Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([NH:32][CH2:33][CH3:34])=[O:31])=[CH:26][CH:25]=3)[C:11]=2/[CH:12]=[CH:13]/[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[O:6])[CH2:3][CH2:2]1>C(O)(=O)C.C(O)C.[C].[Pd]>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([NH:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:29]=3)[C:11]=2[CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2/C=C/c2ccc(S(C)(=O)=O)cc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCc2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 64.9 %

Procedure:
To a solution of N-cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-5-{(E)-2-[4-(methylsulfonyl)phenyl]vinyl}-1H-1,2,3-triazole-4-carboxamide (230 mg, 0.48 mmol) obtained in Example 401 in acetic acid (12 ml) and ethanol (4.0 ml) was added palladium-carbon (25 mg). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 5 days, and the insoluble material was filtered off. The solvent was evaporated, and the residue was purified by silica gel column (ethyl acetate/methanol=20/1 to 10/1). The resultant product was recrystallized from ethyl acetate/hexane to give the title compound as a colorless powder (150 mg, 65%).
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:5]=[CH:6][C:7]2[N+:12]([O-:13])=[N:11][C:10]([NH:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[N:9][C:8]=2[CH:20]=1.[CH3:21][O:22][CH2:23][CH2:24][OH:25]>C1COCC1>[CH3:21][O:22][CH2:23][CH2:24][O:25][C:4]1[CH:5]=[CH:6][C:7]2[N+:12]([O-:13])=[N:11][C:10]([NH:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[N:9][C:8]=2[CH:20]=1
Reactant: CN(C)CCNc1nc2cc(F)ccc2[n+]([O-])n1
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1ccc2c(c1)nc(NCCN(C)C)n[n+]2[O-]
Temperature: 20 °C
Yield: 96.3 %

Procedure:
NaH (66 mg, 60% dispersion in oil, 1.7 mmol) was added to a stirred solution of fluoride 12 (261 mg, 1.0 mmol) and 2-methoxyethanol (0.12 mL, 1.6 mmol) in THF (10 mL) at 20° C. and the mixture stirred at reflux temperature for 2 h. More NaH (66 mg, 1.6 mmol) and 2-methoxyethanol (0.12 mL, 1.6 mmol) were added and the mixture stirred at reflux temperature for 16 h. The mixture was cooled to 20° C. and carefully quenched with water (5 mL). The solvent was evaporated and the residue partitioned between DCM (50 mL) and water (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 13 (296 mg, 93%) as a yellow solid, mp (MeOH/EtOAc) 139-141° C.; 1H NMR δ 8.14 (d, J=9.4 Hz, 1 H, H-8), 6.91 (dd, J=9.4, 2.6 Hz, 1 H, H-7), 6.84 (d, J=2.6 Hz, 1 H, H-5), 5.91 (br s, 1 H, NH), 4.20-4.23 (m, 2 H, CH2O), 3.71-3.74 (m, 2 H, CH2O), 3.51-3.56 (m, 2 H, CH2N), 3.46 (s, 3 H, OCH3), 2.55 (br dd, J=6.0, 5.9 Hz, 2 H, CH2N), 2.28 [s, 6 H, (CH3)2]; 13C NMR δ 164.6, 159.6, 151.4, 126.1, 122.1, 118.0, 104.6, 70.5, 68.0, 59.3, 57.5, 45.1 (2), 38.7. Anal. Calcd for C14H21N5O3: C, 54.7; H, 6.9; N, 22.8. Found: C, 54.5; H, 6.7; N, 22.7%.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([Cl:15])[CH:9]=1)[C:5]([OH:7])=[O:6].[N+](=[CH2:18])=[N-]>>[CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([Cl:15])[CH:9]=1)[C:5]([O:7][CH3:18])=[O:6]
Reactant: C=[N+]=[N-]
Reactant: CON=C(C(=O)O)c1ccc(O)c(Cl)c1
Product: CON=C(C(=O)OC)c1ccc(O)c(Cl)c1

