Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1.O(C([N:37]1[CH:41]=[C:40](B(O)O)[CH:39]=[N:38]1)=O)C(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:40]4[CH:41]=[N:37][NH:38][CH:39]=4)=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=4)[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Reactant: CC(C)(C)OC(=O)n1cc(B(O)O)cn1
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+]
Product: Cc1cccc(-c2c(-c3cn[nH]c3)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 120 °C

Procedure:
A suspension of N-[2-bromo-6-methyl-3-(3-methylphenyl)thieno[2,3-b]pyridin-4-yl]-3-chlorobenzenesulfonamide (Description 60) (214 mg, 0.421 mmol), 1-tert-butoxylcarbonyl-1H-pyrazole-4-boronic acid, pinacol ester (124 mg, 0.421 mmol), tetrakis(triphenylphosphine)palladium(0) (48.7 mg, 0.042 mmol) and aqueous sodium carbonate (2M) (0.421 mL, 0.843 mmol) was degassed under a nitrogen atmosphere for ca. 10 min before being subjected to microwave heating at 120° C. for 30 min. The reaction mixture was then partitioned between ethyl acetate and water (ca. 30 mL each). The aqueous layer was separated and re-extracted with ethyl acetate (ca. 25 mL) and the combined organic layer passed through a phase separator and the solvent removed in vacuo. Purification by chromatography on silica, eluting with a gradient of 0-80% ethyl acetate in cyclohexane, afforded the title compound (75 mg). LCMS (A) m/z: 495 [M+1]+, Rt 1.31 min (acidic).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[F-:16].[K+].[F-].[F-].[Ca+2]>>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([F:16])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: [F-]
Agent: [Ca+2]
Agent: [K+]
Product: CC#CCOc1ccc(S(=O)(=O)F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.3 %

Procedure:
To a solution of 4-but-2-ynyloxybenzenesulfonyl chloride (prepared from Example 30, step 4) (2.0 g, 8.18 mmol) in acetonitrle (10 ml) was added KF-CaF2 (2.85 g, 16.3 mmol) and the resulting mixture was stirred for 4 hours at room temperature. The reaction mixture was filtered and the filterate was concentrated. The crude product was dissolved in EtOAc and washed with water. The organic layer was dried over anhydrous Na2SO4 and the solvent was removed to obtain 1.5 g (80%) of the product as solid.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(N(CC)CC)C.[Br:22][CH2:23][C:24](Br)=[O:25]>C(Cl)Cl>[C:7]([O:6][C:4]([C:3]1[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=1[NH:1][C:24](=[O:25])[CH2:23][Br:22])=[O:5])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)c1ccccc1N
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccccc1NC(=O)CBr
Yield: 102.5 %

Procedure:
To a mixture of tert-butyl 2-aminobenzoate (5.79 g.), triethylamine (3.99 g.) in methylene chloride (100 ml.) was added dropwise bromoacetyl bromide (8.01 g.) over a period of 15 minutes with stirring under ice-cooling at 5° to 10° C. followed by stirring for 1.75 hours at the same temperature. The reaction mixture was washed successively with 1M aqueous solution of citric acid (50 ml.×2), water a satirated aqueous solution of sodium bicarbonate (25 ml.×2), water and an aqueous solution of sodium chloride, dried over magnesium, treated with activated charcoal and then evaporated to give an oil of the title compound (9.65 g.).
Reaction SMILES: CCN=C=NCCCN(C)C.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([C:25]3[S:26][CH:27]=[CH:28][N:29]=3)[CH:22]=[C:21]([C:30]([OH:32])=O)[CH:20]=2)=[CH:15][CH:14]=1.C1C=CC2N(O)N=NC=2C=1.CN1C(=O)CCC1.[CH3:50][C@H:51]([NH2:59])[CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>C(Cl)Cl>[CH3:50][C@@H:51]([NH:59][C:30]([C:21]1[CH:20]=[C:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:12])=[CH:14][CH:15]=2)[CH:24]=[C:23]([C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[CH:22]=1)=[O:32])[CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-c3nccs3)c2)cc1
Reactant: C[C@H](N)CN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)CN3CCOCC3)cc(-c3nccs3)c2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
EDCI (54.0 mg, 0.282 mmol) was added in one portion at 0° C. to a solution of 4′-methyl-5-thiazol-2-yl-biphenyl-3-carboxylic acid (63 mg, 0.214 mmol), HOBt (40.0 mg, 0.296 mmol) and NMP (101.5 mg, 1.0 mmol) in CH2Cl2 (3 mL). After the reaction stirred at 0° C. for 1 hour, (S)-1-Methyl-2-morpholin-4-yl-ethylamine (50.0 mg, 0.230 mmol) was added. The reaction mixture was allowed to warm to room temperature and was stirred overnight. Solvent was removed under reduced pressure and the residue was purified by column chromatography (EtOAc) to afford (R)-4′-methyl-5-thiazol-2-yl-biphenyl-3-carboxylic acid (1-methyl-2-morpholin-4-yl-ethyl)-amide as a white solid (72 mg, 81%). MS (M+H)=422.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:13])[CH:4]=1)#[N:2].[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[C:1]([C:3]1[C:12]([N+:14]([O-:16])=[O:15])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:13])[CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccc(C#N)cc1C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(C#N)cc1C
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 65 %

