Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[CH:18]/[C:19]([OH:21])=O)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:22][C:23]1[CH:35]=[CH:34][C:26]([C:27]([NH:29][NH:30][CH:31]([CH3:33])[CH3:32])=[O:28])=[CH:25][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[Br:22][C:23]1[CH:35]=[CH:34][C:26]([C:27]([NH:29][N:30]([C:19](=[O:21])/[CH:18]=[CH:17]/[C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:9]=2)[CH:31]([CH3:32])[CH3:33])=[O:28])=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)n1cc(/C=C/C(=O)O)c2ccccc21
Reactant: CC(C)NNC(=O)c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)N(NC(=O)c1ccc(Br)cc1)C(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)acrylic acid (100 mg, 0.35 mmol), 4-bromo-N′-isopropylbenzohydrazide (134.24 mg, 0.52 mmol) and HATU (198.5 mg, 0.52 mmol) dissolved in DMF (4.0 ml), N,N-diisopropylethylamine (DIPEA)(0.09094 ml, 0.52 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (n-hexane:EtOAc=3:1) and dried so that ivory (E)-tert-butyl 3-(3-(2-(4-bromobenzoyl)-1-isopropylhydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (85.5 mg, 46.7%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH2:9]1[O:20][C:19]2[CH:18]=[CH:17][C:13]([CH2:14][CH2:15][NH2:16])=[CH:12][C:11]=2[O:10]1>ClCCl.C(N(CC)CC)C>[CH2:9]1[O:20][C:19]2[CH:18]=[CH:17][C:13]([CH2:14][CH2:15][NH:16][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:7])=[CH:12][C:11]=2[O:10]1
Reactant: O=C(Cl)c1ccco1
Reactant: NCCc1ccc2c(c1)OCO2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCc1ccc2c(c1)OCO2)c1ccco1

Procedure:
N-[2-(3,4-methylenedioxyphenyl)ethyl]furan-2-carboxamide was prepared by condensation of 2-furoyl chloride and 3,4-methylenedioxyphenethylamine in dichloromethane with triethylamine as catalyst.
Reaction SMILES: C([CH:5]([C:9]1[CH:18]=[CH:17][C:16]2[O:15][C:14]([CH3:20])([CH3:19])[CH:13]3[O:21][CH:12]3[C:11]=2[CH:10]=1)[C:6]([NH2:8])=[O:7])CCC.[NH3:22]>C(O)C>[NH2:22][CH:12]1[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([CH2:5][C:6]([NH:8][CH2:6][CH2:5][CH2:9][CH3:10])=[O:7])[CH:10]=2)[O:15][C:14]([CH3:19])([CH3:20])[CH:13]1[OH:21]
Reactant: CCCCC(C(N)=O)c1ccc2c(c1)C1OC1C(C)(C)O2
Reactant: N
Solvent: CCO
Product: CCCCNC(=O)Cc1ccc2c(c1)C(N)C(O)C(C)(C)O2

