Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH:24][C:25]4[CH:29]=[CH:28][O:27][N:26]=4)(=[O:23])=[O:22])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:30])[C:5]([O:9][CH3:10])=[N:6][C:7]=1Cl.[CH:31]1(B(O)O)[CH2:33][CH2:32]1>CCOC(C)=O.CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH:24][C:25]4[CH:29]=[CH:28][O:27][N:26]=4)(=[O:22])=[O:23])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:30])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH:31]1[CH2:33][CH2:32]1
Reactant: COc1nc(Cl)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Reactant: OB(O)C1CC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1nc(C2CC2)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 50 °C
Reaction time: 12 h
Yield: 42.1 %

Procedure:
A 20-mL vial was charged with 1-(5,6-dichloro-2-methoxypyridin-3-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (200 mg, 0.428 mmol), cyclopropyl boronic acid (66.2 μl, 0.856 mmol), and (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (62.6 mg, 0.086 mmol) then purged with nitrogen. The reaction vessel was then sequentially charged with dioxane (3.2 mL) and an aqueous solution of sodium carbonate (1.1 mL, 1.9 M) via syringe. The vial was sealed with a PTFE line cap and the resultant red reaction mixture was heated to 50° C. After 12 h, the reaction mixture was allowed to cool to ambient temperature and an aqueous solution of 1.0 N HCL (5 mL) was added and the mixture diluted with EtOAc (5 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to furnish a brown oil, which was dissolved in DMSO (2 mL) filtered through a 0.2 micron filter and purified by reverse-phase HPLC (Waters XBridge Prep Shield RP18 10 μm OBD 19×100 mm) gradient, 20 to 75% MeCN in water (containing 0.1% trifluoroacetic acid as an additive), flow rate 40 mL/min to afford 1-(5-chloro-6-cyclopropyl-2-methoxy-3-pyridinyl)-N-3-isoxazolyl-2-oxo-1,2-dihydro-6-quinolinesulfonamide (85 mg, 0.180 mmol, 42.0% yield) as a white amorphous solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.23 (d, J=1.76 Hz, 1 H) 8.13 (d, J=1.97 Hz, 1 H) 7.74-7.80 (m, 2 H) 7.46 (s, 1 H) 6.82 (d, J=9.64 Hz, 1 H) 6.75 (d, J=9.02 Hz, 1 H) 6.56 (d, J=1.66 Hz, 1 H) 3.76 (s, 3 H) 2.41-2.61 (m, 1 H) 1.14-1.23 (m, 2 H) 1.09 (dd, J=8.09, 3.21 Hz, 2 H). m/z (ESI) 473.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([CH3:12])[CH:4]=1.[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14]>S(Cl)(Cl)=O.O>[CH2:13]([N:15]([CH2:16][CH3:17])[C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH3:12])[CH3:14]
Reactant: COc1ccc(C(=O)O)c(C)c1
Reactant: CCNCC
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)c1ccc(OC)cc1C
Temperature: 80 °C
Yield: 57.6 %

Procedure:
4-methoxy-2-methylbenzoic acid (3.0 g, 18.05 mmol) was taken in thionyl chloride (20 ml) and refluxed for 1 h at 80° C. The reaction mixture was evaporated under reduced pressure. Under nitrogen the crude was quenched with diethyl amine (1.870 ml, 18.05 mmol) slowly under cooling condition. The reaction mixture was dissolved in water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (20% ethyl acetate in pet ether) to get desired compound (2.3 g, 54.7%) as an oil. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.06-7.04 (d, J=8 Hz, 1H), 6.79 (s, 1H), 6.78-6.76 (d, J=8 Hz, 1H), 3.75 (s, 3H), 3.43 (br, s, 2H), 3.06-3.05 (m, 2H), 2.16 (s, 3H), 1.14 (d, J=8 Hz, 3H), 0.95 (d, J=8 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:24]=[CH:23][C:8]([CH:9]=[C:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:7][CH:6]=1)=[O:4]>CO.[C].[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][CH2:15]2)=[CH:23][CH:24]=1)=[O:4]
Reactant: COC(=O)c1ccc(C=C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(CC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 101.6 %