Procedure:
2-Methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid (a mixture of syn and anti isomers) (7 g.) and diazomethane (1.5 g.) were reacted and the product was purified by column chromatography according to a similar manner to that of Preparation 5-(3)(b) to give crystals of methyl 2-methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetate (syn isomer) (3.0 g.).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:28]=[CH:29][N:30]=[CH:31][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[C:41]([O:44][CH2:45][C:46](Cl)=[O:47])(=[O:43])[CH3:42]>CN(C=O)C>[C:41]([O:44][CH2:45][C:46]([N:25]1[CH2:26][CH2:27][N:22]([C:19]2[CH:18]=[N:17][C:16]([NH:15][C:12]3[N:13]=[CH:14][C:9]4[C:8]5[CH:28]=[CH:29][N:30]=[CH:31][C:7]=5[N:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[C:10]=4[N:11]=3)=[CH:21][CH:20]=2)[CH2:23][CH2:24]1)=[O:47])(=[O:43])[CH3:42]
Reactant: c1cc2c3cnc(Nc4ccc(N5CCNCC5)cn4)nc3n(C3CCCC3)c2cn1
Reactant: CC(=O)OCC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCC(=O)N1CCN(c2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of compound 7 (207 mg, 0.50 mmol) in DMF (5 mL) were added N,N-diisopropylethylamine (174 uL, 1.0 mmol) and acetoxyacetyl chloride (65 uL, 0.60 mmol) and the resulted mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated to give compound 189 as a yellow solid which was used in next step without further purification. LCMS-ESI (POS), M/Z, M+1: Found 514.2, Calculated 514.2.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[Br:24][C:25]1[C:26]([O:36][CH3:37])=[C:27]([C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)[C:28](O)=[O:29].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:28](=[O:29])[C:27]3[C:31]([O:34][CH3:35])=[CH:32][CH:33]=[C:25]([Br:24])[C:26]=3[O:36][CH3:37])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: COc1ccc(Br)c(OC)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Br)c(OC)c1C(=O)Nc1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O
Reaction time: 18 h

Procedure:
A mixture of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (25 mg), 3-bromo-2,6-dimethoxybenzoic acid (23 mg), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (68 mg) and N,N-diisopropylethylamine (32 μl) in dichloromethane (4 ml) was stirred for 18 h. The reaction mixture was concentrated in vacuo, the residue was dissolved in ethyl acetate and washed with 0.5 M HCl, water, 5% aq. NaHCO3, water and brine. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silicagel in heptane/ethyl acetate=1/0=>0/1 (v/v) as eluent.
Reaction SMILES: [CH2:1](N(CC)CC)C.[Cl:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].[C:15]([Si:19](Cl)([CH3:21])[CH3:20])(C)(C)C>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[Cl:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][Si:19]([CH3:21])([CH3:1])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCCCCl
Reactant: CCN(CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[Si](C)(C)COCCCCCCl
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
13.8 ml of triethylamine and then 200 mg of 4-dimethyl amino-pyridine were added under a nitrogen atmosphere to a solution of 10.2 g of 5-chloropentanol in 80 ml of methylene chloride. The mixture was cooled down to −10° C. and 13.75 g of tertbutyl chloro dimethyl-silane were added. The mixture was stirred for 15 minutes at −10° C. then left to reheat to ambient temperature and diluted with a saturated solution of sodium bicarbonate. The oily crude derivative was separated out and chromatographed on silica (eluant:cyclohexane-ethyl acetate 95-5) to obtain 18 g of the expected product.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:14]([F:17])([F:16])[F:15])[C:8]([O:12][CH3:13])=[C:9]([NH2:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:18]1([CH2:24][CH2:25][O:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]([C:37](=[O:41])[C:38](Cl)=[O:39])=[CH:29][CH:28]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([C:14]([F:15])([F:16])[F:17])[C:8]([O:12][CH3:13])=[C:9]([NH:11][C:38](=[O:39])[C:37]([C:30]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:27]([O:26][CH2:25][CH2:24][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[CH:28][CH:29]=2)=[O:41])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(N)cc(C(C)(C)C)cc1C(F)(F)F
Reactant: O=C(Cl)C(=O)c1ccc(OCCN2CCOCC2)c2ccccc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(NC(=O)C(=O)c2ccc(OCCN3CCOCC3)c3ccccc23)cc(C(C)(C)C)cc1C(F)(F)F

