)no1
Yield: 7 %

Procedure:
The title compound was prepared by following the procedure as described for Example-40 by using methyl 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (step-2 of Intermediate-15, 0.100 g, 0.26 mmol), 3-fluoro-N′-hydroxy-5-(trifluoromethyl)benzimidamide (Intermediate-22, 0.088 g, 0.39 mmol), sodium hydride (0.017 g, 0.42 mmol) and dry THF (5.0 mL) at RT to afford 0.010 g of desired product. 1HNMR (DMSO-d6): δ 4.01 (s, 3H), 7.50 (m, 1H), 7.60 (m, 1H), 7.70 (m, 1H), 7.84 (m, 1H), 7.92 (br s, 1H), 8.02 (d, 1H), 8.18 (m, 2H), 8.25 (d, 1H), 12.95 (br s, 1H); MS (m/z): 550.07 [M]+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.C([O:27][C:28](=O)[C:29](=[O:36])[CH2:30][C:31](=[O:35])[CH2:32][CH2:33][CH3:34])C>C(O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:21]([C:20]4[CH:23]=[CH:24][C:17]([C:12]5[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=5)=[CH:18][CH:19]=4)[C:30]([C:31](=[O:35])[CH2:32][CH2:33][CH3:34])=[C:29]([OH:36])[C:28]3=[O:27])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Reactant: Nc1ccc2[nH]cnc2c1
Reactant: CCCC(=O)CC(=O)C(=O)OCC
Solvent: CCO
Product: CCCC(=O)C1=C(O)C(=O)N(c2ccc3[nH]cnc3c2)C1c1ccc(-c2ccccn2)cc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
1H-Benzoimidazol-5-ylamine (1 mmol) and 4-Pyridin-2-yl-benzaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 2,4-Dioxo-heptanoic acid ethyl ester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].C(O[C:20](=O)/[CH:21]=[CH:22]/CC)C.C(O)(=O)C>C(O)C>[CH2:10]([O:9][C:7]([C:6]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:20]([CH2:21][CH3:22])[CH2:3][C:2](=[O:4])[NH:5]1)=[O:8])[CH3:11]
Reactant: CC/C=C/C(=O)OCC
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C1(C(=O)OCC)NC(=O)CC1CC
Yield: 87.1 %

Procedure:
To 150 mg of sodium dissolved in 150 mL of absolute ethanol was added diethyl acetamidomalonate (5.3 g, 25 mmol) and ethyl-(2E)-pent-2-enoate (3.5 g, 27.3 mmol). The reaction mixture was then refluxed for 20 h. After this period of time, 2 mL of glacial acetic acid was added, volatiles were removed under pressure with the aid of a water aspirator and heating bath. On cooling the residue solidified. The residue was dissolved in 50 mL of toluene and to this was added 20 mL of petroleum ether. The product precipitated when the mixture was cooled. The crystals were collected and washed with water and further dried in vacuo to obtain a white solid (5.6 g, 79.77%). Mass Spectrum (+ESI): 258 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][CH:13]([CH3:15])[CH3:14])[CH:3]=1.[CH2:16]([N:23]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:16]([N:23]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][CH:13]([CH3:15])[CH3:14])[CH:3]=2)=[CH:28][CH:27]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(B(O)O)cc1)Cc1ccccc1
Reactant: COC(=O)c1ccc(Br)cc1NC(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2ccc(CCN(Cc3ccccc3)C(=O)OC(C)(C)C)cc2)cc1NC(C)C
Temperature: 70 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of methyl 4-bromo-2-(isopropylamino)benzoate (433 mg) in 1,2-dimethoxyethane (6.5 ml) were added [4-[2-[benzyl(tert-butoxycarbonyl)amino]ethyl]phenyl]boronic acid (848 mg), tetrakis(triphenylphosphine)palladium (184 mg) and aqueous solution of sodium carbonate (2M, 3.5 ml), and the mixture was stirred at 70° C. for 2 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=17/3) to give methyl 4′-[2-[benzyl(tert-butoxycarbonyl)amino]ethyl]-3-(isopropylamino)-4-biphenylcarboxylate (768 mg).
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C>[CH2:27]([O:20][C:9]1[CH:8]=[CH:7][C:6]2[C@@H:5]3[C@H:14]([C@H:15]4[C@@:2]([CH2:3][CH2:4]3)([CH3:1])[C:18](=[O:19])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1CCC2=O
Reaction time: 24 h
Yield: 77.9 %

