Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].Cl[S:9]([OH:12])(=O)=[O:10].[OH-].[NH4+:14]>C(Cl)(Cl)Cl>[CH3:7][C:6]1[CH:5]=[C:4]([S:9]([NH2:14])(=[O:12])=[O:10])[S:3][C:2]=1[CH3:1]
Reactant: O=S(=O)(O)Cl
Reactant: [NH4+]
Reactant: Cc1ccsc1C
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1cc(S(N)(=O)=O)sc1C

Procedure:
The procedure of Example 3A was followed with 2,3-dimethylthiophene (6.0 g, 53.6 mmole), chlorosulfonic acid (27.5 g), dry chloroform (160 ml total), and concentrated ammonium hydroxide to provide solid 4,5-dimethyl-2-thiophenesulfonamide. The sulfonamide (1.5 g, 7.7 mmole), 1N NaOH (7.7 ml), acetone (7.0 ml) were combined and 4-chlorophenyl isocyanate (1.14 g, 7.7 mmole), 1N HCl (7.7 ml) to provide the named product (1.0 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.C([C:24]1([OH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:25]1[C:26](Cl)=[O:27])(=O)C>C(Cl)Cl>[OH:33][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([NH:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1)=[O:27]
Reactant: CC(=O)C1(O)C=CC=CC1C(=O)Cl
Reactant: NCCSc1cccc2nccn12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCSc1cccc2nccn12)c1ccccc1O
Yield: 56 %

Procedure:
To a solution of 5-[2-(amino)ethylthio]imidazo[1,2-a]pyridine (3.87 g, 20 mmoles) and triethylamine (5.58 ml, 40 mmoles) in methylene chloride (200 ml) was added o-acetylsalicyloyl chloride (4.77 g, 24 mmoles) under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. After the solvent was distilled off, ethanol (60 ml) and 1N NaOH (40 ml) were added to the residue, followed by stirring for 1 hour. 1N HCl (40 ml) was added and ethanol was distilled off, and then the residue was extracted with chloroform and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography (eluent: ethyl acetate/ethanol=10:1) to obtain 3.51 g of the desired product (56.0%, colorless solid).
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([OH:13])=O)[C:6]1=[O:14])(=[O:3])[CH3:2].[CH3:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH:18]([CH3:22])[N:17]1[CH2:23][CH2:24][NH2:25]>O1CCCC1>[CH3:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([CH3:22])[N:17]1[CH2:23][CH2:24][NH:25][C:11](=[O:13])[CH2:10][N:7]1[CH2:8][CH2:9][CH:5]([O:4][C:1](=[O:3])[CH3:2])[C:6]1=[O:14]
Reactant: CC(=O)OC1CCN(CC(=O)O)C1=O
Reactant: CC1CCCC(C)N1CCN
Solvent: C1CCOC1
Product: CC(=O)OC1CCN(CC(=O)NCCN2[C@H](C)CCC[C@@H]2C)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.0 g of (R/S)-2-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetic acid is placed in 15 ml of absolute tetrahydrofuran, whereupon 0.89 g of N,N'-carbonyldiimidazole is added in one portion. The mixture is stirred at room temperature until the gas evolution is complete. Thereafter, 0.86 g of 94.7% cis-(2-(2,6-dimethyl-1-piperidinyl)ethylamine is added and the mixture is left to stand overnight at room temperature and then evaporated. The residue is chromatographed on 60 g of aluminum oxide (activity grade III, neutral). The (R/S)-cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetamide which is eluted with methylene chloride has a melting point of 121°-122° after trituration with diethyl ether.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].N#N.[CH2:7]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][Si:23]([CH2:26][CH2:27][CH2:28][CH3:29])([CH3:25])[CH3:24])[CH:8]1[O:10][CH2:9]1>C(O)C>[OH:2][CH2:1][CH2:3][NH:4][CH2:9][CH:8]([OH:10])[CH2:7][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][Si:23]([CH2:26][CH2:27][CH2:28][CH3:29])([CH3:25])[CH3:24]
Reactant: NCCO
Reactant: CCCC[Si](C)(C)CCCCCCCCCCCOCC1CO1
Agent: N#N
Solvent: CCO
Product: CCCC[Si](C)(C)CCCCCCCCCCCOCC(O)CNCCO
Temperature: 80 °C
Yield: 73.3 %

