Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([Br:17])=[CH:16][C:3]=12.CC(C)([O-])C.[Na+].[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.CN(C=O)C>[Br:17][C:15]1[S:14][C:4]2=[N:5][C:6]([CH3:13])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]([NH:1][S:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:32])=[O:31])=[C:3]2[CH:16]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)c1c(C)nc2sc(Br)cc2c1N
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nc2sc(Br)cc2c1NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
To a stirring mixture of ethyl 4-amino-2-bromo-6-methylthieno[2,3-b]pyridine-5-carboxylate (Description 66) (5.84 g, 18.53 mmol) in THF (110 mL) and DMF (55 mL) was added sodium tert-butoxide (4.45 g, 46.3 mmol) and benzenesulfonyl chloride (4.75 mL, 37.1 mmol). The resulting mixture was stirred at RT for 30 min. The reaction mixture was quenched with saturated ammonium chloride solution (ca. 150 mL) and extracted with DCM (80 mL×3). The combined organic layers were dried and concentrated. The residue was purified via normal phase chromatography, eluting with 0-30% ethyl acetate in DCM, to give the title compound (6.27 g). LCMS (A) m/z: 455/457 [M+1]+, Rt 1.35 min (acidic).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([I:15])[N:12]=[C:11]1[CH3:16])(C)(C)C.[ClH:18].O1CCOCC1>C(Cl)Cl>[I:15][C:13]1[N:12]=[C:11]([CH3:16])[N:10]([CH2:9][CH2:8][NH2:7])[CH:14]=1.[ClH:18]
Reactant: Cc1nc(I)cn1CCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1nc(I)cn1CCN
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of [2-(4-iodo-2-methyl-imidazol-1-yl)-ethyl]-carbamic acid tert-butyl ester (2.800 g; 7.973 mmol) in DCM (45 ml) was added slowly 4N HCl in dioxane (28.25 ml; 113.000 mmol). The resulting suspension was stirred at 0° C. for 15 min., then at rt for 1 h. The volatiles were removed under reduced pressure, then under HV. The product 2-(4-iodo-2-methyl-imidazol-1-yl)-ethylamine was obtained as a pale beige solid (2.880 g; 100%; presence of 3 eq. of HCl). LC-MS: tR=0.14 min.; [M+H]+=251.92 g/mol.
Reaction SMILES: [CH:1]1C=C(Cl)C=C(C(OO)=O)C=1.[Cl:12][C:13]1[C:33]2[O:32][C@:19]3([C@H:28]([CH3:29])[CH2:27][C:26]4[N:25]=[C:24]([CH3:30])[CH:23]=[CH:22][C:21]=4[C:20]3=[O:31])[C:18](=[O:34])[C:17]=2[C:16]([O:35][CH3:36])=[CH:15][C:14]=1[O:37][CH3:38]>ClCCl>[Cl:12][C:13]1[C:33]2[O:32][C@:19]3([C@H:28]([CH3:29])[CH2:27][C:26]4[N:25]=[C:24]([CH2:30][CH3:1])[CH:23]=[CH:22][C:21]=4[C:20]3=[O:31])[C:18](=[O:34])[C:17]=2[C:16]([O:35][CH3:36])=[CH:15][C:14]=1[O:37][CH3:38]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(OC)c2c(c1Cl)O[C@@]1(C(=O)c3ccc(C)nc3C[C@H]1C)C2=O
Solvent: ClCCl
Product: CCc1ccc2c(n1)C[C@@H](C)[C@]1(Oc3c(Cl)c(OC)cc(OC)c3C1=O)C2=O
Reaction time: 16 h
Yield: 102.1 %

