Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11](NC(OC(C)(C)C)=O)[C:12]([NH:14][C@H:15]([C:20](=[O:23])NC)[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C[C@@H]([C:47]1[CH:51]=[CH:50][N:49]([C:52]2[CH:57]=[CH:56][C:55]([C:58]3[CH:63]=[CH:62][C:61]([C:64]#[N:65])=[CH:60][CH:59]=3)=[CH:54][CH:53]=2)[CH:48]=1)C(O)=O)C1C=CC=CC=1.N[C@@H]1C(C)(C)C[O:70]C1=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>>[CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11]([C:51]1[CH:47]=[CH:48][N:49]([C:52]2[CH:53]=[CH:54][C:55]([C:58]3[CH:63]=[CH:62][C:61]([C:64]#[N:65])=[CH:60][CH:59]=3)=[CH:56][CH:57]=2)[CH:50]=1)[C:12]([NH:14][C@H:15]1[C:16]([CH3:17])([CH3:18])[CH2:19][O:70][C:20]1=[O:23])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(-c2ccc(-n3ccc([C@H](CC(=O)OCc4ccccc4)C(=O)O)c3)cc2)cc1
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Reactant: CC1(C)COC(=O)[C@@H]1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Product: CC1(C)COC(=O)[C@H]1NC(=O)[C@@H](CC(=O)OCc1ccccc1)c1ccn(-c2ccc(-c3ccc(C#N)cc3)cc2)c1
Yield: 29 %

Procedure:
According to the procedure described in Example 1(b) for the preparation 3(R)-t-butoxycarbonylamino-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid benzyl ester, 2(S)-[1-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]succinic acid 4-benzyl ester (prepared as described in Example 14(b)) and 3(R)-amino-4,4-dimethyl-2-oxo-tetrahydrofuran (see Freskos, J. N. Syn Commun. 1994, 24, 557-563) were coupled using TBTU with N-methylmorpholine as the base to provide a mixture of diastereomers which were separated using chromatography on silica gel column with 0 to 5% MeOH gradient in CH2Cl2. Mixed fraction was repurified on a chromatotron using 0-2.5% MeOH/CH2Cl2 then 0-1.25% MeOH/CH2Cl2 as eluent to obtain 3(S)-[1-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-N-(4,4-dimethyl-2-oxo-tetrahydrofuran-3(S)-yl)succinamic acid benzyl ester in 29% yield as an amorphous solid: 1H NMR (CDCl3): δ 7.75 (d, 2H, 8.1 Hz), 7.69 (d, 2H, J=8.5 Hz), 7.64 (d, 2H, J=8.5 Hz), 7.46 (d, 2H, J=8.5 Hz), 7.32 (s, 5H), 7.13 (s, 1H), 7.09 (t, 1H, J=2.2 Hz), 6.32 (s, 1H), 6.06 (d, 1H, J=7.7 Hz), 5.13 (s, 2H), 4.67 (d, 1H, J=7.7 Hz), 4.08 -4.01 (m, 3H), 3.31 (dd, 1H, J=16.9, 8.5 Hz), 2.82 (dd, 1H, J=16.7, 6.1 Hz), 1.23 (s, 3H), 0.98 (s, 3H); Anal. Calculated for C34H31N3O5•0.2 H2O: C, 72.25; H, 5.60; N, 7.43. Found: 72.32, 72.26; H, 5.88, 5.91; N, 7.07, 7.02.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:17]([OH:36])[C@H:18]([OH:35])[C@@H:19]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Rh]>[C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:17]([OH:36])[C@H:18]([OH:35])[C@@H:19]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Rh]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Yield: 65 %

Procedure:
A mixture of 180 mg (0.36mmol) of (2S,3R, 4R, 5S)-2,5-di-(N-((t-butyloxy)carbonyl)amino)-3,4-dihydroxy-1,6-diphenylhexane and 180 mg of 5% rhodium on carbon in 50 ml of methanol was shaken under 4 atmospheres of hydrogen for 24 h. The resulting mixture was filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using 5% ethyl acetate in hexane to provide 120 mg (65%) of the desired compound (Rf 0.35, 30% ethyl acetate in hexane) as a white solid, m.p. 224°-226° C. Mass spectrum: (M+H)+ =513.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6](Cl)=[N:7][CH:8]=1)#[N:2].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.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>[C:10]1([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1
Reactant: N#Cc1ccc(Cl)nc1
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: CCOC(C)=O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(-c2ccccc2)nc1
Yield: 93.8 %