Procedure:
A solution of methyl 4-cyano-2-methylbenzoate (18.1 g, 0.103 mol) in concentrated sulfuric acid (130 mL) was cooled to −10° C. While maintaining this internal temperature, fuming nitric acid (15.6 mL) was slowly added over a period of 30 min. The reaction mixture was stirred an additional 2.5 h at 0° C., at which time it was poured over 1.0 L of ice and then partitioned with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, and then concentrated in vacuo. The residue was triturated with 10% ethyl acetate/hexanes to afford methyl 4-cyano-2-methyl-5-nitrobenzoate (14.8 g, 65%) as a white powder. The title product was isolated as the major isomer in a 9:1 regioisomeric mixture. 1H NMR (400 MHz, CDCl3), Major: 8.85 (s, 1H), 7.81 (s, 1H), 4.00 (s, 3H), 2.77 (s, 3H); Minor: 8.07 (d, 1H), 7.72 (d, 1H), 3.98 (s, 3H), 2.57 (s, 3H). MS (EI) for C10H8N2O4: 238 (M+H2O).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:23])[C:10]([C:16]1[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].CC([O-])(C)C.[K+].[CH3:30][O:31][C:32](=[O:35])[CH2:33]Br.O>C1COCC1>[CH3:30][O:31][C:32](=[O:35])[CH2:33][N:19]1[CH:20]=[CH:21][C:16]([C:10]([OH:15])([C:11]([F:14])([F:13])[F:12])[CH:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH3:23])=[CH:17][C:18]1=[O:22]
Reactant: CC(c1ccc(Cl)cc1Cl)C(O)(c1cc[nH]c(=O)c1)C(F)(F)F
Reactant: COC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)Cn1ccc(C(O)(C(C)c2ccc(Cl)cc2Cl)C(F)(F)F)cc1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-[2-(2,4-Dichloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1H-pyridin-2-one (Example 119, 100 mg) was dissolved in THF (10 mL), and treated with t-BuOK (34 mg). After 5 minutes stirring, bromo-acetic acid methyl ester (0.03 mL) was added and the reaction mixture was stirred at 55° C. for 17 h. The reaction mixture was then cooled down to r.t., poured into water (50 mL) and extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (10 g silica gel, ethyl acetate/heptane 30:70) to give the title compound as colorless waxy solid (49 mg). MS (m/e)=438.1 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][C:3]=1[N:11]1[N:15]=[C:14]2[CH:16]=[CH:17][C:18](Cl)=[CH:19][C:13]2=[N:12]1.OC1C=CC(CCCO)=CC=1N1N=C2C=CC(Cl)=CC2=N1.OC1C=CC(CCCO)=CC=1N1N=C2C=CC=CC2=N1>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][C:3]=1[N:11]1[N:15]=[C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]2=[N:12]1
Reactant: OCCc1ccc(O)c(-n2nc3ccc(Cl)cc3n2)c1
Agent: OCCCc1ccc(O)c(-n2nc3ccc(Cl)cc3n2)c1
Agent: OCCCc1ccc(O)c(-n2nc3ccccc3n2)c1
Product: OCCc1ccc(O)c(-n2nc3ccccc3n2)c1

