Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16][C:17]1[C:18]2[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=2[O:20][CH:21]=1)C)(C)(C)C.C(OCC)C.Cl>CO>[O:20]1[CH:21]=[C:17]([S:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][NH:7][CH3:6])[C:18]2[CH:25]=[CH:24][CH:23]=[CH:22][C:19]1=2
Reactant: CN(Cc1ccccc1Sc1coc2ccccc12)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CNCc1ccccc1Sc1coc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[2-(Benzo[b]furan-3-ylsulfanyl)-benzyl]-methyl-carbamic acid tert-butyl ester (9.2 g, 24.9 mmol) is dissolved in methanol (75 mL) and diethyl ether saturated with hydrochloric acid (75 mL) is added. The mixture is stirred at ambient temperature for 1 hour and then concentrated in vacuo. Water (50 mL) is added to the remanence and the mixture is basified by addition of aqueous ammonia (conc.). The aqueous fraction is extracted with ethyl acetate (3×100 mL). The combined organic fractions are dried (MgSO4) and concentrated in vacuo. The product is purified by preparative HPLC or by silica gel chromatography eluting with ethyl acetate-triethyl amine (25:1) to furnish the title compound as an oil. This oil can be redissolved in ethyl acetate (75 mL). Diethyl ether saturated with hydrochloric acid can be added hereto until pH 2. The precipitated material can then be filtered off and dried in vacuo to give 6.9 g (91%) of [2-(benzo[b]furan-3-ylsulfanyl)-benzyl]-methyl-amine hydrochloride as a white crystalline material.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:6]1[C:11]([Cl:12])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][N:7]=1)[C:4]#[N:5].C(N(CC)CC)C.[C:24](Cl)(=[O:26])[CH3:25]>ClCCl>[Cl:12][C:11]1[C:6]([CH:3]([C:4]#[N:5])[NH:2][C:24](=[O:26])[CH3:25])=[N:7][CH:8]=[C:9]([C:13]([F:15])([F:16])[F:14])[CH:10]=1
Reactant: CC(=O)Cl
Reactant: N#CC(N)c1ncc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC(C#N)c1ncc(C(F)(F)F)cc1Cl
Reaction time: 0.17 h

Procedure:
0.67 g of amino[3-chloro-5-(trifluoromethyl)-2-pyridinyl]acetonitrile hydrochloride (0.00245 mol) are dissolved in 15 mL of dichloromethane, 0.68 mL of triethylamine are added. After 10 min. at room temperature, 0.18 mL of acetyl chloride (0.00245 mol) are added, the reaction mixture is stirred overnight. The reaction is quenched with 20 mL of water.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]>CO.C(OCC)(=O)C.[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([NH2:14])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-n2ccc([N+](=O)[O-])n2)cc1C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(-n2ccc(N)n2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of 1-(3,4-dimethylphenyl)-3-nitro-1H-pyrazole (900 mg, 4.15 mmol, 1.00 equiv) in methanol/ethyl acetate (20/10 mL). The solution was treated with Pd/C (500 mg) and stirred under an atmosphere of hydrogen overnight at room temperature. The reaction progress was monitored by LCMS. The solids were filtered out. The resulting mixture was concentrated under vacuum to yield 750 mg (97%) of 1-(3,4-dimethylphenyl)-1H-pyrazol-3-amine as a yellow solid.
Reaction SMILES: C([O:4][CH:5]1[C:10]2[CH:11]=[CH:12][S:13][C:9]=2[CH2:8][CH2:7][CH2:6]1)(=O)C.[Br:14]N1C(=O)CCC1=O.O.[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:14][C:12]1[S:13][C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([OH:4])[C:10]=2[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)OC1CCCc2sccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: OC1CCCc2sc(Br)cc21
Yield: 82 %

