Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([NH2:17])=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)[CH2:3][CH3:4].[H-].[Na+].Cl[CH2:21][CH2:22][S:23](Cl)(=[O:25])=[O:24].O>C1COCC1.CCCCCC>[CH3:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3=[N:17][S:23](=[O:25])(=[O:24])[CH2:22][CH2:21][N:13]3[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)[CH2:3][CH3:4]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CCC(C)c1ccc(-c2cccnc2N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCC(C)c1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
A mixture of 3-[4-(1-methylpropyl)phenyl]pyridin-2-amine (300 mg) in dehydrated THF (5 mL) was added to a mixture of sodium hydride (60%, 265 mg) and 2-chloroethanesulfonyl chloride (648 mg) in dehydrated THF (5 mL) under ice-cooling. The reaction mixture was stirred at room temperature overnight, and water and hexane were added. The resulting precipitate was collected by filtration, and washed with water and diisopropyl ether to give the title compound (376 mg) as a white solid. The obtained solid was crystallized from THF, acetonitrile and diisopropyl ether to give a white solid.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[CH3:20][O:21][C:22]1[CH:31]=[CH:30][C:25]2[NH:26][C:27](=[O:29])[O:28][C:24]=2[CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[CH3:20][O:21][C:22]1[CH:31]=[CH:30][C:25]2[N:26]([CH2:2][C:3]([N:5]3[CH2:10][CH2:9][N:8]([C:11]4[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=4)[CH2:7][CH2:6]3)=[O:4])[C:27](=[O:29])[O:28][C:24]=2[CH:23]=1
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Reactant: COc1ccc2[nH]c(=O)oc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ccc2c(c1)oc(=O)n2CC(=O)N1CCN(c2ccc(Cl)c(OC)c2)CC1

Procedure:
In a 4 mL vial was added 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (200 mg, 0.66 mmol, 1.0 equiv), 6-methoxy-3H-benzooxazol-2-one (114 mg, 0.69 mmol, 1.05 equiv), K2CO3 (365 mg, 2.64 mmol, 4.0 equiv) and 2.5 mL of NMP. A stir bar was placed in the vial and the vial was then capped. The resultant mixture stirred at 60° C. overnight. The crude product was purified by reversed phase HPLC (acetonitrile —H2O with 0.1% TFA as the eluent) to yield 6-methoxy-3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (17): HPLC retention time, 2.33 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 431.9, found, 431.9.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:9])=[CH:6][N:5]=[C:4](S(CC)(=O)=O)[N:3]=1.[CH:23]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)([CH3:25])[CH3:24]>C(O)(C)C>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:9])=[CH:6][N:5]=[C:4]([NH:38][C:35]2[CH:34]=[CH:33][C:32]([N:29]3[CH2:28][CH2:27][N:26]([CH:23]([CH3:25])[CH3:24])[CH2:31][CH2:30]3)=[CH:37][CH:36]=2)[N:3]=1
Reactant: CC(C)N1CCN(c2ccc(N)cc2)CC1
Reactant: CCS(=O)(=O)c1ncc(C(=O)c2ccccc2OC)c(N)n1
Solvent: CC(C)O
Product: COc1ccccc1C(=O)c1cnc(Nc2ccc(N3CCN(C(C)C)CC3)cc2)nc1N
Temperature: 110 °C
Yield: 42.2 %