Procedure:
In a like manner there are prepared 2-(2'-Hydroxy-5'-hydroxyethylphenyl)-5-chloro-2H-benzotriazole, 2-(2'-Hydroxy-5'-hydroxypropylphenyl)-5-chloro-2H-benzotriazole and 2-(2'-Hydroxy-5'-hydroxypropylphenyl)-2H-benzotriazole from which the corresponding methacrylyloxyalkylphenyl-2H-benzotriazoles are readily prepared in good yield and purity following the general procedures set forth above.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([CH2:34][CH:35]([CH3:37])[CH3:36])(=[O:33])=[O:32]>>[F:1][C:2]1[CH:7]=[C:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([CH2:34][CH:35]([CH3:37])[CH3:36])(=[O:32])=[O:33])[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: CC(C)CS(=O)(=O)c1ccccc1Br
Product: CC(C)CS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 1-bromo-2-(isobutylsulfonyl)benzene. MS (ESI): mass calcd. for C20H20FN3O2S, 385.13; m/z found, 386.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 8.12 (dd, J=7.9, 1.1, 1H), 8.05 (d, J=1.4, 1H), 7.96 (m, 1H), 7.81 (m, 1H), 7.73 (m, 1H), 7.49 (dd, J=7.5, 1.0, 1H), 7.37 (dd, J=12.4, 1.5, 1H), 7.32 (dd, J=8.0, 1.6, 1H), 6.76 (s, 2H), 2.81 (d, J=6.4, 2H), 1.85-1.75 (m, 1H), 0.82 (d, J=6.7, 6H).
Reaction SMILES: [CH:1]([C:4]1[CH:14]=[C:13]([OH:15])[CH:12]=[C:11]2[C:5]=1[C:6](=[O:24])[N:7]([CH2:16][S:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[S:8]2(=[O:10])=[O:9])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:44]([Si:47]([CH:55]([CH3:57])[CH3:56])([CH:52]([CH3:54])[CH3:53])[O:48][CH2:49][CH2:50]O)([CH3:46])[CH3:45].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH:1]([C:4]1[CH:14]=[C:13]([O:15][CH2:50][CH2:49][O:48][Si:47]([CH:52]([CH3:53])[CH3:54])([CH:44]([CH3:46])[CH3:45])[CH:55]([CH3:56])[CH3:57])[CH:12]=[C:11]2[C:5]=1[C:6](=[O:24])[N:7]([CH2:16][S:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[S:8]2(=[O:10])=[O:9])([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(O)cc2c1C(=O)N(CSc1ccccc1)S2(=O)=O
Reactant: CC(C)[Si](OCCO)(C(C)C)C(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1cc(OCCO[Si](C(C)C)(C(C)C)C(C)C)cc2c1C(=O)N(CSc1ccccc1)S2(=O)=O
Reaction time: 16 h
Yield: 86 %

Procedure:
To a solution of 4-isopropyl-6-hydroxy-2-phenylthiomethylsaccharin. (2.0 g, 5.509 mmol) in THF (35 mL) containing triphenylphosphine (1.59 g, 6.06 mmol) and 2-(triisopropylsilyloxy) ethanol (1.13 g, 6.0 mmol) at room temperature was added diethylazodicarboxylate (1.04 mL, 6.6 mmol). The mixture was stirred overnight (16 hours), the solvent was removed in vacuo and the residue was purified by column chromatography on silica eluting with 10% ethyl acetate/hexane to afford 2.66 g (86%) of 4-isopropyl-6-[2-(triisopropylsilyloxy)ethoxy]-2-phenylthiomethylsaccharin as an oil.
Reaction SMILES: Br[C:2]1[N:6]2[C@@H:7]([CH3:14])[CH2:8][N:9]([CH2:12][CH3:13])[C:10](=[O:11])[C:5]2=[C:4]([O:15][CH3:16])[C:3]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:41][N:42](C=O)C>[Zn].[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:41]([C:2]1[N:6]2[C@@H:7]([CH3:14])[CH2:8][N:9]([CH2:12][CH3:13])[C:10](=[O:11])[C:5]2=[C:4]([O:15][CH3:16])[C:3]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:42]
Reactant: CCOC(=O)c1c(OC)c2n(c1Br)[C@@H](C)CN(CC)C2=O
Reactant: CN(C)C=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [C-]#N
Product: CCOC(=O)c1c(OC)c2n(c1C#N)[C@@H](C)CN(CC)C2=O
Temperature: 140 °C
Reaction time: 0.5 h