Procedure:
5-Cyano-2-chloropyridine (5.0 g, 36.1 mmol), phenylboronic acid (6.6 g, 54 mmol), tetrakis(triphenylphosphine)palladium (0) (0.5 g), and aqueous Na2CO3 (7.6 g), in toluene (100 mL) were heated at 90° C. for 16 h. The mixture was diluted with EtOAc and washed with H2O. The organic layer was dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (hexanes/EtOAc 2/1) to afford the title compound (6.1 g, 94%). MS (ESI) m/z 181 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:16][CH3:17])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:7]=1.[C:18]([OH:22])(=O)[CH2:19]O>>[CH2:9]([O:8][C:5]1[N:4]=[C:3]2[N:16]([CH3:17])[C:19]([CH2:18][OH:22])=[N:1][C:2]2=[CH:7][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CNc1nc(OCc2ccccc2)ccc1N
Reactant: O=C(O)CO
Product: Cn1c(CO)nc2ccc(OCc3ccccc3)nc21
Yield: 46.5 %

Procedure:
A procedure similar to that described in Preparation 43 was repeated, except that 7.50 g of 3-amino-6-benzyloxy-2-methylaminopyridine (prepared as described in Preparation 93) and 7.46 g of glycolic acid were reacted. After working up the product as described in Preparation 43, the resulting crude product was purifying by column chromatography through silica gel, using a 10: 1 by volume mixture of ethyl acetate and methanol as the eluent, and was then crystallized by trituration with ethyl acetate, to give 4.10 g of the title compound, melting at 133°-135° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].CN(C=O)C.S(Cl)([Cl:19])=O.C(=O)(O)[O-].[Na+]>ClC(Cl)C>[Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([Cl:19])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cnc(Cl)c(Cl)c1
Temperature: 75 °C

Procedure:
To a well stirred suspension of 5,6-dichloronicotinic acid 5 (600 g, 3.125 mole, Sigma-Aldrich) and DMF (20.0 mL) in dichloroethane (1.2 L) was added drop wise with stirring thionyl chloride (743.56 g, 6.25 mole). The reaction mixture was set up for heating with reflux, fitted with a gas trap filled with saturated aqueous sodium bicarbonate and heated at a temperature of 75° C. until the reaction mixture formed a clear solution, about 3 h. LC/MS of a sample quenched in methanol showed only the presence of the methyl ester. The reaction mixture was cooled to a temperature of about 25° C. and concentrated under reduced pressure to provide 5,6-dichloronicotinoyl chloride 6 as a thick paste.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].CCN(C(C)C)C(C)C.CO[CH:21]1[N:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:24]([CH3:34])([CH3:33])[CH2:23][CH2:22]1.[NH4+].[Cl-]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:29]([O:28][C:26]([N:25]1[C:24]([CH3:34])([CH3:33])[CH2:23][CH2:22][CH:21]1[CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: COC(=O)CC(=O)OC
Reactant: COC1CCC(C)(C)N1C(=O)OC(C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C(=O)OC)C1CCC(C)(C)N1C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 75.9 %