Procedure:
A suspension of (4-amino-2-ethanesulfonylpyrimidin-5-yl)-(2-methoxyphenyl)-methanone (26.6 mg, 0.0828 mmol, Example 6) and 4-(4-isopropylpiperazin-1-yl)phenylamine (19.5 mg, 0.0889 mmol) in isopropanol (2.5 mL) was placed in a sealed tube and heated at 110° C. under microwave conditions for 1 hour. The resulting mixture was concentrated and the crude product was purified on silica gel with 95:5 of dichloromethane/methanol to give [4-amino-2-[4-(4-isopropyl-piperazin-1-yl)-phenylamino]-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone as a light yellow solid (15.6 mg, 42% yield). HRMS, observed: 447.2507; Calcd for (M+H)+: 447.2503.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:19][C:14]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:13][CH2:12][C:5]=2[C:6]=1[C:7](OCC)=[O:8].C([O-])=O.[NH4+].[CH:24]([NH2:26])=O>>[O:15]1[CH2:16][CH2:17][O:18][C:14]21[CH2:13][CH2:12][C:5]1[C:6]3[C:7](=[O:8])[NH:26][CH:24]=[N:1][C:2]=3[S:3][C:4]=1[CH2:19]2
Reactant: CCOC(=O)c1c(N)sc2c1CCC1(C2)OCCO1
Reactant: NC=O
Agent: O=C[O-]
Agent: [NH4+]
Product: O=c1[nH]cnc2sc3c(c12)CCC1(C3)OCCO1
Temperature: 140 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
To a stirring solution of ethyl 2-amino-4,7-dihydro-5H-spiro[1-benzothiophene-6,2′-[1,3]dioxolane]-3-carboxylate (40.0 g, 0.142 mol) in formamide (225 mL) was added ammonium formate (17.8 g, 0.282 mol). The resulting mixture was stirred with at 140° C. for 16 h, after which time the heterogeneous contents were removed from heating, and allowed to cool to rt. The contents were filtered, the solid filter cake was washed with water (2×60 mL), and suction dried overnight to afford the desired product as an off-white solid (33.0 g, 88%). 1H-NMR (DMSO-d6) δ 12.35 (broad s, 1H), 8.00 (s, 1H), 3.92 (s, 4H), 2.95 (t, 2H), 2.91 (s, 2H), 1.83 (t, 2H); LCMS RT=1.87 min; [M+H]+=265.2.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]=[N:6][N:7]([C:9]2[CH2:10][C@@H:11]3[CH2:28][C:27](=[O:29])[N:12]3[C:13]=2[C:14]([O:16]CC2C=CC([N+]([O-])=O)=CC=2)=[O:15])[CH:8]=1.N1(CCCS(O)(=O)=O)CCOCC1>O1CCOCC1.O.C(O)C.[Pd]>[OH:1][CH2:2][CH2:3][C:4]1[N:5]=[N:6][N:7]([C:9]2[CH2:10][C@@H:11]3[CH2:28][C:27](=[O:29])[N:12]3[C:13]=2[C:14]([OH:16])=[O:15])[CH:8]=1
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)C1=C(n2cc(CCO)nn2)C[C@@H]2CC(=O)N12
Agent: [Pd]
Agent: O=S(=O)(O)CCCN1CCOCC1
Solvent: O
Solvent: C1COCCO1
Solvent: CCO
Product: O=C(O)C1=C(n2cc(CCO)nn2)C[C@@H]2CC(=O)N12
Reaction time: 0.67 h

Procedure:
A solution of p-nitrobenzyl 2-(4-[2-hydroxyethyl]-1,2,3-triazol-1-yl)-carbapen-2-em-3-carboxylate (3.5 mg, 8.8 micromol) in dioxane (300 microliter), deionized water (180 microliter), absolute ethanol (24 microliter), and pH 7.0 4-morpholinepropanesulfonic acid buffer (60 microliter of 0.5M) was shaken with 10% (w/w) palladium on charcoal (7.0 mg) under hydrogen (50 psig) at ambient temperature. After 40 min. the mixture was centrifuged and the pellet washed with deionized water (3×0.5 ml). The combined supernate and washes were extracted with ethyl acetate (3×0.5 ml) and concentrated under vacuum to provide 0.5 ml of a solution of 2-(4-[2-hydroxyethyl]-1,2,3-triazol-1-yl)-carbapen-2-em-3-carboxylic acid, UV λmax 299 nm which quenched upon addition of hydroxylamine hydrochloride and dipotassium hydrogen phosphate.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][S:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1>ClC(Cl)Cl>[ClH:3].[Cl:3][CH2:6][CH2:7][S:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1
Reactant: OCCSc1ccncc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cl
Product: ClCCSc1ccncc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 35.3 %