Procedure:
To a mixture of ethyl (4S)-6-bromo-2-ethyl-8-methoxy-4-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-carboxylate (4.1 g, 11.41 mmol; Example 62, step 7), zinc dust (0.15 g, 2.28 mmol), zinc cyanide (1.11 g, 9.47 mmol), triphenylphosphine (0.46 g, 1.77 mmol), and tris(dibenzylideneacetone)dipalladium (0) (1.57 g, 1.71 mmol) in anhydrous DMF (10 mL) was purged with argon gas for 15 minutes. The mixture was heated in a sealed tube in an oil bath at 140° C. overnight. The reaction mixture was filtered through a pad of Celite, and the filtrate concentrated under vacuum. The residue was partitioned between chloroform and aqueous EDTA monosodium salt. The mixture was stirred at room temperature for 30 minutes. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with 0 to 40% ethyl acetate in chloroform gradient. Collection and concentration of appropriate fractions provided the title nitrile.
Reaction SMILES: [C:1]([OH:24])(=O)[CH2:2][CH2:3][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][CH2:21][CH3:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:38][NH2:39]>C(O)CC>[C:1]([NH:38][NH2:39])(=[O:24])[CH2:2][CH2:3][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][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCCO
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)NN
Temperature: 25 °C

Procedure:
17.0 Grams of docosanoic acid, 1.0 g of p-toluenesulfonic acid monohydrate and 200 ml of n-propanol were charged in a flask equipped with a stirrer, a condenser and a calcium chloride drying tube and refluxed with heating for 4 hours. To the resulting solution was added 12.5 g of hydrazine monohydrate, followed by continuing the refluxing with heating for 20 hours. The reaction mixture was cooled to room temperature and the precipitated crystal was filtered off under reduced pressure and washed with distilled water. The crystal was recrystallized from 2-propanol to obtain 14.2 g of the desired product. m.p. 117° C.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:6]([OH:60])([CH3:59])CCC(C(OC2C=CC([N+]([O-])=O)=CC=2)=O)[CH2:10][C:11]([O:13][CH:14](/[C:19](/[CH3:46])=[CH:20]/[CH:21]=[CH:22]/[CH:23]([CH3:45])[CH2:24][CH:25]2[O:44][CH:26]2[CH:27]([CH3:43])C(C(OC2C=CC([N+]([O-])=O)=CC=2)=O)CC)[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12])(=[O:3])[CH3:2].[CH2:61]([NH:63][CH2:64][CH3:65])[CH3:62]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:4][CH:5]1[C:6]([OH:60])([CH3:59])[CH2:16][CH2:17][CH:5]([O:4][C:1](=[O:3])[N:63]([CH2:64][CH3:65])[CH2:61][CH3:62])[CH2:10][C:11]([O:13][CH:14](/[C:19](/[CH3:46])=[CH:20]/[CH:21]=[CH:22]/[CH:23]([CH3:45])[CH2:24][CH:25]2[O:44][CH:26]2[CH:27]([CH3:43])[CH:14]([O:13][C:11](=[O:12])[N:63]([CH2:64][CH3:65])[CH2:61][CH3:62])[CH2:15][CH3:18])[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12])(=[O:3])[CH3:2]
Reactant: CCNCC
Reactant: CCC(C(=O)Oc1ccc([N+](=O)[O-])cc1)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(C(=O)Oc2ccc([N+](=O)[O-])cc2)CCC(C)(O)C(OC(C)=O)C=CC1C
Agent: CCC(C(=O)Oc1ccc([N+](=O)[O-])cc1)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(C(=O)Oc2ccc([N+](=O)[O-])cc2)CCC(C)(O)C(OC(C)=O)/C=C/C1C
Agent: CCC(OC(=O)N(CC)CC)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(OC(=O)N(CC)CC)CCC(C)(O)C(OC(C)=O)/C=C/C1C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(OC(=O)N(CC)CC)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(OC(=O)N(CC)CC)CCC(C)(O)C(OC(C)=O)C=CC1C
Reaction time: 21 h

