Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2)[C:4](OCC)=[O:5].O.[NH2:20][NH2:21]>C(O)C>[CH3:1][O:2][CH:3]([C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2)[C:4]([NH:20][NH2:21])=[O:5]
Reactant: CCOC(=O)C(OC)c1cccc2ncccc12
Reactant: NN
Solvent: CCO
Solvent: O
Product: COC(C(=O)NN)c1cccc2ncccc12
Temperature: 85 °C
Yield: 76.7 %

Procedure:
To a solution of ethyl 2-methoxy-2-(quinolin-5-yl)acetate (0.9 g, 3.67 mmol) in absolute ethanol (25 mL) was added hydrazine hydrate (1.0 mL, 20.5 mmol) and the mixture was heated at 85° C. for 18.5 hours. After cooling to room temperature, the mixture was poured into ice-water (˜150 mL) then concentrated in vacuo. The residue was taken up in EtOAc, washed with diluted brine once, water twice then brine. The organics were dried over Na2SO4 and concentrated in vacuo to give 2-methoxy-2-(quinolin-5-yl)acetohydrazide as an off-white foam (0.651 g, 77% yield) that was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH:7]([CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8](O)=O)([CH3:4])([CH3:3])[CH3:2].N1CCCCC1.C=O.Cl>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:21])[C:7]([CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH2:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(CCOCc1ccccc1)C(=O)O
Agent: C=O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: C=C(CCOCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A solution of 2-(2-benzyloxyethyl) malonic acid mono tert-butyl ester (23.9 g, 81.2 mmol), piperidine (1.31 mL, 13.2 mmol), and paraformaldehyde (3.7 g, 123 mmol) in pyridine (160 mL) was heated at a temperature of 70° C. for 3 hours. After cooling to room temperature, the mixture was poured over ice. The mixture was acidified using 6N HCl solution and then extracted twice with ether; the extracts were combined, washed with brine, dried over MgSO4 and concentrated under vacuum to leave an oil. The oil was chromatographed on silica gel using 6% ethyl acetate in hexane to afford 2-(2-benzyloxyethyl)acrylic acid tert-butyl ester as a clear oil, 18.51 g (87%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[C:3]=1[C:4]([O:6][CH3:7])=[O:5]>CCO.CC(O)=O.[Fe]>[NH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:2]([F:1])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(F)cccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)c1c(N)cccc1F
Temperature: 25 °C

Procedure:
Methyl 2-fluoro-6-nitrobenzoate (715 mg, 3.59 mmol) was dissolved in EtOH/HOAc/(10 mL/10 mL), followed by addition of iron powder (602 mg, 10.8 mmol) at room temperature. The resulting mixture was refluxed under N2 for 2 hrs. After cooling down to room temperature, the brown suspension was partitioned between H2O (30 mL) and Et2O (100 mL). After separation, the aqueous solution was extracted with Et2O (50 mL). The combined organic layers were washed with 1N NaOH (3×50 mL), brine (50 mL), dried on MgSO4, and concentrated on rotary vacuum to afford the expected product, methyl 2-amino-6-fluorobenzoate, an colorless oil which became wax-type solid on standing. The crude compound was pure enough to be used in next step without further purification; 1H NMR (400 MHz, CDCl3) δ ppm 3.89 (s, 3H), 5.67 (s, 2H), 6.34 (ddd, J=11.58, 8.06, 1.01 Hz, 1H), 6.41 (d, J=8.31 Hz, 1H), 7.13 (td, J=8.18, 5.79 Hz, 1H); Mass spec. 170.06 (MH+), Calc. for C8H8FNO2 169.05.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[OH:6][C:7]1[C:16]([OH:17])=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]3[N:20]=[CH:19][S:18][C:13]3=2)[N:8]=1>S(=O)(=O)(O)O>[OH:6][C:7]1[C:16]([OH:17])=[N:15][C:14]2[C:9](=[CH:10][C:11]([N+:1]([O-:4])=[O:2])=[C:12]3[N:20]=[CH:19][S:18][C:13]3=2)[N:8]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Oc1nc2ccc3ncsc3c2nc1O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc2nc(O)c(O)nc2c2scnc12
Temperature: 0 °C
Reaction time: 4 h
Yield: 63.1 %

