Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:5]=[N:6][C:7]([N:13]=[C:14]=[O:15])([CH2:9][CH:10]([CH3:12])[CH3:11])[CH3:8])([CH2:3][CH3:4])[CH3:2].[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CCCCC>[CH:1]([N:5]=[N:6][C:7]([NH:13][C:14]([NH:22][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:15])([CH3:8])[CH2:9][CH:10]([CH3:11])[CH3:12])([CH2:3][CH3:4])[CH3:2]
Reactant: NC1CCCCC1
Reactant: CCC(C)N=NC(C)(CC(C)C)N=C=O
Solvent: CCCCC
Product: CCC(C)N=NC(C)(CC(C)C)NC(=O)NC1CCCCC1
Reaction time: 0.5 h

Procedure:
To 5.3 grams (0.025 moles) of stirred 2-sec.-butylazo-2-isocyanato- 4-methylpentane (from Example XVII) in a 50 ml erlenmeyer flask was added 2.6 grams (0.026 moles) of cyclohexylamine. A solid quickly formed so 25 ml of pentane was added and the slurry stirred for approximately 1/2 hour, the solid filtered, reslurried in 25 ml of fresh pentane and refiltered. The solid was air dried and weighed. The white powder weighed 4.4 grams (57% crude yield) and had a melting range of 118° to 123° C. The infrared spectrum of the product was in agreement with the structure of N-[ 1-(sec.-butylazo)- 1,3-dimethylbutyl]-N'-cyclohexylurea (sharp NH at 3250 cm-1 and strong carbonyl band at 1625 cm-1).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[NH:3]1.[CH3:10][C:11]1[C:12]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([C:26]3[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=3)=[O:25])[CH2:20][CH2:19]2)=[N:13][CH:14]=[C:15]([CH3:17])[CH:16]=1>>[CH3:1][C:2]1([CH3:9])[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[N:3]1[C:29]1[CH:30]=[CH:31][C:26]([C:24]([N:21]2[CH2:22][CH2:23][N:18]([C:12]3[C:11]([CH3:10])=[CH:16][C:15]([CH3:17])=[CH:14][N:13]=3)[CH2:19][CH2:20]2)=[O:25])=[CH:27][CH:28]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: CC1(C)CCS(=O)(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(C)(C)CCS4(=O)=O)cc3)CC2)c(C)c1
Yield: 1.3 %

Procedure:
Using 3,3-dimethylisothiazolidine 1,1-dioxide (130 mg) described in Preparation Example 11 and [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (367 mg) described in Preparation Example 113 and by the reaction and treatment in the same manner as in Example 1, the title compound (4.9 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11]C)[C:3]=1/[CH:4]=[N:5]/O.S(Cl)(Cl)(=O)=[O:14]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]2[C:4](=[O:14])[NH:5][S:11][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CSc1cccc(Cl)c1/C=N/O
Reactant: O=S(=O)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=c1[nH]sc2cccc(Cl)c12
Temperature: 80 °C

Procedure:
(E)-2-Chloro-6-(methylthio)benzaldehyde oxime (12.37 g) was dissolved in toluene (35 mL). Sulfuryl chloride (5.4 ml, 66.24 mmol) was added, dropwise to the solution at 0° C., followed by heating at 80° C. for 1 h. After the completion of the reaction, the reaction mixture was cooled to room temperature and a white precipitate formed. The solid was collected by vacuum filtration, washed with toluene and air dried to 4-chlorobenzo[d]isothiazol-3(2H)-one (6 g). (This method is general for other 2-(methythio) benzaldehyde oximes.) 1H NMR (300 MHz, DMSO-d6): 7.90 (t, 1H), 7.55 (t, 1H), 7.41 ppm (d, 1H). MW=186 confirmed by LC-MS, tr=2.38 min (Method B) MH+=187.
Reaction SMILES: Br[C:2]1[C:3](=[O:22])[CH2:4][CH2:5][C:6]2([CH2:18][CH2:19][CH2:20][CH3:21])[C:14]=1[C:13]1[C:8](=[C:9]([Cl:17])[C:10]([O:15][CH3:16])=[CH:11][CH:12]=1)[CH2:7]2.C([Sn](CCCC)(CCCC)[C:28]([O:30][CH2:31][CH3:32])=[CH2:29])CCC>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:18]([C:6]12[CH2:5][CH2:4][C:3](=[O:22])[C:2]([C:28]([O:30][CH2:31][CH3:32])=[CH2:29])=[C:14]1[C:13]1[C:8](=[C:9]([Cl:17])[C:10]([O:15][CH3:16])=[CH:11][CH:12]=1)[CH2:7]2)[CH2:19][CH2:20][CH3:21]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CCCCC12CCC(=O)C(Br)=C1c1ccc(OC)c(Cl)c1C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C=C(OCC)C1=C2c3ccc(OC)c(Cl)c3CC2(CCCC)CCC1=O
Temperature: 100 °C
Yield: 76 %