Procedure:
5-tert-Butyl-2-methoxy-3-trifluoromethyl-phenylamine (32 mg, 0.165 mmol) was dissolved in 2 mL DCM. [4-(2-Morpholin-4-yl-ethoxy)-naphthalen-1-yl]-oxo-acetyl chloride (0.232 mmol), prepared as described before, and DIEA (0.02 mL, 0.50 mmol) were added and the reaction was stirred on. The reaction mixture was evaporated and the residue was purified by LC/MS (10-100% AcN). Calculated mass=558. Observed mass=559
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:18][C:19]([O:21]CC)=[O:20])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:24][CH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(N(C(C)C)CC)(C)C>CCOCC>[OH2:20].[C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:18][C:19]([NH:24][CH2:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:21])[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:18][C:19]([NH:24][CH2:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:21])[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)Cn1ncc(-c2ccccc2)c1-c1ccccc1
Reactant: NCCCN1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: O
Product: O=C(Cn1ncc(-c2ccccc2)c1-c1ccccc1)NCCCN1CCCCC1
Reaction time: 18 h
Yield: 150.2 %

Procedure:
A mixture of 15 g (0.049 mol) of ethyl 4,5-diphenyl-1H-pyrazole-1-acetate of Example 1, 10.2 g (0.02 mol) of 3-aminopropylpiperidine, and 62 mL of diisopropylethylamine was stirred on a steam bath under nitrogen for 18 hours. The excess amine was stripped in vacuo. The residue was taken up in about 300 mL of ether and washed twice with water. The product was extracted into 150 mL of cold water containing 18 mL of 10% hydrochloric acid. The water layer was washed two times with ether, treated with decolorizing carbon, filtered, chilled and made basic with solid sodium carbonate. The product was extracted into methylene dichloride, dried over sodium sulfate, filtered, and stripped to 14.7 g of solid residue. The residue was triturated in water, filtered and dried to yield 12.36 g of 4,5-diphenyl-N-[3-(1-piperdinyl)propyl]-1H-pyrazole-1-acetamide hemihydrate, mp 81°-85° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5]([O:23][CH2:24][CH3:25])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)[CH3:2].C(N(CC)CC)C.[CH2:34]([S:41](Cl)(=[O:43])=[O:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.O>ClCCl>[CH2:1]([O:3][C:4](=[O:26])[CH:5]([O:23][CH2:24][CH3:25])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][S:41]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[O:43])=[O:42])=[CH:20][CH:21]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(O)cc2)cc1)OCC
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(OS(=O)(=O)Cc3ccccc3)cc2)cc1)OCC
Temperature: 0 °C
Yield: 71.5 %

Procedure:
2-Ethoxy-3-{4-[2-(4-hydroxyphenyl)ethoxy]phenyl}propanoic acid ethyl ester (described in Example 26b) (0.54 g; 1.5 mmole) was dissolved in dichloromethane (15 ml), triethylamine (0.23 g; 0.31 ml; 2.25 mmole) was added. The solution was cooled to 0° C. and benzylsulfonyl chloride (0.43 g; 2.25 mmole) dissolved in dichloromethane (5 ml) was added. The resulting mixture was allowed to reach room temperature and was stirred over night. Water was added, the organic layer separated and the water phase extracted with dichloromethane. The organic phase was washed with hydrochloric acid (1 M), sodium hydrogen carbonate and brine. After drying with sodium sulfate and evaporation a light yellow oil was obtained. The crude product was purified with flash chromatography on silica. The compound was eluated with heptane:ethyl acetate (9:1 followed by 1:1). Pure fractions were pooled and evaporated yielding 0.55 g (71%) of 2-ethoxy-3-{4-[2-(4-phenylmethanesulfonyloxyphenyl)ethoxy]phenyl}propanoic acid ethyl ester.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][C:16]([CH:19]([OH:23])[C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1>CCCCCC>[CH2:1]([NH2+:3][CH2:4][CH3:5])[CH3:2].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][C:16]([CH:19]([OH:23])[C:20]([O-:22])=[O:21])=[CH:15][CH:14]=1
Reactant: CCNCC
Reactant: O=C(O)C(O)c1ccc(-c2ccccc2Cl)cc1
Solvent: CCCCCC
Product: CC[NH2+]CC
Product: O=C([O-])C(O)c1ccc(-c2ccccc2Cl)cc1

