Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:24])[N:16]([CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:33][OH:34].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:24])[N:16]([CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:17]=2)=[N:33]\[OH:34])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(CCCC(=O)O)c1)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(CCCC(=O)O)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 151, step 3, 4-{5-[3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-2-oxo-2H-pyridin-1-yl}-butyric acid was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI−): m/z=495.1 [M−H]−.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:13]1([C@@H:19]([NH2:21])[CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CCOC(C)=O>[CH:13]1([C@@H:19]([NH:21][C:2]2[S:3][C:4]3[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=3[N:6]=2)[CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C[C@H](N)C1CCCCC1
Reactant: COc1ccc2nc(Cl)sc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1ccc2nc(N[C@@H](C)C3CCCCC3)sc2c1
Temperature: 110 °C
Reaction time: 96 h

Procedure:
To a solution of 2-chloro-6-methoxybenzo[d]thiazole (2.0 g, 10 mmol) in 10 mL of NMP was added (S)-1-cyclohexylethanamine (2.3 g, 18 mmol) and DIPEA (3.5 mL, mmol). The reaction solution was stirred at 110° C. for 96 hours. The reaction was diluted with EtOAc (170 mL) and washed with saturated NaHCO3 (60 mL), 5% NaHCO3 solution (60 mL), water (60 mL), saturated NaCl (60 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give (S)—N-(1-cyclohexylethyl)-6-methoxybenzo[d]thiazol-2-amine as crude solid (3.39 grams). ES/MS m/z 291.1 (MH+).
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[CH:9]=[C:8]([NH:10][CH3:11])[C:7]([NH2:12])=[CH:6][CH:5]=1.[S:13](N)(N)(=[O:15])=[O:14]>N1C=CC=CC=1.C(Cl)Cl>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:12][S:13](=[O:15])(=[O:14])[N:10]([CH3:11])[C:8]=2[CH:9]=1
Reactant: CNc1cc(Br)ccc1N
Reactant: NS(N)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN1c2cc(Br)ccc2NS1(=O)=O

Procedure:
A mixture of 5-bromo-N1-methylbenzene-1,2-diamine dihydrochloride (800.0 mg, 3.00 mmol) and sulfamide (560 mg, 5.80 mmol) in pyridine (10 mL) was heated at reflux for 2 h. Pyridine was removed under reduced pressure and the residue obtained was dissolved in DCM (20 mL) and washed with 1N HCl (20 mL). The DCM layer was separated, dried over Na2SO4, filtered, and concentrated to obtain 6-bromo-1-methyl-1,3-dihydrobenzo[c][1,2,5]thiadiazole 2,2-dioxide. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.98 (d, J=2.0 Hz, 1H), 7.93 (dd, J=8.8, 2.3 Hz, 1H), 7.46 (d, 1H), 3.41 (s, 3H).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][CH:10]1[CH2:15][NH:14][CH2:13][CH2:12][NH:11]1.C([O-])([O-])=O.[K+].[K+]>[Na+].[I-].C(C(C)=O)C>[CH2:1]([N:14]1[CH2:13][CH2:12][NH:11][CH:10]([CH3:9])[CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CNCCN1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC1CN(Cc2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.9 %

Procedure:
To 500 ml of ice cooled methyl ethyl ketone, 126.5 g (1 mol) of benzyl chloride, 100 g (1 mol) of 2-methylpiperazine, 138 g (1 mol) of anhydrous K2CO3 and 2 g of NaI are added. The mixture is stirred at the reflux temperature for 2 hours, then cooled to room temperature; K2CO3 is filtered off and the solvent evaporated. The residue is dissolved in diluted NaOH, extracted with some ethyl ether, washed with water, dried over Na2SO4 and the solvent is evaporated off to provide 55 g of 1-benzyl-3-methylpiperazine. B.p. 140°-150° C./20-25 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]=[C:7]2[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]2=[O:15])=[CH:4][CH:3]=1.[Br:18]Br>ClCCl>[Br:18][CH:6]([CH:7]1[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]1=[O:15])[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:17][CH:16]=1
Reactant: CC1(C)CCC(=Cc2ccc(Cl)cc2)C(=O)C1
Reactant: BrBr
Solvent: ClCCl
Product: CC1(C)CCC(C(Br)c2ccc(Cl)cc2)C(=O)C1
Temperature: 7.5 °C