Procedure:
To a solution of oestrone (3.35 g, 12.39 mmol) in DMF (50 ml) were added potassium carbonate (3.45 g, 25 mmol) and benzyl bromide (2.25 ml, 18.75 mmol) at room temperature under an atmosphere of nitrogen. The reaction mixture was stirred for 24 h, then quenched with H2O, and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and then dried (MgSO4). The desiccant was filtered and the solvent was evaporated at reduced pressure. The residue was triturated with Et2O, filtered and evaporated to afford 3.48 g (78% yield) of 3-benzyloxyestra-1,3,5(10)-trien-17-one BLE99049 as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[N:7]2[CH:10]=[CH:11][NH:12][C:6]2=[N:5][C:4]=1[CH3:13])[CH3:2].[Si]([O:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1)(C(C)(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>CN(C=O)C>[CH2:1]([C:3]1[C:8](=[O:9])[N:7]2[CH:10]=[CH:11][N:12]([CH2:32][C:31]3[CH:30]=[CH:29][C:28]([C:26](=[O:27])[C:25]4[CH:36]=[CH:37][C:22]([OH:21])=[CH:23][CH:24]=4)=[CH:35][CH:34]=3)[C:6]2=[N:5][C:4]=1[CH3:13])[CH3:2]
Reactant: CCc1c(C)nc2[nH]ccn2c1=O
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CCc1c(C)nc2n(Cc3ccc(C(=O)c4ccc(O)cc4)cc3)ccn2c1=O
Yield: 10.6 %

Procedure:
A solution of 6-ethyl-7-methylimidazo[1,2-a]-pyrimidin-5(1H)-one (3.93 g), 4-(4-t-butyldimethylsilyloxybenzoyl)benzyl bromide (14.79 g) and potassium carbonate (5.97 g) in DMF (25 ml)-dimethyl sulfoxide (25 ml) was stirred at room temperature for 20 hours. This reaction mixture was concentrated and the residue was extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane: methanol =9:1) and recrystallized from ethanol-ethyl acetate to provide the title compound as colorless solid (909 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[F:18][C:19]([F:40])([F:39])[C:20]1[C:25]([C:26](O)=[O:27])=[CH:24][N:23]=[C:22]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[CH:21]=1.COC(=O)C1C(C(F)(F)F)=CC(C2C=CC(C(F)(F)F)=CC=2)=NC=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:7])([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][NH:16][C:26]([C:25]2[CH:24]=[N:23][C:22]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:31][CH:30]=3)=[CH:21][C:20]=2[C:19]([F:18])([F:39])[F:40])=[O:27])=[CH:13][CH:14]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN)cc1
Reactant: O=C(O)c1cnc(-c2ccc(C(F)(F)F)cc2)cc1C(F)(F)F
Agent: COC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)cc1C(F)(F)F
Product: CCOC(=O)C(C)(C)Oc1ccc(CNC(=O)c2cnc(-c3ccc(C(F)(F)F)cc3)cc2C(F)(F)F)cc1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-phenoxy)-2-methyl-propionic acid ethyl ester [PCT Int. Appl. (2002), WO 2002/096895A1] was reacted with 4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid (prepared from 4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester (example 108B]) by saponification in analogy to example 53B]) to give 2-methyl-2-[4-({[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-methyl)-phenoxy]-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as amorphous light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1.[CH:16]1([C:19](=[S:21])[NH2:20])[CH2:18][CH2:17]1>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:19]([CH:16]2[CH2:18][CH2:17]2)[S:21][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1)=[O:15]
Reactant: COC(=O)C(=O)C(Cl)c1cccc(F)c1
Reactant: NC(=S)C1CC1
Product: COC(=O)c1nc(C2CC2)sc1-c1cccc(F)c1