Procedure:
Thionyl chloride (0.98 ml, 13.5 mmol) was added slowly to a solution of 4-(2-hydroxyethylthio)pyridine (1.39 g, 9.0 mmol) in trichloromethane (25 ml) at 5° C. The mixture was stirred at 5° C. for 1 hour and then at ambient temperature for 2 hours. The volatiles were removed by evaporation, the residue azeotroped with toluene and dried under vacuum to give 4-(2-chloroethylthio)pyridine hydrochloride (500 mg, 26%) as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](O)=[C:10]([C:15]#[N:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][NH2:18]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[NH:17][N:18]=[C:15]([NH2:16])[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CCC(O)=C(C#N)C1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2[nH]nc(N)c2C1
Temperature: 70 °C

Procedure:
To a solution of 141.5 g of 3-cyano-4-hydroxy-1,2,5,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester in 1.2 L of ethanol were added under stirring 57.8 mL of aqueous 35% hydrazine. The mixture was heated at 70° C. for 4 h. The solution was evaporated at under vacuum, the residue was diluted with 1 L of water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated to dryness. The crude product was taken-up with 300 mL tert-butyl methyl ether and the crystallized compound was collected by filtration to give 115.6 g of the title compound.
Reaction SMILES: [NH2:1][CH:2]1[C:13](=[O:14])[N:4]2[CH:5]([C:10]([OH:12])=[O:11])[C:6](=C)[CH2:7][S:8][C@H:3]12.CS(O)(=O)=[O:17]>CO>[NH2:1][CH:2]1[C:13](=[O:14])[N:4]2[CH:5]([C:10]([OH:12])=[O:11])[CH:6]([OH:17])[CH2:7][S:8][C@H:3]12
Reactant: CS(=O)(=O)O
Reactant: C=C1CS[C@@H]2C(N)C(=O)N2C1C(=O)O
Solvent: CO
Product: NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 65 %

Procedure:
7-Amino-3-methylenecepham-4-carboxylic acid (107 g.) was dissolved in a solution of methanol (6.4 l.) and methanesulfonic acid (57.7 g.). Ozone was bubbled into the solution at -70° to -75° C. until the starting compound was not detected. After bubbling nitrogen gas into the resultant mixture, sodium methoxide (3.5 g.) was added to the mixture below -65° C. Sodium borohydride (56.7 g.) was added to a solution of sodium hydroxide (14.4 g.) in water (3.2 l), stirred at room temperature for 20 minutes and chilled. The oxidized reaction mixture was added to the sodium borohydride solution over 3 minutes, and stirred at -4° to 0° C. for 20 minutes. The solution was adjusted to pH 4.0 with 6N hydrochloric acid, and allowed to stand at 5° C. overnight. The precipitates were collected by filtration, washed with methanol and then dried to give 7-amino-3-hydroxycepham-4-carboxylic acid (70.8 g.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH:5]=[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].C(=O)([O-])[O-].[Na+].[Na+].[C:27]([NH:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:29])[CH3:28].O>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:20][O:19][C:18]1[CH:17]=[CH:16][C:4]([CH:5]=[C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])=[CH:3][C:2]=1[C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([NH:30][C:27](=[O:29])[CH3:28])[CH:36]=1
Reactant: COc1ccc(C=C2C(=O)Nc3ccccc32)cc1Br
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C=C2C(=O)Nc3ccccc32)cc1-c1cccc(NC(C)=O)c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 21.3 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.02 g, 0.02 mmol) was added to a solution of 3-(3-Bromo-4-methoxy-benzylidene)-1,3-dihydroindol-2-one (0.2 g, 0.61 mmol) in toluene (1 ml) and ethanol (2 ml), followed by addition of 2M aqueous sodium carbonate (1.2 ml, 2.4 mmol). To this mixture was added 3-acetamidophenylboronic acid (0.12 g, 0.67 mmol), and the mixture was heated to 100° C. in a sealed tube and held there for 12 hours. The reaction was then poured into water (50 ml) and extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with saturated aqueous sodium bicarbonate (50 ml) and brine (50 ml). The organic layer was dried over magnesium sulfate and concentrated. Chromatography (silica, 30-40% ethyl acetate/hexanes),afforded a waxy solid that was triturated with diethyl ether/hexanes and then dried to afford 0.05 g (22%) of N-[2′-methoxy-5′-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-biphenyl-3-yl]-acetamide as a reddish orange solid.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([CH3:7])([CH3:6])[C:4]#[N:5].C[O-].[Na+].[Na].C(O)(=O)C.[NH4+:18].[Cl-:19]>CO>[ClH:19].[F:1][C:2]([F:9])([F:8])[C:3]([CH3:7])([CH3:6])[C:4]([NH2:18])=[NH:5]
Reactant: CC(C)(C#N)C(F)(F)F
Reactant: [NH4+]
Reactant: [Cl-]
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C(=N)N)C(F)(F)F
Product: Cl
Temperature: 70 °C
Reaction time: 4 h