Procedure:
Anhydrous diethylamine (0.11 moles) is added dropwise to a stirred solution of 2'-chloro-4-biphenylylglycolic acid (0.10 moles) in 100 ml. of n-hexane at 0°C. The precipitated diethylammonium salt is collected on a filter washed with n-hexane and dried in a vacuum desiccator to obtain 2'-chloro-4-biphenylylglycolic acid, diethylammonium salt.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10](C=O)=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:8]([C:20]2C=[CH:24][CH:23]=[CH:22][C:21]=2Cl)[N:7]=1)=[O:5])[CH3:2].ClC1C=CC=C(C(OO)=[O:35])C=1.C(OCC)C.C(N(CC)CC)C.Cl[CH2:51][Cl:52]>CO>[CH2:1]([O:3][C:4]([C:6]1[C:10]([OH:35])=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:8]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:51]=2[Cl:52])[N:7]=1)=[O:5])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1C=O
Reactant: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1O
Reaction time: 6 h

Procedure:
To a stirred solution of 5-(4-chlorophenyl)-1-(2-chlorophenyl)4-formyl-1H-pyrazole-3-carboxylic acid ethyl ester I-1c (2.2 g, 5.6 mmol) in dichloromethane (22 ml) was added m-chloroperbenzoic acid (2.9 g (50% purity), 8.4 mmol) and the resulting slurry was stirred for 6 hours. The mixture was diluted into ethyl ether, washed with half-saturated aqueous sodium bicarbonate, water, brine, dried (Na2SO4) and concentrated in vacuo to afford a yellow solid, 3.5 g. To a slurry of this material in methanol (20 ml), was added triethylamine (1 ml) to produce a solution. After 45 minutes, the reaction was concentrated in vacuo to afford a yellow solid. This material was purified by silica gel chromatograpy (Combiflash instrument, 120 g silica gel column, 5–25% gradient of ethyl acetate/hexanes to afford the title compound (I-1d) as a yellow solid, 1.5 g.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1([C:7](O)=O)[CH2:6][CH2:5][CH2:4]1.[C:12](O)(=O)C.[NH2:16][C:17](=[NH:39])[C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([CH3:36])([CH3:35])[C:31]([O:33][CH3:34])=[O:32])=[CH:26][CH:25]=2)=[N:22][CH:23]=1>>[CH3:36][C:30]([CH3:35])([CH2:29][O:28][C:27]1[CH:26]=[CH:25][C:24]([C:21]2[CH:20]=[CH:19][C:18]([C:17]3[NH:16][C:7]([C:3]4([C:2]([F:11])([F:10])[F:1])[CH2:6][CH2:5][CH2:4]4)=[CH:12][N:39]=3)=[CH:23][N:22]=2)=[CH:38][CH:37]=1)[C:31]([O:33][CH3:34])=[O:32]
Reactant: CC(=O)O
Reactant: COC(=O)C(C)(C)COc1ccc(-c2ccc(C(=N)N)cn2)cc1
Reactant: O=C(O)C1(C(F)(F)F)CCC1
Product: COC(=O)C(C)(C)COc1ccc(-c2ccc(-c3ncc(C4(C(F)(F)F)CCC4)[nH]3)cn2)cc1
Yield: 72.8 %

