Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH:13]1[CH:18]=[C:17]2[C:19]([C:21](O)([OH:24])[C:22](=[O:23])[C:16]2=[CH:15][CH:14]=1)=[O:20]>S(=O)(=O)(O)O>[OH:24][C:21]1([C:5]2[CH:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[CH:3][C:4]=2[NH:9][C:10](=[O:12])[CH3:11])[C:22](=[O:23])[C:16]2[C:17](=[CH:18][CH:13]=[CH:14][CH:15]=2)[C:19]1=[O:20]
Reactant: CC(=O)Nc1ccc(C)c(C)c1
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1cc(C)c(C)cc1C1(O)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 44 %

Procedure:
N-(3,4-dimethylphenyl)acetamide (915 mg, 5.62 mmol) and ninhydrin (1.00 g, 5.62 mmol) were dissolved in conc. sulfuric acid (20 mL) and stirred at room temperature for 1.5 hrs. The reaction was stopped by slowing pouring the solution to 150 g of ice and stirring. The reaction mixture was extracted with ethylacetate and water, washed with brine. The washed organic layer was dried over sodium sulfate, concentrated in a vacuum, and purified through column chromatography (30% ethylacetate in hexane) to afford the title compound (yellow solid, 800 mg, 44%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:17][CH2:18][C:19](OC)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH:34]([OH:37])([CH3:36])[CH3:35]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:17][CH2:18][C:19]([O:37][CH:34]([CH3:36])[CH3:35])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)O
Reactant: COC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)OC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1

Procedure:
To a solution of 0.312 g methyl 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)-propyl]-octanoate in 5 mL isopropanol is added a solution of a catalytic amount of sodium hydride in 1 mL isopropanol. The mixture is refluxed for 18 hours and the solvent is evaporated. The residue is dissolved in methylene chloride and the solution is washed with saturated ammonium chloride solution. The organic phase is dried, filtered, evaporated to give a clear oil which is purified by flash column chromatography using ethyl acetate and hexane (2:3) as the eluent to give as a clear oil isopropyl 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)-propyl]-octanoate.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12](=[O:16])[CH:13]([CH3:15])[CH3:14]>>[CH3:14][CH:13]([CH3:15])[CH:12]([C:11]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[CH:9][CH:10]=1)[OH:16]
Reactant: CC(C)C=O
Reactant: c1ccc(-n2cccn2)cc1
Product: CC(C)C(O)c1ccnn1-c1ccccc1
Yield: 57 %

Procedure:
This compound was prepared from 1-phenyl-1H-pyrazole and isobutyraldehyde using the method described in example 10B and isolated as a clear oil in 57% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11].[N+:25]([CH:28]([CH3:31])[CH2:29]O)([O-:27])=[O:26].S(=O)(=O)(O)O.O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([O:12][CH2:29][CH:28]([N+:25]([O-:27])=[O:26])[CH3:31])=[O:11]
Reactant: CC(CO)[N+](=O)[O-]
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccccc1
Product: CC(COC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])[N+](=O)[O-]
Yield: 41 %

Procedure:
A stirred mixture of 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzoic acid (50 g, 0.139 mole), 2-nitropropanol (13.2 g, 0.126 mole) and conc. sulfuric acid (1 ml) in benzene (500 ml) was heated to reflux for 24 hours, during which time water (1.9 g) was removed via a Dean Stark trap. The solvent was stripped under reduced pressure and the residue poured into water (700 ml). The product was extracted into ether, which was washed with water and then with 5% sodium bicarbonate. The dried ether solution was concentrated to give 23.2 g of an amber oil which slowly solidified to a tacky semi-solid.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[C:13]([C:14]([NH2:16])=O)=[CH:12][N:11]=[C:10]([Cl:17])[CH:9]=1.O=P(Cl)(Cl)Cl.[OH-].[Na+]>C(#N)C>[Cl:7][C:8]1[C:13]([C:14]#[N:16])=[CH:12][N:11]=[C:10]([Cl:17])[CH:9]=1
Reactant: NC(=O)c1cnc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: N#Cc1cnc(Cl)cc1Cl
Temperature: 60 °C
Yield: 88.4 %