Procedure:
Finely powdered potassium nitrate (92 mg, 0.9 mmol) was added to a stirred and ice-cooled solution of 7,8-dihydroxythiazolo[5,4-f]quinoxaline (0.20 g, 0.9 mmol) in 5 ml of conc. sulfuric acid. The mixture was stirred at 0° C. for 30 min, then at room temperature for 4 h, and finally poured into ice/water. The resulting precipitate was isolated by filtration, washed with water, and dried giving 0.15 g (62%) of the nitro compound; m.p.>360° C., IR (KBr): 1680 cm-1 ; 1H-NMR (DMSO-d): 8.06 (s, 1H, ArH), 9.53 (s, 1H, ArH), 12.23 (broad s, 1H, OH), 12.76 (broad s, 1H, OH).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([CH:8]=[C:9](F)[C:10]=1[F:11])[C:5]([OH:7])=[O:6].[CH3:16][CH2:17][O-:18].[Na+]>C(O)C>[NH2:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([CH:8]=[C:9]([O:18][CH2:17][CH3:16])[C:10]=1[F:11])[C:5]([OH:7])=[O:6]
Reactant: CC[O-]
Reactant: Nc1c(F)c(F)cc(C(=O)O)c1[N+](=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc(C(=O)O)c([N+](=O)[O-])c(N)c1F

Procedure:
1.4 g (6.3 mmol) of 2-nitro-3,4,5-trifluoro-benzoic acid was treated with ammonium hydroxide to produce 3-amino-4,5-difluoro-2-nitro-benzoic acid. LCMS: 219 (M+1)+. 1.2 g (5.5 mmol) of 3-amino-4,5-difluoro-2-nitro-benzoic acid was heated with excess 21% NaOEt in ethanol at 90° C. for 6 h to yield 3-amino-5-ethoxy-4-fluoro-2-nitro-benzoic acid. LCMS: 245 (M+1)+.
Reaction SMILES: [CH2:1]([O:5][CH:6]=[C:7]([CH:10]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])[O:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:8]#[N:9])[CH2:2][CH2:3][CH3:4].[CH3:21][CH2:22][CH2:23][CH2:24][O-:25].[Na+].S(=O)(=O)(O)O>C(O)CCC>[CH2:17]([O:16][CH:10]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]([CH:6]([O:25][CH2:24][CH2:23][CH2:22][CH3:21])[O:5][CH2:1][CH2:2][CH2:3][CH3:4])[C:8]#[N:9])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCOC=C(C#N)C(OCCCC)OCCCC
Reactant: CCCC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCCCO
Product: CCCCOC(OCCCC)C(C#N)C(OCCCC)OCCCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 277.8 %

Procedure:
In 100 ml of n-butanol was dissolved 8.49 g (30 mmoles) of 2-n-butoxymethylene-3,3-di-n-butoxypropanenitrile. To the resulting solution was added 0.87 g (9 mmoles) of sodium n-butylate at room temperature, and the mixture was stirred at room temperature for one hour. Then, the reaction mixture was neutralized with a solution of sulfuric acid in butanol and the resulting inorganic salt was removed by filtration. The filtrate was distilled under reduced pressure to obtain 9.10 g (25 mmoles) of 2-di-n-butoxymethyl-3,3-di-n-butoxypropanenitrile as a colorless transparent oil boiling at 170°-175° C./2 mmHg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[N:13]=1.CC1(C)COB([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[N:32][CH:33]=2)OC1.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.C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:28]3[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[N:32][CH:33]=3)=[CH:16][CH:15]=2)[N:13]=1
Reactant: Fc1cccc(F)c1C1=NC(c2ccc(Br)cc2)CO1
Reactant: CC(C)COc1ccc(B2OCC(C)(C)CO2)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+]
Solvent: CCO
Solvent: O
Product: CC(C)COc1ccc(-c2ccc(C3COC(c4c(F)cccc4F)=N3)cc2)cn1