Procedure:
A solution of 4-bromo-9a-butyl-8-chloro-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (90 mg, 0.235 mmol) in anhydrous toluene (1.2 mL) was treated with tributyl(1-ethoxyvinyl)stannane (0.111 mL, 0.352 mmol) and bis(triphenylphosphine)palladium(II) chloride (33 mg, 0.047 mmol). The mixture was placed under a nitrogen atmosphere, stirred, and heated in an oil bath at 100° C. for 3 hours. After cooling to room temperature, the mixture was purified by preparative layer chromatography on two 0.1×20×20 cm silica gel GF plates, developing with 5% EtOAc in CH2Cl2. The product band was eluted with EtOAc and the eluent evaporated under vacuum to afford 9a-butyl-8-chloro-4-(1-ethoxyvinyl)-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (67 mg) as an oil.
Reaction SMILES: [F:1][C:2]1([F:24])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14](=[O:19])[C:13]([C:20]([O:22]C)=[O:21])=[N:12]3)[C:4]=2[O:3]1.[OH-].[Na+]>C1COCC1.CO>[F:24][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14](=[O:19])[C:13]([C:20]([OH:22])=[O:21])=[N:12]3)[C:4]=2[O:3]1
Reactant: COC(=O)c1nn(-c2cccc3c2OC(F)(F)O3)cc(OC)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cn(-c2cccc3c2OC(F)(F)O3)nc(C(=O)O)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
To a solution of methyl 1-(2,2-difluoro-1,3-benzodioxol-4-yl)-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (4.1 g, 12 mmol) in THF (100 mL) and MeOH (50 mL) was added 1 M NaOH aqueous solution (18 mL, 18 mmol), and the mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure, and acidified with 1 M HCl aqueous solution. The mixture was diluted with AcOEt, washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (3.8 g, 97% yield) as a yellow amorphous solid: 1H NMR (300 MHz, CDCl3): δ ppm 4.06 (3H, s), 7.22-7.26 (1H, m), 7.34 (1H, t, J=8.3 Hz), 7.72 (1H, dd, J=8.3, 1.1 Hz), 8.29 (1H, s).
Reaction SMILES: [C:1]1([CH3:33])[CH:6]=[CH:5][C:4]([N:7]([CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]3([CH2:29][C:30](O)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:17][CH2:16]2)[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[C:40]([O:49][CH3:50])(=[O:48])[C:41]1[C:42](=[CH:44][CH:45]=[CH:46][CH:47]=1)[NH2:43].C(N(CC)CC)C>ClCCl.CN(C)C=O>[C:1]1([CH3:33])[CH:6]=[CH:5][C:4]([N:7]([CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]3([CH2:29][C:30]([NH:43][C:42]4[CH:44]=[CH:45][CH:46]=[CH:47][C:41]=4[C:40]([O:49][CH3:50])=[O:48])=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:17][CH2:16]2)[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccccc1N
Reactant: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CC(=O)O)CCCCC3)CC2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccccc1NC(=O)CC1(CCN2CCC(N(C(=O)c3ccco3)c3ccc(C)cc3)CC2)CCCCC1
Reaction time: 2 h
Yield: 39.1 %