Procedure:
prepared by reaction of 3-chloro-3-(3-fluoro-phenyl)-2-oxo-propionic acid methyl ester with cyclopropanecarbothioic acid amide. LC-MS: tR=1.02 min; [M+H]+=278.0.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=O)=[CH:4][C:3]=1[Cl:16].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[S:26])=[CH:4][C:3]=1[Cl:16]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C[Si](C)(C)CNC(=O)c1ccc(Br)c(Cl)c1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CNC(=S)c1ccc(Br)c(Cl)c1
Temperature: 25 °C
Yield: 123.5 %

Procedure:
To a suspension of 4-bromo-3-chloro-N-trimethylsilanylmethyl-benzamide (34.00 g, 106.0 mmol) in toluene (250 mL) was added Lawesson's reagent (30.45 g, 75.28 mmol) at room temperature. The mixture was heated at reflux for 1 h and cooled to ambient temperature. After adsorption of the reaction mixture on silica gel the solvents were distilled off in vacuum. The residue was purified by flash chromatography on silica gel to give the title compound (31.3 g, 88%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1.[I:9][CH2:10][CH2:11][CH2:12][CH3:13]>C1(C)C=CC=CC=1>[IH:9].[CH2:10]([N:6]1[C:5]([CH3:7])=[C:4]([CH3:8])[S:3][C:2]1=[NH:1])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCI
Reactant: Cc1nc(N)sc1C
Solvent: Cc1ccccc1
Product: CCCCn1c(C)c(C)sc1=N
Product: I
Temperature: 80 °C
Yield: 43.2 %

Procedure:
A mixture of 2-amino-4,5-dimethylthiazole (2.56 g, 20 mmol) and iodobutane (2.6 mL, 22 mmol) in toluene (20 mL) was refluxed at 80° C. for 48 hours. The mixture was cooled to room temperature and the precipitated solid was filtered, washed with toluene and dried under reduced pressure to provide 2.7 g of crude product as the hydroiodide salt; MS (ESI+) m/z 185 (M+H)+.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]([OH:28])=O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][C:31]=1[C:42]1[NH:46][C:45]2[CH:47]=[CH:48][CH:49]=[CH:50][C:44]=2[N:43]=1.CCN(C(C)C)C(C)C>C(#N)C>[C:13]([O:17][C:18]([N:20]1[CH2:21][CH2:22][CH:23]([C:26]([N:39]2[CH2:40][CH2:41][N:36]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[C:31]([C:42]4[NH:43][C:44]5[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=5[N:46]=4)[CH:32]=3)[CH2:37][CH2:38]2)=[O:28])[CH2:24][CH2:25]1)=[O:19])([CH3:14])([CH3:15])[CH3:16]
Reactant: Fc1ccc(N2CCNCC2)cc1-c1nc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCN(c3ccc(F)c(-c4nc5ccccc5[nH]4)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 58.4 %

Procedure:
CDI (0.047 g, 0.29 mmol) was added to a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (0.07 g, 0.29 mmol) in acetonitrile (2.50 mL). The resulting solution was stirred at room temperature for 5 hours. 2-(2-Fluoro-5-piperazin-1-yl-phenyl)-1H-benzoimidazole (0.10 g, 0.27 mmol) and DIPEA (0.05 mL, 0.26 mmol) were added and reaction was heated at 65° C. overnight. Reaction was cooled to room temperature and solvent was removed under reduced pressure. DCM (2 mL) was added to the crude, organic solution was washed with water (2×4 mL) and with saturated Na2CO3 solution (2×4 mL) and concentrated. The crude reaction mixture was purified by flash chromatography (eluent: cyclohexane:AcOEt gradient from 100% of cyclohexane to 100% AcOEt) to afford 0.08 g of the title compound (60%).
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[Cl:10][C:11]1[CH:34]=[CH:33][C:14]([CH2:15][N:16]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)[S:17]([C:20]2[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[C:6]([O:5][C:3](=[O:4])[CH2:2][O:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([N:16]([CH2:15][C:14]2[CH:13]=[CH:12][C:11]([Cl:10])=[CH:34][CH:33]=2)[S:17]([C:20]2[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=2)(=[O:19])=[O:18])[CH:27]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cn1ccc(S(=O)(=O)N(Cc2ccc(Cl)cc2)c2cccc(O)c2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1ccc(S(=O)(=O)N(Cc2ccc(Cl)cc2)c2cccc(OCC(=O)OC(C)(C)C)c2)n1
Reaction time: 16 h
Yield: 82.8 %

