Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)=[C:12]([C:23]([F:26])([F:25])[F:24])[CH:11]=1.C(N(CC)CC)C.[CH2:34]([NH2:40])[CH:35]1[O:39][CH2:38][CH2:37][CH2:36]1.Cl>C(OCC)(=O)C>[CH2:34]([NH:40][C:2]([N:19]1[C:20]([CH3:22])=[CH:21][C:17]([O:16][C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][C:12]=2[C:23]([F:25])([F:24])[F:26])=[N:18]1)=[O:3])[CH:35]1[O:39][CH2:38][CH2:37][CH2:36]1
Reactant: NCC1CCCO1
Reactant: Cc1cc(Oc2ccc(Cl)cc2C(F)(F)F)n[nH]1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(Oc2ccc(Cl)cc2C(F)(F)F)nn1C(=O)NCC1CCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.5 %

Procedure:
Trichloromethyl chloroformate (0.58 g, 3.0 mmol) was added to a solution of 3-(4-chloro-2-trifluoromethylphenyloxy)-5-methylpyrazole (0.55 g, 2.0 mmol) in ethyl acetate (10 ml) at 0° C., and the mixture was further stirred at an ambient temperature for 30 minutes. Then, the mixture was refluxed under heating for 1 hour. The solvent was distilled off from the reaction mixture and then the reaction mixture was cooled to 0° C. and dissolved in toluene (10 ml). Triethylamine (0.61 g, 6.0 mmol) and tetrahydrofurfurylamine (1.01 g, 10.0 mmol) were added, and while the mixture was allowed to have room temperature gradually, it was stirred for 1 hour. Then, the mixture was refluxed under heating for 2 hours. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (10 ml), and the mixture was extracted with ethyl acetate (10 ml×2). An organic layer was washed with water (10 ml×3), dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a colorless viscous substance of N-tetrahydrofurfuryl-3-(4-chloro-2-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.40 g, yield: 48.9%). 1H-NMR (CDCl3, TMS, ppm): δ 1.55-1.66 (m, 1H), 1.84-2.02 (m, 3H), 2.59 (d, J=0.8 Hz, 3H), 3.26-3.37 (m, 1H), 3.54 (ddd, J=3.7, 6.2 and 13.8 Hz, 1H), 3.71-3.90 (m, 2H), 4.00-4.16 (m, 1H), 5.74 (q, J=0.8 Hz, 1H), 7.18 (br s, 1H), 7.25 (d, J=8.7 Hz, 1H), 7.48 (dd, J=2.5 and 8.7 Hz, 1H), 7.64 (d, J=2.5 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[C:13]([Cl:14])=[C:12]([C:15]([F:18])([F:17])[F:16])[N:11]([CH3:19])[N:10]=2)=[N:6][C:7]=1Cl.[CH2:20](COC)[O:21]C.C[O-].[Na+]>CO.C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[C:13]([Cl:14])=[C:12]([C:15]([F:18])([F:17])[F:16])[N:11]([CH3:19])[N:10]=2)=[N:6][C:7]=1[O:21][CH3:20]
Reactant: Cn1nc(-c2ccc(Cl)c(Cl)n2)c(Cl)c1C(F)(F)F
Reactant: COCCOC
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: COc1nc(-c2nn(C)c(C(F)(F)F)c2Cl)ccc1Cl
Temperature: 0 °C
Reaction time: 48 h

Procedure:
1.0 g of 3-(5,6-dichloro-2-pyridyl)-4-chloro-5-trifluoromethyl-1-methyl-[1 H]-pyrazole (Example H20) is initially introduced into 5 ml of dry dimethoxyethane. After the solution has been cooled to 0° C., 0.61 ml of a 5.4 molar solution of sodium methylate in methanol is added dropwise and the mixture is subsequently stirred at 25° C. for 2 days. The reaction mixture is taken up in diethyl ether and washed successively with 0.5 N hydrochloric acid, water and brine. After drying over sodium sulfate, the mixture is filtered and the filtrate is concentrated to dryness in vacuo. 0.94 g of the desired title compound is obtained as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](=[O:11])(=[O:10])[NH2:9].Br[CH2:13][C:14]([NH2:16])=[O:15].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][CH2:13][C:14]([NH2:16])=[O:15])(=[O:11])(=[O:10])[NH2:9]
Reactant: NC(=O)CBr
Reactant: NS(=O)(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)COc1ccccc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.1 %