Procedure:
3,3,3-Trifluoro-2,2-dimethyl-propionitrile (Stage 44.3) (12.40 mmol) was added to a solution of sodium methoxide (freshly prepared from 48.40 mmol sodium metal and 102 mL MeOH) at rt. After 4 h, acetic acid (48.40 mmol) and then NH4Cl (14.88 mmol) were slowly added and the reaction mixture was then heated to 70° C. for 40 h. After concentrating (40° C., 100 mbar) the reaction mixture, the residue was suspended in acetone, filtered and dried under vacuum to afford the title compound as a white solid. ESI-MS: [M+H]+ 155.
Reaction SMILES: [CH:1]1([C:7](=[O:19])[CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=2O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([C:7]2[O:19][C:12]3[C:13]([CH3:17])=[CH:14][CH:15]=[CH:16][C:11]=3[C:9](=[O:10])[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cccc(C(=O)CC(=O)C2CCCCC2)c1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc2c(=O)cc(C3CCCCC3)oc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-Cyclohexyl-3-(2-hydroxy-3-methylphenyl)-1,3-propanedione (5.2 g) was dissolved in dichloromethane (50 ml). Trifluoroacetic acid (4 ml) was added to the solution and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and then extracted with ethyl acetate. The extract was washed with water, saturated aqueous sodium bicarbonate and then water and dried (MgSO4). The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (4:1)) to obtain the title compound as crystals. The crystals were recrystallized from ethyl acetate and hexane to obtain prisms (3.66 g), m.p. 108°-109° C., yield 75.6%.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].C[N:7]([CH:9]=O)[CH3:8].C1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C:13](=[O:21])N1.[OH-].[Na+]>C1COCC1.C1(C)C=CC=CC=1>[Cl:3][C:8]1[N:7]=[CH:9][C:20]2[C:15]([C:14]=1[CH:13]=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Reactant: O=C1Cc2ccccc2CN1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=Cc1c(Cl)ncc2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a mixture of POCl3 (0.73 mL, 7.85 mmol, 3.8 eqiv.) and DMF (0.6 g, 8.16 mmol, 4.0 equiv.) in THF was added 1,2-dihydroisoquinolin-3-(4H)-one at 0° C. in portions for 5 min. The mixture was continued to stir at 0° C. for 1 h and poured into a mixture of 2 N NaOH (20 mL), ice (20 g), and toluene (20 mL). The organic phase was separated and the aqueous layer was extracted with toluene one more time. The combined organic layer was washed with water, dried over Na2SO4, and concentrated to half of its volume at low temperature in vacuo. To this mixture was added 2 N H2SO4 (20 mL) under vigorous stirring followed by ground KMnO4 in portions. The mixture was continued to stir for another 4 h. The organic phase was separated, dried over Na2SO4, and concentrated to give 3-chloroisoquinoline-4-carbaldehyde (220 mg, 50% pure) as a oil, which was used for next step without further purification. LRMS (M+H+) m/z 192.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16]S(C2C=NC=CC=2)(=O)=O)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].S1C=CN=C1C1C=CC(CN[S:45]([C:48]2[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=2)(=[O:47])=[O:46])=CC=1.[S:56]1[CH:60]=[CH:59][N:58]=[C:57]1[C:61]1[CH:68]=[CH:67][C:64]([CH2:65]O)=[CH:63][CH:62]=1.C(OC(=O)CN(C(OC(C)(C)C)=O)C1C=CC=C(CO)N=1)CCC>>[C:1]([O:5][C:6](=[O:33])[CH2:7][N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([S:45]([C:48]2[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=2)(=[O:47])=[O:46])([CH2:65][C:64]2[CH:67]=[CH:68][C:61]([C:57]3[S:56][CH:60]=[CH:59][N:58]=3)=[CH:62][CH:63]=2)[NH2:16])[N:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(CNS(=O)(=O)c2cccnc2)n1
Reactant: OCc1ccc(-c2nccs2)cc1
Reactant: O=S(=O)(NCc1ccc(-c2nccs2)cc1)c1cccnc1
Agent: CCCCOC(=O)CN(C(=O)OC(C)(C)C)c1cccc(CO)n1
Product: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(N)(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2cccnc2)n1
Yield: 85 %