Procedure:
By using 1-(trifluoromethyl)-1-cyclobutane carboxylic acid (300 mg), and methyl 3-(4-{5-[amino(imino)methyl]pyridin-2-yl}phenoxy)-2,2-dimethylpropanoate acetate (415 mg), the procedure was carried out in the same manner as in Example 2-1) to obtain methyl 2,2-dimethyl-3-[4-(5-{5-[1-(trifluoromethyl)cyclobutyl]-1H-imidazol-2-yl}pyridin-2-yl)phenoxy)propanoate (369 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[N:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[C:4](=[O:14])[CH:3]=1.C(N(CC)CC)C.[O:22](S(C(F)(F)F)(=O)=O)[S:23]([C:26]([F:29])([F:28])[F:27])(=O)=[O:24].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:27][C:26]([F:29])([F:28])[S:23]([O:1][C:2]1[CH:7]=[N:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[C:4](=[O:14])[CH:3]=1)(=[O:24])=[O:22]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=c1cc(O)cnn1C1CCCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1cc(OS(=O)(=O)C(F)(F)F)cnn1C1CCCCO1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 57.9 %

Procedure:
5-Hydroxy-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (2.4 g, 13 mmol) dissolved in methylene chloride (75 mL) and cooled to 0° C. Triethylamine (3.5 mL, 25 mmol) and Tf2O (2.3 mL, 14 mmol) were added and the mixture stirred for a further 2.5 h. Saturated NaHCO3 solution was added and the organic phase removed, dried over Na2SO4 and concentrated. Purification by flash column chromaotgraphy (silica gel, EtOAc/hexanes) provided the title compound (2.47 g, 60%) as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 7.85 (d, J=2.8 Hz, 1H), 6.86 (d, J=2.7 Hz, 1H), 6.01 (dd, J=10.2, 2.2 Hz, 1H), 4.15-4.12 (m, 1H), 3.75 (dt, J=11.6, 2.5 Hz, 1H), 2.18-2.02 (m, 2H), 1.78-1.66 (m, 3H), 1.62-1.55 (m, 1H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:16]=[C:15]([N:17]3[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]3)[C:14]([N+:24]([O-:26])=[O:25])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].CCN(CC)CC.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C(Cl)Cl>[CH3:23][CH:20]1[CH2:19][CH2:18][N:17]([C:15]2[C:14]([N+:24]([O-:26])=[O:25])=[CH:13][CH:12]=[C:11]([N:8]3[CH2:7][CH2:6][N:5]([C:3](=[O:4])[CH2:2][N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[CH2:10][CH2:9]3)[N:16]=2)[CH2:22][CH2:21]1
Reactant: CC1CCN(c2nc(N3CCN(C(=O)CCl)CC3)ccc2[N+](=O)[O-])CC1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CCN(c2nc(N3CCN(C(=O)CN4CCOCC4)CC3)ccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 76 %

Procedure:
A solution of 2-chloro-1-[4-(4-methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl)-piperazin-1-yl]-ethanone (as prepared in the previous step, 0.18 g, 0.48 mmol) in CH2Cl2 (10 mL) was treated with Et3N (0.10 mL, 0.72 mmol) and morpholine (46 μL, 0.53 mmol). The reaction was stirred at room temperature for 18.5 h. The reaction was diluted with CH2Cl2 and washed with water. The aqueous layer was extracted further with CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated in vacuo to afford the title compound (0.16 g, 76%) as a yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 8.21 (d, 1H, J=9.2 Hz), 6.03 (d, 1H, J=9.2 Hz), 3.85-3.63 (m, 12H), 3.32-3.22 (m, 2H), 3.05-2.93 (m, 2H), 2.66-2.50 (m, 2H), 1.75-1.66 (m, 2H), 1.66-1.60 (m, 2H, partially obscured by water peak), 1.44-1.38 (m, 1H), 1.37-1.16 (m, 4H), 0.98 (d, 3H, J=6.4 Hz). LC-MS (ESI, m/z): Calcd. for C21H32N6O4, 433.2 (M+H), found 432.9.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C[C:13](O)=[O:14].[O-]C#N.[Na+].[OH-].[Na+]>O>[Cl:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[C:13]([OH:14])[N:6]=[C:4]2[OH:5]
Reactant: NC(=O)c1cc(Cl)ccc1N
Reactant: CC(=O)O
Agent: N#C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1nc(O)c2cc(Cl)ccc2n1
Temperature: 35 °C
Reaction time: 1 h