Procedure:
To a solution of crude 1-(hydroxy)-2-sulfamoylbenzene (400 mg, 2.4 mmol.) in 60 mL of acetonitrile was added 2-bromoacetamide (332 mg, 2.4 mmol.), K2CO3 (662 mg, 4.8 mmol.) and KI (400 mg, 2.4 mmol.). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was filtered, concentrated and purified by prep-TLC to afford 2-(2-sulfamoylphenoxy)acetamide (260 mg, 47%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][CH:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[C:28]([O:32][C:33]([NH:35][C@H:36]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:37](O)=[O:38])=[O:34])([CH3:31])([CH3:30])[CH3:29].C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[C:28]([O:32][C:33]([NH:35][C@H:36]([CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:37]([O:10][C@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[CH2:8][C:7]1[C:6]([Cl:26])=[CH:5][N+:4]([O-:27])=[CH:3][C:2]=1[Cl:1])=[O:38])=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: [O-][n+]1cc(Cl)c(CC(O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.3 %

Procedure:
3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (5 g, 11.90 mmol), (R)-2-(tert-butoxycarbonylamino)-3-phenylpropanoic acid (4.73 g, 17.85 mmol), DMAP (1.599 g, 13.09 mmol), and EDC (4.56 g, 23.80 mmol) were dissolved in DMF (5 ml). The reaction was stirred at RT for 2 hours to achieve completion. The reaction mixture was diluted with water, and the precipitate was filtered, washed with water, dissolved in DCM and extracted with HCl 1N, Na2CO3 sat. sol. and brine. The organic phase was dried over Na2SO4 and concentrated under vacuum. The crude product was crystallized in EtOH to give 4-((S)-2-((R)-2-(tert-butoxycarbonylamino)-3-phenylpropanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (3.2 g, 4.79 mmol, 40.3% yield).
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:24]=[C:23]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH:22]=[CH:21][C:17]=3[C:18]([NH2:20])=[O:19])=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CCN(CC)CC.[C:38]1([CH2:44][C:45](Cl)=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1.C(Cl)Cl>[N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:24]=[C:23]([N:25]4[CH2:30][CH2:29][N:28]([C:45](=[O:46])[CH2:44][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH2:27][CH2:26]4)[CH:22]=[CH:21][C:17]=3[C:18]([NH2:20])=[O:19])=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: NC(=O)c1ccc(N2CCNCC2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc(N2CCN(C(=O)Cc3ccccc3)CC2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38.9 %