Procedure:
TiCl4 (1.9 mL, 1.9 mmol) as a 1M DCM solution was added to a solution of dimethyl malonate (0.195 mL, 1.70 mmol) in DCM (10 mL) at 0° C. under N2, and the reaction was stirred for 10 minutes. DIEA (0.3 mL, 1.7 mmol) was then added slowly, and the reaction was stirred for an additional 30 minutes at 0° C. A DCM (2 mL) solution of tert-butyl 5-methoxy-2,2-dimethylpyrrolidine-1-carboxylate (325 mg, 1.4 mmol) was then slowly added dropwise, and the reaction was stirred at 0° C. for 10 minutes. Saturated NH4Cl was then added, and then reaction was diluted with DCM and washed with saturated NaHCO3. The organic fractions were then dried, filtered, and concentrated to give the crude product, which was purified by column chromatography (500:50-500:90 hexanes:EtOAc) to give dimethyl 2-(1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)malonate (0.35 g, 75%).
Reaction SMILES: [CH:1]1([CH2:4][CH:5]([C:8]2[CH:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[N:12][CH:13]=2)[C:6]#[N:7])[CH2:3][CH2:2]1.CI.[CH3:20]C([O-])(C)C.[K+]>O1CCOCC1>[CH:1]1([CH2:4][C:5]([CH3:20])([C:8]2[CH:9]=[N:10][C:11]([C:14]([F:16])([F:17])[F:15])=[N:12][CH:13]=2)[C:6]#[N:7])[CH2:3][CH2:2]1
Reactant: N#CC(CC1CC1)c1cnc(C(F)(F)F)nc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CI
Product: CC(C#N)(CC1CC1)c1cnc(C(F)(F)F)nc1
Reaction time: 1 h
Yield: 36.4 %

Procedure:
To a solution of 3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propanenitrile (310 mg, 1.29 mmol) and MeI (0.27 g, 1.9 mmol) in dioxane (10 ml) was added t-BuOK (1.39 mL, 1.39 mmol, 1M in THF) dropwise at room temperature under N2. The mixture was stirred for 1 h, then quenched by sat.aq. NH4Cl (10 mL), and extracted with EtOAc(3×10 ml). The organic layer was concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (EtOAc/Petroleum ether=1:4) to give compound the title compound (120 mg, yield: 36%). 1H NMR(CDCl3 varian 400): δ9.02 (s, 2H), 1.92 (d, J=6.8 Hz, 2H), 1.87 (s, 3H), 0.80-0.67 (m, 1H), 0.65-0.56 (m, 1H), 0.55-0.45 (m, 1H), 0.30-0.20 (m, 1H), 0.05-0.04 (m, 1H).
Reaction SMILES: [Cu:1].[N+:2]([O-:5])([OH:4])=[O:3]>>[N+:2]([O-:5])([O-:4])=[O:3].[Cu+2:1].[N+:2]([O-:5])([O-:4])=[O:3]
Reactant: O=[N+]([O-])O
Reactant: [Cu]
Product: O=[N+]([O-])[O-]
Product: [Cu+2]

Procedure:
In a regenerative process for etching copper, the steps of: contacting the copper with an aqueous solution of nitric acid to dissolve the copper and form copper nitrate, and adding sulfuric acid to the solution to convert the copper nitrate to nitric acid and a copper precipitate.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([CH3:10])=[CH:8][C:7]([Br:11])=[CH:6][C:5]=1[CH2:12]Br.[O:15]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Br:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([CH3:10])[CH:8]=1)[C:3](=[O:14])[N:27]([CH2:26][C:25]1[CH:28]=[CH:29][C:22]([O:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:23][CH:24]=1)[CH2:12]2
Reactant: COC(=O)c1c(C)cc(Br)cc1CBr
Reactant: NCc1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc(Br)cc2c1C(=O)N(Cc1ccc(Oc3ccccc3)cc1)C2
Temperature: 100 °C
Reaction time: 2 h
Yield: 32.5 %

Procedure:
A mixture of 4-bromo-2-bromomethyl-6-methyl-benzoic acid methyl ester (0.500 g, 1.6 mmol), 4-phenoxy-benzylamine (0.342 mL, 1.92 mmol), and K2CO3 (0.484 g, 3.5 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-bromo-7-methyl-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.212 g, 32%). GC-MS: m/z 407 (M)+, 314 (M−93)+.
Reaction SMILES: [N:1]([CH:4]([CH3:27])[CH2:5][O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[O:14][C:15]3[CH:21]=[C:20]([O:22][CH2:23][CH:24]4[CH2:26][CH2:25]4)[CH:19]=[CH:18][C:16]=3[CH:17]=2)[CH2:9][CH2:8]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[CH:24]1([CH2:23][O:22][C:20]2[CH:19]=[CH:18][C:16]3[CH:17]=[C:13]([C@H:10]4[CH2:11][CH2:12][C@H:7]([O:6][CH2:5][CH:4]([NH2:1])[CH3:27])[CH2:8][CH2:9]4)[O:14][C:15]=3[CH:21]=2)[CH2:26][CH2:25]1
Reactant: CC(CO[C@H]1CC[C@H](c2cc3ccc(OCC4CC4)cc3o2)CC1)N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(N)CO[C@H]1CC[C@H](c2cc3ccc(OCC4CC4)cc3o2)CC1
Temperature: 25 °C