Procedure:
A 100-ml two-necked flask equipped with a stirrer, dropping funnel and N2 inlet tube was charged with 4.58 g (75 mmol) of ethanolamine and 9.2 g of ethanol. The contents were heated to 80° C. with stirring in an N2 atmosphere, and an ethanol solution of 1.71 g (5 mmol) of 11-(butyldimethylsilyl)undecyl glycidyl ether was added dropwise to the contents over 1 hour. The resultant mixture was stirred further for 1 hour at 80° C. After completion of the reaction, ethanol and excess ethanolamine were distilled off under reduced pressure, and the resultant residue was purified by column chromatography on silica gel, thereby obtaining 1.48 g (yield: 73%) of the title compound (Ia-18).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:11])[CH2:9]O.C(N(CC)CC)C.F.F.F.C(N(CC)CC)C.[F:29]C(F)(C(F)(F)F)C(F)(F)C(F)(F)S(F)(=O)=O.C(=O)([O-])O.[Na+]>ClCCl>[F:29][CH2:9][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[O:11]
Reactant: O=C(CO)c1ccccc1F
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CF)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
A solution of 1-(2-fluorophenyl)-2-hydroxyethanone [CAS 218771-68-7; WO9857925, ex. 16) (2.77 g, 18.0 mmol) in dichloromethane (42 ml) was treated consecutively at 0° C. with triethylamine (6.36 g, 62.8 mmol), triethylamine trihydrofluoride (3.05 g, 18.0 mmol) and nonafluoro-n-butanesulfonyl fluoride (8.48 g, 26.9 mmol). The tube was sealed and the reaction mixture stirred overnight at room temperature. For the workup, the dark red solution was poured on a saturated solution of sodium hydrogencarbonate and ice, then extracted with dichloromethane. The organic layer was separated, dried over sodium sulphate and evaporated. The crude material was purified by flash chromatography on silica gel (Telos Flash Silica) using dichloromethane as the eluent to give the 2-fluoro-1-(2-fluoro-phenyl)-ethanone (1.23 g, 61% yield) as a yellow semisolid.
Reaction SMILES: [BH4-].[Na+].[N:3]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.C1COCC1.Cl>O.C(O)C>[N:3]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: O=Cc1ccc(-c2ccc(-n3ccc4ccccc43)cc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: OCc1ccc(-c2ccc(-n3ccc4ccccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium borohydride (783 mg, 20.6 mmol) was added portion-wise to a stirred solution of aldehyde (prepared in example 4) (3.06 g, 10.3 mmol) in a mixture of anhydrous THF and ethanol (1:1; 100 mL) at room temperature. The reaction mixture was stirred for 10 minutes at room temperature (TLC control), poured into water (50 mL) and acidified to pH 4 with 2N hydrochloric acid, and then extracted with diethyl ether (3×20 mL). The combined extract was washed with 0.5 N hydrochloric acid (2×10 mL), water and finally brine. The ethereal solution was dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 30% ethyl acetate/hexane as eluent, afforded the title compound has a white solid (2.80 g, 91%); 1H NMR (CDCl3, 300 MHz) δ 7.55-7.78 (7H, m, Ar-H), 7.52 (2H, d, J=8 Hz, Ar-H), 7.41 (1H, d, J=3.5 Hz, Ar-H), 7.22 (3H, m, Ar-H), 6.72 (1H, d, J=3.5 Hz, Ar-H), 4.79 (2H, d, J=5.5 Hz, CH2O).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:19])=[C:11](F)[C:12]=3[C:14]([F:17])([F:16])[F:15])[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.[NH:24]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH2:35][NH2:36])[CH2:25]1>>[NH2:36][CH2:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH:26]1[CH2:27][CH2:28][N:24]([C:11]2[C:12]([C:14]([F:16])([F:15])[F:17])=[C:13]3[C:8]([C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:19])[CH2:25]1
Reactant: O=C(O)c1cn(C2CC2)c2c(C(F)(F)F)c(F)c(F)cc2c1=O
Reactant: NCc1ccccc1C1CCNC1
Product: NCc1ccccc1C1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2C(F)(F)F)C1