Procedure:
To a suspension of 2-(4-(morpholine-4-carbonyl)phenylamino)-6-(piperazin-1-yl)nicotinamide (28 mg, 0.068 mmol) and Et3N (0.019 mL, 0.136 mmol) in THF (2 mL) and CH2Cl2 (2.000 mL) was added 2-phenylacetyl chloride (10.55 mg, 0.068 mmol). The reaction mixture was stirred at rt for 10 min, diluted with CH2Cl2, washed with satd NaHCO3, separated, and concentrated. The residue was purified by prep-HPLC. The product containing fractions were collected, basified with 1N NaOH, extracted with CH2Cl2, separated, and concentrated to give 14 mg of 2-(4-(morpholine-4-carbonyl)phenylamino)-6-(4-(2-phenylacetyl)piperazin-1-yl)nicotinamide as a white solid. LCMS: (M+H)+=529.40. 1H NMR (400 MHz, CDCl3) δ ppm 11.17 (1H, s), 7.63 (2H, d, J=8.56 Hz), 7.55 (1H, d, J=8.81 Hz), 7.35-7.40 (2H, m), 7.31-7.35 (2H, m), 7.23-7.31 (3H, m), 5.99 (1H, d, J=8.81 Hz), 5.59 (2H, s), 3.50-3.81 (18H, m).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22])#[N:14]>O1CCCC1>[N:1]1([S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:13]#[N:14])(=[O:23])=[O:22])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Reactant: C1CCNC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1ccccc1S(=O)(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(Step 1) To a mixture of pyrrolidine (4.92 ml) and triethylamine (6.91 ml) was added a solution of 2-cyanobenzene-1-sulfonyl chloride (10.0 g) in tetrahydrofuran (40 ml) at 0° C. The mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was suspended in water, and the suspension was filtered. The filtered solid was dissolved in dichloromethane, and the solution was washed with water. The organic layer was dried over sodium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to give 2-(pyrrolidin-1-ylsulfonyl)benzonitrile (11.3 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[C:9]([C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH:27]([CH3:29])[CH3:28])[CH:21]=2)=[N:8][CH:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br:37][CH2:38][CH2:39]Br.C(OCC)(=O)C.CCCCCC>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([O:16][CH2:39][CH2:38][Br:37])[CH:14]=2)[C:9]([C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH:27]([CH3:29])[CH3:28])[CH:21]=2)=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(C(=O)c2cccc(OC(C)C)c2)c2cc(OC)c(O)cc12
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(C(=O)c2cccc(OC(C)C)c2)c2cc(OC)c(OCCBr)cc12
Temperature: 85 °C
Yield: 75.3 %

Procedure:
To a stirred solution of 6-hydroxy-1-(3-isopropoxy-benzoyl)-7-methoxy-isoquinoline-4-carboxylic acid ethyl ester (73 mg, 0.18 mmol) in N,N dimethylformamide (2 mL) was added potassium carbonate (197 mg, 1.42 mmol) and 1,2-dibromoethane (0.046 mL, 0.89 mmol) at room temperature. The reaction mixture was heated 85° C. for 2 hrs. The solvent was evaporated and the crude product was diluted with ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 30% ethyl acetate/hexane) afforded 6-(2-bromo-ethoxy)-1-(3-isopropoxy-benzoyl)-7-methoxy-isoquinoline-4-carboxylic acid ethyl ester as a white solid (70 mg, 75% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[OH:8].I[C:13]1[C:21]2[C:16](=[N:17][CH:18]=[N:19][C:20]=2[NH2:22])[N:15]([CH:23]([CH3:25])[CH3:24])[N:14]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH2:22][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[N:15]([CH:23]([CH3:25])[CH3:24])[N:14]=[C:13]([C:4]3[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([F:1])[CH:3]=3)[C:21]=12
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: OB(O)c1ccc(O)c(F)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: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CC(C)n1nc(-c2ccc(O)c(F)c2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 27.4 %

Procedure:
A solution of 3-fluoro-4-hydroxyphenylboronic acid (103 mg, 0.66 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.33 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP using silica gel column chromatography [MeOH—CH2Cl2, 2:98] to yield BA59 (26 mg, 27% yield). ESI-MS (M+H)+ m/z calcd 288, found 288.
Reaction SMILES: CS(O)(=O)=O.[CH:6]([O:19][C:20]([C:22]1[N:23]2[CH:26]([S:27][CH2:28][C:29]=1[C:30]1[S:34][C:33]([NH:35][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])=[N:32][CH:31]=1)[CH:25]([NH:41]C(OC(C)(C)C)=O)[C:24]2=[O:49])=[O:21])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(#N)C>[NH2:41][CH:25]1[C:24](=[O:49])[N:23]2[CH:26]1[S:27][CH2:28][C:29]([C:30]1[S:34][C:33]([NH:35][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])=[N:32][CH:31]=1)=[C:22]2[C:20]([O:19][CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:21]
Reactant: CN(C)CCNc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)C3SC2)s1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN(C)CCNc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)C3SC2)s1
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 98.9 %