Procedure:
2-(2,6-Difluorophenyl)-4-(4-bromophenyl)oxazoline (1.00 g, 2.96 mmol) was mixed with 5,5-dimethyl-2-(2-isobutyloxypyridin-5-yl)-1,3,2-dioxaborinane (1.4 g, purity 80%, 4.3 mmol), Pd(PPh3)4 (0.17 g, 0.15 mmol) and sodium carbonate (0.62 g, 5.9 mmol) in tolune/ethanol/water 8:2:1 (15 ml) and refluxed for 8 hours under nitrogen. After extraction and chromatography, 2-(2,6-difluorophenyl)-4-[4-(2-isobutyloxypyridin-5-yl)phenyl]oxazoline was obtained, 1.14 g, colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[CH:13][CH:14]=3)[C:9]([S:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:8]2[CH2:29][C:30]([CH3:36])([CH3:35])[C:31]([O:33]C)=[O:32])=[CH:4][CH:3]=1.C1COCC1.[Li+].[OH-]>CO>[Cl:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[CH:13][CH:14]=3)[C:9]([S:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:8]2[CH2:29][C:30]([CH3:36])([CH3:35])[C:31]([OH:33])=[O:32])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3ccccn3)ccc2n1Cc1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)Sc1c(CC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(OCc3ccccn3)cc12

Procedure:
A solution of methyl 3-[1-(4-chlorobenzyl)-3-(1,1-dimethylethylthio)-5-(pyrid-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropionate (8.8 g; 16 mmol), prepared as in step 5, in 100 mL 1:2:1 THF, methanol, 1N aqueous LiOH was heated at reflux for 3 hours. The reaction mixture was concentrated, diluted with water, and acidified to pH 5-6 with solid citric acid. The mixture was extracted with ethyl acetate. The extracts were dried over magnesium sulfate and the solvent was evaporated. The product was recrystallized from ethyl acetate/hexane to give 3-[1-(4-chlorobenzyl)-3-(1,1-dimethylethylthio)-5-(pyrid-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropionic acid as a white solid. m.p. 189°-190° C. 1H NMR (300 MHz, DMSO-d6) δ1.09 (s, 6H), 1.10 (s, 9H), 3.18 (bs, 2H), 5.20 (s, 2H), 5.47 (s, 2H), 6.85 (m, 3H), 7.09 (d, J=3 Hz, 1H), 7.32 (m, 4H), 7.49 (d, J=8 Hz, 1H), 7.79 (m, 1H), 8.57 (m, 1H). MS (DCI/NH3) 537 (M+H)+. Analysis calcd for C30H33ClN2O3S; C, 67.08; H, 6.19; N, 5.22. Found: C, 67.30; H, 6.21; N, 5.18.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=2)=[CH:6][C:5]([CH2:16][N:17]([CH3:30])[C:18]([C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=2)[C:23]([O:25][CH3:26])=[O:24])=[O:19])=[CH:4][CH:3]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)[CH:9]=2)=[CH:6][C:5]([CH2:16][N:17]([CH3:30])[C:18]([C:20]2[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=2)[C:23]([O:25][CH3:26])=[O:24])=[O:19])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(C(=O)N(C)Cc2ccc(F)c(-c3cccc(C=O)c3)c2)c1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cccc(C(=O)N(C)Cc2ccc(F)c(-c3cccc(CN4CCN(C)CC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 92.9 %

Procedure:
To a solution of methyl 3-{[[(6-fluoro-3′-formyl-3-biphenylyl)methyl](methyl)amino]carbonyl}benzoate (0.18 g, 0.444 mmol) in DCM (4.4 mL) was added 1-methylpiperazine (0.0542 mL, 0.488 mmol), and NaBH(OAc)3 (0.141 g, 0.666 mmol). The mixture was stirred at room temperature for 17 h and then the reaction was quenched with H2O (˜1 mL). The organic layer was separated, dried over Na2SO4 and purified by CombiFlash chromatograph to afford the title compound 0.202 g (93%). LC-MS m/z 490 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][N:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC=CC=1.[C:28]([Li])([CH3:31])([CH3:30])[CH3:29]>CCCCC>[C:28]([C:12]1([OH:15])[CH2:13][CH2:14][N:9]([CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11]1)([CH3:31])([CH3:30])[CH3:29]
Reactant: O=C1CCN(CC(c2ccccc2)c2ccccc2)CC1
Reactant: [Li]C(C)(C)C
Solvent: c1ccccc1
Solvent: CCCCC
Product: CC(C)(C)C1(O)CCN(CC(c2ccccc2)c2ccccc2)CC1
Reaction time: 1 h

