Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][Si:10]([CH3:19])([CH3:18])[C:11]1[O:15][CH:14]=[C:13]([CH:16]=[O:17])[CH:12]=1.S(=O)(=O)(O)O>O1CCCC1>[CH:1]1([CH:16]([C:13]2[CH:12]=[C:11]([Si:10]([CH3:19])([CH3:18])[CH3:9])[O:15][CH:14]=2)[OH:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cl[Mg]C1CCCCC1
Reactant: C[Si](C)(C)c1cc(C=O)co1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cc(C(O)C2CCCCC2)co1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of cyclohexylmagnesium chloride (0.24 ml, 0.484 mmol, 2.0M solution in ethyl ether) under argon at 0°, was added dropwise 5-trimethylsilyl-3-furaldehyde (0.072 g., 0.44 mmol) in 5 ml of dry tetrahydrofuran. This solution was allowed to warm to room temperature, stirred for 30 minutes and poured over crushed ice containing several drops of concentrated sulfuric acid. The resulting mixture was partitioned between ethyl ether and 5% sodium bicarbonate. The organic portion was washed with water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a colorless oil. This material was purified by flash chromatography (silica, 10% ethyl ether/pentane) to yield the desired alcohol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]([CH:16]=[CH2:17])=[N:14][N:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:8]=2[N:9]=[C:10]([Cl:12])[CH:11]=1)=[O:5])[CH3:2].I[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15](/[CH:16]=[CH:17]/[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:14][N:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:8]=2[N:9]=[C:10]([Cl:12])[CH:11]=1)=[O:5])[CH3:2]
Reactant: Ic1ccccc1
Reactant: C=Cc1nn(C2CCCCO2)c2nc(Cl)cc(C(=O)OCC)c12
Product: CCOC(=O)c1cc(Cl)nc2c1c(/C=C/c1ccccc1)nn2C1CCCCO1

Procedure:
Utilizing the procedure described in example 14.5 except substituting 4-[6-chloro-1-(tetrahydro-pyran-2-yl)-3-vinyl-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester with 6-chloro-1-(tetrahydro-pyran-2-yl)-3-vinyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester and substituting (3-iodo-benzyl)-dimethyl-amine for iodobenzene, 6-chloro-3-((E)-styryl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester was obtained (2.8 g, 65%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([C:12]3[CH:17]=[CH:16][C:15]4[O:18][CH2:19][O:20][C:14]=4[CH:13]=3)[C:9](=[O:11])[NH:10][C:5]2=[CH:4][CH:3]=1.[OH-].[K+].[CH2:23](Br)[CH:24]=[CH2:25]>CC(C)=O>[CH2:25]([N:10]1[C:5]2[C:6](=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:8]([C:12]2[CH:17]=[CH:16][C:15]3[O:18][CH2:19][O:20][C:14]=3[CH:13]=2)[C:9]1=[O:11])[CH:24]=[CH2:23]
Reactant: O=c1[nH]c2ccc(Cl)nc2n1-c1ccc2c(c1)OCO2
Reactant: C=CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: C=CCn1c(=O)n(-c2ccc3c(c2)OCO3)c2nc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred suspension of 4.6 g. (0.016 mole) of the imidazopyridine product of Step C in 175 ml. of acetone, was added 1.8 g. (0.032 mole) of powdered potassium hydroxide. After stirring at room temperature for 20 minutes, 3.9 g. (0.032 mole) of allylbromide was added. Stirring at room temperature was continued overnight and the mixture then was concentrated to one-half volume. The concentrate was diluted with 150 ml. of water and the crude product was collected by filtration. The crude product was crystallized from 70 ml. of ethanol giving 2.0 g. of needles melting at 146°-148° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[C:16]([OH:26])=[C:17]([CH3:25])[CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[C:16]([O:26][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[C:17]([CH3:25])[CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc2cccnc2c(N2CCCN(C(=O)OC(C)(C)C)CC2)c1O
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)CCCOc1c(C)cc2cccnc2c1N1CCCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-(7-Hydroxy-6-methyl-quinolin-8-yl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (1.3 g, 3.8 mmol) and methyl 4-bromobutyrate (680 mg, 3.8 mmol) were dissolved in DMF (7.5 mL). To this solution was added Cs2CO3 (3.7 g, 11.3 mmol) and reaction was stirred at room temperature for 18 h. The reaction was diluted with CH2Cl2 and washed with H2O (4×50 mL), then brine. The organic was then dried over MgSO4, filtered, and concentrated to give the crude product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:5]=[C:4]([NH:17][CH:18]2[NH:22][C:21](=[O:23])[N:20]([CH3:24])[C:19]2=[O:25])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1>CN(C)C=O.O>[CH3:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:6]2[N:7]=[C:2]([NH:39][CH2:38][C:37]3[CH:40]=[CH:41][C:34]([O:33][CH3:32])=[CH:35][CH:36]=3)[N:3]=[C:4]([NH:17][CH:18]3[NH:22][C:21](=[O:23])[N:20]([CH3:24])[C:19]3=[O:25])[N:5]=2)=[CH:11][CH:12]=1
Reactant: Cc1ccc(CNc2nc(Cl)nc(NC3NC(=O)N(C)C3=O)n2)cc1
Reactant: COc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nc(NCc3ccc(C)cc3)nc(NC3NC(=O)N(C)C3=O)n2)cc1
Reaction time: 20 h
Yield: 77.6 %