Procedure:
In a 250 mL round-bottomed flask 1.3 g (7.7 mmol, 2 eq.) of mCPBA was added to a solution of (2S,7′R)-7-chloro-4,6-dimethoxy-2′,7′-dimethyl-7′,8′-dihydro-3H,5′H-spiro[benzofuran-2,6′-quinoline]-3,5′-dione (1.5 g, 3.9 mmol, 1.0 eq) in 45 mL of dichloromethane. The mixture was left under agitation at ambient temperature for 16 h, then concentrated under reduced pressure. The residue was dissolved in AcOEt. The organic phase was washed with 10% Na2S2O3 solution, then a saturated NaHCO3 solution, then brine solution and dried over Na2SO4, filtered and concentrated under reduced pressure. A yellow solid (1.6 g) was obtained with a yield of 100%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C:4]1[CH:9]=[C:8]([CH:10]=[CH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:7]=[C:6]([CH3:19])[C:5]=1[N:20]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH3:21]>[Pd].C(O)C>[CH3:1][O:2][C:3](=[O:33])[C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH:7]=[C:6]([CH3:19])[C:5]=1[N:20]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH3:21]
Reactant: COC(=O)c1cc(C=CC(=O)OC(C)(C)C)cc(C)c1N(C)S(=O)(=O)c1ccc(OC)cc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cc(CCC(=O)OC(C)(C)C)cc(C)c1N(C)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 2 h
Yield: 95.8 %

Procedure:
A mixture of 340 mg (0.71 mmol) of the product of Example 203 and 35 mg of 10% palladium on carbon in 15 ml of ethanol was hydrogenated on a Parr shaker for 2 hr. The resulting mixture was filtered through Celite and Magnesol to provide 325 mg (95%) of the desired product as a colorless gum. Electrospray Mass Spec 478(M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:17])=[C:5]([CH:14]=[CH:15][CH:16]=1)[C:6]([NH:8][NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:7].[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[C:22](Cl)=[O:23].[OH-].[Na+]>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[C:4]([CH3:17])=[C:5]([CH:14]=[CH:15][CH:16]=1)[C:6]([NH:8][N:9]([C:22](=[O:23])[C:21]1[CH:25]=[C:26]([CH3:28])[CH:27]=[C:19]([CH3:18])[CH:20]=1)[C:10]([CH3:13])([CH3:12])[CH3:11])=[O:7]
Reactant: COc1cccc(C(=O)NNC(C)(C)C)c1C
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1cccc(C(=O)NN(C(=O)c2cc(C)cc(C)c2)C(C)(C)C)c1C
Yield: 84.1 %

Procedure:
To a stirred solution of N-(3-methoxy-2-methylbenzoyl)-N'-tert-butylhydrazine (506 g, 2.14 mole) in methylene chloride (1.5 L) at 5° C. were simultaneously added solutions of 3,5-dimethylbenzoyl chloride (360 g, 2.14 moles) in methylene chloride (500 mL) and sodium hydroxide (50% aqueous, 171.2 g, 2.14 moles) diluted with water (400 mL), at such a rate that the temperature of the mixture did not exceed 10° C. Following the addition, the reaction mixture was allowed to reach room temperature and stirred continuously for 1 additional hour, whereupon the reaction mixture was diluted with methylene chloride (12 L), washed with water, dried over magnesium sulfate, filtered and stripped to give N-(3-methoxy-2-methylbenzoyl)-N'-(3,5-dimethylbenzoyl)-N'-tert-butylhydrazine (663 g), melting at 204°-204.5° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.C(N(CC)CC)C.[CH:29]#[C:30][CH3:31]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:29]#[C:30][CH3:31]
Reactant: C#CC
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC#Cc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: -78 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)4-iodopyrazole (0.904 g, the compound of Example A1) in dimethylformamide(2 ml) and triethylamine (10 ml) contained in a stainless steel bomb was added cuprous iodide (60 mg) and bis(triphenylphosphine)palladium(II) chloride (120 mg). The reaction vessel was cooled to −78° C. and propyne (2 g) condensed into it. The vessel was sealed and then heated at 70° C. for 18 hours and then left at room temperature for 2 days. The reaction mixture was partitioned between ether and water. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel eluted with dichloromethane : hexane (1:1) to provide the title compound as a white solid m.p. 226-8° C.
Reaction SMILES: [C:1]([C:5]1[CH2:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])C.CC(C)=O.N1[CH2:18][CH2:17][CH2:16][CH2:15]1>CO>[CH2:15]([C:8]1[CH:7]=[CH:6][C:5](=[C:1]([CH3:3])[CH3:4])[CH:9]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CC(C)(C)C1=CC=CC1
Reactant: C1CCNC1
Solvent: CC(C)=O
Solvent: CO
Product: CCCCC1=CC(=C(C)C)C=C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
A mixture of t-butylcyclopentadiene (15 g, 123 mmol), acetone (9.0 mL, 135.2 mmol), pyrrolidine (11.7 mL, 135.3 mmol) and methanol (100 mL) was stirred at 0° C., for 30 minutes, and then at room temperature overnight. The reaction mixture was quenched with acetic acid (7.38 g) and with water (100 mL) at 0° C. The mixture was extracted with Et2O (3×200 mL); the organic layers were combined, washed with a saturated solution of NaHCO3, dried over anhydrous magnesium sulphate, filtered and finally concentrated, thus yielding 2-butyl-6,6-dimethylfulvene in the form of a yellow liquid (18.24 g, 92% yield).
Reaction SMILES: [OH-].[Na+].Cl[C:4]([O:6][CH2:7][C:8]([Cl:11])([Cl:10])[Cl:9])=[O:5].Cl.[NH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([OH:19])=[O:18]>>[Cl:9][C:8]([Cl:11])([Cl:10])[CH2:7][O:6][C:4]([NH:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([OH:19])=[O:18])=[O:5]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1cccc(C(=O)O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(Nc1cccc(C(=O)O)c1)OCC(Cl)(Cl)Cl
Yield: 86.5 %