Procedure:
tert-Butyl bromoacetate (87.3 μl, 0.596 mmol) was added to a stirred solution of 1-methyl-1H-pyrazole-3-sulfonic acid (4-chloro-benzyl)-(3-hydroxy-phenyl)-amide (150 mg, 0.40 mmol) and cesium carbonate (388 mg, 1.19 mmol) in anhydrous dimethyl formamide (10 ml) and then stirred at ambient for 16 hours. The reaction was diluted with ethyl acetate (10 ml), washed with water (3×20 ml) and the organic extracts were concentrated in vacuo to obtain crude product. The residue was purified by flash chromatography eluting with 10% methanol/dichloromethane to yield a yellow oil (163 mg, 56% yield). HPLC retention time 6.47 min Mass spectrum (ES+) m/z 509 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:34]=[CH:33][C:6]([NH:7][C:8](=[O:32])[C@@H:9]([C@H:11]2[O:16][CH2:15][CH2:14][N:13]([C:17]3[CH:22]=[CH:21][C:20]([NH:23]C(=O)OC(C)(C)C)=[CH:19][CH:18]=3)[C:12]2=[O:31])[OH:10])=[CH:5][CH:4]=1)#[N:2].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>CCOCC>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([N:13]2[CH2:14][CH2:15][O:16][C@H:11]([C@@H:9]([OH:10])[C:8]([NH:7][C:6]3[CH:33]=[CH:34][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)=[O:32])[C:12]2=[O:31])=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N2CCO[C@H]([C@@H](O)C(=O)Nc3ccc(C#N)cc3)C2=O)cc1
Solvent: CCOCC
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(NC(=O)[C@H](O)[C@H]2OCCN(c3ccc(N)cc3)C2=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To compound 26-4 (1.65 g), was added trifluoroacetic acid (10 mL) with anisole (0.2 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour then Et2O was added into the mixture to precipitate. The precipitate was collected by filtration and washed with Et2O. Then the precipitate was solved in water and the solution was basified with sat. NaHCO3 aq. The precipitate was collected by filtration and washed with H2O to obtain compound 26-5 (1.2 g) as a pale brown amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5](N)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[I:13]I.N(OC(C)(C)C)=O.O>C(#N)C.[Cu]I>[F:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([I:13])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Cc1cc(F)cc([N+](=O)[O-])c1N
Reactant: II
Agent: [Cu]I
Agent: CC(C)(C)ON=O
Solvent: CC#N
Solvent: O
Product: Cc1cc(F)cc([N+](=O)[O-])c1I
Yield: 46.5 %