Procedure:
A solution of 2-[trans-4-(2-azidopropoxy)cyclohexyl]-6-(cyclopropylmethoxy)-1-benzofuran (397 mg) and triphenylphosphine (564 mg) in THF (4 mL)/water (2 mL) was stirred at 60° C. overnight. The reaction mixture was allowed to cool to room temperature, and extracted with ethyl acetate and water. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate/methanol) to give the title compound (373 mg).
Reaction SMILES: [CH:1]1([NH:5][C:6](=[O:27])[C:7]2[CH:12]=[C:11]([O:13][C:14]3[C:19]([Cl:20])=[CH:18][C:17]([CH2:21][O:22][CH3:23])=[CH:16][C:15]=3[Cl:24])[CH:10]=[CH:9][C:8]=2[O:25][CH3:26])[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:30]I>CN(C)C=O.Cl>[CH:1]1([N:5]([CH3:30])[C:6](=[O:27])[C:7]2[CH:12]=[C:11]([O:13][C:14]3[C:19]([Cl:20])=[CH:18][C:17]([CH2:21][O:22][CH3:23])=[CH:16][C:15]=3[Cl:24])[CH:10]=[CH:9][C:8]=2[O:25][CH3:26])[CH2:4][CH2:3][CH2:2]1
Reactant: CI
Reactant: COCc1cc(Cl)c(Oc2ccc(OC)c(C(=O)NC3CCC3)c2)c(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1cc(Cl)c(Oc2ccc(OC)c(C(=O)N(C)C3CCC3)c2)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a solution of the title compound of Step E (170 mg, 0.41 mmol) in dimethylformamide (4 ml) at 0° C. under nitrogen was added sodium hydride (60% dispersion in mineral oil, 41 mg, 1 mmol). The resulting slurry mixture was stirred at 0° C. for about 30 minutes and gradually became a brownish-yellow solution. To this solution at 0° C. was added methyl iodide (0.13 ml, 2 mmol). The resulting solution was warmed to room temperature and stirred for about 19 hours. The solution was diluted with 1N HCl (30 ml) and extracted with ethyl acetate (3×15 ml). The combined organic extracts were washed with 1N HCl (3×50 ml), brine, dried, filtered, and concentrated. The residue was purified by preparative TLC (50% ethyl acetate in hexanes) to afford the title compound (155 mg). MS (APCl+) Calc: 423.1, found: 424.0 (M+1).
Reaction SMILES: [I:1][C:2]1[NH:6][C:5]([CH:7]([CH3:9])[CH3:8])=[N:4][CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:4]2[CH:3]=[C:2]([I:1])[N:6]=[C:5]2[CH:7]([CH3:9])[CH3:8])=[CH:13][CH:12]=1
Reactant: CC(C)c1ncc(I)[nH]1
Reactant: OB(O)c1ccc(F)cc1
Product: CC(C)c1nc(I)cn1-c1ccc(F)cc1

Procedure:
The title compound, MS: m/e=331.1 (M+H+), was prepared in accordance with the general method of example 7 from 5-iodo-2-isopropyl-1H-imidazole and 4-fluorobenzene boronic acid.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C([O-])([O-])OC.C([O-])(=O)C.[NH4+:21].[CH3:22]O>>[N:4]1[C:3]2[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1](=[O:10])[NH:21][CH:22]=1
Reactant: COC(=O)c1ccccc1N
Reactant: CO
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: COC([O-])[O-]
Product: O=c1[nH]cnc2ccccc12
Reaction time: 3 h
Yield: 98 %