Procedure:
Reaction and post-treatment were carried out in the same manner as in Example 2-(a) except for using tert-butyl(tert-butoxycarbonyl{6-[(pyridin-3-ylsulfonyl)aminomethyl]pyridin-2-yl}amino)acetate (126 mg, 0.263 mmol) obtained in Reference Example 12-(d) in place of N-[4-(thiazol-2-yl)benzyl]pyridin-3-ylsulfonamide, and using 4-(thiazol-2-yl)benzyl alcohol (49.7 mg, 0.260 mmol) obtained in Reference Example 4-(a) in place of tart-butyl[tert-butoxycarbonyl(6-hydroxymethylpyridin-2-yl)amino]acetate to afford the title compound (145 mg) as a white foam. (Yield: 85%)
Reaction SMILES: O(C)[Na].[O:4]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:22]([O:24]C)=O)[C:18]([O:20]C)=O)=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH2:26][C:27]([NH2:29])=[O:28].Cl>>[O:4]([C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[C:18](=[O:20])[NH:29][C:27](=[O:28])[NH:26][C:22]2=[O:24])=[CH:15][CH:16]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: NC(N)=O
Reactant: COC(=O)C(C(=O)OC)c1ccc(Oc2ccccc2)cc1
Agent: CO[Na]
Agent: Cl
Product: O=C1NC(=O)C(c2ccc(Oc3ccccc3)cc2)C(=O)N1
Temperature: 0 °C
Yield: 84.1 %

Procedure:
To a NaOCH3 solution (prepared by allowing 0.23 g of Na metal to react with 7.2 mL dry CH3OH) was added dimethyl 2-(4-phenoxyphenyl)malonate (1.0 g, 3.33 mmol) followed by urea (0.4 g, 6.66 mmol). The resulting white reaction mixture was refluxed for 24 hours and then cooled to 0° C. and acidified with 3N HCl. The white solids were filtered and washed with water and dried to give 900 mg of crude product. This was further purified by trituration with EtOAc/hexanes (1:1) to afford 5-(4-phenoxyphenyl)pyrimidine-2,4,6-trione as a white powder (830 mg): 1H NMR (400 mHz, CDCl3) 3:2 keto/enol form δ 11.38 (2×NH keto form, s), 10.58 (2×NH enol form, s), 7.46-6.91(9H, m), 4.85 (H-5, s); HRMS Calcd for C16H12N2O4 296.0796; Found 296.0806.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:28]=[CH:27][C:9]3[C:10]([CH2:13][O:14][C:15]4[CH:23]=[CH:22][CH:21]=[C:20]5[C:16]=4[CH:17]=[C:18]([C:24](O)=[O:25])[NH:19]5)=[CH:11][O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.[NH2:29][CH:30]1[CH2:35][CH2:34][C:33]([CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][C@H:42]([OH:45])[C@@H:41]([CH3:46])[CH2:40]2)([OH:36])[CH2:32][CH2:31]1>>[OH:36][C:33]1([CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][C@H:42]([OH:45])[C@@H:41]([CH3:46])[CH2:40]2)[CH2:34][CH2:35][CH:30]([NH:29][C:24]([C:18]2[NH:19][C:20]3[C:16]([CH:17]=2)=[C:15]([O:14][CH2:13][C:10]2[C:9]4[CH:27]=[CH:28][C:6]([O:5][CH2:4][CH:1]5[CH2:2][CH2:3]5)=[CH:7][C:8]=4[O:12][CH:11]=2)[CH:23]=[CH:22][CH:21]=3)=[O:25])[CH2:31][CH2:32]1
Reactant: O=C(O)c1cc2c(OCc3coc4cc(OCC5CC5)ccc34)cccc2[nH]1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Product: C[C@H]1CN(CCC2(O)CCC(NC(=O)c3cc4c(OCc5coc6cc(OCC7CC7)ccc56)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized analogously to example 1 from 4-(6-cyclopropylmethoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid 30b and amine 14.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:26][CH2:27][CH:28]=[C:29]1[C:35]2[CH:36]=[CH:37][CH:38]=[N:39][C:34]=2[CH2:33][O:32][C:31]2[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:26][CH2:27][CH:28]=[C:29]3[C:35]4[CH:36]=[CH:37][CH:38]=[N:39][C:34]=4[CH2:33][O:32][C:31]4[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]3=4)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: [I-]
Agent: [K+]
Solvent: Cc1cccc(C)n1
Solvent: CC(C)O
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCN(c3ccc(Cl)c(Cl)c3)CC1)c1cccnc1CO2
Temperature: 80 °C
Reaction time: 18 h
Yield: 47.6 %