Procedure:
To an aqueous solution (200 ml) of 8.22 g of m-aminobenzoic acid and 4.8 g of sodium hydroxide was dropwise added 25.0 g of 2,2,2-trichloroethyl chloroformate at room temperature. During the dropwise addition, the reaction solution was controlled to pH 10 or more by appropriately adding a 1N sodium hydroxide aqueous solution. After the reaction, the solution was controlled to pH 1 by adding 1N hydrochloric acid, and the precipitates were collected by filtration. The resultant crude crystals were dried and then washed with a ethyl acetate/n-hexane mixed solvent to obtain 16.2 g (yield 87%) of the title compound as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[CH2:19]([NH2:25])[C:20]1[O:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:25][CH2:19][CH:20]1[CH2:21][CH2:22][CH2:23][O:24]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: NCc1ccco1
Product: CCOC(=O)c1cnc2c(OC)cccc2c1NCC1CCCO1

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (300 mg, 1.13 mmol) was treated with furfurylamine following general procedure B to afford 8-methoxy-4-[(tetrahydro-furan-2-ylmethyl)-amino]-quinoline-3-carboxylic acid ethyl ester (280 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid in quantitative yield using general procedure D and then transformed into the corresponding ethylamide (220 mg) following general procedure E. The above ethylamide (0.67 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 3-ethyl-7-methoxy-1-(tetrahydro-furan-2-ylmethyl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (30 mg). LCMS: m/z 356 [M+1]+.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[CH3:19][N:20]([CH3:31])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=1>>[CH3:31][N:20]([CH3:19])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:29])=[CH:23][CH:22]=1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: CN(C)c1ccc(CC(=O)O)cc1
Product: CN(C)c1ccc(CC(=O)Nn2nc(N3CCOCC3)c3ccccc3c2=O)cc1

Procedure:
The product of Example 1B and 2-[4-(dimethylamino)phenyl]acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ 8.30 (dd, J=7.9, 1.0, 1H), 8.04 (d, J=7.5, 1H), 8.02-7.96 (m, 1H), 7.94-7.88 (m, 1H), 7.47 (d, J=8.7, 2H), 7.37 (d, J=8.6, 2H), 3.85-3.80 (m, 4H), 3.69 (s, 2H), 3.11 (s, 6H), 3.11-3.06 (m, 4H); MS (ESI−) M/Z 406 (M−H)−.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.Br[CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19].[H-].[Na+]>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:7]=1
Reactant: CC(C)=CCBr
Reactant: Ic1ccc(Nc2ncccn2)cc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)=CCN(c1ccc(I)cc1)c1ncccn1
Yield: 94.9 %