Procedure:
To a mixture of diethyl 4-(methoxycarbonyl)benzylphosphonate (20.5 g, 71.5 mmol), 15-crown-5 (1.4 ml, 7.1 mmol) and THF (120 ml) was added sodium hydride (60% in oil, 2.9 g, 71.5 mmol) at 0° C. The mixture was stirred at 0° C. for 0.5 h. A solution of tert-butyl 4-oxo-1-piperidinecarboxylate (11.9 g, 59.6 mmol) in THF (45 ml) was added dropwise to the resulting mixture over period of 10 min at 0° C. The mixture was stirred at room temperature for 20 h. The resulting mixture was poured into ice-water (200 ml) and the whole was extracted with ethyl acetate (100 ml×2). The extracts were washed with 5% aqueous sodium bicarbonate (100 ml), saturated sodium chloride solution (100 ml) successively. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel 200 g, ethyl acetate/hexane=1/10) followed by recrystallization from hexane to give tert-butyl 4-(4-methoxycarbonylbenzylidene)piperidine-1-carboxylate (6.9 g, 35%) as a colorless crystalline powder. A mixture of tert-butyl 4-(4-methoxycarbonylbenzylidene)piperidine-1-carboxylate (6 g, 18 mmol) in methanol (150 ml) was hydrogenated over 10% palladium carbon (50% wet, 1 g) for 5 h at room temperature. The catalyst was, removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel 90 g, ethyl acetate/hexane=1/10) to obtain the title compound (6.1 g, 100%) as pale yellow oil.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:2]1.[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[O:28][CH2:29][CH:30]([CH2:33][OH:34])[O:31][CH3:32]>>[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[O:28][CH2:29][CH:30]([O:31][CH3:32])[CH2:33][O:34][CH2:2][CH:3]([OH:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCCCCCCCCC1CO1
Reactant: COC(CO)COC1CCCCO1
Product: CCCCCCCCCCCCCCCCCCC(O)COCC(COC1CCCCO1)OC
Yield: 58.7 %

Procedure:
The above epoxide (17) (4.75 g, 16 mmoles) was reacted with 6.1 g (32 mmoles) of 2-methylglycerol monotetrahydropyranyl ether in the same manner as Example 1-2 to give 4.57 g of the desired compound as a colorless wax.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].C(N(C(C)C)CC)(C)C.[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]Br)[CH:24]=1>ClCCl>[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][NH:5][CH2:4][C:3]2[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:2]=2[Cl:1])[CH:24]=1
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1cccc(CBr)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cccc(CNCc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
g (5.68 mmol) of 2,4-dichlorobenzylamine was dissolved in 20 ml of dichloromethane and treated with 2.94 g (22.7 mmol) of diisopropylethylamine and 1.43 g (6.25 mmol) of 3-bromomethyl-benzoic acid methyl ester. The solution was stirred for 16 h at RT. The solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with ethyl acetate/n-heptane (1/4).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH:16]=[CH:15][NH:14][C:13]3=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[N:2]1.CN1CCCC1=O.[H-].[Na+].[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[C@@:35]1([CH2:39][N:40]2[CH:44]=[N:43][CH:42]=[N:41]2)[C@H:37]([CH3:38])[O:36]1>C(OCC)(=O)C>[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[C@@:35]([OH:36])([CH2:39][N:40]1[CH:44]=[N:43][CH:42]=[N:41]1)[C@H:37]([N:14]1[CH:15]=[CH:16][N:12]([C:9]2[CH:10]=[CH:11][C:6]([N:1]3[CH:5]=[CH:4][N:3]=[N:2]3)=[CH:7][CH:8]=2)[C:13]1=[O:17])[CH3:38]
Reactant: O=c1[nH]ccn1-c1ccc(-n2ccnn2)cc1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C[C@@H](n1ccn(-c2ccc(-n3ccnn3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.1 %