Procedure:
To a stirred suspension of 5-[4-chloro-6-(4-methyl-benzylamino)-[1,3,5]-triazin-2-ylamino]-3-methyl-imidazolidine-2,4-dione (Example 1.5, Part A) (80 mg, 0.22 mmol) and potassium carbonate (67 mg, 0.49 mmol) in dimethylformamide (5 mL) at 35° was added 4-methoxybenzylamine (0.03 mL, 0.24 mmol). The reaction mixture was stirred at 35° for 20 h and then diluted with water and extracted with ethyl acetate. The ethyl acetate layer was dried and concentrated to give the crude product as a foam (79 mg, 77%). NMR spectrum δH (300 MHz, CD3CN): 7.2-7.0 (br m, 7H, Ar+NH), 6.8 (br d, 2H, Ar), 6.5 (br, 1H, NH), 6.1-5.8 (br m, 2H, NH), 5.45 (br d, 1H, CH), 4.5-4.3 (br, 4H, CH2), 4.15 (d, 2H, CH2) 3.74 (s, 3H, OMe), 2.9-2.7 (br, 3H, NMe), 2.3 (s, 3H, Me). Mass spectrum (ESI) m/z 463 [M+H].
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:36])([CH3:35])[C@@H:11]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]([O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:19])=[O:13])(=[O:7])=[O:6].[N-:37]=[N+:38]=[N-:39].[Na+]>CS(C)=O>[N:37]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:36])([CH3:35])[C@@H:11]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]([O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:19])=[O:13])(=[O:7])=[O:6])=[N+:38]=[N-:39]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(COS(=O)(=O)CCCCl)[C@@H](OCc1ccccc1)C(=O)OCCOC(=O)OC1CCCCC1
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(COS(=O)(=O)CCCN=[N+]=[N-])[C@@H](OCc1ccccc1)C(=O)OCCOC(=O)OC1CCCCC1
Yield: 86.3 %

Procedure:
Following the general procedure for the preparation of azides of Description 16, 0.4 g (0.73 mmol) of (cyclohexyloxycarbonyloxy)ethyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoate (43a) dissolved in 4 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 0.16 g (2.5 mmol) of sodium azide (NaN3). After work-up, 0.35 g (85% yield) of the title compound (43b) was obtained as a colorless oil. Rf=0.35 (EtOAc/Hxn=1:4). 1H NMR (400 MHz, CDCl3, both diastereomers): δ=1.06-1.08 (m, 6H), 1.25-1.58 (br. m, 9H), 1.72-1.78 (br. m, 2H), 1.88-1.96 (br. m, 2H), 2.03-2.10 (m, 2H), 3.10-3.16 (m, 2H), 3.44-3.48 (m, 2H), 3.84-3.85 (2s, 1H), 3.94-3.96 (2d, J=9.2, 8.8 Hz, 1H), 4.18-4.23 (2d, J=9.2, 9.2 Hz, 1H), 4.33-4.38 (2d, J=11.2 Hz, 11.6 Hz, 1H), 4.54-4.72 (m, 2H), 6.81-6.87 (m, 1H), 7.30-7.38 (m, 5H) ppm. MS (ESI) m/z 577.89 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH2:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16](Br)[N:15]=1.C1(P(C2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=C(C3C4C(=CC=CC=4)C=CC=3)C3C(C=2)=CC=CC=3)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:13][C:14]1[N:15]=[C:16]([NH:12][C@H:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH3:11])[CH:17]=[CH:18][CH:19]=1
Reactant: C[C@H](N)c1cccc([N+](=O)[O-])c1
Reactant: Brc1cccc(Br)n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2cc3ccccc3c(-c3cccc4ccccc34)c2P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@H](Nc1cccc(Br)n1)c1cccc([N+](=O)[O-])c1
Temperature: 80 °C
Yield: 32.6 %