Procedure:
To a solution of 4,5,6,7-tetrahydro-1-benzothien-4-yl acetate (5.1 g, 26 mmol) in chloroform (30 ml) was added N-bromosuccinimide (5 g, 28 mmol) at 0° C. with stirring, and the resulting mixture was stirred at room temperature for 3 hours. After stirring, the reaction mixture was poured into water (40 ml) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo. Subsequently, to a solution of the residue thus obtained in a mixed solvent of tetrahydrofuran (20 ml) and water (20 ml) was added sodium hydroxide (2.3 g, 57 mmol) with stirring, and the resulting mixture was stirred for 2 hours. After stirring, the reaction mixture was poured into water (50 ml) to quench the reaction and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (3:7) as the eluent to afford the title compound (5.0 g) in a yield of 82% as a colourless oily product.
Reaction SMILES: [C:1]([C:3]([C:20]#[N:21])=[C:4](OC)[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)#[N:2].O.[NH2:23][NH2:24].O>C(O)C>[NH2:2][C:1]1[C:3]([C:20]#[N:21])=[C:4]([C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][CH:6]=2)[NH:24][N:23]=1
Reactant: COC(=C(C#N)C#N)c1ccc(Oc2ccccc2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: N#Cc1c(N)n[nH]c1-c1ccc(Oc2ccccc2)cc1

Procedure:
1,1-Dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene (22.5 g) and 1,1-dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene oil (15 g) are treated with a solution of hydrazine hydrate (18 mL) in ethanol (25 mL) and heated on the steambath for 1 hour. Ethanol (15 mL) is added followed by water (10 mL). The precipitated solid is collected and washed with ethanol:water (4:1) and then dried in air to give 3-amino-4-cyano-5-(4-phenoxyphenyl)pyrazole as a pale orange solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[NH:18][C:19]([C:22]5[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=5)=[N:20][N:21]=4)[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[NH:18][C:19]([C:22]5[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=5)=[N:20][N:21]=4)[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(-c2nnc(-c3ccc4[nH]nc(-c5ccc(F)cc5)c4c3)[nH]2)cc1
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2nnc(-c3ccc4[nH]nc(-c5ccc(F)cc5)c4c3)[nH]2)cc1
Reaction time: 8 h
Yield: 27 %

Procedure:
To a flask containing 5-[3-(4-fluorophenyl)(1H-indazol-5-yl)]-3-(4-nitrophenyl)-4H-1,2,4-triazole (60 mg) was added ethyl acetate (15 ml). The flask was evacuated and purged with nitrogen. To the flask was added palladium on carbon catalyst (10 mg). The reaction was placed under a hydrogen atmosphere and allowed to stir overnight. The reaction was filtered through celite and the organic layer was concentrated. The product was purified by HPLC to yield the title compound (15 mg, 26% yield). 1H NMR (DMSO-d6) δ 13.5 (s, 1H), 8.65 (s, 1H), 8.1 (d, 1H), 8.05 (t, 2H), 7.77 (d, 2H), 7.7 (d, 1H), 7.4 (t, 2H), 6.7 (d, 2H), ES-MS (m/z) 371 [M+1]+.
Reaction SMILES: [CH3:1][NH:2][C:3](C1N(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)N=CN=1)=O.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]3[C:43]=2[CH2:44][N:45]2[CH:49]=[N:48][C:47]([C:50](OC)=[O:51])=[N:46]2)=[CH:31][CH:30]=1.CNC>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]3[C:43]=2[CH2:44][N:45]2[CH:49]=[N:48][C:47]([C:50]([N:2]([CH3:3])[CH3:1])=[O:51])=[N:46]2)=[CH:31][CH:30]=1
Reactant: COC(=O)c1ncn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)n1
Reactant: CNC(=O)c1ncnn1Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Agent: CNC
Product: CN(C)C(=O)c1ncn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)n1