Procedure:
To a solution of [1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]acetic acid (synthesized in Preparation Example 3B-1) (678 mg) in dichloromethane (15 mL) was added N,N-dimethylformamide (2 drops) dropwise. Oxalyl chloride (228 mg) was then added to the solution under ice cooling. The solution was stirred under ice cooling for 2 hours. A 5-mL aliquot of the reaction solution was taken and was added to a solution of methyl anthranilate (99 mg) and triethylamine (182 mg) in dichloromethane (15 mL) dropwise under ice cooling. The reaction solution was stirred for 18 hours while the temperature was allowed to rise to room temperature. NH Silica gel was then added to the reaction solution, and it was concentrated under reduced pressure. The residue was purified by chromatography [silica gel, chloroform-methanol (20:1)] to give methyl 2-[2-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]acetylamino]benzoate (150 mg).
Reaction SMILES: C1CCCCCCCCCCC1.[CH2:13]([O:25]C(C1C=C2C(=O)N(O)C(=O)C2=CC=1)=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].N(OC(C)(C)C)=O.S(=O)(=O)(O)O.[OH-].[Na+].C1(=NO)CCCCCCCCCCC1.[N+](C1CCCCCCCCCCC1)([O-])=O>C(O)(=O)C>[C:13]1(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CCCCCCCCCCCCOC(=O)c1ccc2c(c1)C(=O)N(O)C2=O
Agent: C1CCCCCCCCCCC1
Agent: CC(C)(C)ON=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C1CCCCCCCCCCC1
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
Cyclododecane (3.32 g; 19.8 mmol), 4-lauryloxycarbonyl-N-hydroxyphthalimide (0.8 mmol), and acetic acid (1 ml) were placed in a flask, t-butyl nitrite (4 mmol) was added to the mixture in four installments of 1 mmol each once every 30 minutes with stirring at 70° C. in an atmosphere of argon gas for a total of 2.5 hours. The resulting mixture was further treated with sulfuric acid having a concentration of 98% by weight (200 mg) with stirring at 70° C. for 15 minutes. The reaction mixture was then neutralized with sodium hydroxide and was analyzed to find that cyclododecanone oxime, nitrocyclododecane, and cyclododecanone were formed in yields of 41%, 6%, and 4%, respectively.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([NH:11][CH:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]([OH:15])=O)=[O:10])[C:5](=[O:22])[C:4]1=[O:23])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[NH2:39][C@H:40]1[C@H:43]([CH3:44])[N:42]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]1=[O:53].C1(C)C(S([O-])(=O)=O)=CC=CC=1.C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([NH:11][CH:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]([NH:39][C@H:40]2[C@H:43]([CH3:44])[N:42]([O:45][CH2:46][C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:41]2=[O:53])=[O:15])=[O:10])[C:5](=[O:22])[C:4]1=[O:23])[CH3:2]
Reactant: C[C@H]1[C@H](N)C(=O)N1OCc1ccccc1
Reactant: CCN1CCN(C(=O)NC(C(=O)O)c2ccccc2)C(=O)C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccccc1S(=O)(=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCN(C(=O)NC(C(=O)N[C@@H]2C(=O)N(OCc3ccccc3)[C@H]2C)c2ccccc2)C(=O)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of α-[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]benzeneacetic acid (0.879 g) hydroxybenzotriazole (0.42 g), and dicyclohexylcarbodiimide (0.56 g), in dimethylformamide (15 ml) is stirred at 26° C. for one hour, at which point a solution of (3S-trans)-3-amino-4-methyl-1-(phenylmethoxy)-2-azetidinone, toluenesulfonate (0.95 g) and diisopropylethylamine (0.44 ml) in dimethylformamide (5 ml) is added. The reaction mixture is stirred at room temperature for about 16 hours, then poured into water (100 ml) and extracted with ethyl acetate (three 100 ml portions). The combined organic extracts are washed with water (three 100 ml portions) and aqueous sodium bicarbonate solution (one 100 ml portion), then dried over sodium sulfate and concentrated under reduced pressure to a semi-solid residue. Liquid chromatography (ethyl acetate) affords the desired product as a foam (0.599 g). Recrystallization from chloroform/isopropyl ether yields the title compound, melting point 100°-105° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:12](OCC)=O)=[C:5]([CH3:11])[C:6]=1[CH:7]([CH3:10])[CH2:8][CH3:9].C=O>>[CH3:1][C:2]1[NH:3][C:4]([CH3:12])=[C:5]([CH3:11])[C:6]=1[CH:7]([CH3:10])[CH2:8][CH3:9]
Reactant: CCOC(=O)c1[nH]c(C)c(C(C)CC)c1C
Agent: C=O
Product: CCC(C)c1c(C)[nH]c(C)c1C

