Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([OH:32])[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[H-].[Na+].[CH:35]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH2:36]>O1CCCC1>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([O:32][CH2:36][CH2:35][S:37]([CH3:40])(=[O:39])=[O:38])[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: C=CS(C)(=O)=O
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(OCCS(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.17 h
Yield: 17 %

Procedure:
To a solution of tert-butyl 4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-4-hydroxypiperidine-1-carboxylate (prepared as described in Part E of Example 4, 1.9 g, 4.3 mmol) in tetrahydrofuran (17 mL) at rt was added solid NaH (60%, 17 mg, 0.43 mmol). After 10 min, methyl vinyl sulfone (0.92 g, 8.6 mmol) was added dropwise. After 1 h, the reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was concentrated under reduced pressure to afford a yellow oil. Purification by flash chromatography (silica gel, eluted with 5% methanol/dichloromethane) yielded tert-butyl 4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-4-[2-(methylsulfonyl)ethoxy]piperidine-1-carboxylate (0.40 g, 19%).
Reaction SMILES: [F:1][C:2]1[C:3]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH3:16][N+:17]([CH3:19])=[CH2:18].[I-]>CN(C=O)C>[CH3:16][N:17]([CH2:19][C:14]1[N:10]([C:3]2[C:2]([F:1])=[CH:9][CH:8]=[CH:7][C:4]=2[C:5]#[N:6])[CH:11]=[N:12][C:13]=1[CH3:15])[CH3:18]
Reactant: Cc1cn(-c2c(F)cccc2C#N)cn1
Reactant: C=[N+](C)C
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1ncn(-c2c(F)cccc2C#N)c1CN(C)C
Yield: 13 %

Procedure:
In analogy to example 5b, 3-fluoro-2-(4-methyl-imidazol-1-yl)-benzonitrile was reacted with Eschenmoser's salt in DMF for 16 h at 90° C. Evaporation of the solvent, aqueous workup and chromatography (SiO2, dichloromethane:methanol=100:0 to 98:2) afforded the title compound as a light yellow oil (yield: 13%). 1H-NMR (400 MHz, DMSO): δ=1.91 (s, 6H), 2.17 (s, 3H), 3.17 (s, 2H), 7.72-7.92 (m, 4H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1>[Pd].C(OCC)(=O)C.C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)/C=C/c1cc(F)cc(F)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)CCc1cc(F)cc(F)c1
Reaction time: 6 h
Yield: 98.9 %