Procedure:
A mixture of (1S)-1-(3-nitrophenyl)ethanamine (365 mg, 2.2 mmol), 2,6-dibromopyridine (474 mg, 2 mmol), tris(dibenzylidene)dipalladium(0) (92 mg, 0.1 mmol), (+/−)-bis(diphenyphosphino)-1,1′-binaphthalene (125 mg, 0.2 mmol) and sodium tert-butoxide (270 mg, 2.8 mmol) in anhydrous toluene (4 mL) was heated at 80° C. for 17 hours. The mixture was cooled, diluted with ethyl acetate (50 mL), washed successively with saturated aqueous sodium hydrogen carbonate (3×30 mL) and brine (30 mL), dried (Na2SO4) and concentrated under reduced pressure to give a black oil which was purified by flash chromatography (silica, ethyl acetate/hexanes) to give 6-bromo-N-[(1S)-1-(3-nitrophenyl)ethyl]pyridin-2-amine (210 mg, 33%) and the di-addition product (205 mg, 50%) both as yellow oils.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.C([O-])(=O)C.[K+].[C:21](#[N:25])[CH2:22][C:23]#[N:24].II>CO>[C:23]([C:22]([C:21]#[N:25])=[C:9]1[CH:10]=[C:11]2[C:6](=[N:5][C:4]3[C:13]([S:12]2)=[CH:14][CH:15]=[C:2]([Cl:1])[CH:3]=3)[CH:7]=[CH:8]1)#[N:24]
Reactant: Clc1ccc2c(c1)Nc1ccccc1S2
Reactant: N#CCC#N
Agent: CC(=O)[O-]
Agent: II
Agent: [K+]
Solvent: CO
Product: N#CC(C#N)=c1ccc2c(c1)Sc1ccc(Cl)cc1N=2
Temperature: 40 °C
Reaction time: 3.5 h
Yield: 26.2 %

Procedure:
A solution of 2-chlorophenothiazine (1.0 g; 4.26 mmol) and potassium acetate (KOAc) (2.5 g) in boiling methanol (MeOH) (70 mL) was allowed to cool to 40° C. then treated with malononitrile (0.42 g; 1.5 eq). This solution was treated at once with a solution of I2 (2.16 g) in MeOH (25 mL) and allowed to stir at ambient temperature for 3.5 h. The dark green solid that separated was collected by filtration, washed with MeOH and dried in vacuo to give 4 (0.33 g, 26%). MS (70 eV) m/e (rel. intensity) 295 (100), 260 (26).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:14]([O-])=O)=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=[O:7].[H][H]>[OH-].[NH4+].[Pd]>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]=1[NH2:14]
Reactant: COc1ccc(C(=O)O)c([N+](=O)[O-])c1OC
Reactant: [H][H]
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Product: COc1ccc(C(=O)O)c(N)c1OC
Yield: 78.1 %

Procedure:
A solution of 3,4-dimethoxy-2-nitro benzoic acid (1011 g., 4.45 moles) in 14 liters of 1.3 N ammonium hydroxide was reduced at 60 psi in presence of 60 grams of palladium on barium carbonate. Hydrogen uptake ceased after four hours. The reaction mixture was filtered through diatomaceous earth and acidified with glacial acetic acid (1.2 liters) to yield 685 grams (78%) of the anthranilic acid, M.P. 183°-184° C.
Reaction SMILES: [C:1]([S:4][CH2:5]/[C:6](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)/[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>>[O:9]=[C:7]([NH:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])/[C:6](/[CH2:5][S:4][C:1](=[O:3])[CH3:2])=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1
Reactant: CC(=O)SC/C(=C\c1ccc(C(F)(F)F)cc1)C(=O)O
Reactant: NCCC(=O)OCc1ccccc1
Product: CC(=O)SC/C(=C\c1ccc(C(F)(F)F)cc1)C(=O)NCCC(=O)OCc1ccccc1
Yield: 47 %