Procedure:
10 g (0.04 mole) of 2-(4-chlorobenzylidene)-5,5-dimethycyclohexanone prepared according to Example 1(a) were dissolved in 50 ml dichloromethane and cooled to 5-10° C. Bromine (6.4 g, 0.04 mole) was added over 5 minutes to give 2-bromo-2-(α-bromo-4-chlorobenzyl-5,5-dimethylcyclohexanone in solution.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[CH:11]=[C:10]([Br:12])[O:9][C:8]=1[CH3:13])=[O:6]>O.CO>[Br:12][C:10]1[O:9][C:8]([CH3:13])=[C:7]([C:5]([OH:6])=[O:4])[CH:11]=1
Reactant: COC(=O)c1cc(Br)oc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1oc(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.4 %

Procedure:
A solution of sodium hydroxide (4.5 g) in water (10 ml) was added to a stirred solution of 5-bromo-2-methyl-furan-3-carboxylic acid methyl ester (5 g, 233 mmoles) in methanol (70 ml) and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was diluted with water (10 ml) and acidified to pH2 with 1M aqueous hydrochloric acid. The precipitate was collected, washed with water, dried at 40° C. to afford 5-Bromo-2-methyl-furan-3-carboxylic acid (14)(4 g). LC/MS System A; Rt=2.86 min.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:7]([O:9]C)=O)[N:6]=1.[NH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>CO>[Br:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:7]([NH:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:9])[N:6]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: COC(=O)c1nc(Br)sc1-c1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNC(=O)c1nc(Br)sc1-c1ccccc1
Yield: 20.3 %

Procedure:
2.0 g (6.7 mmol) of methyl 2-bromo-5-phenyl-4thiazolecarboxylate and 1.61 g (10.1 mmol) of t-butyl (2-aminoethyl)carbamate were stirred under reduced pressure for 2.5 hours at 110° bath temperature, whereby the methanol formed was distilled off continuously. After chromatography on 100 g of silica gel with methylene chloride and a 4:1 mixture of methylene chloride and ethyl acetate there was obtained 0.58 g (26%) of t-butyl [2-(2-bromo-5-phenyl-4-thiazolecarboxamido)ethyl]carbamate as a pale yellow, crystallizing oil which was used directly.
Reaction SMILES: C([CH:5]1[CH2:10][C:9]([C:17]#[N:18])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:7][C:6]1=[O:19])(OC)=O.C(C1CC(C2C=CC(Cl)=CC=2)(C#N)CCC1=O)(OC)=O.S(=O)(=O)(O)O>C(O)(=O)C>[C:17]([C:9]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:8][CH2:7][C:6](=[O:19])[CH2:5][CH2:10]1)#[N:18]
Reactant: COC(=O)C1CC(C#N)(c2ccccc2)CCC1=O
Agent: COC(=O)C1CC(C#N)(c2ccc(Cl)cc2)CCC1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: N#CC1(c2ccccc2)CCC(=O)CC1
Yield: 75 %