Procedure:
The n-butyl-2-(2,2-dimethyl-1a,7b-dihydro-2H-oxireno[c]chromen-6-yl) acetamide obtained above was immediately poured into a mixture of so much ethanol and 25%-strength aqueous ammonia solution (6:5 v/v) that a 0.2 M solution of the compound was obtained and was processed further in a manner corresponding to the procedure of Example 5E). 7.4 g 2-(4-amino-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-N-(n-butyl)acetamide was obtained, which was used without further purification for the subsequent reaction. The other regioisomer, 2-[3-amino-4-hydroxy-2,2-dimethylchromen-6-yl]-N-(n-butyl)acetamide, was not observed.
Reaction SMILES: [C:1]([O:9][C:10]1[C:11]([N:19]=[N:20][C:21](=[C:24]([O:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]#[N:23])=[CH:12][C:13](=[S:16](=[O:18])=[O:17])[CH2:14][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.S(Cl)([Cl:47])=O>>[C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([Cl:47])(=[O:18])=[O:17])=[CH:12][C:11]=1[N:19]=[N:20][C:21](=[C:24]([O:31][C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:22]#[N:23])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC(N=NC1=CC(=S(=O)=O)CC=C1OC(=O)c1ccccc1)=C(OC(=O)c1ccccc1)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: N#CC(N=Nc1cc(S(=O)(=O)Cl)ccc1OC(=O)c1ccccc1)=C(OC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of α-(2-benzoyloxy-5-sulfonylphenylazo)-β-benzoyloxycinnamonitrile (10 g) in 50 ml of thionyl chloride was added 3 ml of dimethylformamide. The reaction mixture was allowed to stir at room temperature for 31/2 hours. The solvent was evaporated to dryness under vacuum at room temperature. The residue was diluted with ethyl ether (50 ml) to form a white precipitate. The product was filtered off and dried to yield 9.4 g, m.p. 153° to 155° C.
Reaction SMILES: [N-:1]=[C:2]=[O:3].[CH3:4][O:5][C:6](=[O:16])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:8].[C:17]1([CH3:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C1C=CN=CC=1)C>[CH3:4][O:5][C:6](=[O:16])[C@H:7]([NH:8][C:6]([O:16][CH2:23][C:17]1[CH:22]=[CH:21][C:20]2[O:3][C:2]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:1][C:19]=2[CH:18]=1)=[O:5])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: Cc1ccccc1
Reactant: [N-]=C=O
Agent: CN(C)c1ccncc1
Product: COC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccc2oc(-c3ccccc3)nc2c1

Procedure:
A mixture of 2-(phenylbenzoxazol-5-yl)methanol 58 (215 mg, 0.95 mmol), (R)-2-isocyanato-3-phenylpropionic acid methyl ester 5(196 mg, 0.95 mmol), DMAP (12 mg, 0.095 mmol) and toluene (12 ml) was heated at reflux under an atmosphere of N2 for 3 hrs. The solvent was removed under reduced pressure and the residue purified by chromatography to yield 381 mg of (R)-2-(2-Phenylbenzoxazol-5-ylmethoxycarbonylamino)-3-phenylpropionic acid methyl ester 59.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[C:11]([F:22])[CH:10]=2)[CH2:4]1.C(N(CC)CC)C.[C:30](SCC)(=[S:32])[CH3:31]>CN(C=O)C.C(OCC)(=O)C>[C:30]([NH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])=[C:11]([F:22])[CH:10]=2)[CH2:4]1)(=[S:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)c1ccc(N2C[C@H](CN)OC2=O)cc1F
Reactant: CCSC(C)=S
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=S)NC[C@H]1CN(c2ccc(C(=O)OC(C)(C)C)c(F)c2)C(=O)O1
Yield: 84.3 %

Procedure:
A solution of 5-(S)-aminomethyl-3-[4′-(tert-butoxy)carbonyl-3′-fluorophenyl]-oxazolidine-2-one (3.00 g, 9.66 mmol), triethylamine (1.35 ml, 19.3 mmol), and ethyl dithioacetate (1.22 ml, 10.6 mmol) in DMF (8 mL) was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate (50 ml), washed with 3% aqueous citric acid (3×30 mL), saturated aqueous sodium bicarbonate (30 mL), brine, and dried (MgSO4). Evaporation afforded the product as a white solid (3.00 g, 84%). MS (m/z): [M+H]+=369.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:38])C(=O)C1>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][Br:38])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCCCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCCc1ccccc1
Reaction time: 2 h
Yield: 87.6 %