Procedure:
The (Z)-2-acetylthiomethyl-3-(4-trifluoromethylphenyl)propenoic acid obtained in step C is coupled with benzyl β-alaninate according to the experimental procedure described in Example 1 (step D). Yield=47% (purification by flash chromatography, eluent: ether/petroleum ether 6/4) m.p. 79° C. IR (nujol): 3280, 1740, 1690, 1640, 1620 cm-1 1H NMR (CDCl3 /TMS): 7.70 (s, 1H); 7.55 (AB, 2H, J=8 Hz); 7.45 to 7.20 (m, 7H); 6.95 (t, 1H, J=6 Hz); 5.15 (s, 2H); 3.90 (s, 2H); 3.40 (q app., 2H, J app.=6 Hz.); 2.65 (t, 2H, J=5 Hz); 2.30 (s, 3H). Microanalysis: C23H22O4NSF3Calc. % C=59.35 H=4.76 N=3.01 Found. % C=59.17 H=4.73 N=2.87
Reaction SMILES: [Se](=O)=O.[F:4][C:5]1[CH:6]=[C:7]([C:11](=[O:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1.CC(=[N:17][OH:18])C>O.O1CCOCC1>[F:4][C:5]1[CH:6]=[C:7]([C:11](=[O:13])[CH:12]=[N:17][OH:18])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)c1cccc(F)c1
Reactant: CC(C)=NO
Agent: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: O=C(C=NO)c1cccc(F)c1
Reaction time: 24 h

Procedure:
To a mixture of selenium dioxide (58.3 g, 525 mmol) in 20 ml of water and 400 ml of 1,4-dioxane was added in one-portion 1-(3-fluoro-phenyl)-ethanone (69.0 g, 500 mmol). The mixture was refluxed overnight, then filtered through diatomaceous earth. The filtrate was added to an equal volume of water and adjusted to pH 4 with 5% aqueous sodium hydroxide. To this mixture was added acetone oxime (40.2 g, 550 mmol) and the mixture was stirred for 24 h. On dilution to 1.5 L with water, the mixture was extracted with ethyl acetate (2×400 ml), and the organic layer was washed with brine, dried with anhydrous sodium sulfate, and concentrated to give a oil residue, which was purified by flash chromatography on silica gel (eluting with pure Petroleum) to return title compound as a pale yellow solid (68.0 g, 81.4%). 1H NMR (DMSO-d6): δ 12.78 (s, 1H), 8.02 (s, 1H), 7.82-7.50 (m, 4H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[N:16][CH:15]=2)[CH:3]=1.Cl.[N:26]1[C:31]2[CH2:32][CH2:33][NH:34][CH2:35][C:30]=2[C:29](=[O:36])[NH:28][CH:27]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:11][C:9]1[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[N:16][CH:15]=3)[CH:3]=[C:2]([N:34]3[CH2:33][CH2:32][C:31]4[N:26]=[CH:27][NH:28][C:29](=[O:36])[C:30]=4[CH2:35]3)[N:7]2[N:8]=1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(F)(F)F)nc3)cc(Cl)n2n1
Reactant: O=c1[nH]cnc2c1CNCC2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2nc(NC(=O)c3ccc(C(F)(F)F)nc3)cc(N3CCc4nc[nH]c(=O)c4C3)n2n1
Temperature: 25 °C
Yield: 64.4 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-6-(trifluoromethyl)nicotinamide (12A, 90 mg, 0.253 mmol), 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one hydrochloride (134 mg, 0.633 mmol), and N,N-diisopropylethylamine (98 mg, 0.757 mmol) in DMF (1.012 mL) was stirred at 100° C. for 90 min, then cooled to rt and maintained overnight. The mixture was filtered and the crude material recrystallized from hot methanol, providing the titled compound as a yellow solid (76.6 mg, 64%). 1H NMR (DMSO-d6) δ: 12.63 (br. s., 1H), 11.45 (s, 1H), 9.29 (s, 1H), 8.53-8.69 (m, 1H), 8.13 (s, 1H), 8.09 (dd, J=8.3, 0.8 Hz, 1H), 7.40 (s, 1H), 6.21 (s, 1H), 4.51 (s, 2H), 4.13 (t, J=5.7 Hz, 2H), 2.73 (s, 2H), 2.41 (s, 3H); ESI-MS: m/z 471.1 (M+H)+.
Reaction SMILES: C(=O)(O)[O-].[Na+].[OH:6][C:7]1[CH:8]=[C:9]([C:13](=O)[C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=1.Cl.[NH2:19][OH:20].Cl>O>[OH:20][N:19]=[C:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([OH:6])[CH:8]=1)[C:14]([OH:16])=[O:15]
Reactant: O=C(O)C(=O)c1cccc(O)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(O)C(=NO)c1cccc(O)c1
Temperature: 25 °C
Yield: 50 %