Procedure:
To palladium on activated charcoal (10 wt %, 2.5 g) was added a solution of (E)-3-(3,5-difluorophenyl)acrylic acid (25 g) in a mixture of ethyl acetate (100 mL) and ethyl alcohol (400 mL). The mixture was put on hydrogenator on 50 psi for 6 h. The catalyst was filtered and the solvent was removed to give 25.0 g the title compound (99% yield): 1H NMR (CDCl3, 500 MHz) δ 2.67 (2H, t, J=10 Hz), 2.93 (2H, t, J=10 Hz), 6.65 (1H, m), 6.72 (2H, m).
Reaction SMILES: Cl[CH2:2][C:3](=[O:19])[C:4](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([F:17])[C:11]=1[F:18])[C:5]([O:7][CH3:8])=[O:6].[S-2:20].[Na+].[Na+]>CO>[F:18][C:11]1[C:12]([F:17])=[C:13]([CH3:16])[CH:14]=[CH:15][C:10]=1[CH:9]1[CH:4]([C:5]([O:7][CH3:8])=[O:6])[C:3](=[O:19])[CH2:2][S:20]1
Reactant: [S-2]
Reactant: COC(=O)C(=Cc1ccc(C)c(F)c1F)C(=O)CCl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1C(=O)CSC1c1ccc(C)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
Compound 371 (18.7 g, 65 mmol) suspended in anhydrous methanol (50 ml) was added slowly to a solution of dry sodium sulfide (10.0 g, 129 mmol) in methanol (50 ml) while keeping the internal temperature below 40° C. The solution was stirred for 1 h at room temperature then quenched by pouring into a rapidly stirred mixture of ice (350 ml) and 2M HCl (200 ml). The mixture was extracted with dichloromethane (3×250 ml) and the combined extracts dried with brine (100 ml) then sodium sulfate and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-30% ethyl acetate in hexane) provided 372 (12.2 g, 66%) as a crystalline solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([C:13]1[S:26][C:16]2[C:17]3[CH:25]=[N:24][CH:23]=[CH:22][C:18]=3[O:19][CH2:20][CH2:21][C:15]=2[CH:14]=1)=[O:12].[CH3:27]I.O>O1CCCC1>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]([CH3:27])[C:11]([C:13]1[S:26][C:16]2[C:17]3[CH:25]=[N:24][CH:23]=[CH:22][C:18]=3[O:19][CH2:20][CH2:21][C:15]=2[CH:14]=1)=[O:12]
Reactant: CI
Reactant: O=C(Nc1ccccc1Cl)c1cc2c(s1)-c1cnccc1OCC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)c1cc2c(s1)-c1cnccc1OCC2)c1ccccc1Cl
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
Sodium hydride, 60% dispersion in mineral oil (80 mg, 2.0 mmol) was added to a solution of N-(2-chlorophenyl)-4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepin-2-carboxamide (71.4 mg, 0.2 mmol) in 10 ml of tetrahydrofuran. The mixture was stirred for 30 min and mixed with methyl iodide (0.12 mL, 2.0 mmol). The reaction mixture was stirred for 1 hour. The mixture was mixed with 50 ml of iced water and extracted with ethyl acetate twice. The combined ethyl acetate solution was washed with brine, dried over MgSO4, concentrated in vacuo, and purified on silica gel column eluting with 25% of ethylacetate in methylene chloride to give 162 (yield 50 mg, 67%). 1H NMR (400 MHz, DMSO) δ 8.57 (s, 1H), 8.25 (d, J=5.5, 1H), 7.68 (t, J=5.9, 2H), 7.60-7.50 (m, 2H), 6.98 (d, J=5.5, 1H), 6.64 (s, 1H), 4.27 (m, 2H), 3.28 (s, 3H), 2.99 (m, 2H). MS (ESI+) 371.1
Reaction SMILES: [F:1][C:2]1[C:11]([C@H:12]2[CH2:14][O:13]2)=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([O:15][CH3:16])=[N:9]2)=[N:4][CH:3]=1.[C:17]1([CH2:23][O:24][C:25](=[O:33])[NH:26][CH2:27][C@@H:28]2[CH2:32][CH2:31][NH:30][CH2:29]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[C:17]1([CH2:23][O:24][C:25](=[O:33])[NH:26][CH2:27][C@@H:28]2[CH2:32][CH2:31][N:30]([CH2:14][C@@H:12]([C:11]3[C:10]4[C:5](=[CH:6][CH:7]=[C:8]([O:15][CH3:16])[N:9]=4)[N:4]=[CH:3][C:2]=3[F:1])[OH:13])[CH2:29]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(NC[C@@H]1CCNC1)OCc1ccccc1
Reactant: COc1ccc2ncc(F)c([C@H]3CO3)c2n1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: COc1ccc2ncc(F)c([C@@H](O)CN3CC[C@@H](CNC(=O)OCc4ccccc4)C3)c2n1
Temperature: 43 °C
Yield: 55 %

Procedure:
To a solution of 7-fluoro-2-(methyloxy)-8-[(2S)-2-oxiranyl]-1,5-naphthyridine (220 mg, 1.0 mmol) in acetonitrile (5 mL) were added phenylmethyl[(3R)-3-pyrrolidinylmethyl]carbamate (235 mg, 1.0 mmol) followed by Lithium perchlorate (106 mg, 1.0 mmol). After heated at 43° C. for 48 h, the resulting mixture was cooled down to room temperature, concentrated and purified with column chromatography (silica, 1-5% methanol in DCM (1% NH4OH)) to provide the title compound as an off-white solid (250 mg, 55%): LC/MS (ES) m/e 455 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=2[Cl:15])[N:5]=[C:4]([NH2:16])[N:3]=1.[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>>[Cl:15][C:9]1[C:10]([Cl:14])=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[N:5]=[C:4]([NH2:16])[N:3]=[C:2]([NH:22][C:21]2[CH:23]=[CH:24][C:18]([Cl:17])=[CH:19][CH:20]=2)[CH:7]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Nc1nc(Cl)cc(-c2cccc(Cl)c2Cl)n1
Product: Nc1nc(Nc2ccc(Cl)cc2)cc(-c2cccc(Cl)c2Cl)n1
Yield: 42 %