Procedure:
The title compound was prepared according to the procedure described for compound 68 from methyl 1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1H-1,2,4-triazole-3-carboxylate and dimethylamine. 1H-NMR (400 MHz, CDCl3, δ) 8.65 (d, J=6.9 Hz, 1H), 7.88 (s, 1H), 7.85 (d, J=8.5 Hz, 2H), 7.66 (d, J=9.1 Hz, 1H), 7.45 (d, J=8.5 Hz, 2H), 7.28 (m, 1H), 6.89 (m, 1H), 6.04 (s, 2H), 3.15 (s, 3H), 3.06 (s, 3H) ppm; m/e 381, 383.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH2:13][CH2:14][OH:15])[CH2:12][CH2:11][NH:10][CH2:9]1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[C:21](Cl)=[O:22]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH2:13][CH2:14][OH:15])[CH2:12][CH2:11][N:10]([C:21](=[O:22])[C:20]2[CH:19]=[C:18]([O:17][CH3:16])[C:26]([O:27][CH3:28])=[C:25]([O:29][CH3:30])[CH:24]=2)[CH2:9]1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: OCCC1(c2ccccc2F)CCNC1
Product: COc1cc(C(=O)N2CCC(CCO)(c3ccccc3F)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.1 using 2-[3-(2-fluoro-phenyl)-pyrrolidin-3-yl]-ethanol (23 mmol) and 3,4,5-trimethoxy-benzoyl chloride (23 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.[Br:17][C:18]1[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[C:20](Br)[CH:19]=1>>[Br:17][C:18]1[CH:19]=[C:20]([C:9]2[CH:10]=[CH:11][C:6]3[NH:5][C:4](=[O:15])[O:3][C:2]([CH3:16])([CH3:1])[C:7]=3[CH:8]=2)[CH:21]=[C:22]([O:24][C:25]([F:26])([F:27])[F:28])[CH:23]=1
Reactant: FC(F)(F)Oc1cc(Br)cc(Br)c1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Product: CC1(C)OC(=O)Nc2ccc(-c3cc(Br)cc(OC(F)(F)F)c3)cc21

Procedure:
6-(3-Bromo-5-trifluoromethoxy-phenyl)-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]-oxazin-2-one was prepared, using (4,4-dimethyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 1,3-dibromo-5-trifluoromethoxybenzene according to the procedure of Example 5, as a white solid: mp 214-216° C.; 1H-NMR (DMSO-d6) δ 10.4 (s, 1H), 7.99 (s, 1H), 7.73 (s, 1H), 7.68-7.62 (m, 3H), 6.97 (d, 1H, J=8.0 Hz), 1.68 (s, 6H); MS (ESI) m/z 414 ([M−H]−, 100%); Anal. Calcd. For C17H13BrF3NO3: C, 49.06; H, 3.15; N, 3.37. Found: C, 49.16; H, 3.05; N, 3.30.
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[C:7]2[C:10]([NH:13][CH3:14])=[N:11][NH:12][C:6]=2[N:5]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:4]1=[O:23])[CH3:2].[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([N:11]1[C:10]([NH:13][CH3:14])=[C:7]2[C:6]([N:5]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)[C:4](=[O:23])[N:3]([CH2:1][CH3:2])[C:8]2=[O:9])=[N:12]1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CCn1c(=O)c2c(NC)n[nH]c2n(Cc2ccc(C)cc2)c1=O
Solvent: c1ccncc1
Product: CCn1c(=O)c2c(NC)n(C(C)=O)nc2n(Cc2ccc(C)cc2)c1=O
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A mixture of 5-ethyl-3-methylamino-7-(4-methylbenzyl)-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (0.5 g, 1.6 mM) and acetic anhydride (0.33 g, 3,2 mM) in pyridine (5 ml) was stirred at 60° C. for 18 hours.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.CN(C)C=O.[C:16]([NH:19][C:20]1[CH:25]=[C:24](Cl)[CH:23]=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28])(=[O:18])[CH3:17]>O>[C:16]([NH:19][C:20]1[CH:25]=[C:24]([S:10][C:7]2[CH:8]=[CH:9][C:4]([CH3:3])=[CH:5][CH:6]=2)[CH:23]=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28])(=[O:18])[CH3:17]
Reactant: Cc1ccc(S)cc1
Reactant: CC(=O)Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1cc(Sc2ccc(C)cc2)ccc1[N+](=O)[O-]