Procedure:
To a solution of 1-(3,4-dichloro-phenyl)-piperazine (0.14 g, 0.601 mmol) in isopropanol (6.0 mL) was added 2,6-lutidine (95 uL, 0.802 mmol) and catalytic potassium iodide. This mixture was heated to 80° C. and treated with 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.37 g, 1.0 mmol), added in three portions over 2 h. The reaction was then stirred at 80° C. for 18 hours. The reaction was concentrated in vacuum, then purified by flash chromatography on silica gel (gradient elution from 95% ethyl acetate/5% methanol to 90% ethyl acetate/10% methanol) to yield the title compound as a white solid (0.15 g, 69%). 1H-NMR (MeOD) δ: 1.55 (6H, s), 2.35-2.65 (8H, m), 3.15-3.25 (4H, m), 5.30 (2H, br s), 6.20 (1H, t), 6.82 (1H, dd), 7.23-7.55 (5H, m), 7.59 (1H, d), 8.50 (1H, dd).
Reaction SMILES: [O:1]=[C:2]([CH3:20])[C:3](=[N:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)[C:4]([O:6][CH3:7])=[O:5].[CH3:21]OC(OC)N(C)C>>[O:1]=[C:2]1[CH:20]=[CH:21][N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[N:8]=[C:3]1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(=NNc1cccc(C(F)(F)F)c1)C(C)=O
Reactant: COC(OC)N(C)C
Product: COC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Temperature: 25 °C
Yield: 87 %

Procedure:
A solution of methyl 3-oxo-2-{[3-(trifluoromethyl)phenyl]hydrazono}butanoate (15.20 g, 52.7 mmol) in N,N-dimethylformamide dimethylacetal (150 mL) was heated at reflux for 2 h. After that time, the reaction was cooled to room temperature and then on an ice water bath. The product was collected by filtration to give methyl 4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxylate (13.7 g, 87%) as pale yellow crystals.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:24](O)=[O:25])[CH2:9]2)=[O:7])[CH2:2]1.O[N:28]=[C:29]([NH2:31])[CH3:30]>>[CH3:30][C:29]1[N:31]=[C:24]([CH:10]2[CH2:11][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=3)[CH2:13][N:8]([C:6]([N:3]3[CH2:4][CH2:5][S:1][CH2:2]3)=[O:7])[CH2:9]2)[O:25][N:28]=1
Reactant: CC(N)=NO
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCSC2)C1
Product: Cc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCSC3)C2)n1
Yield: 14.9 %

Procedure:
250 mg (0.644 mmol) of 1-(1,3-thiazolidin-3-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 102A) and 52.5 mg (0.708 mmol) of N′-hydroxyethanimidamide were reacted according to the General Method 1. Enantiomer separation of the racemate according to Method 16D gave 38.0 mg of the title compound from Example 315 and 41.0 mg of the title compound from Example 316 (29% of theory).