Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](OC1C=CC([N+]([O-])=O)=CC=1)=[O:3].[NH2:14][CH:15]1[CH2:20][CH2:19][CH:18]([C:21]([NH2:23])=[O:22])[CH2:17][CH2:16]1.CCN(C(C)C)C(C)C.CS(O)(=O)=O.[NH2:38][CH2:39][C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[C:45](=[O:49])[N:44]([CH:50]1[CH2:55][CH2:54][C:53](=[O:56])[NH:52][C:51]1=[O:57])[CH2:43]2>CC#N>[O:57]=[C:51]1[CH:50]([N:44]2[CH2:43][C:42]3[C:46](=[CH:47][CH:48]=[C:40]([CH2:39][NH:38][C:2](=[O:3])[NH:14][CH:15]4[CH2:20][CH2:19][CH:18]([C:21]([NH2:23])=[O:22])[CH2:17][CH2:16]4)[CH:41]=3)[C:45]2=[O:49])[CH2:55][CH2:54][C:53](=[O:56])[NH:52]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: NC(=O)C1CCC(N)CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CS(=O)(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: NC(=O)C1CCC(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29.4 %

Procedure:
To the solution of para-nitro-phenyl chloroformate (200 mg, 1 mmol) in CH3CN (5 mL), was added the CH3CN solution (5 mL) of 4-Amino-cyclohexanecarboxylic acid amide (210 mg, 1 mmol) and DIPEA (0.3 mL, 2 mmol) dropwise at room temperature. The mixture was stirred at room temperature for 10 min. 3-(5-Aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonic acid salt (0.37 g, 1 mmol) was added followed by additional DIPEA (0.15 mL, 1 mmol). The mixture was stirred overnight at ambient temperature. The mixture was then filtered. The filtrate was purified on prep-HPLC to give 4-{3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-ureido}-cyclohexanecarboxylic acid amide as a white solid (130 mg, 30% yield). HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 5% grad 95% in 5 min, CH3CN/0.1% H3PO4: tR=4.78 min (92%); mp: 195-197 0C; 1H NMR (DMSO-d6) δ 1.32-1.73 (m, 8H, CHH+CHH+CHH+CHH), 1.97 (br. S., 1H, CHH), 2.09-2.21 (m, 1H, CHH), 2.40 (d, J=13.4 Hz, 1H, CHH), 2.62 (br. S., 1H, CHH), 2.80-3.03 (m, 1H, CHH), 3.70 (br. S., 1H, CHH), 4.18-4.58 (m, 4H, CH2+CH2), 5.11 (dd, 1H, CHN), 6.15 (d, J=7.9 Hz, 1H, NH), 6.38 (t, J=5.9 Hz, 1H, NH), 6.67 (br. S., 1H, NH), 7.19 (br. S., 1H, NH), 7.38 (d, J=7.7 Hz, 1H, Ar), 7.45 (s, 1H, Ar), 7.67 (d, J=7.9 Hz, 1H, Ar), 10.98 (br. S., 1H, NH); 13C NMR (DMSO-d6) δ 0.03, 22.42, 24.06, 24.19, 29.73, 41.73, 42.79, 44.16, 47.03, 51.49, 121.68, 122.80, 126.71, 130.09, 142.26, 145.37, 157.28, 163.37, 167.89, 170.92, 172.78, 176.83: LC-MS: 442; Anal Calcd for C22H27N5O5+0.5HCOOH+1H2O+0.2CH3CN: C, 56.05; H, 6.21; N, 14.84. Found: C, 55.70: H, 6.46; N, 14.78.
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([Cl:18])=[N:6][C:5]=2[CH:4]=1.[O:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][C:26]2=[O:31])[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:18][C:7]1[N:8]=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:10]2[S:11][C:3]([CH2:2][N:28]3[CH2:29][CH2:30][N:25]([CH:22]4[CH2:21][CH2:20][O:19][CH2:24][CH2:23]4)[C:26](=[O:31])[CH2:27]3)=[CH:4][C:5]=2[N:6]=1
Reactant: O=C1CNCCN1C1CCOCC1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CCN1C1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.3 %

Procedure:
To a solution of 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (200 mg, 0.57 mmol), in DMF (4 mL), was added 1-(tetrahydro-pyran-4-yl)-piperazin-2-one (116 mg, 0.63 mmol) and potassium carbonate (238 mg, 1.72 mmol). The mixture was stirred at RT for 4 h, then the reaction mixture was diluted with water and extracted with DCM. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo to give the title compound as a yellow solid (212 mg, 82%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:7][CH2:6]1.[C:20]1([N:26]=[C:27]=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[ClH:19].[ClH:19].[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:27]([NH:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:28])[CH2:6][CH2:7]2)=[CH:18][CH:17]=1
Reactant: NCCCN1CCCN(Cc2ccc(Cl)cc2)CC1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: Cl
Product: O=C(NCCCN1CCCN(Cc2ccc(Cl)cc2)CC1)Nc1ccccc1
Yield: 210.5 %