Procedure:
To a stirred solution of 2 parts of 1-(2,2-diphenylethyl)-4-piperidinone in 50 parts by volume of benzene under nitrogen atmosphere is added 30 parts of 1.6 M solution of tertiary-butyllithium in pentane. The resultant solution is stirred for about 24 hours and then quenched with the careful addition of 60 parts by volume of 10% ammonium chloride solution. After 1 hour, the organic layer is separated, washed with water and brine, dried with magnesium sulfate, and concentrated to give clear red oil. This oil is chromatographed on silica gel using successively methylene chloride and 10% ethanol-methylene chloride solution as eluents to give pale yellow solid which upon sublimation affords 4-tert-butyl-1-(2,2-diphenylethyl)-4-piperidinol. This compound melts at about 105°-110° C. and is represented by the following structural formula ##STR36##
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[C:8]2[CH2:12][CH2:13][OH:14])[CH3:2].N1C2C(=CC=CC=2)C(CCO)=C1.[C:27]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])(=O)[CH:28]([CH3:30])[CH3:29]>>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][C:27]1([CH:28]([CH3:30])[CH3:29])[C:9]2[NH:10][C:11]3[C:7]([C:8]=2[CH2:12][CH2:13][O:14]1)=[CH:6][CH:5]=[CH:4][C:3]=3[CH2:1][CH3:2])[CH3:37]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: CCc1cccc2c(CCO)c[nH]c12
Agent: OCCc1c[nH]c2ccccc12
Product: CCOC(=O)CC1(C(C)C)OCCc2c1[nH]c1c(CC)cccc21

Procedure:
Following the procedure of example 22.A. except using 2-(7-ethyl-1H-indol-3-yl)-ethanol as the 3-indolethanol component and ethyl iso-butyrylacetate as ketone component afforded the title compound as a solid. 1H NMR (500 MHz, CDCl3) δ 9.12 (br, 1H), 7.36 (d, 1H), 7.07 (m, 2H), 4.13 (m, 3H), 3.81 (m, 1H), 3.04 (q, 2H), 2.87 (m, 3H), 2.66 (m, 1H), 2.56 (m, 1H), 1.37 (t, 3H), 1.25 (t, 3H), 1.05 (d, 3H), 0.69 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:18])=[N:6][C:5]=2[N:19]=1.Cl[C@@H:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=1)[CH3:22]>>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:12][OH:13])=[N:8][C:7]([S:18][C@H:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=3)[CH3:22])=[N:6][C:5]=2[N:19]=1
Reactant: C[C@@H](Cl)c1ccc(F)cn1
Reactant: CC(C)C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Product: CC(C)C[C@H](CO)Nc1nc(S[C@@H](C)c2ccc(F)cn2)nc2nc(N)sc12
Yield: 57.3 %