Procedure:
To a solution of 4-phenyl-1-butanol (5.00 g, 33.3 mmol) and CH2Cl2 (250 mL) 15 at 0° C. was added triphenylphosphine (13.1 g, 50.0 mmol) followed by NBS (8.90 g, 50.0 mmol). After stirring at this temperature for 2 h, the mixture was quenched with H2O (50 mL) and extracted with CH2Cl2 (150 mL) The organic layer was washed with brine (40 mL) and dried (Na2SO4). After concentration, the residue was flushed through two quick columns of silica gel using 2% EtOAc/petroleum ether as an eluant to afford 4-phenylbutyl bromide (6.22 g, 88%) as an intermediate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:5]([F:14])=[CH:4][C:3]=1[NH2:15].C1C=[CH:18][C:19](=[O:32])[C:20]2C=1C(C(Cl)=O)=C1C=2C=CC=C1>ClCCl.O1CCCC1.C(N(CC)CC)C>[CH:2]([O:32][CH:19]([CH3:18])[CH3:20])([CH3:7])[CH3:3].[NH2:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[C:5]([F:14])=[CH:4][C:3]=1[NH-:15]
Reactant: Nc1cc(F)c(N2CCOCC2)cc1N
Reactant: O=C(Cl)C1=c2ccccc2=C2C(=O)C=CC=C12
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)OC(C)C
Product: [NH-]c1cc(F)c(N2CCOCC2)cc1N
Temperature: 25 °C
Reaction time: 20 h
Yield: 294.7 %

Procedure:
The procedure used in stage 1 of Example 1 is followed, but starting from 1.5 g of 1,2-diamino-4-fluoro-5-morpholino-benzene in 50 ml of dichloromethane and 15 ml of tetrahydrofuran, 1.95 ml of triethylamine and 1.7 g of fluoren-4-one-9-carboxylic acid chloride. After stirring for 20 hours at room temperature, the precipitate that formed is filtered off, and washed with dichloromethane, with water, then with a 10% saturated aqueous solution of sodium hydrogen carbonate and, finally, with water. After formation of a paste with diisopropyl ether, in this way we obtain 2.2 g of (2-amino-5-fluoro-4-morpholinophenyl)amide of 9-oxo-9H-fluorene-4-carboxylic acid in the form of an orange powder, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9].N[C:11](N)=[O:12]>>[CH3:1][N:2]1[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:9][C:11]1=[O:12]
Reactant: CNc1ccccc1N
Reactant: NC(N)=O
Product: Cn1c(=O)[nH]c2ccccc21
Temperature: 175 °C
Reaction time: 16 h
Yield: 26.5 %

Procedure:
A mixture of 24.4 grams (0.2 mole) of N-methyl-o-phenylenediamine and 14.4 grams (0.24 mole) of urea was prepared. The mixture was stirred for 16 hours in an oil bath maintained at 175° C. The reaction mixture then was cooled to about 80° C., 250 ml. of alcohol were added, and the mixture was refluxed for 20 minutes and then was filtered while hot. The filtrate was allowed to cool to room temperature and was refrigerated overnight. The crystals that formed were filtered, dried, and recrystallized from water to obtain 7.84 grams of 3-methyl-2-oxobenzimidazole, melting point 188°-189° C.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[OH:25][CH2:26][CH:27]1[NH:32][CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>CO.O1CCOCC1.ClCCCl>[ClH:1].[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:32]2[CH2:31][CH2:30][NH:29][CH2:28][CH:27]2[CH2:26][OH:25])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCNC(CO)C1
Reactant: O=CCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Solvent: C1COCCO1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCN2CCNCC2CO)ccc1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 24.4 %

