Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:5][CH:4]=1.C(N(CC)CC)C.C(Cl)CCl.[NH2:26][C@@H:27]([CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)[C@H:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[OH:29]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][C:12]([NH:26][C@@H:27]([CH2:36][N:37]2[CH2:38][CH2:39][O:40][CH2:41][CH2:42]2)[C@H:28]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[OH:29])=[O:14])=[CH:7][CH:8]=1
Reactant: N[C@@H](CN1CCOCC1)[C@@H](O)c1ccccc1
Reactant: COc1ccc(CCCC(=O)O)cc1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCCC(=O)N[C@@H](CN2CCOCC2)[C@@H](O)c2ccccc2)cc1
Reaction time: 8 h
Yield: 66.5 %

Procedure:
Methylene chloride (10 ml), 4-(4-methoxyphenyl)butanoic acid (388.0 mg, 2.0 mmol), triethylamine (0.70 ml, 5.0 mmol) and EDC (580 mg, 3.0 mmol) were added to (1S,2S)-2-amino-3-morpholino-1-phenyl-1-propanol (472.0 mg, 2.0 mmol), followed by stirring overnight. Methylene chloride (100 ml) was added to the reaction solution. After washed with a saturated sodium hydrogen carbonate solution (50 ml), water (50 ml) and saturated brine (50 ml) successively, the organic layer was dried over sodium sulfate and filtered, and the solvent was evaporated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform:ethanol=20:1) to obtain the title compound (549 mg, yield 66%) as colorless oil.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[O:19][C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:21]([CH3:23])[N:22]=2)[CH2:14][C@H:13]1[O:29][CH3:30])=O)C1C=CC=CC=1.C(OCC)(=O)C>[Pd].CO>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[O:19][C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:21]([CH3:23])[N:22]=2)[CH2:14][C@H:13]1[O:29][CH3:30]
Reactant: CCOC(=O)c1oc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)nc1C
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1oc(N2CC[C@H](N)[C@H](OC)C2)nc1C
Yield: 100.8 %

Procedure:
The same operation as in Example (95b) was performed using ethyl cis(±)-2-(4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-methyl-1,3-oxazole-5-carboxylate obtained in Example (107a) (0.32 g, 0.77 mmol), 10% Pd/C (0.3 g), ethyl acetate (3 mL) and methanol (3 mL), to obtain 0.22 g of the title compound as a brown oily substance (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([CH2:14][S:15](Cl)(=[O:17])=[O:16])[N:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH3:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([CH2:14][S:15]([NH2:19])(=[O:17])=[O:16])[N:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N
Reactant: O=S(=O)(Cl)Cc1csc(-c2ccc(Cl)c(Cl)c2)n1
Product: NS(=O)(=O)Cc1csc(-c2ccc(Cl)c(Cl)c2)n1