Procedure:
Starting from 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo -8-trifluoromethyl-3-quinolinecarboxylic acid (1.00 g, 3.0 retool) and 2-(3-pyrrolidinyl)benzenemethanamine, a procedure analogous to that given in Example 1 provided the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C@H:10]2[C@H:15]([N:16]([CH3:31])[C:17](=[O:30])[C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[CH2:14][CH2:13][NH:12][CH2:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9].[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([C:45](O)=[O:46])[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(#N)C.O.C(N(CC)CC)C>[Cl:2][C:3]1[CH:4]=[C:5]([C@H:10]2[C@H:15]([N:16]([CH3:31])[C:17]([C:18]3[CH:19]=[CH:20][C:21]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)=[CH:22][CH:23]=3)=[O:30])[CH2:14][CH2:13][N:12]([C:45]([CH:42]3[CH2:43][CH2:44][N:39]([C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH2:40][CH2:41]3)=[O:46])[CH2:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CN(C(=O)c1ccc(N2CCOCC2)cc1)[C@@H]1CCNC[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(C(=O)c1ccc(N2CCOCC2)cc1)[C@@H]1CCN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 78.6 %

Procedure:
To a solution of N-[(3R,4R)-3-(3,4-dichlorophenyl)piperidin-4-yl]-N-methyl-4-morpholin-4-ylbenzamide monohydrochloride (800 mg) obtained in Example 614, step 3, 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (566 mg) and triethylamine (684 μL) in acetonitrile (5 mL) were added WSC.HCl (473 mg) and HOBt (378 mg), and the mixture was stirred at room temperature for 14 hr. To the reaction solution was added water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (855 mg, 79%) as a white powder.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:10]=1[C:11](Cl)=[O:12].[CH3:19][O:20][C:21](=[O:41])[CH:22]([NH2:40])[CH2:23][CH:24]=[CH:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]([CH3:39])[C:33]2[N:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[CH:28][CH:27]=1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:19][O:20][C:21](=[O:41])[CH:22]([NH:40][C:11](=[O:12])[C:10]1[C:9]([F:8])=[CH:17][CH:16]=[CH:15][C:14]=1[F:18])[CH2:23]/[CH:24]=[CH:25]/[C:26]1[CH:27]=[CH:28][C:29]([N:32]([CH3:39])[C:33]2[N:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[CH:30][CH:31]=1
Reactant: COC(=O)C(N)CC=Cc1ccc(N(C)c2ncccn2)cc1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(C/C=C/c1ccc(N(C)c2ncccn2)cc1)NC(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under an argon atmosphere, triethylamine (0.028 ml) and 2,6-difluorobenzoyl chloride (0.015 ml) were added to a solution of 2-amino-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (31.7 mg) in dichloromethane (2 ml), and the resulting mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution and the resulting mixture was extracted with ethyl acetate. Organic layer was washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by thin layer chromatography (silica gel, mobile phase: cyclohexane/ethyl acetate=3/2) to obtain (E)-2-(2,6-difluorobenzamido)-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (42 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[C:10](Cl)=[CH:9][C:8]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:7][C:6]=1[CH3:22])[CH3:2].[CH3:24][S-:25].[Na+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[C:10]([S:25][CH3:24])=[CH:9][C:8]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:7][C:6]=1[CH3:22])[CH3:2]
Reactant: C[S-]
Reactant: CCOC(=O)c1c(Cl)cc(-c2c(CC)cccc2CC)nc1C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(SC)cc(-c2c(CC)cccc2CC)nc1C
Temperature: 70 °C