Procedure:
Prepared according to the method described in Example 66c from 2-chloro-5-(2-oxoethyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.094 g, Example 66b), 3-(hydroxymethyl)-1-piperazinecarboxylic acid, 1,1-dimethylethyl ester (0.117 g), sodium triacetoxyborohydride (0.081 g) and 1,2-dichloroethane (2 ml). After work-up, the residue was purified by HPLC eluting with a gradient of 0-5% ethanol in dichloromethane then chromatography eluting with ethyl acetate then ethyl acetate: ethanol (95:5). The white powder obtained was dissolved in methanol (2 ml) and a solution of hydrochloric acid in dioxane (4N, 1 ml) was added. The mixture was stirred for 14 h at room temperature. Solvents were then removed under reduced pressure and the product obtained was triturated with diethyl ether to afford the title compound as a white powder (0.016 g).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:27]=[C:28]([C:34]2([C:51]([F:54])([F:53])[F:52])[O:38][N:37]=[C:36]([C:39]3[N:40]4[C:44]([C:45]([C:48](O)=[O:49])=[CH:46][CH:47]=3)=[CH:43][CH:42]=[CH:41]4)[CH2:35]2)[CH:29]=[C:30]([Cl:33])[C:31]=1[F:32].Cl.[NH2:56][CH2:57][C:58]1[CH:69]=[CH:68][C:61]2[B:62]([OH:67])[O:63][C:64]([CH3:66])([CH3:65])[C:60]=2[CH:59]=1.Cl>CC#N>[Cl:33][C:30]1[CH:29]=[C:28]([C:34]2([C:51]([F:53])([F:54])[F:52])[O:38][N:37]=[C:36]([C:39]3[N:40]4[C:44]([C:45]([C:48]([NH:56][CH2:57][C:58]5[CH:69]=[CH:68][C:61]6[B:62]([OH:67])[O:63][C:64]([CH3:66])([CH3:65])[C:60]=6[CH:59]=5)=[O:49])=[CH:46][CH:47]=3)=[CH:43][CH:42]=[CH:41]4)[CH2:35]2)[CH:27]=[C:26]([Cl:25])[C:31]=1[F:32]
Reactant: CC1(C)OB(O)c2ccc(CN)cc21
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)n2cccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: CC1(C)OB(O)c2ccc(CNC(=O)c3ccc(C4=NOC(c5cc(Cl)c(F)c(Cl)c5)(C(F)(F)F)C4)n4cccc34)cc21
Reaction time: 0.08 h

Procedure:
HATU (350 mg, 0.92 mmol) can be added to CH3CN (5 mL) at 0° C. After stirring for 5 min, the mixture can be added to a solution of 5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid (0.46 mmol), 5-(aminomethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (157 mg, 0.69 mmol), and TEA (186 mg, 1.83 mmol) in CH3CN (8 mL). Then the solution can be stirred at rt for 2 h. The solution can be acidified with HCl (1 N) and extracted with EA. The combined organic layers can be washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue can be purified by prep-TLC to give the final title compound.
Reaction SMILES: [CH3:1][C:2]1[C:12](=[O:13])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:4](=[O:5])[CH:3]=1.[C:14]([O:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28]C(O)=O)=[CH:24][CH:23]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19](=[O:20])[NH:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][C:3]2[C:4](=[O:5])[CH:6]3[CH:11]([C:12](=[O:13])[C:2]=2[CH3:1])[CH:10]=[CH:9][CH:8]=[CH:7]3)=[CH:26][CH:27]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC1=CC(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(CC(=O)O)cc1
Product: CC1=C(Cc2ccc(NC(=O)OC(C)(C)C)cc2)C(=O)C2C=CC=CC2C1=O
Yield: 12 %