Procedure:
The sulfonyl chloride intermediate prepared in Step C above (15.3 g., 0.049 mol) was allowed to react with concentrated ammonia (150 ml) at room temperature for 10 minutes. On filtration there was obtained 8.75 g. of sulfonamide intermediate, m.p. 165°-167° C. Recrystallization from tetrahydrofuran-ether-petroleum ether gave m.p. 168°-170° C. Anal. Calc'd. for C10H8Cl2N2O2S2 : % C, 37.16; % H, 2.49; % N, 8.67. Found: % C, 37.13; % H, 2.36; % N, 8.36.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20]C)[N:13]([CH2:22][C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26]([NH2:28])=[O:27])[N:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[OH:20])[N:13]([CH2:22][C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26]([NH2:28])=[O:27])[N:12]=2)(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(C(N)=O)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)c1cccc(Cn2nc(NS(=O)(=O)c3ccc(Cl)s3)c3c(O)cccc32)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A suspension of 3-{[3-{[(5-chloro-2-thienyl)sulfonyl]amino}-4-(methyloxy)-1H-indazol-1-yl]methyl}benzamide (for a preparation see Example 64) (50.0 mg, 0.105 mmol) in anhydrous DCM (1.5 mL) under nitrogen atmosphere was treated with boron tribromide solution in DCM (1M, 0.105 mL, 0.105 mmol) at room temperature, and the mixture was stirred at room temperature for 45 min. A further 0.2 ml portion of boron tribromide solution was added and the reaction mixture was stirred at room temperature for 90 min. Saturated aqueous sodium bicarbonate solution was added dropwise to quench the reaction. The reaction was then partitioned between further saturated aqueous sodium bicarbonate solution and 10% methanol in ethyl acetate (off white precipitate was present, which was insoluble in both the organic and aqueous layer). The organic layer was separated, passed through a hydrophobic frit and evaporated in-vacuo to yield an off white solid (58 mg), which was dissolved in MeOH-DMSO (1:1) (1 mL) and purified by MDAP on Sunfire C18 column eluting with solvents A/B (A: 0.1% v/v solution of formic acid in water, B: 0.1% v/v solution of formic acid in acetonitrile 25 min run). The appropriate fraction was evaporated in-vacuo to yield a white solid (17 mg, 35%). LCMS (System B) RT=2.18 min, ES+ve m/z 463/465 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:28]=[CH:27][C:6]2[N:7]3[C:11]([CH2:12][NH:13][CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[N:25]=[C:24]([CH3:26])[O:23][N:22]=2)[CH2:17][CH2:16]1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[Cl:2][C:3]1[CH:28]=[CH:27][C:6]2[N:7]3[C:11]([CH2:12][N:13]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([C:21]2[N:25]=[C:24]([CH3:26])[O:23][N:22]=2)[CH2:17][CH2:16]1
Reactant: Cc1nc([C@H]2CC[C@H](c3nnc4n3-c3ccc(Cl)cc3CNC4)CC2)no1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc([C@H]2CC[C@H](c3nnc4n3-c3ccc(Cl)cc3CN(S(C)(=O)=O)C4)CC2)no1
Reaction time: 16 h

Procedure:
To a solution of trans-8-chloro-1-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene hydrochloride (0.100 g, 0.24 mmol) and triethylamine (0.70 ml, 0.50 mmol) in dichloromethane (4.8 ml) was added methanesulfonyl chloride (0.020 ml, 0.26 mmol) at room temperature. After stirring for 16 h the reaction mixture was concentrated in vacuo. Flash-chromatography with n-heptane/2-propanol as eluent gave the title compound (0.053 g, 48%) as white solid. MS m/e: 463 ([M+H]+).
Reaction SMILES: Br[C:2]1[C:3]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:4]=2[C:5](=[O:8])[NH:6][CH:7]=1.[C:16]([Cu])#[N:17].Cl.C>CN1C(=O)CCC1.C(C(C)=O)C>[O:8]=[C:5]1[C:4]2[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:3]=2[C:2]([C:16]#[N:17])=[CH:7][NH:6]1
Reactant: N#C[Cu]
Reactant: O=c1[nH]cc(Br)c2sc3ccccc3c12
Agent: Cl
Solvent: CCC(C)=O
Solvent: CN1CCCC1=O
Product: N#Cc1c[nH]c(=O)c2c1sc1ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 4-bromo[1]benzothieno[3,2-c]pyridin-1(2H)-one and CuCN (1.5 equiv) in NMP (0.41 M) was heated to reflux for 1.5 h. The mixture was cooled to room temperature and added to a stirring 2 N HCl solution. The mixture was stirred at room temperature for 1 h, filtered, washed with H2O and dried to give a dark grey solid. The crude product was heated to reflux with activated charcoal in methyl ethyl ketone (MEK) for 0.5 h and filtered through a short pad of silica gel, eluted with more MEK to give after concentration the title compound as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH:13][C:14](=[O:31])[CH2:15][S:16][C:17]2[S:18][CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-])=O)[CH:23]=3)[N:21]=2)[CH2:7]1.[Cl-].[NH4+]>O1CCCC1.CO.[Fe]>[NH2:28][C:24]1[CH:23]=[C:22]([C:20]2[N:21]=[C:17]([S:16][CH2:15][C:14]([NH:13][CH2:12][C@@H:8]3[O:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]4[CH:32]=[CH:33][C:34]([Cl:35])=[C:2]([Cl:1])[CH:3]=4)[CH2:7]3)=[O:31])[S:18][CH:19]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: O=C(CSc1nc(-c2cccc([N+](=O)[O-])c2)cs1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cccc(-c2csc(SCC(=O)NC[C@H]3CN(Cc4ccc(Cl)c(Cl)c4)CCO3)n2)c1