Procedure:
2,4-Dimethyl-3(α methyl n-propyl)-5-carbethoxy-pyrrole was reductively alkylated with paraformaldehyde to yield 2,4,5-trimethyl-3-(αmethyl n-propyl)pyrrole. ##STR99##
Reaction SMILES: C([O:8][C:9]1[C:10]([CH:24]=[O:25])=[C:11]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:12](N(CC)CC)=[O:13])C1C=CC=CC=1.C(O)(=[O:28])C>Cl>[OH:28][CH:24]1[C:10]2[C:11](=[CH:19][CH:20]=[C:21]([O:22][CH3:23])[C:9]=2[OH:8])[C:12](=[O:13])[O:25]1
Reactant: CCN(CC)C(=O)c1ccc(OC)c(OCc2ccccc2)c1C=O
Reactant: CC(=O)O
Agent: Cl
Product: COc1ccc2c(c1O)C(O)OC2=O

Procedure:
A solution of 3-benzyloxy-N,N-diethyl-2-formyl-4-methoxy-benzamide (11.6 g, 34 mmoles), prepared as described in example 56, in 10% HCl (80 ml) and acetic acid (80 ml) was refluxed for 18 hours. The solvents were evaporated and the crude taken up in toluene. The solid was washed with ethyl ether and brought to dryness to give 6.66 g of the title compound (quantitative yield) which was used as such in the subsequent step.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])(C)(C)C.C(O[C:27](=[O:50])[CH2:28][C:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[S:37][CH:38]=[C:39]([CH2:41][O:42]C3CCCCO3)[N:40]=2)[CH:31]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:13][C:8]2[N:7]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]4[S:37][CH:38]=[C:39]([CH2:41][OH:42])[N:40]=4)[CH:31]=3)[CH2:28][C:27](=[O:50])[NH:20][C:9]=2[CH:10]=1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nc(COC3CCCCO3)cs2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nc(CO)cs3)c1)=N2

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(methyl-propyl-amino)-phenyl]-carbamic acid tert-butyl ester (0.16 g) (Example J8) and 3-oxo-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl)-thiazol-2-yl]-phenyl]-propionic acid tert-butyl ester (0.23 g) (Example K27) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (0.10 g).
Reaction SMILES: [N:1]1([CH2:14][CH2:15][OH:16])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=1.[OH-].[Na+]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.ClCCl.O>[N:1]1([CH2:14][CH2:15][O:16][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=2)[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: OCCn1cnc2cnc3ccccc3c21
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc(COCCn2cnc3cnc4ccccc4c32)cc1
Yield: 78.3 %

Procedure:
2-(1H-Imidazo[4,5-c]quinolin-1-yl)ethanol (1.5 g, 7.0 mmol) was added to a stirring mixture of α-bromo-p-tolunitrile (1.79 g, 9.1 mmol), sodium hydroxide (20 ml, 50%), dichloromethane (20 ml), and benzyltrimethylammonium chloride (0.06 g, 0.3 mmol). The reaction was maintained for 18 hours and then diluted with dichloromethane (20 ml) and water (20 ml). The two phases were separated and the aqueous fraction was extracted with additional dichloromethane. The organic fractions were combined, washed with water, dried (MgSO4), filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 9/1 dichloromethane/methanol) to provide 1.8 g of 4-{[2-(1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]methyl}benzonitrile.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:19](Cl)(=[O:21])[CH3:20]>>[C:19]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:21])[CH3:20]
Reactant: CCN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: CC(=O)Cl
Product: CCN1CCC(c2c[nH]c3ccc(NC(C)=O)nc23)CC1