Procedure:
In the same manner as in Reference Example 13, N-(4-iodophenyl)pyrimidin-2-amine (150 mg) and 1-bromo-3-methyl-2-butene (90 mg) were reacted in the presence of sodium hydride to obtain N-(4-iodophenyl)-N-(3-methyl-2-butenyl)pyrimidin-2-amine (175 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])[CH:6]=[CH:7][CH:8]=1.[H][H]>C(O)C.[Pt]=O>[OH:15][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C:9]1([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: [H][H]
Reactant: CCOC(=O)CC1(c2cccc(OC)c2)CCCCC1=O
Agent: O=[Pt]
Solvent: CCO
Product: CCOC(=O)CC1(c2cccc(OC)c2)CCCCC1O

Procedure:
200 g of ethyl 1-(m-methoxyphenyl)-2-oxo-cyclohexaneacetate are dissolved in 2000 ml of ethanol, and after treatment with 20 g of platinum oxide, the mixture is reduced with hydrogen at 50° C. and 50 bar. After separation of the catalyst, the solvent is removed by distillation, and there is obtained ethyl 2-hydroxy-1-(m-methoxyphenyl)-cyclohexaneacetate in the form of a light yellow oil.
Reaction SMILES: N1C=CN=C1.[OH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:17])([CH3:16])[CH3:15])[N:9]=1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C=O)C>[Si:18]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:17])([CH3:15])[CH3:16])[N:9]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(O)c1cccc(CO)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(O)c1cccc(CO[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.8 %

Procedure:
Imidazole (2.27 g, 33.3 mmol) was added to a stirred solution of 2-hydroxymethyl-6-(1-hydroxy-1-methylethyl)pyridine (5.30 g, 31.7 mmol) and tert-butyldimethylsilylchloride (5.02 g, 33.3 mmol) in DMF (70 mL) and the mixture was stirred for 16 h at room temperature. The mixture was poured onto water, extracted with EtOAc, the organic portion was separated, dried (MgSO4), filtered and evaporated to give the title compound (8.19 g, 92%) as a colourless oil; NMR δH (400 MHz, CDCl3) 7.74-7.70 (1H, m), 7.40-7.38 (1H, m), 7.20-7.18 (1H, m), 5.34 (1H, s), 4.83 (2H, s), 1.52 (6H, s), 0.97 (9H, s), 0.13 (6H, s); (M+H)+ 282.
Reaction SMILES: O1[C:5]2([CH2:15][CH2:14][C:8]3([CH2:12][CH2:11][C:10](=[O:13])[NH:9]3)[CH2:7][CH2:6]2)[O:4]CC1.Cl>C1COCC1>[NH:9]1[C:8]2([CH2:14][CH2:15][C:5](=[O:4])[CH2:6][CH2:7]2)[CH2:12][CH2:11][C:10]1=[O:13]
Reactant: O=C1CCC2(CCC3(CC2)OCCO3)N1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCC2(CC1)CCC(=O)N2
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.2 %