Procedure:
A solution of the resultant product (4.65 g) of (6-2) in tetrahydrofuran (24 mL) and methanol (16 mL) was added dropwise to an aqueous (16 mL) suspension of ammonium chloride (2.25 g) and iron powder (1.41 g) at 60° C. The reaction mixture was heated under reflux for 3.5 hrs. After allowing to cool, the reaction mixture was filtered through celite. A 1 mol/L aqueous sodium hydroxide solution was added to the filtrate, and the organic solvent alone was evaporated under reduced pressure. The residue was extracted with ethyl acetate, the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (3.87 g) as a pale-yellow amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:18][C:19]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[C:22]([Cl:28])[C:20]=1[NH2:21].[H-].[Na+]>O=S(Cl)Cl.C1COCC1>[Cl:18][C:19]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[C:22]([Cl:28])[C:20]=1[NH:21][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH:9]=[CH:10][C:2]=1[F:1]
Reactant: O=C(O)c1cc(-c2cccc(F)c2)ccc1F
Reactant: COc1ccc(Cl)c(N)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: COc1ccc(Cl)c(NC(=O)c2cc(-c3cccc(F)c3)ccc2F)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.3 %

Procedure:
A solution of 2-fluoro-5-(3-fluorophenyl)benzoic acid (intermediate III(a)) (1.6 g, 7 mmol, 3.0 eq) in SOCl2 (20 mL) was heated at reflux for 3 h. The excess thionyl chloride was removed in vacuo and the residue obtained dissolved in THF (10 mL) and added dropwise to a solution of 2,6-dichloro-3-methoxy-aniline (450 mg, 2.3 mmol, 1.0 eq) and NaH (85 mg, 3.4 mmol, 1.5 eq) in THF (10 mL). The reaction was stirred at room temperature for 2 h then quenched by addition of aqueous NH4Cl. The mixture was extracted with EtOAc and the combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:4) to give the title compound (200 mg, 21%).
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].ClCCl.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>O>[CH3:28][S:29]([O:17][CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:14][CH:13]=1)(=[O:31])=[O:30]
Reactant: CCCCCCCCc1ccc(CCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCc1ccc(CCOS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-(4-Octylphenyl)ethanol (53 g) and dichloromethane (500 mL) are charged into a 1 liter three-neck round bottom flask equipped with guard tube and addition funnel. Triethylamine (83.5 g) is added, the mixture is stirred for 30 minutes, then it is cooled to 0° C. Methanesulphonyl chloride (35.2 mL) is added drop-wise at 0° C. and the mass is stirred for 3 hours at room temperature. The mass is diluted with water (700 mL) and the organic layer is separated and the aqueous layer is extracted with dichloromethane (2×250 mL). The combined organic layers is washed with saturated sodium bicarbonate (500 mL) and brine solution (500 mL). The organic layer is separated, dried with sodium sulphate, and concentrated under vacuum to obtain the title compound. Yield: 70 g.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14]Cl)=[CH:10][N:9]=1.[CH2:16]([O:20][C:21]1[N:29]=[C:28]2[C:24]([NH:25][CH:26]=[N:27]2)=[C:23]([NH2:30])[N:22]=1)[CH2:17][CH2:18][CH3:19]>CN(C=O)C>[CH2:16]([O:20][C:21]1[N:29]=[C:28]2[C:24]([N:25]=[CH:26][N:27]2[CH2:14][C:11]2[CH:10]=[N:9][C:8]([Cl:7])=[CH:13][CH:12]=2)=[C:23]([NH2:30])[N:22]=1)[CH2:17][CH2:18][CH3:19]
Reactant: ClCc1ccc(Cl)nc1
Reactant: CCCCOc1nc(N)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2ncn(Cc3ccc(Cl)nc3)c2n1
Temperature: 80 °C