Procedure:
In a 2-mL volume stainless steel pressure-resistant vessel were placed 302 mg (2.0 mmol) of methyl anthranilate, 424 mg (4.0 mmol) of methyl orthoformate, 308 mg (4.0 mmol) of ammonium acetate, and 1.0 mL of methanol. The reaction was carried out at 120° C. for 3 hours. After the reaction was complete, the reaction mixture was analyzed (according to absolute quantitative analysis) by high performance liquid chromatography. There was produced 285 mg (reaction yield: 98%) of quinazolin-4-one.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:24][N:25]([C:27]([NH2:29])=[O:28])[NH2:26]>>[CH3:24][N:25]([C:27]([NH2:29])=[O:28])/[N:26]=[C:21](/[C:18]1[N:17]=[C:16]2[N:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[N:13]=[N:14][C:15]2=[N:20][CH:19]=1)\[CH3:22]
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: CN(N)C(N)=O
Product: C/C(=N\N(C)C(N)=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1

Procedure:
The title compound was prepared as a white solid in analogy to the synthesis of example 52 from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone and 1-methylhydrazine-carboxamide. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.68 (s, 1H), 8.89 (m, 1H), 8.36 (d, 1H), 8.03 (s, 1H), 8.01 (d, 1H), 7.82 (dd, 1H), 7.53 (dd, 1H), 6.75 (s, 2H), 6.21 (s, 2H) 2.50 (s, 3H), 2.49 (s, 3H). LCMS (method B): [MH]+=376, tR=1.88 min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([Cl:14])=[C:11]([Cl:13])[Cl:12])[CH:9]=1)[CH2:5]Br.[N-:15]=[N+:16]=[N-:17].[Na+]>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([Cl:14])=[C:11]([Cl:13])[Cl:12])[CH:9]=1)[CH2:5][N:15]=[N+:16]=[N-:17]
Reactant: Cc1cc(CBr)cc(C(Cl)=C(Cl)Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(CN=[N+]=[N-])cc(C(Cl)=C(Cl)Cl)c1
Yield: 95.6 %

Procedure:
A solution of 3-methyl-5-(trichlorovinyl)benzyl bromide (3.14 g) and sodium azide (1.0 g) in 25 ml of ethanol was heated at reflux for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting oil triturated with 50 ml of hexane. The mixture was filtered and the filtrate concentrated to give 2.64 g of azide.
Reaction SMILES: [CH2:1]1[O:6][C:4](=[O:5])[NH:3][CH:2]1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Li]CCCC.[Br:19]CCCCC(Cl)=O.[CH2:27]1[CH2:31][O:30][CH2:29][CH2:28]1>>[CH2:7]([C@H:2]1[CH2:1][O:6][C:4](=[O:5])[N:3]1[C:29](=[O:30])[CH2:28][CH2:27][CH2:31][Br:19])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1NC(Cc2ccccc2)CO1
Reactant: O=C(Cl)CCCCBr
Reactant: C1CCOC1
Agent: [Li]CCCC
Product: O=C(CCCBr)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of S-(−)-4-benzyl-2-oxazolidinone (8.0 g, 45.1 mmol) in THF (75 mL) at −70° C., is added n-BuLi (19.8 mL, 49.6 mmol, 2.5 M in hexane) slowly. After stirring at −70° C. for 1 hour, 5-bromovaleryl chloride (11.7 g, 58.7 mmol) is added dropwise. After stirring at −70° C. for 20 minutes, the cooling bath is removed and the reaction mixture is warmed to 25° C. and stirred for 2 hours. The solution is diluted with 150 mL of ether, and washed with 2×100 mL of water. The combined organic layers is dried over Na2SO4 and concentrated. The crude product is purified by chromatography (hexane/EtOAc:85/15) to give a white solid (15.3 g, 99.7%). (NMR and MS data confirmed, U-3133-51-24).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8]>S(Cl)(Cl)=O>[CH:6]([NH:9][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]([OH:8])=[C:2]([OH:1])[CH:3]=1)([CH3:7])[CH3:5]
Reactant: O=C(O)CCCCc1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Product: CC(C)NC(=O)CCCCc1cc(O)c(O)c([N+](=O)[O-])c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution containing 0.5 g of the product obtained in Example 24 in 2.5 ml of thionyl chloride was refluxed for 10 min. The excess of thionyl chloride was evaporated in vacuo and the residue dissolved in 25 ml of dichloromethane. To this solution 0.47 g of isopropylamine was added and the mixture was stirred for 1 h at 20° C. Dichloromethane phase was washed with 1 N hydrochloric acid and evaporated in vacuo. The residue was crystallized from toluene. Yield 0.44 g (75%), m.p. 113°-115° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[F:23])[NH2:19]>COCCOC>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][C:2]2[C:11]3[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:13]#[N:14])[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: N#Cc1cnc2cnc(F)cc2c1Cl
Solvent: COCCOC
Product: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(F)c(Cl)c1
Temperature: 140 °C
Yield: 99 %