Procedure:
Pyridine (20.3 mL, 250 mmol) was added to a suspension of 4,6-dichloro-nicotinamide (8.00 g, 41.9 mmol) in acetonitrile (180 mL) at room temperature POCl3 (11.7 mL, 126 mmol) was added over 3 minutes at room temperature. The reaction mixture was heated at 60° C. with for 1.5 hours. The reaction solution was cooled to room temperature and poured into aqueous NaOH (0.8M, 600 mL) followed by extraction with EtOAc (6×400 mL). The organic extracts were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash column chromatography (30% ethyl acetate/hexanes) to give the title compound as a light orange solid (6.41 g, 88%)
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:11][CH:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)=[O:20].C(N(C(C)C)CC)(C)C.[C:39](Cl)(=[O:41])[CH3:40].O>C(Cl)Cl>[CH3:28][O:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[C:19]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]([N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:39](=[O:41])[CH3:40])[CH2:11][C:2]1([CH3:29])[CH3:1])=[O:20]
Reactant: COc1cccc(C(=O)N2c3ccccc3C(Nc3ccccc3)CC2(C)C)c1
Reactant: CC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(C(=O)N2c3ccccc3C(N(C(C)=O)c3ccccc3)CC2(C)C)c1
Temperature: 25 °C

Procedure:
To a solution of (2,2-dimethyl-4-phenylamino-3,4-dihydro-2H-quinolin-1-yl)-(3-methoxy-phenyl)-methanone in methylene chloride (5 mL) was added diisopropylethylamine followed by acetyl chloride. The mixture was stirred at room temperature over night. The mixture was poured into water and extracted with dichloromethane. The extracts were washed with 1 M (aq) NaOH and brine, dried over magnesium sulfate, filtered, dried and concentrated. The crude residue was purified by silica gel chromatography (50% hexanes/50% ethyl acetate) to afford N-[1-(3-methoxy-benzoyl)-2,2-dimethyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-acetamide.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:42](=[O:43])[N:6]2[C:7]([C:29]([O:31]CC3C=CC([N+]([O-])=O)=CC=3)=[O:30])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([C:21]([C:23]5[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=5)=[O:22])[N:17]=[C:18]([S:19][CH3:20])[N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N+](C1C=CC(COC([NH:55][S:56]([NH:59][CH2:60][CH2:61][CH2:62]O)(=[O:58])=[O:57])=O)=CC=1)([O-])=O>>[OH:1][C@@H:2]([C@H:4]1[C:42](=[O:43])[N:6]2[C:7]([C:29]([O-:31])=[O:30])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([C:21]([C:23]5[CH:24]=[N+:25]([CH2:62][CH2:61][CH2:60][NH:59][S:56](=[O:58])(=[O:57])[NH2:55])[CH:26]=[CH:27][CH:28]=5)=[O:22])[N:17]=[C:18]([S:19][CH3:20])[N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CSc1nc(C(=O)c2cccnc2)c2sc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)cn12
Reactant: O=C(NS(=O)(=O)NCCCO)OCc1ccc([N+](=O)[O-])cc1
Product: CSc1nc(C(=O)c2ccc[n+](CCCNS(N)(=O)=O)c2)c2sc(C3=C(C(=O)[O-])N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)cn12
Yield: 18.4 %