Procedure:
Potassium carbonate (2.85 g, 20.6 mmol) and 2-chloro-5-chloromethylpyridine (3.33 g, 20.6 mmol) were added to the DMF solution (125 ml) of 2-butoxyadenine (2.60 g, 12.5 mmol) obtained in Reference Example 1. The resultant was stirred while heating at 80° C. for 2.5 hours. The reaction solution was concentrated under reduced pressure, water (100 ml) was added thereto, and the resultant was neutralized with 1N hydrochloric acid. The precipitated solid was collected by filtration. The resulting solid was dissolved in methylene chloride (100 ml), hexane (150 ml) was added under ice cooling, and the precipitated crystal was collected by filtration. Thus, 2-butoxy-9-(6-chloro-3-pyridylmethyl)adenine was obtained (yield: 3.12 g). Bromine (1.92 ml, 37.5 mmol) was added to an acetic acid suspension (186 ml) comprising sodium acetate (3.05 g, 37.2 mmol) and 2-butoxy-9-(6-chloro-3-pyridylmethyl)adenine (3.1 g, 9.31 mmol) at room temperature, and the resultant was allowed to react for 4 hours. The reaction solution was removed by distillation under reduced pressure, water (200 ml) was added to the residue, and the resultant was neutralized with 5N sodium hydroxide under ice cooling. The precipitated crystal was collected by filtration, and crude crystal was recrystalized with the aid of methanol. The resultant was dried under reduced pressure at 40° C. for 15 hours. Thus, 2.38 g of the title compound was obtained as a white powdery crystal (yield: 62%).
Reaction SMILES: C(Cl)(Cl)Cl.[O:5]1[C:10]2[CH:11]=[CH:12][C:13]([CH2:15][N:16]([CH:24]3[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][N:32]4[C:41]5[C:36](=[C:37]([NH2:42])[CH:38]=[CH:39][CH:40]=5)[CH:35]=[CH:34][C:33]4=[O:43])[CH2:26][CH2:25]3)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1.[CH2:44]([N:46]=[C:47]=[O:48])[CH3:45]>C(N(CC)CC)C>[O:5]1[C:10]2[CH:11]=[CH:12][C:13]([CH2:15][N:16]([CH:24]3[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][N:32]4[C:41]5[C:36](=[C:37]([NH:42][C:47]([NH:46][CH2:44][CH3:45])=[O:48])[CH:38]=[CH:39][CH:40]=5)[CH:35]=[CH:34][C:33]4=[O:43])[CH2:26][CH2:25]3)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1
Reactant: CCN=C=O
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3c(N)cccc32)CC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.2 %

Procedure:
To 2 mL of a chloroform solution containing 80 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-amino-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 45 mg of triethylamine and 31 mg of ethyl isocyanate were added, and stirred at room temperature for 3 days. The reaction mixture was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; ethyl acetate: methanol=10:1], to give 60 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-(3-ethylureido)-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a yellow oil.
Reaction SMILES: [CH2:1]1[C:12]2[C:11]3[C:6](=[C:7]([CH:13]=O)[CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH2:3][CH2:2]1.Cl.[NH2:16]O.[H-].[H-].[H-].[H-].[Li+].[Al+3].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1.N1C=CC=CC=1>[CH2:1]1[C:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([CH2:13][NH2:16])[C:6]=3[NH:5][C:4]=2[CH2:3][CH2:2]1
Reactant: O=Cc1cccc2c3c([nH]c12)CCC3
Reactant: NO
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: NCc1cccc2c3c([nH]c12)CCC3
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 58.2 %

Procedure:
A mixture of 1,2,3,4-tetrahydrocyclopenta[b]indole-5-carbaldehyde (578 mg, 3.12 mmol), hydroxylamine hydrochloride (238 mg, 3.42 mmol) and pyridine (3 mL) in THF (15 mL) was stirred at rt. After 5.5 h, the reaction mixture was cooled to 0-5° C. in an ice-bath before LAH power (474 mg, 12.5 mmol) was added portionwise. The reaction mixture was then warmed to rt overnight before a sat'd Na2SO4 solution (1 mL) was added dropwise to quench the excess reagent. After 30 min of stirring, solid Na2SO4 and Et2O (30 mL) were added. The suspension was filtered and concentrated in vacuo to give 338 mg (58%) of the title compound as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[N:5][C:4]=1[O:14][CH3:15].C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH3:15][O:14][C:4]1[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[S:7][C:3]=1[CH:2]=[O:1]
Reactant: COc1nc(-c2ccncc2)sc1CO
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: COc1nc(-c2ccncc2)sc1C=O
Yield: 36.2 %