Procedure:
A mixture of 4-chloro-6-(2,6-diethyl-phenyl)-2-methyl-nicotinic acid ethyl ester (200 mg, 0.60 mmol) and sodium thiomethoxide (126 mg, 1.80 mmol) in DMF (5 mL) is heated at 70° C. overnight. After cooling, water (20 mL) is added and the resulting mixture is extracted with EtOAc. The combined extracts are washed with brine, dried over sodium sulfate and concentrated. The residue is chromatographed on silica gel to give 6-(2,6-diethyl-phenyl)-2-methyl-4-methylsulfanyl-nicotinic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[O:12][C:11]([CH3:14])=[CH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[Br:15]Br>C(Cl)Cl.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:13]2[O:12][C:11]([CH3:14])=[C:10]([Br:15])[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: BrBr
Reactant: COC(=O)c1cccc2cc(C)oc12
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1cccc2c(Br)c(C)oc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A solution of 2-methyl-benzofuran-7-carboxylic acid methyl ester (0.55 g, 2.87 mmol), prepared according to a literature procedure (Ishikawa, T.; Nagai, K.; Ohkubo, N.; Ishii, H. Heterocycles 1994, 39, 371), in CH2Cl2 (15 mL) at 0° C. is treated with bromine (147 μL, 2.87 mmol). The reaction is stirred at 0° C. for 30 min, then at RT overnight. The reaction is diluted with EtOAc 960 mL); washed with 5% Na2S2O3 (2×20 mL); brine (20 mL); dried with Na2SO4, filtered and concentrated gives the title compound (0.79 g, 2.87 mmol, 100%). 1H NMR (CDCl3): δ 2.55 (s, 3H), 4.00 (s, 3H), 7.33 (t, J=7.5 Hz, 1H), 7.63 (dd, J=7.9, 0.9 Hz, 1H), 7.93 (dd, J=7.9, 0.9 Hz, 1H) ppm.
Reaction SMILES: [CH:1]1([CH2:5][CH:6]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([O:17][C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=3[F:25])[CH:12]=[N:11]2)[C:7](O)=[O:8])[CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:62][C:63]1[CH:67]=[CH:66][N:65]([CH2:68][C:69]([CH3:72])([OH:71])[CH3:70])[N:64]=1>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([CH2:5][CH:6]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([O:17][C:18]3[C:19]([F:25])=[CH:20][CH:21]=[CH:22][C:23]=3[F:24])[CH:12]=[N:11]2)[C:7]([NH:62][C:63]2[CH:67]=[CH:66][N:65]([CH2:68][C:69]([OH:71])([CH3:70])[CH3:72])[N:64]=2)=[O:8])[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCC1)n1ncc(Oc2c(F)cccc2F)cc1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCC2)n2ncc(Oc3c(F)cccc3F)cc2=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
A solution of 3-cyclobutyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 29, 151.8 mg, 0.43 mmol) in N,N-dimethylformamide (1.67 mL, 0.26M) at 25° C. was treated with N,N-diisopropylethylamine (0.21 mL, 1.29 mmol), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (0.28 g, 0.64 mmol) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1, 0.08 g, 0.51 mmol). The reaction was stirred at 25° C. overnight. After this time, the reaction was diluted with ethyl acetate (100 mL) and was washed with a saturated aqueous ammonium chloride solution (1×150 mL), a saturated aqueous sodium bicarbonate solution (1×150 mL) and a saturated aqueous sodium chloride solution (1×150 mL), dried over sodium sulfate, filtered, rinsed and concentrated in vacuo. Silica gel column chromatography (AnaLogix 12 g, 75-100% gradient ethyl acetate/hexanes) afforded 3-cyclobutyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (107 mg, 51%) as an off-white solid; ES+-HRMS m/e calcd for C24H27N5O4F2 [M+H+] 488.2104 found 488.2103. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.06 (br s, 3H) 1.07 (br s, 3H) 1.45-1.66 (m, 1H) 1.69-1.89 (m, 4H) 1.88-2.03 (m, 1H) 2.02-2.41 (m, 3H) 3.90 (s, 2H) 4.67 (s, 1H) 5.35 (dd, J=10.1, 4.4 Hz, 1H) 6.02 (d, J=2.9 Hz, 1H) 6.40 (d, J=2.1 Hz, 1H) 7.34-7.44 (m, 2H) 7.44-7.51 (m, 1H) 7.53 (d, J=2.1 Hz, 1H) 8.27 (d, J=2.9 Hz, 1H) 10.83 (s, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(N(CC)CC)C.Cl.[C:28]([C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1)([O:30][CH3:31])=[O:29].O>C(#N)C>[CH3:31][O:30][C:28]([C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH:37][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[N:12]=3)=[CH:4][C:3]=2[N+:17]([O-:19])=[O:18])=[CH:34][CH:33]=1)=[O:29]
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CNc2ccc(-c3nc4ccccc4o3)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 95.3 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (250 mg, 0.968 mmol) in acetonitrile (5 mL) was added triethylamine (245 mg, 2.42 mmol) and 4-carbomethoxybenzylamine hydrochloride (215 mg, 1.07 mmol), and this was heated to reflux for 2 hours. After the reaction was complete, this was cooled to room temperature, water was added, and after the precipitated crystals were filtered and washed with water, they were dried to yield the title compound (372 mg, 95% yield).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].C[O:6]C1C=CC(O)=CC=1.[CH3:14][C:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH2:16].O>C1(C)C=CC=CC=1.COC1C=CC(O)=CC=1>[CH3:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][C:2](=[CH2:3])[C:1]([NH2:4])=[O:6]
Reactant: C=C(C)CC(C)(C)C
Reactant: COc1ccc(O)cc1
Reactant: C=CC#N
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(CC(C)CC(C)(C)C)C(N)=O
Temperature: 120 °C