Procedure:
Following the method described in Example 53, 4-chloro-6-(2,3-dichloro-phenyl)-pyrimidin-2-ylamine and 4-chloroaniline provided the title compound (42% yield). 1H NMR (CD3OD) δ 6.19 (s, 1H, Ar), 7.29 (d, 2H, Ar), 7.31 (d, 2H, Ar) 7.4 (d, 1H, Ar) 7.55 (d, 2H, Ar).
Reaction SMILES: [F:1][C:2]([F:17])([O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12]C)=[O:11])[CH:3]([F:5])[Cl:4].[OH-].[K+].O.Cl>O1CCCC1>[F:1][C:2]([F:17])([O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([OH:12])=[O:11])[CH:3]([F:5])[Cl:4]
Reactant: COC(=O)c1cccc(OC(F)(F)C(F)Cl)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(OC(F)(F)C(F)Cl)c1
Temperature: 95 °C
Reaction time: 0.25 h

Procedure:
40 Parts by weight of methyl 3-(1',1',2'-trifluoro-2'-chloroethoxy)-benzoate, in a mixture of 8.4 parts by weight of potassium hydroxide, 100 parts by weight of water and 5 parts by weight of tetrahydrofuran, are stirred for 15 minutes at 95° C. The resulting solution is acidified with concentrated hydrochloric acid and the precipitate formed is filtered off and dried; 35 parts of 3-(1',1',2'-trifluoro-2'-chloroethoxy)benzoic acid of melting point 79°-85° C. are obtained.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:20])[NH:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)=[N:9][N:10]=1)[CH2:3][CH3:4].[C:21]([C@@H:25]1[CH2:30][CH2:29][C@H:28]([C:31](Cl)=[O:32])[CH2:27][CH2:26]1)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([C@@H:25]1[CH2:26][CH2:27][C@H:28]([C:31]([NH:1][CH:2]([C:5]2[C:6](=[O:20])[NH:7][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)=[N:9][N:10]=2)[CH2:3][CH3:4])=[O:32])[CH2:29][CH2:30]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CCC(N)c1nnc(-c2cccc([N+](=O)[O-])c2)[nH]c1=O
Reactant: CC(C)(C)[C@H]1CC[C@@H](C(=O)Cl)CC1
Product: CCC(NC(=O)[C@H]1CC[C@@H](C(C)(C)C)CC1)c1nnc(-c2cccc([N+](=O)[O-])c2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 16A, 3.2 g (11.6 mmol) 6-(1-aminopropyl)-3-(3-nitrophenyl)-1,2,4-triazin-5(4H)-one (Example 15A), 2.4 g (11.6 mmol) cis-4-tert.-butylcyclohexanecarbonyl chloride (Example 42A) and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:11]([O:18][CH3:19])=[N:12][CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:3][CH:4]([CH3:9])[C:5]([O:7]C)=O.[CH3:20][C:21]1[S:25][C:24]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)=[N:23][CH:22]=1>>[CH3:19][O:18][C:11]1[C:10]([CH:2]2[N:1]([CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:26]([C:24]4[S:25][C:21]([CH3:20])=[CH:22][N:23]=4)[CH:27]=3)[C:5](=[O:7])[CH:4]([CH3:9])[CH2:3]2)=[C:15]([O:16][CH3:17])[CH:14]=[CH:13][N:12]=1
Reactant: Cc1cnc(-c2cccc(C=O)c2)s1
Reactant: COC(=O)C(C)CC(N)c1c(OC)ccnc1OC
Product: COc1ccnc(OC)c1C1CC(C)C(=O)N1Cc1cccc(-c2ncc(C)s2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,4-dimethoxypyridin-3-yl)-2-methylbutanoate with 3-(5-methylthiazol-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.75 min.; [M+H]+: 423.87 g/mol.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.[CH3:18][C:19](=O)[CH2:20][C:21](=[O:23])[CH3:22]>C(O)(=O)C.S(=O)(=O)(O)O>[CH3:18][C:19]1[N:1]=[C:2]2[S:6][C:5]3[CH2:7][CH2:8][CH2:9][C:4]=3[C:3]2=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:20]=1[C:21](=[O:23])[CH3:22]
Reactant: CC(=O)CC(C)=O
Reactant: Nc1sc2c(c1C(=O)c1ccccc1)CCC2
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)c1c(C)nc2sc3c(c2c1-c1ccccc1)CCC3
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 46.7 %