Procedure:
5-(Hydroxymethyl)-4-methoxy-2-(4-pyridyl)-thiazole (182 mg, 0.777 mmol) was dissolved in methylene chloride (4 mL) and treated with 4-methylmorpholine-N-oxide (135 mg, 1.15 mmol), powdered 4A molecular sieves (385 mg), and tetrapropylammonium perruthenate (TPAP) (14 mg, 0.040 mmol) overnight at room temperature. The mixture was applied to a column of silica gel and eluted with 25% acetone in hexane to afford 62 mg of title compound.
Reaction SMILES: C[Si](C)(C)[O-].[K+].C([O:9][C:10](=[O:45])[CH2:11][N:12]([CH3:44])[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[CH3:42])=[O:34])=[CH:28][CH:27]=3)[C:21]2=[O:43])=[CH:15][CH:14]=1)C.Cl>O1CCCC1.C(OCC)C>[CH3:44][N:12]([CH2:11][C:10]([OH:45])=[O:9])[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[CH3:42])=[O:34])=[CH:28][CH:27]=3)[C:21]2=[O:43])=[CH:15][CH:14]=1
Reactant: CCOC(=O)CN(C)c1ccc(Cn2cccc(-c3ccc(NC(=O)Nc4ccccc4C)cc3)c2=O)cc1
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccccc1NC(=O)Nc1ccc(-c2cccn(Cc3ccc(N(C)CC(=O)O)cc3)c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Potassium trimethylsilanolate (0.035 g, 0.25 mmol) was added to a solution of [methyl-(4-{2-oxo-3-[4-(3-o-tolyl-ureido)phenyl]-2H-pyridin-1-ylmethyl}phenyl)amino]acetic acid ethyl ester (0.90 g, 0.17 mmol) in tetrahydrofuran (5 mL) and the mixture stirred at room temperature for 2 hours. A solution of hydrochloric acid in diethyl ether (1 M, 1 mL) was added and solvent evaporated. The residue was triturated with diethyl ether, filtered and dried to give the title compound as a solid.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C:7]([C:26]#[N:27])([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[CH2:8][CH2:9][CH2:10][O:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)C>CCO.[NH4+].[OH-].[Ni]>[Cl:25][C:20]1[CH:19]=[C:18]([C:7]2([CH2:8][CH2:9][CH2:10][O:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH2:26][NH:27][C:4](=[O:3])[CH2:5][CH2:6]2)[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: CCOC(=O)CCC(C#N)(CCCOC1CCOCC1)c1ccc(Cl)c(Cl)c1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: O=C1CCC(CCCOC2CCOCC2)(c2ccc(Cl)c(Cl)c2)CN1
Reaction time: 64.5 h
Yield: 84.8 %

Procedure:
Raney Ni is added to a solution of cyanoester (5) (8.5 g, 19.84 mmol) in absolute EtOH (200 mL) and concentrated NH4OH (40 mL), The mixture was subjected to a H2 (51.8 psi) Par for 64.5 hours. The reaction mixture was filtered through celite, and N2 gas was passed through the solution to remove NH3. EtOH was then evaporated, and water is azeotropically removed with toluene. The crude oil is purified by flash chromatography (Ch2Cl2—MeOH/95:5) to give a colorless solid (6.5 g, 84.8% yield), mp ˜45° C.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([F:15])[C:12]([N+:16]([O-])=O)=[CH:11][C:3]=1[CH2:4][N:5]([O:9][CH3:10])[C:6](=[O:8])[CH3:7]>C(O)(=O)C.[Pt]=O>[C:6]([N:5]([CH2:4][C:3]1[C:2]([Cl:1])=[CH:14][C:13]([F:15])=[C:12]([CH:11]=1)[NH2:16])[O:9][CH3:10])(=[O:8])[CH3:7]
Reactant: CON(Cc1cc([N+](=O)[O-])c(F)cc1Cl)C(C)=O
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CON(Cc1cc(N)c(F)cc1Cl)C(C)=O
Yield: 99.3 %