Procedure:
The title compound was prepared by General method A starting from (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol (940 mg, 3.1 mmol) and 2-[(1R)-1-chloroethyl]-5-fluoropyridine (0.81 g, 5.1 mmol). The product was purified by flash column chromatography to yield 0.75 g (56% yield) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[CH2:10][CH:11]([OH:13])[CH3:12])[CH:5]=[N:6][CH:7]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>N1C=CC=CC=1>[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([O:13][CH:11]([CH2:10]/[CH:9]=[CH:8]/[C:4]2[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH3:12])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: CC(O)C/C=C/c1cncc(Br)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC(C)C/C=C/c2cncc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirring solution of (4E)-5-(5-bromo-3-pyridyl)-4-penten-2-ol (3.14 g, 13.0 mmol) in dry pyridine (30 mL) at 0 °C. was added p-toluenesulfonyl chloride (3.71 g, 19.5 mmol). The reaction mixture was stirred for 24 h at ambient temperature. The pyridine was removed by rotary evaporation. Toluene (50 mL) was added to the residue and subsequently removed by rotary evaporation. The crude product was stirred with a saturated solution of sodium bicarbonate (100 mL) and extracted with chloroform (3×100 mL). The combined chloroform extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation to give (4E)-5-(5-bromo-3-pyridyl)-4-penten-2-ol p-toluenesulfonate. The resulting tosylate was treated with excess methylamine (40% solution in water), ethyl alcohol (10 mL), and stirred at ambient temperature for 18 h. The resulting solution was extracted with chloroform (3×100 mL). The combined chloroform extracts were dried over sodium sulfate and filtered. Removal of solvent by rotary evaporation followed by column chromatography over silica gel eluting with chloroform-methanol (95:5, v/v) produced 1.50 g (45.0%) of a pale-yellow oil.
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].C(O[CH:9]1[NH:12][C:11](=[O:13])[CH:10]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=O)C>[OH-].[Na+].O1CCOCC1>[C:1]([S:3][CH:9]1[NH:12][C:11](=[O:13])[CH:10]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:4])[CH3:2]
Reactant: CC(O)=S
Reactant: CC(=O)OC1NC(=O)C1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(=O)SC1NC(=O)C1Cc1ccccc1
Reaction time: 3 h

Procedure:
A solution of 0.76 g (10 mmole) of thioacetic acid in 10 ml of 1N sodium hydroxide solution is added dropwise to a solution of 2.19 g (10 mmole) of 4-acetoxy-3-benzylazetidin-2-one (racemic mixture of cis- and trans-isomer in the ratio of 9:13) in 10 ml of dioxan at room temperature under a nitrogen atmosphere, and the mixture is stirred at the same temperature for 3 hours. The reaction mixture is exhaustively extracted with methylene chloride. The combined organic phases are dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed over silica gel with toluene/ethyl acetate (9:1) and yields a cis-trans mixture of the title compound in the ratio of 2:10. By recrystallisation from methylene chloride/hexane at -10° the pure trans-compound having a melting point of 42°-43° is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][N:16]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7]2.O.[CH3:26]O>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][N:16]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH3:26])=[O:12])=[CH:7]2
Reactant: CO
Reactant: CS(=O)(=O)c1ccc(Oc2cc(O)c3[nH]c(C(=O)O)cc3c2)nc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cn3)cc(O)c2[nH]1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
To a suspension of 7-hydroxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxylic acid (8.71 g) in a mixture of methanol (300 mL) and toluene (300 mL) was added dropwise 2M trimethylsilyldiazomethane diethyl ether solution (12.5 mL) at 0° C., and the mixture was stirred at 0° C. for 1.5 h. Furthermore 2M trimethylsilyldiazomethane diethyl ether solution (10 mL) was added to the mixture and the mixture was stirred at 0° C. for 1 h, which was repeated three times. And then 2M trimethylsilyldiazomethane diethyl ether solution (5 mL) was added and the mixture was stirred at 0° C. for 30 min, which was repeated two times. To quench the reaction, 1M hydrochloric acid (80 mL) was added to the mixture. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residual solid was washed with diethyl ether to give the title compound (8.25 g, 92%) as a purple solid. MS 363 (MH+).
Reaction SMILES: [OH:1][C:2]([C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH2:29][CH:30]([CH3:32])[CH3:31])[S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:15][CH:14]=1)([C:9]([F:12])([F:11])[F:10])[C:3]#[C:4][Si](C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl.C1COCC1>[OH:1][C:2]([C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH2:29][CH:30]([CH3:32])[CH3:31])[S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:15][CH:14]=1)([C:9]([F:12])([F:11])[F:10])[C:3]#[CH:4]
Reactant: CC(C)CN(c1ccc(C(O)(C#C[Si](C)(C)C)C(F)(F)F)cc1)S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C#CC(O)(c1ccc(N(CC(C)C)S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.25 g (0.51 mmol) of N-[4-(1-hydroxy-1-trifluoromethyl-3-trimethylsilanyl-prop-2-ynyl)-phenyl]-N-isobutyl-benzenesulfonamide (Example 74) in 6 mL of CH2Cl2 was added 0.4 mL of a 1 M solution of tetrabutylammonium fluoride in THF. The mixture was stirred at room temperature for 1 hour. CH2Cl2 (60 mL) was added and the solution was washed with saturated aqueous NH4Cl-solution (20 mL) and brine (15 mL). The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica gel, (hexane:EtOAc, 7:3) to give the title compound.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:3]1=2.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[OH-].[Na+]>C(Cl)(Cl)Cl>[F:17][C:15]1[CH:14]=[CH:13][C:4]2[O:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[CH:2]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:3]=2[CH:16]=1
Reactant: C1CNCCN1
Reactant: Fc1ccc2c(c1)C(Cl)c1ccccc1CO2
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Fc1ccc2c(c1)C(N1CCNCC1)c1ccccc1CO2
Temperature: 25 °C
Yield: 66.7 %