Procedure:
To a stirred solution of 56 mg (0.23 mmol) (2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-phenyl-methanone in 2 ml acetic acid was added 0.016 ml (0.24 mmol) of pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 6:1) afforded 33 mg (47%) 1-(2-methyl-4-phenyl-6,7-dihydro-5H-cyclopenta[4,5]thieno [2,3-b]pyridin-3-yl)-ethanone as a yellow solid. ES-MS m/e (%): 308 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=3[CH3:22])=[C:6]2[N:5]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:3]=1.[CH3:29][O-:30].[Na+]>CO>[CH3:29][O:30][C:2]1[N:7]2[N:8]=[CH:9][C:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=3[CH3:22])=[C:6]2[N:5]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:3]=1
Reactant: Cc1c(Cc2cnn3c(Cl)cc(N4CCOCC4)nc23)cccc1C(F)(F)F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(N2CCOCC2)nc2c(Cc3cccc(C(F)(F)F)c3C)cnn12
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(7-chloro-3-(2-methyl-3-(trifluoromethyl)benzyl)pyrazolo[1,5-a]pyrimidin-5-yl)morpholine (181 mg, 0.44 mmol) in methanol (5 mL) stirred under nitrogen at 0° C. was added a 33% solution of sodium methoxide in dropwise. The reaction mixture was stirred at 40° C. for 1 hour. Solvent was removed in vacuo. The residue was dissolved with ethyl acetate (30 mL) and water (10 mL). Two layers were separated. Organic layer was dried and concentrated. The crude product was purified by reverse-phase HPLC to provide the titled compound. (15 mg, 8.4%); LC/MS: MS (ES+) m/e 407 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.39-2.47 (m, 3H) 3.60 (br. s., 2H) 3.61 (d, J=4.55 Hz, 2H) 3.65-3.73 (m, 4H).
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[NH:17][C:18](=[O:25])[C:19](=[CH:23][CH:24]=3)[C:20](O)=O)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)[Cl:27].C[Si](Cl)(C)C.S(Cl)(Cl)=O>C(N(CC)CC)C>[N:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[NH:17][C:18](=[O:25])[C:19](=[CH:23][CH:24]=3)[CH2:20][Cl:27])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClCCl
Reactant: O=C(O)c1ccc(-c2ccc(S(=O)(=O)N3CCCCC3)cc2)[nH]c1=O
Agent: C[Si](C)(C)Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: O=c1[nH]c(-c2ccc(S(=O)(=O)N3CCCCC3)cc2)ccc1CCl

Procedure:
From 5.0 g. of 6-[4-(1-piperidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic acid in 150 ml. of methylene chloride, 2.0 ml. of triethylamine, 1.75 ml. of trimethylsilyl chloride and 2.0 ml. of thionyl chloride, following the procedure of a) above, there is obtained 6-[4-(1-piperidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloride.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH:12]1([C:15]2[O:19][N:18]=[CH:17][C:16]=2[C:20](=[O:33])[C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=2[S:31][CH3:32])[CH2:14][CH2:13]1>ClCCl>[CH:12]1([C:15]2[O:19][N:18]=[CH:17][C:16]=2[C:20](=[O:33])[C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:23][C:22]=2[S:31]([CH3:32])=[O:6])[CH2:14][CH2:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cc(C(F)(F)F)ccc1C(=O)c1cnoc1C1CC1
Solvent: ClCCl
Product: CS(=O)c1cc(C(F)(F)F)ccc1C(=O)c1cnoc1C1CC1
Temperature: -20 °C