Procedure:
In a microwave vial, 4-chloro-6-fluoro-1,7-naphthyridine-3-carbonitrile (1.25 g, 6.02 mmol, prepared as described in Wissner et. al., Bioorg. Med. Chem. Lett., 14, 2004, 1411-1416) and 3-chloro-4-fluoroaniline (0.96 g, 6.6 mmol) were taken up in DME. The vial was crimp-sealed and heated in a microwave reactor at 140° C. for 10 minutes. This was repeated with a second batch of reagents. The contents of the two vials were transferred together to a separatory funnel and partitioned between EtOAc and 5% Na2CO3, and the aqueous layer extracted two additional times with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous MgSO4, filtered and evaporated to give 4-(3-chloro-4-fluorophenylamino)-6-fluoro-1,7-naphthyridine-3-carbonitrile of sufficient purity to be used directly in the next step (3.78 g, 99% yield): 1H NMR (400 MHz, DMSO-D6) δ 7.32-7.49 (m, 1 H) 7.53 (t, J=9.0 Hz, 1 H) 7.72 (dd, J=6.3, 2.3 Hz, 1 H) 8.16 (s, 1 H) 8.69 (s, 1 H) 9.08 (s, 1 H) 10.14 (s, 1 H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:11]1[N:12]=[N+:13]([O-:24])[C:14]2[C:23]3[CH2:22][CH2:21][CH2:20][C:19]=3[CH:18]=[CH:17][C:15]=2[N:16]=1>COCCOC>[N:1]1([CH2:7][CH2:8][NH:9][C:11]2[N:12]=[N+:13]([O-:24])[C:14]3[C:23]4[CH2:22][CH2:21][CH2:20][C:19]=4[CH:18]=[CH:17][C:15]=3[N:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCN1CCCCC1
Reactant: [O-][n+]1nc(Cl)nc2ccc3c(c21)CCC3
Solvent: COCCOC
Product: [O-][n+]1nc(NCCN2CCCCC2)nc2ccc3c(c21)CCC3
Yield: 93.4 %

Procedure:
2-(1-Piperidinyl)ethylamine (0.32 mL, 2.2 mmol) was added to a stirred solution of chloride 5 (165 mg, 0.7 mmol) in DME (30 mL) and the solution stirred at reflux temperature for 5 h. The solvent was evaporated and the residue was partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 12 (205 mg, 88%) as a pale yellow solid: mp (MeOH) 152-155° C.; 1H NMR δ 7.53 (d, J=8.4 Hz, 1H, H-5), 7.38 (d, J=8.4 Hz, 1H, H-6), 5.90 (br s, 1H, NH), 3.60-3.66 (m, 2H, H-9), 3.48-3.54 (m, 2H, CH2N), 2.97 (br t, J=7.7 Hz, 2H, H-7), 2.57 (dd, J=6.1, 5.9 Hz, 2H, CH2N), 2.38-2.45 (m, 4H, 2×CH2N), 2.17 (br p, J=7.7 Hz, 2H, H-8), 1.55-1.61 (m, 4H, 2×CH2), 1.41-1.48 (m, 2H, CH2); 13C NMR δ 158.4, 149.0, 142.0, 137.3, 132.2, 129.1, 124.6, 56.9, 54.2 (2), 37.9, 35.3, 32.8, 25.9 (2), 24.8, 24.4. Anal. calcd for C17H23N5O: C, 65.2; H, 7.4; N, 22.4. Found: C, 65.1; H, 7.2; N, 22.5%.