Procedure:
2-Amino-5-chlorobenzamide (Avocado) (3.00 g, 17.5 mmol, 1.0 eq.) was suspended in 105 mL of H2O and 1.75 mL of HOAc at rt. A 12 mL solution of H2O and sodium cyanate (2.80 g, 43.0 mmol, 2.46 eq.) was then added slowly. Stirred at 35° C. for 1 hour. Added 31.26 mL of 1.0 N NaOH slowly. Solids precipitated. Cooled to 0° C. Carefully added conc. HCl to pH=3. Filtered solids. Solids were then stirred in diethyl ether then refiltered and pumped under high vacuum to give 3.36 grams of tan solids as product. LCMS detects (M+H)+=197.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[N:14]=[CH:13][C:12]([NH:15][C:16](=[O:21])[CH2:17][C:18](=[O:20])[CH3:19])=[CH:11][N:10]=3)[N:7]=[C:6]([C:22]([F:25])([F:24])[F:23])[CH:5]=2)[CH2:3][CH2:2]1.CO[CH:28](OC)[N:29]([CH3:31])[CH3:30]>>[CH:1]1([C:4]2[N:8]([C:9]3[N:14]=[CH:13][C:12]([NH:15][C:16](=[O:21])[C:17](=[CH:28][N:29]([CH3:31])[CH3:30])[C:18](=[O:20])[CH3:19])=[CH:11][N:10]=3)[N:7]=[C:6]([C:22]([F:24])([F:25])[F:23])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)CC(=O)Nc1cnc(-n2nc(C(F)(F)F)cc2C2CC2)nc1
Product: CC(=O)C(=CN(C)C)C(=O)Nc1cnc(-n2nc(C(F)(F)F)cc2C2CC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
Step-2: N-{2-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]pyrimidin-5-yl}-3-oxobutanamide (445 mg, 1.3 mmol) and N,N-Dimethylformamide dimethylacetal (859 mg, 7.2 mmol) were mixed and stirred at rt for overnight. Workup (AcOEt/H2O) followed by purification on 60-120 mesh silicagel using AcOEt and Peteher (1:1) as eluent afforded N-{2-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]pyrimidin-5-yl}-2-[(dimethylamino)methylene]-3-oxobutanamide (0.3 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(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>[Cl:27][C:24]1[CH:25]=[C:26]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)[CH:21]=[CH:22][C:23]=1[Cl:28]
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
Reactant: [O-]B([O-])Oc1ccc(Cl)c(Cl)c1
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: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C1=Cc2cc(-c3ccc(Cl)c(Cl)c3)ccc2S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
Under argon atmosphere, a mixture of methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.80 g), 3,4-dichlorophenyl borate (0.54 g) and potassium carbonate (0.67 g) in toluene/ethanol/water (30/3/3 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (0.14 g), and the mixture was refluxed for 18 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (ethyl acetate/hexane=1:2→1:1) to give pale yellow crystals of methyl 7-(3,4-dichlorophenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (631.3 mg).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([C:19]([OH:21])=[O:20])[CH2:17][NH2:18])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:22]O>>[ClH:3].[CH3:22][O:20][C:19](=[O:21])[C@H:16]([NH:15][C:13]([O:12][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:14])[CH2:17][NH2:18]
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: NC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Product: COC(=O)[C@@H](CN)NC(=O)OCc1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Thionyl chloride (3.22 ml) was added dropwise to methanol (25 ml) at 4° C. under a nitrogen atmosphere. After stirred for 30 minutes, to the reaction mixture was added 2(R)-benzyloxycarbonylamino-β-alanine (3 g), followed by warming to the ambient temperature and stirring overnight. The insoluble material was collected by filtration, washed with diisopropyl ether, and dried under a reduced pressure to give 2(R) -benzyloxycarbonylamino-β-alanine methyl ester hydrochloride (3.15 g) as a white solid.