Procedure:
3-Chloroperoxybenzoic acid (0.95 g) was added to a cooled solution of 5-cyclopropyl-4-(2-methylsulphenyl-4-trifluoromethylbenzoyl)isoxazole (1.2 g) in dichloromethane with stirring at -20° C. The mixture was stirred at -20° C. for 2 hours and allowed to warm slowly to 0° C. It was stirred for 1 hour and recooled to -20° C. 3-Chloroperoxybenzoic acid (0.4 g) was added at -20° C. and the mixture was allowed to warm slowly to 0° C. and stirred for 1 hour. The mixture was then filtered and the filtrate was washed with water, aqueous sodium metabisulphite solution, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness and the residue was triturated with ethyl acetate and filtered to give 5-cyclopropyl-4-(2-methylsulphinyl-4-trifluoromethylbenzoyl)isoxazole, compound 264 (0.59 g) as a white solid, m.p. 149°-151° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][C:15]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)([SH:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:8]=1[CH3:30])([CH3:4])([CH3:3])[CH3:2].[NH2:32]OS(O)(=O)=O.[OH-].[K+]>O1CCCC1>[C:1]([O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:14][C:15]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)([C:16]([F:19])([F:18])[F:17])[S:20][N:32]=2)=[CH:9][C:8]=1[CH3:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(=O)CC(S)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Reactant: NOS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C2=NSC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-[3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-3-mercapto-butyryl]-2-methyl-benzoic acid tert-butyl ester (1.875 g) in tetrahydrofuran (6 mL) was added a solution of Hydroxylamine-O-sulfonic acid (2 equiv.) in a solution of potassium hydroxide (1.2 g in 75 mL of water). After stirring at room temperature for 30 minutes, the mixture was quenched with a solution of hydrochloric acid (1N), extracted with ethyl acetate and washed with brine. The collected organic phases were dried over magnesium sulfate, filtered and the filtrate was evaporated under vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane/dichloromethane) to give 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isothiazol-3-yl]-2-methyl-benzoic acid tert-butyl ester (881 mg)
Reaction SMILES: C(O)(C(F)(F)F)=O.[Br:8][C:9]1[C:10]([O:22][C:23]2[C:30]([CH3:31])=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[CH3:32])=[N:11][C:12]([NH:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[N:13][CH:14]=1.Br[CH:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH3:35]>CC#N>[Br:8][C:9]1[C:10]([O:22][C:23]2[C:30]([CH3:31])=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[CH3:32])=[N:11][C:12]([NH:15][CH:16]2[CH2:17][CH2:18][N:19]([CH:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH3:35])[CH2:20][CH2:21]2)=[N:13][CH:14]=1
Reactant: CC(Br)c1ccccc1
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(NC2CCNCC2)ncc1Br
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Cc1cc(C#N)cc(C)c1Oc1nc(NC2CCN(C(C)c3ccccc3)CC2)ncc1Br
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of the TFA salt of 56 (1 mmol) in MeCN was added TEA (1.5 mmol) and (1-bromo-ethyl)-benzene (1 mmol) and the resulting mixture was stirred at RT for 6 h. After the reaction was complete, the solvent was removed and the residue was purified by preparative HPLC on a 30×100 mm C18 ODB column eluting with MeCN/H2O to afford 0.120 g (24.6%) of I-61.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:15]=1[NH:16][C:17]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:18]=1[C:19]([OH:21])=O.Cl.[CH2:35]([O:42][NH2:43])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(CC)CC)C>>[F:13][C:14]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:15]=1[NH:16][C:17]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:18]=1[C:19]([NH:43][O:42][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:21]
Reactant: O=C(O)c1cc(F)c(F)cc1Nc1cc(F)c(F)cc1F
Reactant: NOCc1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Product: O=C(NOCc1ccccc1)c1cc(F)c(F)cc1Nc1cc(F)c(F)cc1F
Yield: 103.6 %