Procedure:
A mixture of 4.4 grams (0.026 mole) of 4-fluoro-2-nitro-6-methylaniline, 13.2 grams (0.052 mole) of iodine, and 5.5 grams (0.029 mole) of copper(I) iodide in 125 mL of acetonitrile was stirred, and a solution of 4.6 mL (0.039 mole) of tert-butyl nitrite in 25 mL of acetonitrile was added dropwise during a 10 minute period. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 16 hours. After this time the reaction mixture was poured into 300 mL of water. Excess iodine was destroyed using sodium meta-bisulfite. The mixture was then extracted with two 250 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 1:3 methylene chloride:petroleum ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding 3.4 grams of 4-fluoro-2-nitro-6-methylphenyl iodide. The NMR spectrum was consistent with the proposed structure. The reaction was repeated to obtain more product.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([C:15]2[C:19]([CH2:20]O)=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[N:16]=2)=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].C(N(S(F)(F)[F:33])CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([C:15]2[C:19]([CH2:20][F:33])=[C:18]([C:22]([F:24])([F:25])[F:23])[N:17]([CH3:26])[N:16]=2)=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:8])[CH3:9])=[O:5]
Reactant: CC(C)OC(=O)c1cc(-c2nn(C)c(C(F)(F)F)c2CO)c(F)cc1Cl
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)OC(=O)c1cc(-c2nn(C)c(C(F)(F)F)c2CF)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.5 g 2-chloro-4-fluoro-5-[4-(hydroxymethyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzoic acid, 1-methylethyl ester in 50 ml methylene chloride was added 5 mL of diethyl aminosulfurtrifluoride and the solution stirred overnight at room temperature. The reaction mixture was poured onto ice water and the organic layer washed with brine, dried over anhydrous magnesium sulfate, filtered and the concd in vacuo to give 2-chloro-4-fluoro-5-[4-(fluoromethyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzoic acid, 1-methylethyl ester as a tan solid: mp 74° C.; 1HNMR (CDCl3) δ 8.02 (d, 1H, J=8.0), 7.30 (d, 1H, J=9.6), 5.29 (d, 2H, J=48.0), 5.26 (m, 1H, J=6.0), 4.09 (s, 3H), 1.37 (d, 6H, J=6.4).
Reaction SMILES: [CH3:1][C:2]([C:9]1[N:13]2[CH:14]=[C:15]([O:18][C@H:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:22]([NH2:29])[CH2:21][CH2:20]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1)([N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)[CH3:3].CCN(C(C)C)C(C)C.ClC(Cl)(Cl)C[O:42][C:43](=O)[NH:44][C:45]1[N:46]([C:54]2[CH:59]=[CH:58][C:57]([CH3:60])=[CH:56][CH:55]=2)[N:47]=[C:48]([C:50]([CH3:53])([CH3:52])[CH3:51])[CH:49]=1>O1CCOCC1>[C:50]([C:48]1[CH:49]=[C:45]([NH:44][C:43]([NH:29][C@@H:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@H:19]([O:18][C:15]3[CH:16]=[CH:17][C:12]4[N:13]([C:9]([C:2]([CH3:1])([N:4]5[CH2:8][CH2:7][CH2:6][CH2:5]5)[CH3:3])=[N:10][N:11]=4)[CH:14]=3)[CH2:20][CH2:21]2)=[O:42])[N:46]([C:54]2[CH:59]=[CH:58][C:57]([CH3:60])=[CH:56][CH:55]=2)[N:47]=1)([CH3:53])([CH3:51])[CH3:52]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CC(C)(c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12)N1CCCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(C(C)(C)N5CCCC5)n4c3)c3ccccc32)cc1
Temperature: 60 °C

Procedure:
To a solution of Intermediate 80c (180 mg, 0.46 mmol) in 1,4-dioxane (5.00 mL) was added DIPEA (160 μL, 0.92 mmol) and (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 185 mg, 0.46 mmol). The reaction was heated to 60° C. overnight then cooled and partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-8% MeOH in DCM. Further purification by HPLC (C18 X-select column, 10-98% MeCN in H2O, 0.1% HCO2H) gave the title compound as a white powder after freeze-drying (58 mg, 20%). LCMS (Method 5): Rt 3.84 min, m/z 647.2 [MH+]. 1H NMR (400 MHz, d4-MeOD): 1.30 (9H, s), 1.60 (6H, s), 1.70-1.76 (4H, m), 1.86-2.06 (2H, m), 2.11 (1H, m), 2.20 (1H, m), 2.38 (3H, s), 2.45-2.52 (2H, m), 2.55-2.62 (2H, m), 4.89 (1H, dd, J 5.6, 8.9), 5.29 (1H, t, J 4.2), 6.33 (1H, s), 7.20-7.36 (9H, m), 7.62 (1H, d, J 9.9), 8.77 (1H, d, J 2.0).