Procedure:
Following the procedure of Example 1, Part C, but substituting 44.7 gm. (0.174 mole) of 2-carbomethoxy-4-cyano-4-phenylcyclohexanone (prepared as in Part B, above) for the 29.8 gm. of the 2-carbomethoxy-4-(p-chlorophenyl)-4-cyanocyclohexanone and using 1200 ml. of the glacial acetic acid, and 600 ml. of the 10% aqueous sulfuric acid instead of the 660 ml. and the 330 ml., respectively, and finally recrystallizing the residual solid from a mixture of ethyl acetate and hexane, there is obtained 25.75 gm. (75% yield) of the desired 4-cyano-4-phenylcyclohexanone having a melting range from 112° to 115.5° C.
Reaction SMILES: BrC1C=NC([O:8][CH2:9][CH2:10][O:11][C:12]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[C:15]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[N:14]([CH3:38])[N:13]=2)=NC=1.C[OH:40]>>[OH:40][CH2:35][C:34]([C:31]1[CH:32]=[CH:33][C:28]([S:25]([NH:24][C:15]2[N:14]([CH3:38])[N:13]=[C:12]([O:11][CH2:10][CH2:9][OH:8])[C:16]=2[C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)(=[O:27])=[O:26])=[CH:29][CH:30]=1)([CH3:37])[CH3:36]
Reactant: CO
Reactant: Cc1ccc(-c2c(OCCOc3ncc(Br)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: Cc1ccc(-c2c(OCCO)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)CO)cc2)cc1
Reaction time: 48 h

Procedure:
Streptomyces rimosus subsp. rimosus ATCC10970 maintained on a ¼ strength ATCC172 agar slope was inoculated as a loopful of spores into five 300 ml Erlenmeyer flask containing 50 ml of AS7-H inoculum medium. This was allowed to incubate for 2 days at 28° C., 200 rpm on an Infors Multitron™ Shaker with 1″ throw. 2 mls of this inoculum medium was then transferred to each of sixty 300 ml Erlenmeyer flask containing 50 ml of AP-5H production medium and incubated under the same conditions for a further 24 hours. At this point 10 mg of N-[3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]-4-(tert-butyl)benzenesulfonamide (Example 3) dissolved in 0.5 ml of methanol was added to each of the flasks and the fermentation allowed to continue under the same conditions for a further 6 hours. Each flask was then extracted with 200 mls of ethyl acetate and the combined ethyl acetate solubles concentrated to dryness to give a gum solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[OH-].[K+].[CH2:11]([OH:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:11]([O:19][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C(O)CCCCBr
Reactant: CCCCCCCCO
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCOCCCCC(=O)O
Temperature: 97 °C
Reaction time: 27 h
Yield: 9 %

Procedure:
5-bromopentanoic acid (2g, 11.0 mmol) was added to a solution of potassium hydroxide (2.48 g, 44.2 mmol) in 1-octanol (20 mL) and stirred at 97° C. for 27 hrs. After cooling, the product was extracted at pH=1 with ethyl acetate and water. The organic phase was dried over sodium sulfate and solvent was removed. 1-octanol was removed by short path (Kugelrohr) distillation (50°-70° C., 0.5 mm Hg). To ensure complete cleavage of the octyl ester, the residue was stirred 3 hrs with methanol/water/KOH (50%/50%/2.5 g, 40 mL) at 25° C. 1-octanol was extracted into ethyl acetate at pH=12. 5-(octyloxy)pentanoic acid was extracted from the aqueous phase into ethyl acetate after adjusting the pH to 1.5 with HCl. After drying over sodium sulfate, the solvent was removed at reduced pressure. Silica column chromatography in 10% ethyl acetate/hexane/0.3% formic acid, yielded 5-(octyloxy)pentanoic acid (235 mg, 9%): mp<30° C.; 1H NMR (300 MHz, CDCl3) δ 0.88 (t, 3H, J=6.6), 1.18-1.39 (bm, 10H, methylene envelope), 1.48-1.77 (bm, 6H, CH2CH2OCH2CH2, CH2CH2COOH), 2.39 (t, 2H, J=7.1, CH2COOH), 3.34-3.49 (bm, 4H, CH2OCH2), 10.66 (br, 1H, COOH); 13C NMR (75.4 MHz, CDCl3) 14.18, 21.59, 22.73, 26.22, 29.03, 29.32, 29.51, 29.72, 31.89, 33.85, 70.22, 71.07, 179.55; m/z 231 (M+H).
Reaction SMILES: B(Br)(Br)Br.C(Cl)Cl.[CH2:8]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([O:23]C)=[CH:20][CH:21]=2)[C:16]([CH2:25][C:26]([NH2:28])=[O:27])=[C:15]1[CH3:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>C(Cl)Cl.C(OCC)(=O)C>[CH2:8]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([OH:23])=[CH:20][CH:21]=2)[C:16]([CH2:25][C:26]([NH2:28])=[O:27])=[C:15]1[CH3:29])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCn1c(C)c(CC(N)=O)c2cc(OC)ccc21
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCCCn1c(C)c(CC(N)=O)c2cc(O)ccc21
Reaction time: 16 h
Yield: 101 %