Procedure:
Methanesulphonic acid (0.3 cc) is added to a suspension of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-[2-(2-dimethylamino-ethylamino)-thiazol-5-yl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.3 g) in acetonitrile (3 cc). The yellow solution obtained is stirred at 23° C. for 5 minutes and is poured onto a mixture of a saturated sodium bicarbonate solution (50 cc) and ethyl acetate (50 cc). The organic phase is dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure (20 mm Hg; 2.7 kPa). 7-Amino-2-benzhydryloxycarbonyl-3-[2-(2-dimethylamino-ethylamino)-thiazol-5-yl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.25 g) is thus obtained in the form of a yellow froth.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].I[C:12]1[S:13][CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].BrCC>CS(C)=O.C(OCC)(=O)C.[Cu]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: Ic1cccs1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCBr
Solvent: CS(C)=O
Product: CCOC(=O)c1cnn(-c2cccs2)c1
Temperature: 150 °C
Reaction time: 6 h
Yield: 20.1 %

Procedure:
1H-Pyrazole-4-carboxylic acid ethyl ester (7.0 g) and 2-iodothiophene (10.5 g) were dissolved in DMSO (50 mL), potassium carbonate (6.91 g) and copper powder (31.7 mg) were added, and the mixture was stirred at 150° C. for 6 hr. The reaction mixture was cooled to 80° C., bromoethane (2 mL) was added, and the mixture was stirred for 2 hr and cooled to room temperature. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=9:1) to give 1-(2-thienyl)-1H-pyrazole-4-carboxylic acid ethyl ester (2.23 g) as a white solid. The obtained compound was subjected to reactions in the same manner as in Reference Examples 17 to 18 to give the title compound.
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:30]=[CH:29][C:13]([O:14][CH:15]([C:19]3[CH:28]=[CH:27][C:22]([C:23](OC)=[O:24])=[CH:21][CH:20]=3)[CH2:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2.[C:31]([OH:37])([C:33](F)(F)F)=[O:32].[C:38](#[N:40])C>>[N:1]1[N:2]([C:10]2[CH:11]=[CH:12][C:13]([O:14][CH:15]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([NH:40][CH2:38][CH2:33][C:31]([OH:37])=[O:32])=[O:24])=[CH:27][CH:28]=3)[CH2:16][CH2:17][CH3:18])=[CH:29][CH:30]=2)[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2
Reactant: CCCC(Oc1ccc(-n2cc3ccccc3n2)cc1)c1ccc(C(=O)OC)cc1
Reactant: CC#N
Reactant: O=C(O)C(F)(F)F
Product: CCCC(Oc1ccc(-n2cc3ccccc3n2)cc1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
The title compound was prepared by a method analogous to that described for Example 20 using methyl 4-(1-(4-(2H-indazol-2-yl)phenoxy)butyl)benzoate. Column: Waters Atlantis C18 4.6×50 mm, 5 μm; Modifier: TFA 0.05%; Gradient 95% H20/5% acetonitrile linear to 5% H20/95% acetonitrile over 4.0 min, hold at 5% H20/95% acetonitrile to 5.0 min. Flow: 2.0 mL/min.; Retention time: 3.23 minutes. MS (M+1): 458.2.
Reaction SMILES: [CH:1]1([N:4]([C:9]2[CH:14]=[C:13]([Cl:15])[N:12]=[C:11](Cl)[N:10]=2)[CH2:5][CH2:6][CH2:7][OH:8])[CH2:3][CH2:2]1.[OH-:17].[Na+]>O1CCOCC1.O>[Cl:15][C:13]1[CH:14]=[C:9]([N:4]([CH:1]2[CH2:3][CH2:2]2)[CH2:5][CH2:6][CH2:7][OH:8])[NH:10][C:11](=[O:17])[N:12]=1
Reactant: OCCCN(c1cc(Cl)nc(Cl)n1)C1CC1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=c1nc(Cl)cc(N(CCCO)C2CC2)[nH]1
Temperature: 100 °C
Reaction time: 4 h
Yield: 45.2 %