Procedure:
Beginning with 0.015 gm (0.061 mMol) 5-amino-3-(1-ethylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.006 mL (0.080 mMol) acetyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:14])[CH2:5][C:6]([CH3:13])([CH3:12])[O:7]2.[I:15](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](CC)(CC)CC)C1C=CC=CC=1.C(=O)(O)[O-].[Na+].C(Cl)Cl>CO>[NH2:1][C:2]1[C:11]([I:15])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:14])[CH2:5][C:6]([CH3:12])([CH3:13])[O:7]2
Reactant: CC1(C)CC(=O)c2c(N)cccc2O1
Reactant: O=I(=O)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC1(C)CC(=O)c2c(ccc(I)c2N)O1
Temperature: 40 °C
Yield: 43.8 %

Procedure:
To a 100 mL round bottom flask equipped with a magnetic stir bar was added 6 (234 mg, 1.23 mmol), benzyltriethylammonium dichloroiodate (11, 480 mg, 1.23 mmol), sodium bicarbonate (113 mg, 1.35 mmol), CH2Cl2 (5 mL) and reagent grade methanol (2 mL). The flask was equipped with a water condenser, and the mixture was heated to 40° C. with stirring until all of compound 6 was consumed, as determined by TLC analysis. CH2Cl2 (10 mL) and 10% aqueous sodium bisulfite (10 ml) were added, the organic phase was washed with brine (1×10 mL), dried over MgSO4, filtered, concentrated and dried under high vacuum. The dry, crude product was passed through a silica gel column using straight CH2Cl2 (Rf=0.5) as eluent. The reaction provided 171 mg (44%) of 7 as a yellow solid. 1H NMR (300 MHZ, CDCl3): δ 7.58 (d, J=9 Hz, 1H), 6.00 (d, J=9 Hz, 1H), 2.67 (s, 2H), 1.40 (s, 6H). 13C NMR (75.5 MHZ, CDCl3): δ 193.9, 161.3, 149.6, 145.4, 106.9, 105.8, 78.2, 73.6, 48.8, 26.5. HRMS (EI+): calculated for C11H12INO2 [M+] m/z 316.9913, found 316.9906.
Reaction SMILES: FC1C=CC(C2C=NC(N3CCN(S(C[C@H](C(C)C)C([NH:27][OH:28])=O)(=O)=O)CC3)=NC=2)=CC=1.[Cl:32][C:33]1[CH:34]=[C:35]([C:40]2[CH:41]=[N:42][C:43]([N:46]3[CH2:51][CH2:50][N:49]([S:52]([CH2:55][C@H:56]([CH:60]([CH3:62])[CH3:61])[C:57](O)=[O:58])(=[O:54])=[O:53])[CH2:48][CH2:47]3)=[N:44][CH:45]=2)[CH:36]=[CH:37][C:38]=1[Cl:39]>>[Cl:32][C:33]1[CH:34]=[C:35]([C:40]2[CH:41]=[N:42][C:43]([N:46]3[CH2:47][CH2:48][N:49]([S:52]([CH2:55][C@H:56]([CH:60]([CH3:61])[CH3:62])[C:57]([NH:27][OH:28])=[O:58])(=[O:53])=[O:54])[CH2:50][CH2:51]3)=[N:44][CH:45]=2)[CH:36]=[CH:37][C:38]=1[Cl:39]
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)NO
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(Cl)c(Cl)c3)cn2)CC1)C(=O)O
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(Cl)c(Cl)c3)cn2)CC1)C(=O)NO
Yield: 29 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-N-hydroxy-3-methylbutyramide, from 2-(R)-{4-[5-(3,4-dichlorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-3-methylbutyric acid (0.270 g), to yield the title compound as a white solid (0.080 g, 29%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[C:14]([C:27]3[N:32]=[C:31](S(C)(=O)=O)[N:30]=[C:29]([N:37]4[CH2:42][CH2:41][CH:40]([NH:43]C(=O)OC(C)(C)C)[CH2:39][CH2:38]4)[CH:28]=3)=[CH:15][N:16](S(C3C=CC(C)=CC=3)(=O)=O)[C:11]2=[CH:10][CH:9]=1.[OH-].[Na+].C(O)(C(F)(F)F)=[O:54]>O1CCOCC1.C(Cl)(Cl)Cl.CC(O)C>[NH2:43][CH:40]1[CH2:39][CH2:38][N:37]([C:29]2[CH:28]=[C:27]([C:14]3[C:12]4=[N:13][C:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])=[CH:9][CH:10]=[C:11]4[NH:16][CH:15]=3)[N:32]=[C:31]([OH:54])[N:30]=2)[CH2:42][CH2:41]1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cc(N4CCC(NC(=O)OC(C)(C)C)CC4)nc(S(C)(=O)=O)n3)c3nc(-c4ccccc4F)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: NC1CCN(c2cc(-c3c[nH]c4ccc(-c5ccccc5F)nc34)nc(O)n2)CC1
Temperature: 100 °C
Yield: 64 %