Procedure:
As starting materials for the coupling reaction menadione and (4-tert-Butoxycarbonylamino-phenyl)-acetic acid were used. Synthesis is realized according to the general procedure described in general procedure of example 1. After chromatography on silica gel (cyclohexane:ethyl acetate=3:1, UV), 527 mg (1.4 mmol, 12% yield) of P_TM45 were isolated as yellow solid.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:8]=[CH:7][C:6]=1[CH2:18][C:19]([O:21]C)=[O:20].O.O[Li].O.Cl>C1COCC1>[F:24][C:2]([F:1])([F:23])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:8]=[CH:7][C:6]=1[CH2:18][C:19]([OH:21])=[O:20]
Reactant: COC(=O)Cc1ccc(Oc2ccccn2)cc1OCC(F)(F)F
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1ccc(Oc2ccccn2)cc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred solution of methyl 2-(2,2,2-trifluoroethoxy)-4-(2-pyridyloxy)phenylacetate (0.45 g, 1.3 mmol) from Step 3 above in THF (4 mL) and water (1 mL) was added LiOH·H2O (0.065 g, 1.5 mmol). The mixture was stirred at ambient temperature for 14 h. The solution was adjusted to pH 3 by the addition of 5 N aqueous HCl and the solvents were removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using a gradient elution of 0-20% MeOH:CH2Cl2 to give 2-(2,2,2-trifluoroethoxy)-4-(2-pyridyloxy)-phenylacetic acid as a gum (HPLC retention time=5.4 min (method A)).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[C:25]1([CH3:34])[C:26]([N:31]=[C:32]=[S:33])=[CH:27][CH:28]=[CH:29][CH:30]=1>>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[C:22]([CH:23]=[CH:24][C:9]=2[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:32]([NH:31][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[CH3:34])=[S:33])=[CH:3][CH:4]=2)[C:14](=[O:15])[CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: Cc1ccccc1N=C=S
Product: Cc1ccccc1NC(=S)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 29.9 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (150 mg, 0.473 mmol), and o-tolyl isothiocyanate (159 μL, 1.183 mmol), the title compound (66 mg, yield 30%) was obtained in the same manner as that of Example 24.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][C:24]1[C:32]2[CH:31]3[CH2:33][CH:28]([CH2:29][CH2:30]3)[C:27]=2[N:26]([CH3:34])[N:25]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][C:24]1[C:32]2[CH:31]3[CH2:33][CH:28]([CH2:29][CH2:30]3)[C:27]=2[N:26]([CH3:34])[N:25]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1nc(CON)c2c1C1CCC2C1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cn1nc(CONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)c2c1C1CCC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (10.0 mL) were added 3-[(aminooxy)methyl]-1-methyl-4,5,6,7-tetrahydro-1H-4,7-methanoindazole 149 (0.172 g, 1.358 mmol), 1-hydroxybenzotriazole (0.183 g, 1.358 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 150 (0.34 g, 83%) as a white foam.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[N:10][C:11]([C:17]2[CH:18]=[C:19]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:20]=[N:21][CH:22]=2)=[N:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N([CH2:40][CH3:41])CC)C.[P:42](Cl)(=[O:49])([O:46][CH2:47][CH3:48])[O:43][CH2:44][CH3:45]>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1.C(Cl)Cl.O>[CH2:44]([O:43][P:42]([N:26]([S:23]([C:19]1[CH:20]=[N:21][CH:22]=[C:17]([C:11]2[N:10]=[C:9]([NH:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:8]3[C:13](=[CH:14][CH:15]=[CH:16][C:7]=3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:12]=2)[CH:18]=1)(=[O:24])=[O:25])[P:42](=[O:43])([OH:49])[O:46][CH2:40][CH3:41])([O:46][CH2:47][CH3:48])=[O:49])[CH3:45]
Reactant: CCN(CC)CC
Reactant: CCOP(=O)(Cl)OCC
Reactant: NS(=O)(=O)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOP(=O)(O)N(P(=O)(OCC)OCC)S(=O)(=O)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 19.7 %