Procedure:
A cesium phosphotungstate catalyst is prepared according to the procedure of Example 1. A Parr pressure reactor is charged with 2.05 g of Cs2.5 H0.5 PW12O40, 32.24 g of acrylonitrile plus 30 ppm MEHQ, 13.54 g of 2,4,4 trimethyl-1-pentene, 3.27 g of distilled H2O, and 0.025 g of MEHQ. The reactor is sealed with air in the head space. The contents are heated to 120° C. for 12 hours, developing a pressure of 50 psig. Upon cooling the contents are diluted with toluene and centrifuged to separate the solids. The liquid organic phase is reduced to constant weight on a rotary evaporator with heating up to 45° C. to isolate 2.07 g of 2,4,4-trimethylpentylacrylamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9]C(=O)C)[CH:5]=[C:6]([F:8])[CH:7]=1.[ClH:13]>C(O)C>[ClH:13].[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[NH2:9]
Reactant: CC(=O)Nc1cc(F)cc(Br)c1
Agent: Cl
Solvent: CCO
Product: Nc1cc(F)cc(Br)c1
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of N-(3-bromo-5-fluorophenyl)acetamide (3.5 g, 15.13 mmole) in absolute ethanol (40 mL) was added HCl (50 mL of a 11% aqueous solution). The reaction mixture was stirred while refluxing in an oil bath set at 110° C. overnight. Conc hydrochloric acid (5 mL) was added and stirred for an additional 5 h prior to concentrating under reduce pressure. The resulting 3-bromo-5-fluoroaniline hydrochloride (2.9 g, 85% yield) was used in the next reaction without further purification. Retention time (min)=2.077, method [4], MS(ESI) 192.0 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@@H:10](OS(C)(=O)=O)[C@@H:9]([NH:17][C:18](=[O:20])[CH3:19])[C@H:8]([O:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH:7]=1)=[O:5])[CH3:2].CS(C)=O.[N-:31]=[N+:32]=[N-:33].[Na+].C([O-])(O)=O.[Na+]>COC(C)(C)C.CCO>[CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@H:10]([N:31]=[N+:32]=[N-:33])[C@@H:9]([NH:17][C:18](=[O:20])[CH3:19])[C@H:8]([O:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH:7]=1)=[O:5])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@H](OS(C)(=O)=O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CS(C)=O
Solvent: COC(C)(C)C
Product: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N=[N+]=[N-])C1
Temperature: 87.5 °C
Reaction time: 21 h
Yield: 20.4 %

Procedure:
To a solution of 340 mg of 22, 1.2 mL of DMSO and 1.2 mL of EtOH in a 5.0 mL round-bottom flask equipped with a magnetic stirrer, a reflux condenser and an inert gas supply was added 113 mg of sodium azide and the reaction mixture was stirred for 21 h at 85-90° C. The brown reaction mixture was cooled to RT, treated with 7.0 mL of a aqueous 1 M NaHCO3 and extracted with 7.0 mL tert-butyl methyl ether. The organic phase was dried with (Na2SO4), filtered and evaporated at 40° C./250-10 mbar to afford 280 mg of the crude product as brown crystals. The crude product was dissolved in 3.0 mL of tert-butyl methyl ether and stirred for 16 h at −20° C. which resulted in the formation of a beige suspension. The suspension was filtered over a pre cooled (−20° C.) glass filter frit and washed with 1.5 mL of pre cooled (−20° C.) tert-butyl methyl ether. The white crystals were dried at 40° C./10 mbar for 2 h to afford 60 mg of 24 as white crystals
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].S([O-])(O)(=O)=O.[Na+]>C(Cl)Cl.CC(O)C.O>[Cl:3][C:4]1[C:11]([C:12]([F:14])([F:15])[F:13])=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7]
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Agent: O=S(=O)([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(C)O
Product: OCc1cccc(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.9 %

Procedure:
Sodium borohydride (2.54 g, 67.1 mmol) was added to a solution of 2-chloro-3-(trifluoromethyl)benzaldehyde (purchased at Interchim, cat. # 21117, 10.0 g, 47.9 mmol) in a mixture of DCM (40 ml) and 2-propanol (20 ml), while the mixture was cooled with a water bath. The reaction mixture was stirred for 16 hours at room temperature. At 0° C., a 10% aqueous solution of sodium hydrogensulphate (20 ml) was added dropwise. The reaction mixture was diluted with DCM (100 ml) and water (100 ml). The phases were separated. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (100 ml) and dried over magnesium sulphate. The solvent was removed in vacuo to give 9.37 g of crude (2-chloro-3-(trifluoromethyl)phenyl)methanol, which was used for the next step without further purification.