Procedure:
To a solution of sodium bicarbonate (5.56 g.) in water (200 ml.) was added and dissolved with stirring 3-hydroxyphenylglyoxylic acid (11 g.) under cooling. On the other hand, hydroxylamine hydrochloride (4.60 g.) was added and dissolved into a solution of sodium bicarbonate (5.56 g.) in water (70 ml.) with stirring at room temperature. Thus obtained solution was added with stirring to the above obtained solution under cooling. The mixture was stirred for 20 hours at room temperature and was subjected for salting-out treatment. Then, the reaction solution was acidified with hydrochloric acid and was extracted with ethyl acetate. The extract was washed with saturated aqueous solution of sodium chloride and dried. After solvent was distilled off, the residue was crystallized from benzene. The crystals were collected by filtration to obtain 2-hydroxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (6 g.).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[BrH:15].[NH+]1C=CC=CC=1.O.S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[Br:15][C:10]1[CH:11]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[C:8]=1[NH2:9]
Reactant: CC(C)(C)c1ccc(N)c([N+](=O)[O-])c1
Reactant: Br
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(Br)c(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
A suspension of 4-tert-butyl-2-nitroaniline (1.033 g, 5.32 mmol) in glacial acetic acid (7.8 mL) was warmed with a heat gun until all solids had dissolved. The solution was then cooled and treated portion wise with pyridinium hydrobromide perbromide (1.96 g, 6.12 mmol). After addition, the solution was stirred at room temperature for 1 h. The mixture was added to water (50 mL) and treated with a small amount of sodium sulfite. After stirring for 30 min, the precipitate was collected by filtration. The solid obtained was washed with water and dissolved in EtOAc. Washed with water and brine. Dried over Na2SO4, filtered and concentrated under vacuum to provide the title compound as a yellow-orange solid (1.36 g, 94%).
Reaction SMILES: CS(O[C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:7]=1[C:16]([CH3:19])([CH3:18])[CH3:17])(=O)=O.C([O-])=O.[Na+].CO>[Pd].[C].O>[C:12]([C:9]1[CH:10]=[CH:11][CH:6]=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:8]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1ccc(OS(C)(=O)=O)c(C(C)(C)C)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1cccc(C(C)(C)C)c1
Temperature: 65 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
In a nitrogen atmosphere, 2,4-di-tert-butylphenyl methanesulfonate (500 g, 1.76 mols), sodium formate (239 g, 3.52 mols), methanol (2400 g) and water (600 g) were mixed at 25° C., and with stirring, 10 mass % Pd/carbon (50 mass water-containing product) (30 g) (as metal palladium; 0.3 mass % relative to 2,4-di-tert-butylphenyl methanesulfonate) as supported by a carbon carrier having a specific surface area of 780 m2/g (by BET method) was put into it. Still kept stirred, this was heated up to 65° C., taking 1 hour, and reacted for 6 hours. Water (100 mL) was added to the reaction liquid and Pd-carbon was separated through filtration, then heptane (500 g) was added to the filtrate. The organic layer obtained after extraction was concentrated under reduced pressure to give crude 1,3-di-tert-butylbenzene (331 g, yield 99% by mass). The result is shown in Table I-1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][N:9]([CH2:20][C:21]2[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=2)[CH2:24][N:25]2[CH:29]([C:30](O)=[O:31])[CH2:28][CH2:27][S:26]2(=[O:34])=[O:33])[C@H:10]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:6]([F:38])[C:5]([O:39][CH3:40])=[CH:4][CH:3]=1.[Cl:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2([OH:54])[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)=[CH:44][CH:43]=1>>[Cl:1][C:2]1[C:7]([CH2:8][N:9]([CH2:20][C:21]2[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=2)[CH2:24][N:25]2[CH:29]([C:30]([N:51]3[CH2:50][CH2:49][C:48]([C:45]4[CH:46]=[CH:47][C:42]([Cl:41])=[CH:43][CH:44]=4)([OH:54])[CH2:53][CH2:52]3)=[O:31])[CH2:28][CH2:27][S:26]2(=[O:34])=[O:33])[C@H:10]([CH2:16][N:17]([CH3:18])[CH3:19])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:6]([F:38])[C:5]([O:39][CH3:40])=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: COc1ccc(Cl)c(CN(Cc2cccc(CN3C(C(=O)O)CCS3(=O)=O)c2)[C@H](CN(C)C)CC(C)(C)C)c1F
Product: COc1ccc(Cl)c(CN(Cc2cccc(CN3C(C(=O)N4CCC(O)(c5ccc(Cl)cc5)CC4)CCS3(=O)=O)c2)[C@H](CN(C)C)CC(C)(C)C)c1F
Yield: 61.7 %