Procedure:
A glass microwave reaction vessel was charged with tert-butyl 1-(6-(5-(2-fluorophenyl)-1-tosyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-2-(methylsulfonyl)pyrimidin-4-yl)piperidin-4-ylcarbamate (100 mg, 0.139 mmol) and NaOH (0.3 mL, 0.600 mmol) in p-dioxane (2 mL). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 1 h. The mixture was diluted with CHCl3/iPrOH (4:1) and washed with water. The organic layer was dried, filtered and concentrated. The residue was dissolved in DCM (1 mL) and TFA (200 μL, 2.60 mmol) was added. The reaction was stirred at RT for 15 min, then the solvent was removed. The residue was purified with preparative HPLC (eluting with 5-30% ACN in water in 30 min) to give 4-(4-aminopiperidin-1-yl)-6-(5-(2-fluorophenyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)pyrimidin-2-ol (36.0 mg, 0.089 mmol, 64.2% yield) as a TFA salt. MS (ESI, pos. ion) m/z: 405.0 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 12.51 (1 H, br. s.), 8.79 (1 H, d, J=3.1 Hz), 8.12 (1 H, d, J=8.6 Hz), 7.85-8.05 (4 H, m), 7.76 (1 H, dd, J=8.5, 1.9 Hz), 7.46-7.61 (2 H, m), 7.32-7.44 (2 H, m), 4.19-4.55 (2 H, m), 3.37-3.52 (2 H, m), 3.10-3.33 (2 H, m), 2.04 (2 H, d, J=11.2 Hz), 1.47-1.68 (2 H, m).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].CC(C)[O-].[Zr+4:13].CC(C)[O-].CC(C)[O-].CC(C)[O-]>C1(C)C=CC=CC=1>[C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O-:4])[O-:2].[Zr+4:13].[C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O-:4])[O-:2]
Reactant: Oc1ccccc1O
Agent: [Zr+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Product: [O-]c1ccccc1[O-]
Temperature: 100 °C

Procedure:
A solution of catechol (2.20 g, 20 mmol) and toluene (25 ml) was dehydrated by distilling 5 mL of the solution. Thereafter, 5.00 g (10.6 mmol) of zirconium(IV) isopropoxide was added to the solution while stirring. The mixed solution was refluxed for 1 hour, and then, while the distillation temperature was 100° C. or higher, distilled until the amount of the solution became half. After the distillation, solid content of the product was isolated by suction filtering using a membrane suction filter. The residual solid content was heated to 100° C. under vacuum using a vacuum dryer so that remaining volatile components were completely removed. The solid content (catechol-zirconium complex) was black in color. The yield amount was 3.07 g (10.0 mmol), and the yield percentage was 100%.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[NH:14][CH3:15])[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(OCC)(=O)C>[CH3:15][NH:14][C:13]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[S:2]([CH:18]1[O:19][CH2:20][CH2:21][NH:16][CH2:17]1)(=[O:4])=[O:3]
Reactant: C1COCCN1
Reactant: CNc1ccc(C(=O)O)cc1S(=O)(=O)Cl
Solvent: CCOC(C)=O
Product: CNc1ccc(C(=O)O)cc1S(=O)(=O)C1CNCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
3-(Chlorosulfonyl)-4-(methylamino)benzoic acid (1.2, 1.0 g) was dissolved in 20 mL of ethyl acetate and morpholine (Aa, 1.0 mL, 3 eq) was added. The mixture was stirred at room temperature for 2 hours, then extracted with 15 mL of 0.5M HCl. The organic layer was washed with H2O and brine, and the solvent evaporated to yield 4-(methylamino)-3-(morpholino-sulfonyl)-benzoic acid (1.3.Aa) as an off-white powder (0.30 g, 30% yield). MS analysis (m−1)=299.