Procedure:
0.84 G. of 57% sodium hydride is added to 3.0 g. p-methylthiophenol in 20 ml. dimethylformamide, 4.3 G. 2-acetamido-4-chloro-1-nitrobenzene is added and the mixture heated at 140°-145°C for 5 hours, cooled and treated with water. The crude product is filtered off, washed with water and pentane. Recrystallization from methanol gives 2-acetamido-4-(p-methylthiophenoxy)-1-nitrobenzene.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:6][C:3]=1[C:4]#[N:5].[S:14](Cl)(=[O:17])(=[O:16])[NH2:15]>>[C:4]([C:3]1[CH:6]=[C:7]([CH2:10][CH:11]([CH3:13])[CH3:12])[CH:8]=[CH:9][C:2]=1[NH:1][S:14]([NH2:15])(=[O:17])=[O:16])#[N:5]
Reactant: NS(=O)(=O)Cl
Reactant: CC(C)Cc1ccc(N)c(C#N)c1
Product: CC(C)Cc1ccc(NS(N)(=O)=O)c(C#N)c1

Procedure:
Prepared as in Example 77a from 2-Amino-5-isobutylbenzonitrile (Example 88b) and sulfamoyl chloride.
Reaction SMILES: [Cl-].[NH4+].O.[Br:4][C:5]1[CH:6]=[C:7]([N+:17]([O-])=O)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14]>[Fe].C(O)C>[Br:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[NH2:17]
Reactant: CC(C)(C)COc1ccc([N+](=O)[O-])cc1Br
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)COc1ccc(N)cc1Br
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
Furthermore, ammonium chloride (10 g) and iron powder (75 g) were added to a mixed solvent of water (286 ml) and ethanol (753 ml), and the mixture was heated to 65° C. 3-Bromo-4-neopentyloxynitrobenzene (80 g) was added in parts over 20 min and the mixture was stirred at a refluxing temperature for 30 min. The reaction mixture was ice-cooled and filtrated. The solvent was evaporated under reduced pressure. To the residue was added sodium hydroxide and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (70 g), melting point: 45° C.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:10]3[CH:12]=[C:13]([CH2:16][NH:17][C:18]4[CH:39]=[CH:38][C:21]([C:22]([NH:24][C@H:25]([C:33]([O:35]CC)=[O:34])[CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[O:23])=[CH:20][CH:19]=4)[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]=[C:4]([NH:40]C(=O)C(C)(C)C)[NH:3]1.Cl>CO.[OH-].[Na+]>[NH2:40][C:4]1[NH:3][C:2](=[O:1])[C:11]2[C:10]3[CH:12]=[C:13]([CH2:16][NH:17][C:18]4[CH:19]=[CH:20][C:21]([C:22]([NH:24][C@H:25]([C:33]([OH:35])=[O:34])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:23])=[CH:38][CH:39]=4)[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(NCc2ccc3ccc4nc(NC(=O)C(C)(C)C)[nH]c(=O)c4c3c2)cc1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1nc2ccc3ccc(CNc4ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc4)cc3c2c(=O)[nH]1
Yield: 91.7 %

Procedure:
A solution of diethyl N-(4-(((1,2-dihydro-1-oxo-3-pivalamidobenzo[f]quinazolin-9-yl)methyl)amino)benzoyl)-L-glutamate (0.31 g, 0.49 mmol) in methanol (15 ml) and 1N NaOH (5 ml) was stirred under nitrogen at reflux for 1.5 hours and then allowed to cool. The solution was adjusted to pH 3 with 1N-HCl under nitrogen and the resulting precipitate was filtered under nitrogen, washed with water, and dried under high vacuum to give N-(4-(((3-amino-1,2-dihydro-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)benzoyl)-L-glutamic acid (0.22 g) as a white solid. 1H NMR (DMSO-d6, 300 MHz δ: 1.82-2.12 (m, 2H, glu CH2), 2.31 (t, J=7 Hz, 2H, glu CH2), 4.27-4.38 (m, 1H, glu CH), 4.50 (d, J=6 Hz, 2H, C9 -CH2), 6.55 (br s, 2H, NH2), 6.62 (d, J=9 Hz, 2H, Ar), 6.96 (t, J=6 Hz, 1H, ArNH), 7.26 (d, J=9 Hz, 1H, Ar), 7.44 (dd, J=8,2 Hz, 1H, Ar), 7.63 (d, J=9 Hz, 2H, Ar), 7.84 (d, J=8 Hz, 1H, Ar), 7.99 (d, J=9 Hz, 1H, Ar), 8.09 (d, J=8 Hz, 1H, glu NH), 9.67 (s, 1H, Ar), 11.14 (br s, 1H, N2H), 12.32 (br s, 2H, CO2H's). Anal. Calculated for C25H23N5O6.H2O: C, 59.17; H, 4.97; N, 13.80. Found: C, 59.31; H, 4.90; N, 13.72.
Reaction SMILES: [CH:1]1([C@H:4]([NH:11][C:12]([C:14]2[C:23]3[C:18](=[C:19](F)[CH:20]=[CH:21][CH:22]=3)[C:17](=[O:25])[N:16]([NH:26][CH2:27][CH3:28])[C:15]=2[CH3:29])=[O:13])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.N([O-])=[O:31].[Na+]>CN(C)C=O>[CH:1]1([C@H:4]([NH:11][C:12]([C:14]2[C:23]3[C:18](=[C:19]([OH:31])[CH:20]=[CH:21][CH:22]=3)[C:17](=[O:25])[N:16]([NH:26][CH2:27][CH3:28])[C:15]=2[CH3:29])=[O:13])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2]1
Reactant: CCNn1c(C)c(C(=O)N[C@H](c2ccccc2)C2CC2)c2cccc(F)c2c1=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNn1c(C)c(C(=O)N[C@H](c2ccccc2)C2CC2)c2cccc(O)c2c1=O
Temperature: 220 °C