Procedure:
A mixture of 1 mL of 1M BBr3/methylene chloride and 0.24 g (0.79 mmol) of 1-hexyl-5-methoxy-2-methyl-1H-indole-3-acetamide in 20 mL of methylene chloride as stirred for 16 hours, diluted with ethyl acetate and washed twice with water. The solution was dried (Na2SO4) and the solvent removed at reduced pressure to give 0.23 g of crude 1-hexyl-5-hydroxy-2-methyl-1H-indole-3-acetamide.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Si:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:10]=1)C1C=CC=CC=1.O.[H][H]>[Pd].C(O)C>[CH3:22][Si:15]([CH3:23])([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=1
Reactant: [H][H]
Reactant: CCCCCC[Si](C)(C)c1cccc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CCCCCC[Si](C)(C)c1cccc(O)c1

Procedure:
A mixture of 34.8 g. (0.107 mole) of 1-benzyloxy-3-(dimethyl-hexylsilyl)benzene, 2.0 g. of a 1:1 mixture by weight to volume of 5% by weight palladium on carbon and water, and 100 ml. ethanol was stirred under 1 atm. hydrogen at 25° C. until hydrogen uptake ceased (after an uptake of 2.5 liters). The reaction was filtered through Supercel with ethanol and the filtrate evaporated to a quantitative yield of the title compound as an oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=O)[CH:7]=[CH:6]2.C([O-])([O-])=O.[Na+].[Na+].O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:2]([F:15])([F:14])[F:1])[CH:4]=2)[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ccc2cc(C(F)(F)F)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: FC(F)(F)c1ccc2nc(Cl)ccc2c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
6-(trifluoromethyl)-1,2-dihydroquinolin-2-one (1.0 g, 4.7 mmol) was dissolved in POCl3 (15 ml) and stirred for 2 h at 110° C. (oil bath). The resulting mixture was dissolved in ice-water (100 ml) and adjusted pH to 8 with aqueous Na2CO3 solution (3N). The crude product was then extracted with dichloromethane (3×80 ml) and the organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to afford 2-chloro-6-(trifluoromethyl)quinoline as a dark red solid (944 mg, 87%). (ES, m/z): [M+H]+ 232. 1H NMR (300 MHz, DMSO): δ 8.59-8.66 (m, 2H), 8.01-8.17 (m, 2H), 7.75 (d, J=8.7 Hz, 1H).
Reaction SMILES: C([BH3-])#N.[Na+].[NH2:5][C:6]1[C:11]2[N:12]=[C:13]([CH2:28][O:29][N:30]=[C:31]([CH3:33])[CH3:32])[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:10]=2[C:9]([CH3:34])=[C:8]([CH3:35])[N:7]=1.C(O)(=O)C.CO>O1CCCC1>[NH2:5][C:6]1[C:11]2[N:12]=[C:13]([CH2:28][O:29][NH:30][CH:31]([CH3:32])[CH3:33])[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:10]=2[C:9]([CH3:34])=[C:8]([CH3:35])[N:7]=1
Reactant: CC(C)=NOCc1nc2c(N)nc(C)c(C)c2n1CCCCNC(=O)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(N)c2nc(CONC(C)C)n(CCCCNC(=O)c3ccccc3)c2c1C
Reaction time: 8 h
Yield: 30.4 %