Procedure:
To a solution of 3-(cyclopropyl(2,6-dichloropyrimidin-4-yl)amino)propan-1-ol (5.0 g, 19.07 mmol) in 1,4-dioxane (50 mL) was added a solution of NaOH (7.63 g, 191 mmol) in water (50 mL) at r.t, stirred for 4 h at 100° C. The organic solvent was removed under reduce vacuum and the PH was adjusted to 8 with aq. HCl (12 N). Purification via reverse C-18 column afforded the title compound (2.1 g) as a white solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].Br[CH:11](Br)[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[CH3:1][N:2]1[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[O:9][CH2:12][CH2:11]1
Reactant: CC(Br)Br
Reactant: CNc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CN1CCOc2ccccc21
Yield: 78.7 %

Procedure:
To a mixture of 104A (2.33 g, 18.9 mmol) and dibromoethane (6.5 mL, 75.7 mmol) in a mixture of acetone (80 mL) and water (20 mL) at room temperature was added potassium carbonate (10.46 g, 75.7 mmol). The mixture was heated at reflux for 3 days. HPLC indicated that the reaction was complete, and the acetone was removed under reduced pressure. The aqueous residue was extracted with DCM, washed with water, and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by silica gel chromatography afforded 104B (2.22 g, 79%). HPLC retention time=2.07 min. (Condition B) and LC/MS M+1=150.08. 1H-NMR (500 MHz, CDCl3) δ 2.91 (s, 3H), 3.28 (t, 2H), 4.33 (t, 2H), 6.70 (t, 1H, J=7.5 Hz), 6.72 (d, 1H, J=7.5 Hz), 6.82 (d, 1H, J=7.5 Hz), and 6.89 (t, 1H, J=7.5 Hz).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][C:22]1=[O:28].C(N(CC)CC)C.CC(C)(O)C#N>C(Cl)Cl.CCOCC>[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH:23]([C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[C:2]([F:13])([F:12])[F:1])[C:22]1=[O:28]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: O=C1CCC(c2ccccc2F)C(=O)C1
Agent: CC(C)(O)C#N
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C1CCC(c2ccccc2F)C(=O)C1C(=O)c1ccccc1C(F)(F)F
Reaction time: 1 h
Yield: 34.2 %