Procedure:
To a mixture of 1-[4-(1H-1,2,3-triazol-1-yl)phenyl]-2(1H,3H)-imidazolone (2.72 g) and 1-methyl-2-pyrrolidone (100 ml) was added sodium hydride (70% in oil, 0.40 g), and the mixture was stirred at room temperature for 1 hour. (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane (2.51 g) was added thereto, and the mixture was stirred at 100° C. for 8 hours under an argon atmosphere. After cooling, the reaction solution was diluted with ethyl acetate (400 ml), and washed with water (100 ml), 1N-hydrochloric acid (100 ml×2) and a saturated aqueous solution of sodium chloride (50 ml) successively. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent:ethyl acetate to ethyl acetate/acetone=5/1) and recrystallized from ethyl acetate-diisopropyl ether to give 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol -1-yl)propyl]-3-[4-(1H-1,2,3-triazol-1-yl)phenyl]-2(1H,3H) -imidazolone (Compound 11; 1.82 g) as a pale yellow crystalline powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:18]([CH3:34])=[C:19]4[C:24](=[CH:25][CH:26]=3)[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[C:18]([CH3:34])=[C:19]4[C:24](=[CH:25][CH:26]=3)[CH2:23][NH:22][CH2:21][CH2:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: Cc1c(-c2noc(-c3ccc(OC(C)C)c(Cl)c3)n2)ccc2c1CCN(C(=O)OC(C)(C)C)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(-c2noc(-c3ccc(OC(C)C)c(Cl)c3)n2)ccc2c1CCNC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1,1-dimethylethyl 6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 19; 210 mg; 0.434 mmol) in dichloromethane (3 ml) at 0° C. was added trifluoroacetic acid (3 ml) dropwise. The resulting mixture was stirred at 0° C. for 1 h, giving a pale yellow solution. Removal of the solvent and co-evaporation with toluene gave a white solid, which was triturated with diethyl ether to give the title compound as a white solid (206 mg).
Reaction SMILES: [CH3:1][O:2][N:3]1[CH2:9][CH2:8][N:7]2[C:10](=[O:23])[CH:11]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])[C:12](=[O:13])[N:6]2[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:1][O:2][N:3]1[CH2:4][CH2:5][N:6]2[C:12](=[O:13])[C:11]([C:14]3[C:15]([CH3:22])=[CH:16][C:17]([CH3:21])=[CH:18][C:19]=3[CH3:20])=[C:10]([O:23][C:32](=[O:33])[O:34][CH2:35][CH3:36])[N:7]2[CH2:8][CH2:9]1
Reactant: CON1CCN2C(=O)C(c3c(C)cc(C)cc3C)C(=O)N2CC1
Reactant: CCOC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)Oc1c(-c2c(C)cc(C)cc2C)c(=O)n2n1CCN(OC)CC2
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-methoxy-8-(2,4,6-trimethyl-phenyl)-tetrahydro-pyrazolo[1,2-a][1,2,5]triazepine-7,9-dione (106 mg, 0.33 mmol), triethylamine (0.070 ml, 51 mg, 0.50 mmol) and a catalytic amount of 4-dimethylaminopyridine in tetrahydrofuran (2 ml) at 0° C. was added ethyl chloroformate (0.035 ml, 40 mg, 0.37 mmol) dropwise. The suspension was stirred at 0° C. for 20 minutes, treated with more triethylamine (0.070 ml, 51 mg, 0.50 mmol) and ethyl chloroformate (0.035 ml, 40 mg, 0.37 mmol) dropwise, and further stirred at 0° C. for 10 minutes. The solvent was evaporated, the residue diluted with ethyl acetate, the organic phase washed with water and brine, dried over sodium sulfate and concentrated. The gummy residue was triturated in cyclohexane and diethyl ether, stirred at room temperature, filtered and dried. Yield: 100 mg of carbonic acid ethyl ester 3-methoxy-9-oxo-8-(2,4,6-trimethyl-phenyl)-2,3,4,5-tetrahydro-1H,9H-pyrazolo[1,2-a][1,2,5]triazepin-7-yl ester (title compound P1.2) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[OH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:11][C:12]2[CH:19]=[CH:18][CH:17]=[C:14]([CH:15]=[O:16])[CH:13]=2)[CH:3]=1
Reactant: O=Cc1cccc(O)c1
Reactant: N#Cc1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1
Yield: 91.7 %

Procedure:
4-Chloro-2-fluorobenzonitrile (1.00 g, 6.43 mmol), 3-hydroxybenzaldehyde (0.79 g, 6.43 mmol) and cesium carbonate (2.09 g, 6.43 mmol) were heated with stirring in dry DMF (5 ml) at 50° C. for 23 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with water (3×), 10% aqueous sodium carbonate (2×), water, brine, and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 4-chloro-2-(3-formyl-phenoxy)-benzonitrile (1.52 g, 91%) as a yellow oil which solidified.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[N:23]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[N:22]=[CH:21]4)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+]>C(O)C.C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[N:23]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[N:22]=[CH:21]4)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: CCOC(=O)CCn1ncc2cc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(cnn4CCC(=O)O)c3)no2)cc1C#N
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 28.5 %