Procedure:
A suspension of 1,4-dioxa-9-aza-dispiro[4.2.4.2]tetradecan-10-one (prepared according to J. Org. Chem. 2004, 69, 2755) (500 mg, 2.4 mmol) in THF (7 mL) was treated with 1M aqueous HCl (7 mL) and the resulting mixture stirred at ambient temperature for 20 hours. The reaction mixture was quenched with 1M aqueous NaOH (7 mL) and the mixture concentrated under vacuum. The resulting solid was purified by column chromatography on silica gel (gradient: DCM then 2 to 10% methanol in ethyl acetate) to afford 398 mg (quant.) of 1-aza-spiro[4.5]decane-2,8-dione. LCMS (Method B, ESI): RT=1.63 min, 168; 1H NMR (400 MHz, CDCl3) δ: 3.95 (s, 1H), 3.77-3.71 (m, 1H), 2.46-2.44 (m, 3H), 2.05-2.03 (m, 3H), 1.81-1.65 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([CH:18]2O[CH:21]=[N:20][C:19]2([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:40])S(C2C=CC(C)=CC=2)(=O)=O)[N:9]=[N:8]1.C[NH2:51].CO>C1(C)C(C)=CC=CC=1>[F:47][C:44]([F:46])([F:45])[C:42]1[CH:41]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:49])[F:48])[CH:43]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([C:18]2[N:51]=[CH:21][NH:20][C:19]=2[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:40])[N:9]=[N:8]1
Reactant: Cc1ccc(S(=O)(=O)C2(Cc3ccccc3Cl)N=COC2c2nnn(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2-c2ccccc2)cc1
Reactant: CN
Solvent: CO
Solvent: Cc1ccccc1C
Product: FC(F)(F)c1cc(Cn2nnc(-c3nc[nH]c3Cc3ccccc3Cl)c2-c2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Combine 1-(3,5-bis-trifluoromethyl-benzyl)-4-[4-(2-chloro-benzyl)-4-(toluene-4-sulfonyl)-4,5-dihydro-oxazol-5-yl]-5-phenyl-1H-[1,2,3]triazole (0.100 mmol), 2.5 mL of xylene, and 2N solution of methylamine in methanol (0.2 mL, 0.40 mmol) and heat in a sealed pyrex tube to 135° C. After 19 hours, cool to RT. Concentrate the mixture to 1.0 mL and apply to a 2 mm chromatotron plate with CH2Cl2 and EtOAc and elute with a 100 mL of Hexanes, and 200 mL each of 20:80 EtOAc/Hexanes, 30:70 EtOAc/Hexanes, 50:50 Hexanes/EtOAc, 85:15 EtOAc/Hexanes to provide the title compound: Exact Mass 561.1: mass spectrum (IS): m/z=563.1 (M+1), 561.1 (M−1); 1H NMR (250 MHz, CDCl3) 7.74 (s, 1H), 7.62 (s, 1H), 7.48-7.32 (m, 6H), 7.30-7.00 (m, 6H), 5.52 (s, 2H), 4.20 (s, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:12]1([CH2:18][CH2:19][CH:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[NH:22][C:21]2=[O:28])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([CH2:18][CH2:19][C:20]2([C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]=[CH:4][N:3]=3)[C:25](=[O:26])[NH:24][C:23](=[O:27])[NH:22][C:21]2=[O:28])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1NC(=O)C(CCc2ccccc2)C(=O)N1
Reactant: Clc1ncnc2ccccc12
Product: O=C1NC(=O)C(CCc2ccccc2)(c2ncnc3ccccc23)C(=O)N1
Temperature: 170 °C

Procedure:
A mixture of 3.3 g of 4-chloroquinazoline and 4.65 g of 5-(2-phenylethyl) barbituric acid was heated to 170° C. for two and one-half hours, then cooled to form the 5-(2-phenylethyl)-5-(4-quinazolyl) barbituric acid. This compound was hydrolyzed, without isolation, by adding 40 ml of water and 4.5 g of NaOH to the mixture, heating to reflux for four hours. The mixture was cooled, acidified with HCl, refluxed two additional hours, then cooled, and neutralized. Product was extracted into CH2Cl2, which was then separated, dried, and evaporated. The residue was absorbed onto silica gel and eluted with 10% EtOAc/CH2Cl2 →20% EtOAc/CH2Cl2. Fractions containing product were combined. TLC showed impurities present. The product was rechromatographed using 15% EtOAc/CH2Cl2, however, impurities remained. Solvent was evaporated and the residue was redissolved in pentane. The product dissolved in pentane leaving impurities as a gummy residue. The pentane solution was decanted, filtered, and evaporated to give 0.75 g of the title product as a light oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34](=[O:36])[NH2:35])[N:33]=[C:29]4[N:28]=[C:27]([CH3:37])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.[NH2:39][O:40][CH2:41][C:42]1[NH:43][CH:44]=[C:45]([OH:49])[C:46](=[O:48])[N:47]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:39]/[O:40][CH2:41][C:42]2[NH:43][CH:44]=[C:45]([OH:49])[C:46](=[O:48])[N:47]=2)/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34](=[O:36])[NH2:35])[N:33]=[C:29]4[N:28]=[C:27]([CH3:37])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: NOCc1nc(=O)c(O)c[nH]1
Reactant: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(=O)c4csc(N)n4)[C@H]3SC2)n2nc(C(N)=O)nc2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)/C(=N\OCc4nc(=O)c(O)c[nH]4)c4csc(N)n4)[C@H]3SC2)n2nc(C(N)=O)nc2n1
Reaction time: 0.33 h