Procedure:
A solution of sodium cyanoborohydride in tetrahydrofuran (1 M, 6 mL) was added to a solution of N-{4-[4-amino-6,7-dimethyl-2-({[(1-methylethylidene)amino]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]butyl}benzamide (260 mg, 0.62 mmol) in 1:2 acetic acid/methanol (9 mL). The reaction mixture was stirred overnight, concentrated under reduced pressure, and partitioned between 1 M aqueous hydrochloric acid (20 mL) and chloroform (5 mL). After the bubbling subsided, the layers were separated and the aqueous phase was washed with chloroform (2×5 mL). The organic layers were combined and back-extracted with 1 M aqueous hydrochloric acid (2×5 mL). The aqueous layers were combined and adjusted to pH 10 with 1 M aqueous sodium hydroxide, then were extracted with chloroform (4×). The organic layers were combined, washed with saturated aqueous sodium bicarbonate (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield a foam. The foam was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 3-35% CMA in chloroform) followed by crystallization from acetonitrile. The crystals were isolated by filtration and dried under vacuum at 70° C. to yield 80 mg of N-[4-(4-amino-2-{[(isopropylamino)oxy]methyl}-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]benzamide as a white powder, mp 161.0-162.0° C.
Reaction SMILES: [ClH:1].C(OC([NH:9][C:10]1[CH:15]=[C:14]([CH2:16][S:17][C:18]2[C:23]([C:24]([NH:26][C:27]3[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=3)=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:13]=[CH:12][N:11]=1)=O)(C)(C)C.C(O)C>O1CCOCC1>[ClH:1].[NH2:9][C:10]1[CH:15]=[C:14]([CH2:16][S:17][C:18]2[C:23]([C:24]([NH:26][C:27]3[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=3)=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Cc1cc(C)cc(NC(=O)c2cccnc2SCc2ccnc(NC(=O)OC(C)(C)C)c2)c1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1cc(C)cc(NC(=O)c2cccnc2SCc2ccnc(N)c2)c1
Yield: 88 %

Procedure:
A solution of 4 N hydrochloric acid in 1,4-dioxane (5.0 mL) was added to a solution of 2-(2-tert-butoxycarbonylaminopyridin-4-ylmethylthio)-N-(3,5-dimethylphenyl)pyridine-3-carboxamide (Compound No. 2-1, 420 mg, 0.90 mmol) in 1,4-dioxane (5.0 mL) at room temperature, and the mixture was stirred for 12 hours. Ethanol (6.0 mL) was added to the reaction mixture, and the precipitated solid was filtered off. The solid was dried under reduced pressure at 60° C. to give 320 mg of the target compound as a colorless crystal. (Yield 88%)
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[NH:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].S(C1C=CC(C)=CC=1)(O[CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)(=O)=O>CC(N(C)C)=O>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CCOCC2)cc1
Reactant: Nc1ncnc2[nH]nc(-c3ccc(Oc4ccccc4)cc3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCOCC1
Temperature: 105 °C
Reaction time: 3.5 h
Yield: 17.8 %

Procedure:
3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (Compound 15) (0.97 g) in 33 mL dry dimethylacetamide was stirred under nitrogen while adding 60% sodium hydride (0.22 g). After 30 minutes tetrahydropyran-4-yl tosylate (1.0 g) was added and the mixture heated at 105° C. for 4 hours then 135° C. for 3.5 hours. Evaporation in vacuo and treating with water gave pale brown solid which was collected and washed well with water then dried in air. Flash chromatography in 19:1 ethyl acetate:triethylamine afforded 0.22 g (18%) of 3-(4-phenoxyphenyl)-1-(tetrahydropyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine m.p. 187-187.5° C. Calculated for C22H21N5O2 C, 68.2; H, 5.4; N, 18.1; Found C, 68.1; H, 5.5; N, 18.0.
Reaction SMILES: CCN=C=NCCCN(C)C.[Cl:12][C:13]1[CH:14]=[C:15](/[CH:33]=[C:34](\[F:38])/[C:35](O)=[O:36])[CH:16]=[N:17][C:18]=1[NH:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:21]1.[O:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]1[O:45][NH2:46].C1C=CC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[Cl:12][C:13]1[CH:14]=[C:15](/[CH:33]=[C:34](\[F:38])/[C:35]([NH:46][O:45][CH:40]2[CH2:41][CH2:42][CH2:43][CH2:44][O:39]2)=[O:36])[CH:16]=[N:17][C:18]=1[NH:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)[CH2:21]1
Reactant: NOC1CCCCO1
Reactant: O=C(O)/C(F)=C/c1cnc(N[C@@H]2CCCN(CC3CCCCC3)C2)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NOC1CCCCO1)/C(F)=C/c1cnc(N[C@@H]2CCCN(CC3CCCCC3)C2)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 67 %