Procedure:
The title compound (41 mg) was prepared in the same manner as in steps a) and b) of Example 4, except that 222 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[5-methylthio-7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate and 166 mg of 3-(4-nitrobenzyloxycarbonylaminosulfonyl)aminopropanol were used as the starting compounds.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C@H:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:5]2[C:14]([CH3:21])=[C:15]([NH2:20])[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]=2[O:3]1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27][CH:26]=1>C(OCC)(=O)C.CCCCCC>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([NH:20][C:15]2[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]3[O:3][C:2]([CH3:22])([CH3:1])[C@H:6]([C:7]4[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=4)[C:5]=3[C:14]=2[CH3:21])=[O:33])=[CH:27][CH:26]=1
Reactant: Cc1ccc([C@@H]2c3c(C)c(N)c(C)c(C)c3OC2(C)C)cc1
Reactant: COc1ccc(CC(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(CC(=O)Nc2c(C)c(C)c3c(c2C)[C@@H](c2ccc(C)cc2)C(C)(C)O3)cc1
Yield: 74 %

Procedure:
Using (+)-(3R)-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 134 and-4-methoxyphenylacetic acid, the title compound was synthesized in the same manner as in Reference Example 359. Yield 74%. Melting point: 186-188° C. (ethyl acetate-hexane).
Reaction SMILES: [CH:1]1([NH:6][C:7](=[O:23])[NH:8][C@H:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([O:12]C(C)(C)C)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([NH:6][C:7](=[O:23])[NH:8][C@H:9]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:10]([OH:12])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)[C@H](NC(=O)NC1CCCC1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CCCC1)N[C@@H](C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.2 %

Procedure:
To a stirred solution of (R)-tert-butyl 2-(3-cyclopentylureido)-2-phenylacetate (1.31 g, 4.10 mmol) in CH2Cl2 (25 mL) was added TFA (4 mL) and trietheylsilane (1.64 mL; 10.3 mmol) dropwise, and the resulting solution was stirred at room temperature for 6 hours. The volatile components were removed under reduced pressure and the crude product was recrystallized in ethyl acetate/pentanes to yield (R)-2-(3-cyclopentylureido)-2-phenylacetic acid as a white solid (0.69 g, 64%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.17-1.35 (m, 2H) 1.42-1.52 (m, 2H) 1.53-1.64 (m, 2H) 1.67-1.80 (m, 2H) 3.75-3.89 (m, 1H) 5.17 (d, J=7.93 Hz, 1H) 6.12 (d, J=7.32 Hz, 1H) 6.48 (d, J=7.93 Hz, 1H) 7.24-7.40 (m, 5H) 12.73 (s, 1H). LCMS: Anal. Calcd. for C14H18N2O3: 262.31. Found: 263.15 (M+H)+. HPLC XTERRA® C-18 3.0×50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.2% H3PO4, B=10% water, 90% methanol, 0.2% H3PO4, RT=1.24 min, 100% homogeneity index.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH3:2].[CH2:11]1[O:13][CH:12]1[CH2:14][OH:15].N1C=CC=CC=1>C(O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH:12]([OH:13])[CH2:14][OH:15])[CH3:2]
Reactant: OCC1CO1
Reactant: CCOc1ccccc1O
Solvent: CCO
Solvent: c1ccncc1
Product: CCOc1ccccc1OCC(O)CO
Yield: 65.6 %

Procedure:
A solution of 41.5 g (0.3 mole) of 2-ethoxyphenol, 29.6 g (0.4 mole) of glycidol, 2 ml of pyridine and 150 ml of absolute ethanol was heated at reflux temperature for 18 hr. The mixture was concentrated to a thick oil that crystallized slowly over several days. The crude product was chromatographed on a silica gel column (1.2 kg) using increasing portions of acetone in methylene chloride to elute the product. The desired fractions were combined and concentrated to give a yellow oil that crystallized on standing. The solid was triturated with petroleum ether and the mixture filtered to obtain 41.8 g of solid. Recrystallization from carbon tetrachloride yielded 37.2 g (58%) of white solid, mp 64°-65° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.[C:24](=O)([O:27]C)[O:25][CH3:26]>CCOCC>[CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([C:24]([O:25][CH3:26])=[O:27])[C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCCN1Cc1ccccc1
Reactant: COC(=O)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Product: COC(=O)C1CCCCN(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A cooled (−78° C.) solution of 1-2 (2 g, 9.84 mmol) in Et2O (50 ml) was treated with LDA (9.84 ml, 19.68 mmol) and stirred for 1 h. The mixture was treated with dimethyl carbonate (1.658 ml, 19.68 mmol), warmed to RT and stirred overnight. The mixture was quenched with 1N HCl and extracted twice with EtOAc. The organic phase was dried over Na2SO4, filtered and concentrated. The crude material was purified by gradient elution on silica gel (0 to 60% EtOAc in Hex) to yield a 1:1 mixture of 1-3 and starting material as a tan oil. Data for 1-3: LRMS m/z (M+H): 262.1.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][N:19]([C:22](=[O:30])[CH2:23][NH:24][C:25](=[O:29])[O:26][CH2:27][CH3:28])[CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1>C(O)C.[H][H].[C].[Pd]>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:17][CH2:18][N:19]([C:22](=[O:30])[CH2:23][NH:24][C:25](=[O:29])[O:26][CH2:27][CH3:28])[CH2:20][CH2:21]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)NCC(=O)N1CCC(=C2c3ccccc3CCc3ccccc32)CC1