Procedure:
2-(3-{[(6-Chloro-2-fluoro-3-methoxy-benzyl)-((S)-1 dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid (Intermediate 7, 0.081 g, 0.135 mmol) was reacted with 4-(4-chlorophenyl)-4-hydroxypiperidine (available from Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233, USA; 0.035, 0.166 mmol) to form [2-(3-{[(6-Chloro-2-fluoro-3-methoxy-benzyl)-((S)-1-dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidin-3-yl]-[4-(4-chloro-phenyl)-4-hydroxy-piperidin-1-yl]-methanone (0.066 g, 62%). m/z=791 (M+1); HRMS: calcd for C40H54Cl2FN4O5S. Calc [M+H+] 791.3171. found 791.3169.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[C:24]([C:29]([F:32])([F:31])[F:30])=[N:25][N:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:33].[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=2)[CH2:37][CH2:36]1.CC(C)=O>C1COCC1>[CH3:34][N:35]1[CH2:36][CH2:37][N:38]([C:41]2[CH:46]=[CH:45][C:44]([NH:47][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[C:24]([C:29]([F:31])([F:32])[F:30])=[N:25][N:26]([CH3:28])[CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:33])=[CH:43][CH:42]=2)[CH2:39][CH2:40]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: Cn1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)c(C(F)(F)F)n1
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CN1CCN(c2ccc(NC=C3C(=O)Nc4cc(C(=O)c5cccc(NC(=O)c6cn(C)nc6C(F)(F)F)c5)ccc43)cc2)CC1
Temperature: 65 °C
Reaction time: 24 h

Procedure:
A small screw cap test tube was charged with 1-Methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 100 mg, 0.249 mmol) and THF (2 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (47.5 mg, 0.249 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was dissolved in EtOAc. The resulting solution was diluted with Hexanes to initiate the precipitation of the product. The solid precipitate that formed was filtered then washed with 3 mL of acetone yielding 32% (45 mg, 0.076 mmol) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:21]CCC)=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][N:12]=1)[CH2:9][CH3:10].[OH-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][N:12]=1)[CH2:9][CH3:10]
Reactant: CCCOc1ccc(Br)cc1CN(CC)c1ccc(C(=O)O)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(Cc1cc(Br)ccc1O)c1ccc(C(=O)O)cn1
Temperature: 40 °C
Yield: 88 %

Procedure:
A solution of methyl 2-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]pyridine-5-carboxylate (see reference example 1) (10.2 g, 0.55 mmol) in THF (3 ml) and methanol (5 ml) was treated with 1N aqueous sodium hydroxide solution (2.7 ml) and was heated to 40° C. for 24 hours. The solvents were evaporated at reduced pressure, the residue treated with 1N acetic acid (2.7 ml) and the precipitate filtered, washed with water and air dried to give the title compound (0.17 g, 92%).