Procedure:
A mixture of 2-ethylamino-8-fluoro-3-methyl-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid ((S)-cyclopropyl-phenyl-methyl)-amide (47.0 mg, 0.119 mmol, sodium nitrite (80.0 mg, 1.16 mmol), and N,N-dimethylformamide (0.2 mL) was heated under microwave irradiation at 220° C. for 60 min. Partitioned between EtOAc and water (4×10 ml), then combined aqueous phases were extracted with ether (15 ml), which was washed with water (4×10 ml). The combined organic solution was concentrated in vacuo, and purified by flash chromatography (with a gradient of heptane-ethylacetate) to give 2-ethylamino-8-hydroxy-3-methyl-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid ((S)-cyclopropyl-phenyl-methyl)-amide as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[N:5][N:4]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20].C1(C)C(S(O)(=O)=O)=CC=CC=1>C1C=CC=CC=1>[F:18][C:2]([F:1])([F:17])[C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:19](=[O:21])[CH3:20])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[N:5][N:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: CN1CCC(O)N(c2nnc(C(F)(F)F)s2)C1=O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: c1ccccc1
Product: CC(=O)OC1CCN(C)C(=O)N1c1nnc(C(F)(F)F)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.1mole), acetic anhydride (0.11 mole), toluenesulfonic acid (0.05 gram) and benzene (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is heated on a steam bath with stirring for a period of about 2 hours. After this time the reaction mixture is cooled to room temperature and is stripped of solvent under reduced pressure leaving a residue. The residue is recrystallized to yield the desired product tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-acetyloxy-2(1H)-pyrimidinone.
Reaction SMILES: FC1C=CC(C[N:7]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)=CC=1.[CH3:24][C:25]1[N:26]=[C:27]([N:33]2[CH2:37][CH2:36][N:35]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][C:46]([F:49])([F:48])[F:47])=[CH:41][CH:40]=3)[C:34]2=[O:50])[S:28][C:29]=1[C:30]([OH:32])=O>>[CH3:24][C:25]1[N:26]=[C:27]([N:33]2[CH2:37][CH2:36][N:35]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][C:46]([F:48])([F:47])[F:49])=[CH:41][CH:40]=3)[C:34]2=[O:50])[S:28][C:29]=1[C:30]([NH2:7])=[O:32]
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: Cc1nc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(N)=O

Procedure:
Following the procedure as described in Example 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methyl-thiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-(4-(trifluoromethoxy)benzyl)-imidazolidin-1-yl)thiazole-5-carboxylic acid, the title compound was obtained as a colorless solid: mp 185-187° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.42 (d, J=8.7 Hz, 2H), 7.33 (d, J=8.2 Hz, 2H), 7.29 (br, 2H), 4.44 (s, 2H), 4.01 (t, J=7.3 Hz, 2H), 3.48 (t, J=7.3 Hz, 2H), 2.46 (s, 3H); MS (ES+) m/z 400.7 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.CN([CH:23]=[O:24])C>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][N:12]=[C:23]=[O:24])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Reactant: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C=NCCc1ccc([N+](=O)[O-])cc1