Procedure:
2-Trifluoromethylbenzoyl chloride (7.1 g, 0.034 mole) and 4-(2-fluorophenyl)-1,3-cyclohexanedione (7.0 g, 0.034 mole) were dissolved in methylene chloride. Triethylamine (4.1 g, 0.041 mole) was added dropwise and the resulting solution stirred for one hour. The solution was washed with 2 normal hydrochloric acid (2N HCl), 5% potassium carbonate solution, and saturated sodium chloride solution, dried over anhydrous magnesium sulfate (MgSO4) and concentrated under vacuum. The residue ws dissolved in 40 ml of acetonitrile. Triethylamine (1 equivalent) and acetone cyanohydrin (0.4 ml) were added and the solution stirred for 1 hour at room temperature. After dilution with ether (150 ml), the solution was washed with 2N HCl. The ether layer was then stirred with 100 ml of 5% copper (II) acetate. The resulting copper salt was filtered, washed with hexane, and stirred with 6N hydrochloric acid to destroy the salt. the acidic aqueous solution was extracted with ether. The ether solution was then washed with water and dried over MgSO4. Concentration of the ether solution under vacuum afforded 4.4 g of the desired product as a brown oil (34.2% yield). The structure was confirmed by instrumental analysis.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[C:20]([C:22]#[N:23])[C:19]3[N:24]=[N:25][N:26]([CH3:27])[C:18]=3[CH:17]=2)=[CH:12][C:11]=1[C:28]([F:31])([F:30])[F:29].C(N(C(C)C)CC)(C)C.CO>O>[CH3:1][S:2]([O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[C:20]([C:22]#[N:23])[C:19]3[N:24]=[N:25][N:26]([CH3:27])[C:18]=3[CH:17]=2)=[CH:12][C:11]=1[C:28]([F:30])([F:29])[F:31])(=[O:4])=[O:3]
Reactant: Cn1nnc2c(C#N)nc(-c3ccc(OCCO)c(C(F)(F)F)c3)cc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CO
Product: Cn1nnc2c(C#N)nc(-c3ccc(OCCOS(C)(=O)=O)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
Methanesulfonyl chloride (3.95 ml, 4.53 g) was added dropwise at 0° C. to a solution of 6-(4-(2-hydroxyethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (5.7 g) and diisopropylethylamine (17.28 ml, 12.79 g). The mixture was stirred at room temperature for 1 hour. 10 ml methanol added and stirred for 5 minutes, followed by cold water (20 ml). Product precipitated, collected by filtration and washed with diethyl ether. Sample dried in the oven to give 2-(4-(4-cyano-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)-phenoxy)ethyl methanesulfonate (6.3 g). 1H NMR (DMSO) δ: 8.99 (s, 8.99), 8.48 (m, 2H), 7.53 (d, 1H), 4.60 (m, 4H), 4.46 (s, 3H), 3.24 (s, 3H). MS m/z 442 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:16][C:17]2[N:27]=[C:26]3[C:20]([N:21]([CH3:34])[C:22](=[O:33])[CH2:23][CH2:24][N:25]3[CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:19][N:18]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9]C(C)(C)C)=[O:8].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:16][C:17]2[N:27]=[C:26]3[C:20]([N:21]([CH3:34])[C:22](=[O:33])[CH2:23][CH2:24][N:25]3[CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:19][N:18]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([OH:9])=[O:8]
Reactant: CN1C(=O)CCN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)OC(C)(C)C)cc3Cl)ncc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)CCN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)O)cc3Cl)ncc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
tert-butyl 5-chloro-4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]-2-fluoro-benzoate (Intermediate 220; 220 mg, 0.45 mmol) was dissolved in DCM (7.5 mL) and trifluoroacetic acid (2.5 mL) added. The mixture was stirred at room temperature for 2 hours. The refraction mixture was evaporated, the residue dissolved in methanol/DCM and absorbed on to an SCX column, which was subsequently washed with methanol and eluted with ammonia in methanol. Product containing fractions were combined and evaporated to yield the title compound as a white solid (195 mg, 100%).
Reaction SMILES: ClC1C=CC([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:32])([F:31])[C:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])([OH:22])[CH2:16][N:17]3[CH:21]=[N:20][N:19]=[N:18]3)=[N:12][CH:13]=2)=C(F)C=1.BrC1C=CC(OC)=CN=1>>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[C:15]([OH:22])([CH2:16][N:17]1[CH:21]=[N:20][N:19]=[N:18]1)[C:14]([F:32])([F:31])[C:11]1[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:13][N:12]=1
Reactant: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(OCc2ccc(Cl)cc2F)cn1
Agent: COc1ccc(Br)nc1
Product: COc1ccc(C(F)(F)C(O)(Cn2cnnn2)c2ccc(F)cc2F)nc1

Procedure:
Compound 8 was prepared in a similar manner to compound 1 from 2-bromo-5-methoxypyridine to afford a tan solid (28 mg, 10%). 1H NMR (500 MHz, CDCl3): δ 8.74 (s, 1H), 8.19 (s, 1H), 7.63 (br s, 1H), 7.51 (d, J=8.5 Hz, 1H), 7.34-7.33 (m, 1H), 7.24-7.23 (m, 1H), 6.75-6.74 (m, 1H), 6.67-6.66 (m, 1H), 5.58 (d, J=14.0 Hz, 1H), 5.07 (d, J=14.0 Hz, 1H), 3.88 (s, 3H). MS(ESI): m/z 382 [M+−1]. HPLC: 92.37%.