Procedure:
100 mg of palladium carbon (10% w/v) was added to 105 mg (0.261 mmol) of ethyl 2-[4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-piperidinyl]-2-oxoethylcarbamate in 3 ml of ethanol, and they were stirred at 3.6 MPa in hydrogen gas atmosphere overnight. After the filtration, the solvent was evaporated under reduced pressure to obtain the title compound.
Reaction SMILES: [CH3:1][NH2:2].C(O)C.[C:6]1([CH3:16])[CH:11]=[CH:10][CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=1>>[CH3:1][NH:2][S:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH3:16])[CH:7]=1)(=[O:14])=[O:13]
Reactant: CN
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Solvent: CCO
Product: CNS(=O)(=O)c1cccc(C)c1

Procedure:
A round-bottom flask with methylamine solution 40% (0.9 ml, 28 mmol) in ethanol (2 ml, 34 mmol), was chilled to 0° C. in an ice bath with stirring under inert atmosphere. Then m-toluenesulfonyl chloride (0.8 ml, 6 mmol) was added slowly into the mixture. The mixture was allowed to stir at 0° C., while under inert atmosphere for 30 minutes. The progress of the reaction was monitored by LC/MS, which showed mostly desired product peak. The mixture was diluted with ethyl acetate and water and then extracted the organic layer with EtOAc (3×25 ml) and brine solution. The organics were combined, dried over sodium sulfate, filtered and concentrated in vacuo. This gave N,3-dimethylbenzenesulfonamide (1.00 g, 98% yield) as a colorless oil. MS (ESI pos. ion) m/z: 186 (MH+). Calc'd exact mass for C8H11NO2S: 185. 1H NMR (400 MHz, chloroform-d): 2.35-2.46 (m, 3H), 2.64 (s, 3H), 4.91 (s, 1H), 7.36-7.46 (m, 2H), 7.64-7.73 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:23][OH:24])[C:8](N2[C@@H](CC3C=CC=CC=3)COC2=O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:25]O.O.[OH-].[Li+]>C1COCC1.O>[CH:1]1([CH2:6][C@H:7]([CH2:23][OH:24])[C:8]([OH:9])=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H](CO)CC1CCCC1
Reactant: OO
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H](CO)CC1CCCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
(4S)-3-[(2R)-3-Cyclopentyl-2-(hydroxymethyl)propanoyl]-4-(phenylmethyl)-1,3-oxazolidin-2-one (33.1 g, 0.1 mol) was stirred in a mixture of THF (330 mL) and water (55 mL) and cooled to 0° C. 30% Hydrogen peroxide (96 mL, 1 mol) was added, followed by lithium hydroxide monohydrate (8.4 g, 0.2 mol). The reaction was warmed to room temperature, and then stirred overnight. The THF was removed by rotary evaporation. The aqueous residue was washed with dichloromethane (3×100 mL), was acidified with 6N HCl, and was extracted with ethyl acetate (4×100 mL). The organic extracts were dried (MgSO4) and were evaporated to provide (2R)-3-cyclopentyl-2-(hydroxymethyl)propanoic acid as a clear, colorless oil (18.5 g, >100%). LCMS: (M+H)+: not detected. 1H NMR (400 MHz, CDCl3): δ 7.3 (br s, 1H), 3.79 (d, J=5.83 Hz, 2H), 2.64-2.71 (m, 1H), 1.45-1.87 (m, 9H), 1.05-0.14 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:11]2[N:12]=[C:13]3[C:19]([C:20]([NH:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25])=[O:21])=[CH:18][N:17](COCC[Si](C)(C)C)[C:14]3=[N:15][CH:16]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[OH:25][CH2:24][C:23]([NH:22][C:20]([C:19]1[C:13]2[C:14](=[N:15][CH:16]=[C:11]([N:8]3[C:9]4[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=4)[CH:6]=[N:7]3)[N:12]=2)[NH:17][CH:18]=1)=[O:21])([CH3:27])[CH3:26]
Reactant: CC(C)(CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3ncc4ccc(Cl)cc43)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)c1c[nH]c2ncc(-n3ncc4ccc(Cl)cc43)nc12
Yield: 0.1 %