Procedure:
(8E,12E,14E)-7-Acetoxy-6-hydroxy-6,10,12,16,20-pentamethyl-3,21-di(4-nitro-phenylcarboxy)-18,19-epoxytricosa-8,12,14-trien-11-olide (12.6 mg) was dissolved in tetrahydrofuran (0.5 mL), and diethylamine (20 μL) was added thereto, followed by stirring for 21.0 hours. The reaction solution was diluted with ethyl acetate (20 mL), and washed with purified water (4 mL) twice and brine (4 mL). The resulting organic layer was dried over anhydrous sodium sulfate, filtered and then concentrated. The resulting crude product was purified by thin layer chromatography (MERCK Silicagel 60 F254, 0.5 mm, developing solution; ethyl acetate) to obtain the title compound (10.7 mg, 14.5 μmol, 100.0%) as a colorless oil.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]([CH3:26])[CH3:25])[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:4][N:3]=1.[CH:27]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([NH:32][C:2]2[CH:7]=[C:6]([C:8]3[C:16]([C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]([CH3:25])[CH3:26])[N:18]=4)=[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][N:10]4[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NC1CCCC1
Reactant: CC(C)Nc1nccc(-c2c(-c3ccnc(F)c3)nn3ccccc23)n1
Product: CC(C)Nc1nccc(-c2c(-c3ccnc(NC4CCCC4)c3)nn3ccccc23)n1
Yield: 64 %

Procedure:
A solution of crude 4-[2-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]-N-isopropyl-2-pyrimidinamine (204 mg, 0.586 mmol) in cyclopentylamine (2 mL, 20.3 mmol) was heated at 135° C. in a sealed glass tube for 16 hours. The reaction mixture was cooled and the excess cyclopentylamine was removed in vacuo. The resultant residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine and dried over magnesium sulfate. Filtration and concentration, followed by flash chromatography (1:1 hexanes:ethyl acetate to 100% ethyl acetate) provided N-cyclopentyl-N-(4-{3-[2-(isopropylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}-2-pyridinyl)amine (155 mg, 640%). Rf 0.16 (1:2 hexanes:ethyl acetate); 1H NMR (CDCl3) δ 8.49 (d, 1H), 8.39 (d, 1H), 8.13–8.08 (m, 2H), 7.29 (t, 1H), 6.89 (t, 1H), 6.80 (d, 1H), 6.63 (s, 1H), 6.46 (d, 1H), 5.23 (br, 1H), 4.86 (d, 1H), 4.21 (m, 1H), 3.93 (m, 1H), 1.95 (m, 2H), 1.70–1.42 (m, 6H), 1.27 (d, 6H); MS m/z 414 (M+1).
Reaction SMILES: C([O:4][CH2:5][CH:6]([CH3:49])[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:39][C:19]3[N:20]([CH2:30][C:31]4[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=4[F:38])[CH:21]=[C:22]([C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[C:23](=[O:24])[C:18]=3[C:17]=2N(CC2C=CC=CC=2)C)=[CH:12][CH:11]=1)=[O:8])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:30]([N:20]([CH2:21][C:17]1[C:18]2[C:23](=[O:24])[C:22]([C:25](=[O:29])[CH:26]([CH3:27])[CH3:28])=[CH:21][N:20]([CH2:30][C:31]3[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=3[F:38])[C:19]=2[S:39][C:16]=1[C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[CH:6]([CH3:49])[CH2:5][OH:4])=[CH:11][CH:12]=1)[CH3:19])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(=O)OCC(C)C(=O)Nc1ccc(-c2sc3c(c2N(C)Cc2ccccc2)c(=O)c(C(=O)C(C)C)cn3Cc2c(F)cccc2F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)C(=O)c1cn(Cc2c(F)cccc2F)c2sc(-c3ccc(NC(=O)C(C)CO)cc3)c(CN(C)Cc3ccccc3)c2c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 141.5 %