Procedure:
To a solution of 15 g of 11-chloro-2-fluoro-6,11-dihydrodibenz[b,e]oxepin, which is prepared according to the procedure of Reference Example 1, in 300 ml of chloroform is added a solution of 25 g of anhydrous piperazine in 50 ml of chloroform at 0° C. After the temperature of the reaction mixture is raised to room temperature over 2 hours, it is added with 10% aqueous sodium hydroxide and extracted with chloroform. After the extract is washed with a saturated saline solution and dried over anhydrous potassium carbonate, the solvent is distilled off under reduced pressure. After the residue is added with 500 ml of toluene, an excess amount of piperazine is distilled off under reduced pressure to give 12 g of the objective compound as an oil. Mass spectrum m/z:298(M+).
Reaction SMILES: [F:1][C:2]1[C:10]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])=[CH:9][CH:8]=[C:7]([F:18])[C:3]=1[C:4]([OH:6])=O.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.[N:41]1([C:46]2[C:54]3[C:49](=[N:50][CH:51]=[C:52]([NH2:55])[CH:53]=3)[NH:48][N:47]=2)[CH:45]=[CH:44][N:43]=[CH:42]1>CN(C=O)C>[N:41]1([C:46]2[C:54]3[C:49](=[N:50][CH:51]=[C:52]([NH:55][C:4](=[O:6])[C:3]4[C:7]([F:18])=[CH:8][CH:9]=[C:10]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])[C:2]=4[F:1])[CH:53]=3)[NH:48][N:47]=2)[CH:45]=[CH:44][N:43]=[CH:42]1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1F
Reactant: Nc1cnc2[nH]nc(-n3ccnc3)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc(-n4ccnc4)c3c2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.8 %

Procedure:
2,6-Difluoro-3-(propylsulfonamido)benzoic acid (140 mg, 0.495 mmol), HOBt.H2O (89 mg, 0.584 mmol), and EDCI (120 mg, 0.674 mmol) was added to 3-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-5-amine (90 mg, 0.450 mmol) in DMF (10 mL). The mixture was stirred at ambient temperature overnight. The reaction mixture was evaporated, and the residue partitioned between ethyl acetate and water. The ethyl acetate was washed with brine, dried over magnesium sulfate, filtered, and concentrated to an oil. The crude product was purified by column chromatography (10:1 DCM:MeOH), which was followed by trituration with DCM to afford N-(3-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (57.7 mg, 28% yield) as a solid. 1H NMR (400 MHz, CD3OD) δ 8.80 (d, 1H), 8.74 (d, 1H), 8.36 (s, 1H), 7.80 (s, 1H), 7.70-7.64 (m, 1H), 7.27 (s, 1H), 7.17-7.12 (m, 1H), 3.14-3.09 (m, 2H), 1.92-1.82 (m, 2H), 1.06 (t, 3H); m/z (ESI-pos) M+1 462.2.