Procedure:
To a stirred solution of 2-(6-chloro-1H-indazol-1-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (124 mg, 241 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). After 15 h the mixture was concentrated and 25 mL of a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane added. After 1 h the mixture was concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-4% of a methanol containing 10% ammonium hydroxide solution in dichloromethane) gave 2-(6-chloro-indazol-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (75 mg, 81%). MS (M+H)+=385; 1H NMR (DMSO-d6) δ: 8.97 (s, 1H), 8.56 (s, 2H), 8.44 (s, 1H), 7.99 (d, J=8.7 Hz, 1H), 7.64 (s, 1H), 7.36-7.48 (m, 1H), 3.62 (d, J=5.7 Hz, 2H), 1.43 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:11](=[N:12][N:13]([CH:17]4[CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]4)[C:14]=3[CH3:16])[C:10](=[O:28])[N:9]2[C:29]2[CH:34]=[C:33]([CH3:35])[C:32](=[O:36])[N:31]([CH3:37])[CH:30]=2)=[CH:4][CH:3]=1>C(Cl)Cl.CO>[NH:19]1[CH2:18][CH:17]([N:13]2[C:14]([CH3:16])=[C:15]3[CH:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[N:9]([C:29]4[CH:34]=[C:33]([CH3:35])[C:32](=[O:36])[N:31]([CH3:37])[CH:30]=4)[C:10](=[O:28])[C:11]3=[N:12]2)[CH2:20]1
Reactant: Cc1cc(N2C(=O)c3nn(C4CN(C(=O)OC(C)(C)C)C4)c(C)c3C2c2ccc(Cl)cc2)cn(C)c1=O
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(N2C(=O)c3nn(C4CNC4)c(C)c3C2c2ccc(Cl)cc2)cn(C)c1=O

Procedure:
The title compound was prepared using an analogous procedure to that described in Step 138.2 using tert-butyl 3-(4-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-methyl-6-oxo-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)azetidine-1-carboxylate (Step 138.1 b). tR: 0.61 min (LC-MS 2); ESI-MS: 424.1 [M+H]+ (LC-MS 2); Rf=0.05 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][CH:43]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[C:23]([N:27]5[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]5)[CH:24]=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:40])=[N:7]1.Cl>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][CH:43]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([N:27]5[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]5)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:40])=[N:7]1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3cccc(N4CCN(C(=O)OC(C)(C)C)CC4)c3)cc12
Agent: Cl
Solvent: CO
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3cccc(N4CCNCC4)c3)cc12
Yield: 25.2 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(3-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (96 mg, 0.165 mmol) was deprotected in methanol (5 ml), HCl in dioaxane (5 ml). This afforded 20 mg (23.5% yield) of the titled compound. 1H NMR (CD3OD, 400 MHz): δ 8.759-8.755 (d, 1H), 8.639-8.635 (d, 1H), 7.818 (s, 1H), 7.482-7.370 (m, 3H), 7.284-7.265 (d, 1H), 7.154-7.087 (m, 3H), 6.995-6.971 (m, 1H), 5.489 (s, 2H), 3.530-3.516 (m, 4H), 3.413-3.387 (m, 4H), 2.288 (s, 6H). MS: m/z=481.1 (M+1); HPLC: 85.59% in method A.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=O)[CH3:8])[CH:2]=1.Cl.[NH2:11][OH:12].C(=O)(O)[O-].[Na+]>CO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[N:11][OH:12])[CH3:8])[CH:2]=1
Reactant: NO
Reactant: CC(=O)c1cccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=NO)c1cccnc1
Temperature: 25 °C
Yield: 99.2 %