Procedure:
The compound obtained in Example 2 (1.40 g) was dissolved in methanol (100 ml), and then to the solution was added potassium carbonate (2.0 g, 15 mmol), followed by stirring at room temperature for 15 minutes. The reaction mixture was partitioned between ethyl acetate (200 ml) and distilled water (300 ml), and then the water layer was extracted with ethyl acetate (100 ml). The combined extracts were washed with saline, and dried (Na2SO4), the solvent was distilled off under reduced pressure. The obtained residue was chromatographed on silica gel and recrystallized from ether to yield white crystals (0.95 g, 72%).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Cl:6][C:7]([Cl:19])([Cl:18])[CH:8]=[CH:9][C:10]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)=[O:11]>>[Cl:19][C:7]([Cl:6])([Cl:18])[C:8]([OH:2])=[CH:9][C:10]([C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)=[O:11]
Reactant: O=C(C=CC(Cl)(Cl)Cl)c1ccncc1
Reactant: O=S(=O)(O)O
Product: O=C(C=C(O)C(Cl)(Cl)Cl)c1ccncc1

Procedure:
5 g (0.018 moles) of this substance were treated with sulfuric acid as described in Example 1b. Obtained were 4.2 g (95% of the theoretical) of 4,4,4-trichloro-1-(4-pyridyl)-but-2-ene-1-one, in the form of brown crystals. Decomposition point 150° C.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.C1COCC1.[O:18]=[C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH:21]([C:30](O)=[O:31])[CH2:20]1.[BH4-].[Na+]>O>[OH:31][CH2:30][CH:21]1[CH2:22][N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19](=[O:18])[CH2:20]1
Reactant: O=C(O)C1CC(=O)N(c2ccccc2)C1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CC(CO)CN1c1ccccc1
Temperature: 25 °C

Procedure:
1,1′-Carbonylbisimidazole was added to a THF solution of 5-oxo-1-phenylpyrrolidine-3-carboxylic acid and stirred at room temperature for 1.5Hours. Successively sodium borohydride and 2.0 ml of water were added thereto and stirred at room temperature for 1Hour. Thereafter, its work-up and purification were carried out in the standard method to obtain 4-(hydroxymethyl)-1-phenylpyrrolidin-2-one. EP: 192.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O-:23])=O)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:26])=O>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([Cl:26])=[O:23])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1

Procedure:
Methyl-4.-hydroxybiphenyl is reacted with benzyl bromide to obtain 4'-benzyloxybiphenyl-4-carboxylate, which is converted through hydrolysis to 4'-benzyloxybiphenyl-4-carboxylate, which is then reacted with thionyl chloride to obtain 4'-benzyloxybiphenyl-4-carboxylic acid chloride. The chloride is reacted with optically active 1-trifluoro-2-octanol 1-trifluoromethylheptyl-4'-benzyloxybiphenyl-4-carboxylate, which is subjected to catalytical hydrogenolysis to obtain 1-trifluoroheptyl-4'-hydroxybiphenyl-4-carboxylate (III).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][N:6]([CH3:24])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:12](=[O:15])[C:13]=1[OH:14])=[O:8].[CH3:29][N:30]([CH3:35])[S:31](Cl)(=[O:33])=[O:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][N:6]([CH3:24])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][N:21]([S:31](=[O:33])(=[O:32])[N:30]([CH3:35])[CH3:29])[CH2:22][CH2:23]2)[C:12](=[O:15])[C:13]=1[OH:14])=[O:8]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN2CCNCC2)C1
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN2CCN(S(=O)(=O)N(C)C)CC2)C1

Procedure:
Compound 765 was prepared from 4-hydroxy-5-oxo-1-(2-piperazin-1-yl-ethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide and dimethylsulfamoyl chloride using the method described for compound 759. The title compound was purified by preparative HPLC (C18, ODS-A, S-75 μm, 30% acetonitrile/water/0.5% HCl) and isolated as a brown solid (0.0231 g, 19% yield). HRMS (M+H) calcd for C21H30N5Cl2O5S: 534.13448. found: 534.1322.