Procedure:
Ethyl 3-[5-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl]propanoate (D58) (523 mg, 1.17 mmol) was dissolved in mixture of ethanol (20 ml) and THF (10 ml) by warming at 50° C. Cooled to RT and added 2N NaOH (1 ml, 2 mmol) and left standing at RT for 30 minutes. Evaporated off the solvent, added water (50 ml) and washed with EtOAc (50 ml). Acidified aqueous layer and extracted product into EtOAc (50 ml). The EtOAc layer was dried (MgSO4) and the solvent evaporated. Triturating with diethyl ether gave the title compound (139 mg) as a beige solid. δH (d6-DMSO, 400 MHz): 1.39 (6H, d), 2.90 (2H, t), 4.66 (2H, t), 4.94-5.03 (1H, m), 7.57 (1H, d), 7.90 (1H, d), 8.07 (1H, dd), 8.28 (1H, d), 8.42 (1H, dd), 8.54 (2H, dd), 12.35 (1H, broad s). MS (ES): C22H19N5O4 requires 417; found (MH+) 418.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12](OCC(F)(F)F)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:45])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[CH:29]=1)(C)(C)C.[C:47](O)([C:49]([F:52])([F:51])[F:50])=[O:48]>C(Cl)Cl>[F:50][C:49]([F:52])([F:51])[CH2:47][O:48][C:12]1[C:11]([C:20]([F:21])([F:23])[F:22])=[CH:10][C:9]2[NH:24][C:25](=[O:45])[CH2:26][C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]4[CH:39]=[CH:38][N:37]=[C:36]([C:40]([F:41])([F:42])[F:43])[CH:35]=4)[CH:29]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(C(F)(F)F)c2)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3ccnc(C(F)(F)F)c3)c2)=Nc2cc(OCC(F)(F)F)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from [2-{3-oxo-3-[3-(2-trifluoromethyl-pyridin-4-yl)-phenyl]-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M247) (0.43 g, 0.65 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (260 mg, 74%).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(F)(F)F.[C:18](O)(=[O:20])[CH3:19]>>[OH:13][C:10]1[CH:9]=[CH:8][C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:12][C:11]=1[C:18](=[O:20])[CH3:19]
Reactant: CC(=O)O
Reactant: Oc1ccc(C2CCCCC2)cc1
Agent: FB(F)F
Product: CC(=O)c1cc(C2CCCCC2)ccc1O
Reaction time: 0.25 h

Procedure:
35.25 g of 4-cyclohexyl-phenol were added in small amounts at 5° to 10° C. to a solution of 46 g of boron trifluoride in 110 ml of concentrated acetic acid and the mixture was held at 50° C. for 15 minutes and then at 75° C. for 21 hours. The mixture was poured into ice and the aqueous phase was extracted 3 times with 200 ml of ether. The ether phase was treated with powdered sodium bicarbonate and was stirred for 16 hours and was then filtered. The filtrate was washed with water until the wash water was neutral, dried over magnesium sulfate and was evaporated to dryness under reduced pressure. The residue was pressure chromatographed over silica gel and was eluted with a 1-4 ether-petroleum ether (b.p.=60° to 80° C.) mixture to obtain 39.9 g of 1-(2-hydroxy-5-cyclohexylphenyl)-ethanone melting at <50° C.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[C:39]([C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1)#[N:40]>>[NH2:30][C:29]1[S:28][C:27]([C:45]2[CH:44]=[CH:43][CH:42]=[C:41]([C:39]#[N:40])[CH:46]=2)=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][NH2:8])[CH2:11][CH2:12]1)=[O:24]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Product: Cn1ncc(NC(=O)c2nc(-c3cccc(C#N)c3)sc2N)c1N1CCC(CN)CC1
Yield: 42 %

Procedure:
Following Example 278, Suzuki coupling of tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and 3-cyanophenyl boronic acid gave 250 as a pale brown solid (36 mg, 42% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 9.09 (s, 1H), 8.42 (s, 1H), 8.11 (d, J=7.9 Hz, 1H), 7.86 (d, J=7.9 Hz, 1H), 7.68 (t, J=7.9 Hz, 1H), 7.56 (s, 2H), 7.33 (s, 1H), 3.66 (s, 3H), 3.16-2.99 (m, 4H), 2.47 (d, J=5.7 Hz, 2H), 1.82-1.73 (m, 4H), 1.30-1.17 (m, 3H). LCMS (ES+) m/z 437 (M+1)
Reaction SMILES: [C:1]([OH:15])(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[CH:19][C:18]=1O.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:1]([O:15][C:18]1[CH:19]=[C:20]([Cl:24])[C:21]([Cl:23])=[CH:22][C:17]=1[Cl:16])(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Reactant: CCCCCCCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCCCCCC(=O)Oc1cc(Cl)c(Cl)cc1Cl
Yield: 95.9 %