Procedure:
2-(4-Nitrophenyl)ethylamine (0.5 mmol) and p-nitrophenylchloroformate (0.5 mmol) were allowed to react in the presence of triethylamine (1 mmol) in 5 ml of DMF to provide 2-(4-nitrophenyl)ethyl isocyanate. Without isolation, the isocyanate was mixed with N-(2(S)-amino-4-methylpentyl)-N-(1-naphthylmethyl)-glycyl-methionine methyl ester dihydrochloride (0.4 mmol) and triethylamine (1 mmol) in 4 mL of DMF to provide the title compound. C34H45N5O6S.0.15 hexane
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[C:8]([CH3:13])=[CH:7][C:6]=2[CH:14]=1.[F:15][C:16]([F:21])([F:20])C([O-])=O.[K+]>CN(C)C=O.C1(C)C=CC=CC=1>[F:15][C:16]([F:21])([F:20])[C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[C:8]([CH3:13])=[CH:7][C:6]=2[CH:14]=1
Reactant: CC1=Cc2cc(Br)ccc2OC1(C)C
Reactant: O=C([O-])C(F)(F)F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC1=Cc2cc(C(F)(F)F)ccc2OC1(C)C
Temperature: 25 °C
Yield: 51.8 %

Procedure:
A suspension containing 6-bromo-2,2,3-trimethyl-2H-1-benzopyran (38.0 g, 0.15 mol), potassium trifluoroacetate (62.0 g, 0.408 mol) and cuprous iodide (57.0g, 0.30 mol) in dimethylformamide (530 ml) and toluene (225 ml) was heated under nitrogen until a total of 70 ml of toluene was collected by distillation. Toluene was distilled off until the temperature of the reaction mixture reached 140° C. After a further four hours at this temperature the mixture was cooled to room temperature, water and diethyl ether were added, and the organic phase separated and evaporated under reduced pressure. The residue was chromatographed on silica gel, eluting with heptane to give 18.82 g of 6-trifluoromethyl-2,2,3-trimethyl-2H-1-benzopyran as an oil, ms 242 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[C:8](=[O:12])[N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]2.Cl>C(Cl)Cl.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Cl)ncc2C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1NCCc2cc(Cl)ncc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 191.2 %

Procedure:
To a solution of tert-butyl 6-chloro-1-oxo-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (3.0 g, 10.6 mmol) in DCM (20 mL) was added 4N HCl solution in dioxane (10 mL). After stirring 20 minutes at room temperature, the reaction was diluted with DCM (50 mL, then sonicated and filtered to give 6-chloro-3,4-dihydro-2,7-naphthyridin-1(2H)-one hydrochloride (2.22 g, 93% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.70 (s, 1H), 8.23 (br. s., 1H), 7.57 (s, J=0.6 Hz, 1H), 3.40 (t, J=6.6, 2.8 Hz, 2H), 2.96 (t, J=6.6 Hz, 2H); MS (EI) m/z=183.6 [M+1]+.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Cs+].[CH2:20](Br)[CH2:21][CH2:22][CH3:23]>C1COCC1.CCOC(C)=O>[CH2:20]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1)[CH2:21][CH2:22][CH3:23]
Reactant: COC(=O)c1ccc2c(c1)NCCC2
Reactant: CCCCBr
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCN1CCCc2ccc(C(=O)OC)cc21
Temperature: 25 °C
Yield: 67.1 %

Procedure:
To a stirred solution of methyl 1,2,3,4-tetrahydroquinoline-7-carboxylate (180 mg, 0.94 mmol) and cesium bicarbonate (1.5 g, 4.7 mmol) in THF (2 mL) was added n-butyl bromide (1.0 mL, 9.4 mmol), and the reaction mixture was heated at reflux for 48 h. The reaction mixture was cooled to room temperature, and diluted with EtOAc. The organic layer was washed with water, and brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:3 ethyl acetate/hexanes) afforded methyl 1-butyl-1,2,3,4-tetrahydroquinoline-7-carboxylate (156 mg): ESI MS m/z 248 [M+H]+.