Procedure:
N-(2-chloro-4-fluoro-5-nitrobenzyl)-N-methoxyacetamide (1.1 g, 0.0040 mole) was hydrogenated with a small amount (0.1 g) of platinum oxide in 50 ml of acetic acid. The reaction mixture was filtered to leave a solution of 5-[(N-acetyl-N-methoxyamino)methyl]-4-chloro-2-fluoroaniline (0.98 g) dissolved in 50 ml of acetic acid.
Reaction SMILES: [C:1]12([C:11](=[O:12])OC(C)(C)[O:6][C:4]1=[O:5])[CH2:3][CH2:2]2.Cl.[CH3:14][O:15][C:16](=[O:23])[C@H:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[NH2:18].C(N(CC)CC)C.S(=O)(=O)(O)O>CN(C=O)C.C(OCC)(=O)C>[CH3:14][O:15][C:16](=[O:23])[C@@H:17]([N:18]1[CH2:2][CH2:3][CH:1]([C:4]([OH:6])=[O:5])[C:11]1=[O:12])[CH2:19][CH:20]([CH3:22])[CH3:21]
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CC(C)C)N1CCC(C(=O)O)C1=O
Temperature: 25 °C

Procedure:
2(S)(3-carboxy-2-oxo-1-pyrrolidinyl)-4-methyl pentanoic acid methyl ester was prepared according to the method of R. M. Freidinger, J.Org.Chem., 1985, 50 (19):3631-3633. A solution of isopropylidene cyclopropane-1,1-dicarboxylate (5.0 g, 29.30 mmol), leucine methyl ester hydrochloride (5.31 g, 29.3 mmol), and triethylamine (2.97 g, 29.3 mmol) in degassed DMF (50 mL) was heated at 65° C. for 1 hour. The solution was cooled to ambient temperature and poured into a mixture of 10% aqueous sulfuric acid (H2SO4) (100 mL) and ethyl acetate (100 mL). The organic layer was separated. After drying with Na2SO4, the solvent was removed in vacuo to yield 7.55 g of a brown oil. To the crude oil (7.55 g) in degassed DMF (50 mL) were added 3-(dimethylaminomethyl)indole (gramine) methiodide (13.2 g, 42.94 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (5.16 g, 33.90 mmol). The mixture was heated at 85° C. for 18 hours and cooled to ambient temperature. The mixture was poured into ethyl acetate (100 mL) and saturated aqueous NaHCO3 (100 mL). The aqueous phase was separated, acidified to pH 3-4 with 10% aqueous H2SO4, and extracted with ethyl acetate (3×). After drying with Na2SO4, the solvent was removed in vacuo and the residue chromatographed (eluting with 1% acetic acid/ethyl acetate) to yield 1.56 g of the title compound as a white solid; MS(FAB+) m/e 387 (M+H)+. 1H NMR(DMSO-d6, 300 MHz) δ0.65 (m, 6H), 1.23-1.80 (m, 3H), 1.90 (m, 1H), 2.12 (m, 1H), 2.77-3.48 (m, 6H), 3.51 (m, 3H), 4.98 (m, 1H), 6.92 (m, 3 H), 7.28 (d, 1H), 7.97 (d, 1H), 10.90 (br s, 1H), 12.70 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH:28][C:29](=[O:38])[CH2:30][CH2:31][NH:32]C(=O)COC)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.C(O)(=O)C1C=CC=CC=1>>[NH2:32][CH2:31][CH2:30][C:29]([NH:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][N:19]=[C:18]2[NH:17][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[C:2]([Cl:1])[CH:3]=1)=[O:38]
Reactant: COCC(=O)NCCC(=O)Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Agent: O=C(O)c1ccccc1
Product: NCCC(=O)Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1

Procedure:
The procedure of (20-2) of Example 20 was repeated except for using benzoic acid and 0.05 g of the compound obtained in (20-1) of Example 20 instead of methoxyacetic acid to obtain the title compound (0.03 g, 49%).