Procedure:
To a suspension of 5-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)pyridine-3-sulfonamide (1) (0.150 g, 0.320 mmol) in CHCl3 (10 mL) was added triethylamine (0.268 mL, 1.92 mmol) followed by 4-dimethylaminopyridine (7.8 mg, 0.064 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 5 min and diethyl phosphorochloridate (0.331 g, 1.92 mmol) was added dropwise. The reaction mixture was allowed to warm up to room temperature and stirred overnight. The reaction mixture was diluted with DCM (20 mL) and water (20 mL), and extracted with DCM (3×50 mL). The combined organic layers were washed with water and brine and dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by HPLC purification to afford ethyl hydrogen diethoxyphosphoryl((5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)quinazolin-2-yl)pyridin-3-yl)sulfonyl)phosphoramidate (9) (0.045 g, 0.063 mmol, 20% yield) as a yellow solid. Preparative (Water mass) HPLC Conditions: Column: Atlantis dc18 (19×250 mm) 10 μm, Mobile Phase A: 10 mm ammonium acetate. Mobile Phase B: acetonitrile, Gradient: 10 to 60% B over 10 min, Flow Rate: 15 mL/min., Retention time: 11.35 min.; 1H NMR (400 MHz, chloroform-d) (δ ppm) 1.20-1.34 (m, 9H) 4.06-4.22 (m, 6H) 4.60-4.77 (m, 2H) 6.63 (br. s., 1H) 7.09-7.20 (m, 3H), 7.44-7.54 (m, 5H) 7.61-7.72 (m, 2H) 7.85-7.96 (m, 1H) 8.42 (d, J=4.02 Hz, 1H) 9.21 (dd, J=6.78, 2.01 Hz, 2H) 9.67 (d, J=2.01 Hz, 1H); LCMS Method D: retention time 1.56 min, [M+l]=713.2.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[C:12]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Cl:1][C:2]1[C:3](=[O:11])[N:4]([CH3:12])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cnc(O)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc([N+](=O)[O-])cc(Cl)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a stirred suspension of 3-chloro-2-hydroxy-5-nitropyridine (10 g, 57.3 mmol) and K2CO3 (15.84 g, 115 mmol) in DMF (100 mL) under Ar was added MeI (5.37 mL, 86 mmol) at 0° C. The reaction mixture was stirred for 1 hr at rt, concentrated, diluted with water, and extracted with EtOAc. The combined organic layers were washed with water, dried over Na2SO4, and evaporated to afford the title product (10.38 g, 55.0 mmol, 96% yield) as a yellow solid. tR: 2.90 min (HPLC 1).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:40])[C:21]([CH3:39])=[C:22]([C:24]3[N:29]=[CH:28][C:27]([C:30]([NH:32][C@@H:33]([CH3:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl.CO>[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:40])[C:21]([CH3:39])=[C:22]([C:24]3[N+:29]([O-:9])=[CH:28][C:27]([C:30]([NH:32][C@@H:33]([CH3:38])[C:34]([CH3:36])([CH3:35])[CH3:37])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)N[C@@H](C)C(C)(C)C)cn1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)N[C@@H](C)C(C)(C)C)c[n+]1[O-]
Temperature: 60 °C

Procedure:
mCPBA (57-86%, 10 mg) dissolved in chloroform (0.1 ml) was added to a solution of 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1S)-1,2,2-trimethylpropyl]-3-pyridinecarboxamide (Intermediate 15, 10 mg) in chloroform (2 ml) at 60° C. and the reaction maintained at 60° C. for 5 hrs. The reaction was allowed to cool, diluted with methanol, and passed through an aminopropyl SPE (1 g). The filtrate was reduced to dryness under vacuum and the residue triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1S)-1,2,2-trimethylpropyl]-3-pyridinecarboxamide 1-oxide as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-:23].[K+].[K+]>O1CCOCC1.O>[O:23]=[C:2]1[N:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:4][NH:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(Cl)n2)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc[nH]c(=O)n2)CC1
Temperature: 25 °C
Yield: 103.5 %

Procedure:
A mixture of tert-butyl 4-(2-chloropyrimidin-4-yloxy)piperidine-1-carboxylate (341.5 mg, 0.90 mmol), potassium carbonate (225.6 mg, 1.64 mmol, EMD) and 1,4-diazacyclo[2,2,2]octane (48.8 mg, 0.44 mmol, commercially available from Alfa Aesar) in dioxane/H2O (10 mL/10 mL) was heated at 70° C. for 6 h, cooled to room temperature and then evaporated. The residual was purified by flash chromatography (0 to 10% MeOH/CH2Cl2) to yield 275 mg (85%) of the product as an off-white solid.