Procedure:
A solution of n-tridecanoic acid (Sigma Chemical Co.) (12.5 g), 2,4,5-trichlorophenol (11.5 g), and N,N'-dicyclohexylcarbodiimide (12.0 g) in methylene chloride (650 ml) is stirred at room temperature for 16 hours. The reaction mixture is then filtered and dried in vacuo to give 2,4,5-trichlorophenyl n-tridecanoate (22 g). The material is purified by column chromatography over silica gel (Woelm) using toluene as the eluent. Fractions are monitored by TLC using a shortware UV light for detection. Fractions containing the purified product are pooled and concentrated in vacuo to dryness.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C[Al](C)C.[NH2:13][C:14]1[C:15]2[N:16]([C:20]([CH:27]3[CH2:30][CH2:29][CH2:28]3)=[N:21][C:22]=2[C:23](OC)=[O:24])[CH:17]=[CH:18][N:19]=1>C1(C)C=CC=CC=1>[NH2:13][C:14]1[C:15]2[N:16]([C:20]([CH:27]3[CH2:28][CH2:29][CH2:30]3)=[N:21][C:22]=2[C:23]([NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH2:8])=[O:24])[CH:17]=[CH:18][N:19]=1
Reactant: COC(=O)c1nc(C2CCC2)n2ccnc(N)c12
Reactant: Nc1ccccc1N
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Nc1ccccc1NC(=O)c1nc(C2CCC2)n2ccnc(N)c12
Temperature: 120 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A suspension of 1,2-phenylenediamine (60 mg, 0.6 mmol) in toluene (2.0 mL) was treated with a 2M solution of trimethylaluminum in toluene (0.5 mL) effecting the formation of a pink solution. After 5 min this solution was treated with solid methyl 8-amino-3-cyclobutylimidazo[1,5-a]pyrazine-1-carboxylate (30 mg, 0.1 mmol) and the mixture heated at 120° C. for 30 min then stirred at rt overnight. The mixture was then partitioned between 2M NaOH (10 mL) & EtOAc (10 mL) and stirred for 15 min. The organic layer was separated and the aqueous layer extracted further with EtOAc (3×10 mL). The combined organics were washed with brine, dried and concentrated in vacuo to give -85% pure 8-amino-N-(2-aminophenyl)-3-cyclobutylimidazo[1,5-a]pyrazine-1-carboxamide which was used without purification.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH3:5][C:6]([C:9]1[CH:10]=[C:11]([S:20][CH2:21][CH2:22][C:23]([NH:25][NH2:26])=[O:24])[CH:12]=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:14]=1[OH:15])([CH3:8])[CH3:7].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:8][C:6]([C:9]1[CH:10]=[C:11]([S:20][CH2:21][CH2:22][C:23]2[O:24][C:1](=[S:2])[NH:26][N:25]=2)[CH:12]=[C:13]([C:16]([CH3:17])([CH3:18])[CH3:19])[C:14]=1[OH:15])([CH3:5])[CH3:7]
Reactant: CC(C)(C)c1cc(SCCC(=O)NN)cc(C(C)(C)C)c1O
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(SCCc2n[nH]c(=S)o2)cc(C(C)(C)C)c1O
Reaction time: 0.17 h
Yield: 62 %

Procedure:
Thiophosgene (0.34 mL, 4.40 mmol) is added dropwise to a -78° C. solution of 3-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]propanoic acid hydrazide (1.5 g, 4.40 mmol) in tetrahydrofuran (150 mL). The reaction mixture is stirred for 10 minutes then poured into a separatory funnel containing ethyl acetate and aqueous sodium bicarbonate. The organic phase is washed three times with water and once with brine. Drying the organic phase over magnesium sulfate and evaporation gives a heavy oil which is crystallized from ethyl acetate/hexane to afford 1.0 g (59%) of 5-[2-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]ethyl]-1,3,4-oxadiazole-2(3H)-thione, mp 123.5°-124.5° C.