Procedure:
A mixture of 50 g (0.41 mol) of 1-(3-pyridinyl)ethanone and 29 g (0.42 mol) of hydroxylamine hydrochloride in 250 ml of methanol was heated under reflux for five hours. Upon cooling to room temperature, a white solid separated from the reaction mixture. This material was collected by filtration and the filtrate was concentrated to yield additional white solid. The combined solids were dissolved in water and the solution was made weakly basic by the addition of sodium bicarbonate solution while cooling. The white precipitate which formed was separated by filtration to yield 55.4 g of 1-(3-pyridinyl)ethanone oxime, mp 115° -117° C.
Reaction SMILES: [C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[NH2:16][C:17]1[CH:45]=[CH:44][C:20]([O:21][C:22]2[N:27]=[CH:26][N:25]=[C:24]([NH:28][C:29](=[O:43])[N:30]([CH:32]3[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][N:40]([CH3:42])[CH3:41])[CH2:34][CH2:33]3)[CH3:31])[CH:23]=2)=[CH:19][CH:18]=1.[F:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][C:54]([N:56]=[C:57]=[S:58])=[O:55])=[CH:49][CH:48]=1>C(O)C>[CH3:42][N:40]([CH3:41])[CH2:39][CH2:38][N:35]1[CH2:36][CH2:37][CH:32]([N:30]([CH3:31])[C:29]([NH:28][C:24]2[CH:23]=[C:22]([O:21][C:20]3[CH:44]=[CH:45][C:17]([NH:16][C:57]([NH:56][C:54](=[O:55])[CH2:53][C:50]4[CH:51]=[CH:52][C:47]([F:46])=[CH:48][CH:49]=4)=[S:58])=[CH:18][CH:19]=3)[N:27]=[CH:26][N:25]=2)=[O:43])[CH2:33][CH2:34]1
Reactant: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3)ncn2)CC1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Product: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3)ncn2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
After adding (1S)-(+)-10-camphorsulfonic acid (127 mg) to a solution of crude 3-[6-(4-aminophenoxy)pyrimidin-4-yl]-1-[1-(2-dimethylaminoethyl)piperidin-4-yl]-1-methylurea (119 mg) in ethanol (3.0 ml), the mixture was stirred for 15 minutes at room temperature. After then adding 2-(4-fluorophenyl)acetyl isothiocyanate (4.08 ml, 0.25 M solution in toluene) thereto, the mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between saturated aqueous sodium hydrogencarbonate (10 ml) and ethyl acetate (30 ml). The organic layer was washed with brine and dried over anhydrous sodium sulfate. The dried organic layer was concentrated and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=20:1 to 10:1). Fractions containing the target compound were concentrated, and the residue was purified by LC-MS (water-acetonitrile-trifluoroacetic acid system). Fractions containing the target compound were concentrated, saturated aqueous sodium hydrogencarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was then dried over anhydrous sodium sulfate. The dried organic layer was concentrated. Diethyl ether was added to the obtained solid to produce a suspension. The resulting precipitate was filtered and then dried to provide the title compound (12.4 mg) as white powder.