Procedure:
Using General Method 2, the reaction of carbonyldiimidazole (2.85 g, 17.6 mmol), 2-(2,4,5-trifluoro-anilino)-4,5-difluorobenzoic acid (Example T, 4.54 g, 14.7 mmol), O-benzylhydroxylamine hydrochloride (2.34 g, 14.7 mmol), and triethylamine (2.45 mL, 17.6 mmol) provided 6.22 g of the crude title compound.
Reaction SMILES: [C:1]([C:5]1[C:6]([NH:17][C:18]([C:20]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[O:19])=[CH:7][C:8]2[O:12][C:11](=[O:13])[C:10]([CH3:15])([CH3:14])[C:9]=2[CH:16]=1)([CH3:4])([CH3:3])[CH3:2].[OH-:31].[Na+]>CO>[C:1]([C:5]1[C:6]([NH:17][C:18]([C:20]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[O:19])=[CH:7][C:8]([OH:31])=[C:9]([C:10]([CH3:15])([CH3:14])[C:11]([OH:12])=[O:13])[CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc2c(cc1NC(=O)c1c[nH]c3ccccc3c1=O)OC(=O)C2(C)C
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1cc(C(C)(C)C(=O)O)c(O)cc1NC(=O)c1c[nH]c2ccccc2c1=O
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a stirred solution of compound 21 (0.9 g, 2.45 mmol) in MeOH (50 mL) was added NaOH (1.5 g, 37.5 mmol) at 0° C. After stirring for 16 hours at 40° C., the solvent was evaporated in vacuo, then the residue was dissolved in H2O (50 ml). The precipitate was filtered and the filtrate was washed with DCM (100 mL×1) and ethyl acetate (100 mL×1). The aqueous layer was acidified with 2N HCl to pH 1-2. The precipitate was filtered and washed with H2O (80 mL) and heptane (50 mL). It was dried in vacuo to give compound 28 as a white solid. 1H NMR (DMSO-d6; 400 MHz) δ 12.85 (s), δ 11.84 (s), δ 11.77 (s), δ 9.39 (s), δ 8.86 (s), δ 8.33 (s), δ 7.79 (m), δ 7.52 (m), δ 7.18 (s), δ 7.09 (s), δ 1.44 (s), δ 1.40 (s). MS found (M+H) 423.08
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3[C:20](=[O:32])[N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:22]([CH3:25])[C:23]=3[CH3:24])=[O:18])=[C:11]([F:33])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[O:41](C(C)=O)[C:42]([CH3:44])=O>>[C:42]([NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3[C:20](=[O:32])[N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:22]([CH3:25])[C:23]=3[CH3:24])=[O:18])=[C:11]([F:33])[CH:10]=2)[CH:5]=[CH:4][N:3]=1)(=[O:41])[CH3:44]
Reactant: Cc1c(C(=O)Nc2cc(F)c(Oc3ccnc(N)c3)cc2F)c(=O)n(-c2ccccc2)n1C
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(Oc2cc(F)c(NC(=O)c3c(C)n(C)n(-c4ccccc4)c3=O)cc2F)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a solution of N-(4-((2-aminopyridin-4-yl)oxy)-2,5-difluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (220 mg, 0.48 mmol) in (Ac)2O (8 mL) was added Et3N (0.5 mL, 1.32 mmol). The reaction mixture was stirred at rt for 8 hours and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/CH3OH (v/v)=10/1) to give the title compound as a white solid (175 mg, 73%).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[C:10]([C:13]1[CH:14]=[CH:15][C:16]([F:22])=[C:17](B(O)O)[CH:18]=1)(=[O:12])[NH2:11].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO>[F:22][C:16]1[CH:17]=[CH:18][C:13]([C:10]([NH2:11])=[O:12])=[CH:14][C:15]=1[C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[CH:6][N:7]=1
Reactant: NC(=O)c1ccc(F)c(B(O)O)c1
Reactant: O=Cc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: NC(=O)c1ccc(F)c(-c2ccc(C=O)cn2)c1
Temperature: 80 °C

Procedure:
To a solution of 6-bromo-3-pyridinecarboxaldehyde (336 mg, 1.80 mmol) in DME (8 mL) and EtOH (4 mL) under argon, was added (5-carbamoyl-2-fluorophenyl)boronic acid (300 mg, 1.64 mmol) followed by palladium tetrakistriphenylphosphine (190 mg, 0.16 mmol) and 2M Na2CO3 (4 mL). The mixture was heated to 80° C. for 16 h and then allowed to cool to rt. The mixture was partitioned between EtOAc (50 mL), THF (50 mL) and Na2CO3 (20 mL). The aqueous was extracted with EtOAc (50 mL) and the combined organics washed with brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue purified by column chromatography (0.4% NH3: 4% MeOH: DCM) to give the title compound: RT=2.50 min; m/z (ES+)=245.0 [M+H]+.