Procedure:
EDCI (0.32 g) was added to the solution of (2Z)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)-2-fluoroacrylic acid (0.68 g), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.24 g), and HOBT (0.28 g) in DMF (13.6 ml) and the mixture was stirred at ambient temperature for 20 hr. The reaction mixture was poured into a mixture of AcOEt and aq NaHCO3. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallization with solution of iPE and hexane to give (2Z)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)-2-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (0.57 g).
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1.[CH:17](Cl)(Cl)Cl>O1CCOCC1.CO>[Br:5][CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([O:14][CH3:17])=[O:13])=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccc(CCBr)cc1
Reactant: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1ccc(CCBr)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of thionyl chloride (4.8 g) in chloroform (10 ml) was added, dropwise, to a solution of 4-(2-bromoethyl)benzoic acid (5.7 g) in chloroform (40 ml) and anhydrous dioxan (20 ml). When the addition was complete, the mixture was heated under reflux for 2 hours then cooled to room temperature and further thionyl chloride (2.4 g) in chloroform (10 ml) was added. The mixture was heated under reflux for 2 hours then allowed to cool to room temperature and concentrated in vacuo to give an oil which was dissolved in methanol (50 ml) and heated under reflux for 10 minutes. On cooling to room temperature, the mixture was stirred for 48 hours then concentrated in vacuo. The residue was parititoned between ethyl acetate (200 ml) and 5% aqueous sodium carbonate (200 ml), the layers were separated and the organic layer was washed with water (150 ml) then dried (MgSO4) and concentrated in vacuo to give the title compound as an oil, yield, 5.7 g.
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([C:17]([O:19]CC)=[O:18])=[CH:15][C:14]([C:22]([CH3:25])([CH3:24])[CH3:23])=[N:13]2)=[CH:8][CH:7]=1.C1COCC1.[OH-].[Li+].Cl>O.CO>[O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]([C:22]([CH3:25])([CH3:24])[CH3:23])=[N:13]2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1cc(C(C)(C)C)nn1-c1ccc(-c2nnco2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(=O)O)n(-c2ccc(-c3nnco3)cc2)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
A solution of ethyl 1-(4-(1,3,4-oxadiazol-2-yl)phenyl)-3-tert-butyl-1H-pyrazole-5-carboxylate (440 mg, 1.29 mmol) in a mixture comprised of THF (3 mL), methanol (1 mL) and water (1 mL) was cooled to 0° C. and treated with lithium hydroxide (62 mg, 2.59 mmol). The reaction mixture was stirred 3 h at 0° C. and was then allowed to warm to RT over 4 h. Water (15 mL) was added and the mixture was extracted with ether (2×10 mL). The aqueous portion was acidified by addition of 1 M aq HCl (2.5 mL, 2.5 mmol) and was extracted with EtOAc (3×20 mL). The organics were dried (Na2SO4) and concentrated in vacuo to provide 1-(4-(1,3,4-oxadiazol-2-yl)phenyl)-3-tert-butyl-1H-pyrazole-5-carboxylic acid (355 mg, 88% yield). 1H NMR (400 MHz, DMSO-d6): δ 13.35 (br s, 1 H), 9.40 (d, J=3.4 Hz, 1 H), 8.11 (m, 2 H), 7.69 (m, 2 H), 7.01 (d, J=3.2 Hz, 1 H), 1.32 (s, 9 H); MS (ESI) m/z: 313.0 (M+H+).