Procedure:
0.230 g (0.4 mmol) of (6R,7R)-7-(2-amino-4-thiazoleglyoxylamido) -3-[[(2-carbamoyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0] oct-2-ene-2-carboxylic acid was dissolved in 3.5 ml of dimethylacetamide. Within 6 hours 0.11 g (0.7 mmol) of 2-(aminooxy)methyl-5-hydroxy-4(1H)-pyrimidinone and 0.133 g (0.7 mmol) of p-toluenesulfonic acid hydrate were added. After further stirring for 18 hours the dimethylacetamide was evaporated off at strongly reduced pressure, and the residue was taken up in water and stirred for 20 minutes in order to completely precipitate the product. The product was filtered off, washed well with water and dried under strongly reduced pressure at room temperature. (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[(1,4-dihydro -5-hydroxy-4-oxo-2-pyrimidinyl) methoxy]imino]-acetamido]-3-[[(2-carbamoyl -5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid was obtained as a beige powder.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C@@H:14]([NH:19]C(=O)OC(C)(C)C)[C:13]2=[O:27])[CH2:10][CH2:9]1>ClCCl>[NH2:19][C@@H:14]1[CH2:15][CH2:16][CH2:17][CH2:18][N:12]([CH2:11][CH:8]2[CH2:10][CH2:9]2)[C:13]1=[O:27]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCCN(CC2CC2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CCCCN(CC2CC2)C1=O
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of tert-butyl (3R)-1-(cyclopropylmethyl)-2-oxoazepan-3-ylcarbamate (257 mg, 0.91 mmol) in dichloromethane (10 mL). After 1 h, the mixture was concentrated and azeotroped with dichloromethane (3×) to give the crude amine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:22])[C:5](C(O)=O)=[N:6][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH:8]=1.C1C=CC(P([N:37]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CCN(CC)CC.[OH-].[Na+]>C1(C)C=CC=CC=1>[NH2:37][C:5]1[C:4](=[O:22])[C:3]([O:2][CH3:1])=[CH:8][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:6]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COc1cn(-c2cccc(C(F)(F)F)c2)nc(C(=O)O)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cn(-c2cccc(C(F)(F)F)c2)nc(N)c1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 65.5 %

Procedure:
A mixture of 5-methoxy-4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxylic acid (6.00 g, 19.1 mmol), DPPA (6.16 mL, 28.6 mmol) and Et3N (3.99 mL, 28.6 mmol) in toluene (60 mL) was heated to 100° C. for 2 h. To the mixture was added 8 M NaOH aqueous solution (23.8 mL) at 0° C. The mixture was stirred at room temperature for 3 h, extracted with EtOAc, dried over Na2SO4, filtered and concentrated in vacuo. The residue was washed with EtOAc/i-Pr2O and filtered. The filtrate was concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/EtOAc=50/50 to 0/100) and recrystallized with EtOAc/hexane to yield the title compound (3.57 g, 66% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.83 (3H, s), 6.31 (2H, s), 7.64-7.79 (2H, m), 8.13 (2H, s), 8.64 (1H, s).