Procedure:
1-(3-Aminopropyl)-4-(4-chlorobenzyl)homopiperazine (1.03 g; 3.7 mmole) was reacted with phenyl isocyanate (0.55 g; 4.6 mmole) in methylene chloride (15 ml) for two hours in the manner described in Example 17. The crude product was isolated, purified on silica gel and converted into the hydrochloride in analogous manner. The title compound (1.23 g; 83% yield) was obtained as colorless crystals, m.p. 125°-135° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH:15]2[CH2:17][O:16]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:18]=[N+:19]=[N-:20].[Na+].CO.C(OC)=O>O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH:15]([OH:16])[CH2:17][N:18]=[N+:19]=[N-:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: c1ccc(CCCCCCOCC2CO2)cc1
Agent: [Na+]
Solvent: O
Solvent: COC=O
Solvent: CO
Product: [N-]=[N+]=NCC(O)COCCCCCCc1ccccc1
Yield: 95 %

Procedure:
A procedure similar to that described in Preparation 12 was repeated, except that 4 g of 6-phenylhexyloxymethyloxirane (prepared as described in Preparation 61), 5.5 g of sodium azide, 100 ml of an 8:1 by volume mixture of methanol and water and 25 ml of methyl formate were used, to give 4.5 g of the title compound as a pale yellow oil having an Rf value of 0.39 (on silica gel thin layer chromatography, using a 1:5 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: CN(C=O)C.O[C:7]1[C:12]([C:13]#[N:14])=[CH:11][N:10]=[C:9]2[N:15]=[C:16]([S:18][CH3:19])[S:17][C:8]=12.O=S(Cl)[Cl:22]>O>[Cl:22][C:7]1[C:12]([C:13]#[N:14])=[CH:11][N:10]=[C:9]2[N:15]=[C:16]([S:18][CH3:19])[S:17][C:8]=12
Reactant: O=S(Cl)Cl
Reactant: CSc1nc2ncc(C#N)c(O)c2s1
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc2ncc(C#N)c(Cl)c2s1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of Compound 1f (34.6 g, 120 mmol), DMF-dimethyl acetal (34.0 mL, 240 mmol, 94% purity) and DMF (200 mL) were combined and heated to 80° C. for 90 minutes. The conversion to the cyclized intermediate, 7-hydroxy-2-methylsulfanyl-thiazolo[4,5-b]pyridine-6-carbonitrile was confirmed by LCMS (MS 298, MH+). The mixture was then cooled to 0° C. and SOCl2 was added dropwise (44 mL, 600 mmol). The reaction mixture was stirred for 2 hrs at ambient temperature. The mixture was then cooled back down to 0° C. and water (approximately 300 mL) was added dropwise. The resulting brown solid was collected by filtration and subsequently washed with water and MeOH to provide 7-chloro-2-methylsulfanyl-thiazolo[4,5-b]pyridine-6-carbonitrile Compound 1g (16.1 g) as a tan solid. 1H NMR (CDCl3) δ 8.82 (s, 1H), 2.91 (s, 3H). MS 242, 244 (MH+), 264, 266 (MNa+).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1(C)C=CC=C[CH:19]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[C:1]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][CH2:18][CH3:19])=[O:14])=[CH:16][CH:17]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1ccc(C(=O)c2ccccc2)cc1
Yield: 90.5 %

Procedure:
A mixture of 4-benzoylbenzoic acid (20 g, 88.4 mmole), toluene (5 mL), p-toluenesulfonic acid (1 g) and ethanol (20 mL) was refluxed for 12 hours, cooled, washed with 5% sodium carbonate, and neutralized by water wash. The organic layer was dried over anhydrous magnesium sulfate and concentrated to obtain 22 g ethyl 4-benzoylbenzoate in a yield 90.5%.
Reaction SMILES: [CH:1]1[C:12]2[CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[O:8][CH:7]([C:17](Cl)=[O:18])[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:20]([O:24][CH2:25][CH2:26]O)[CH2:21][CH2:22][CH3:23].C(N(CC)CC)C.[OH2:35]>C1(C)C=CC=CC=1>[CH:1]1[C:12]2[CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[O:8][CH:7]([C:17]([O:18][CH2:26][CH2:25][O:24][CH2:20][CH2:21][CH2:22][CH3:23])=[O:35])[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C1Oc2ccccc2Cc2ccccc2O1
Reactant: O
Reactant: CCCCOCCO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCOCCOC(=O)C1Oc2ccccc2Cc2ccccc2O1
Temperature: 25 °C
Yield: 69 %

Procedure:
Crude 12H-dibenzo[d,g][1,3]dioxocin-6-carbonyl chloride (4.8 g, 17.5 mmol) is dissolved in toluene and treated with a solution of 2-butoxyethanol (2.77 ml, 21 mmol) and 5 ml of triethylamine in toluene at 0° C. under argon. The mixture is heated at reflux for 2 hours and then cooled to room temperature The mixture is poured into 150 ml of water and extracted with 4×100 ml of ethyl acetate. The organic solution is washed with 5 percent hydrochloric acid, 5 percent sodium hydroxide and then brine, dried with magnesium sulfate and filtered. The solvent is removed to leave a yellow liquid which is chromatographed on dry column silica gel, using ethyl ether/hexane (1:2) as the solvent, to give a yellowish oil (4.3 g, 69 percent) An analytically pure material is obtained by using prep thin layer chromatography. IR (neat) 1770, 1582 cm-1. 1H NMR (CDCl3) δ 0.75-1.3 (m, 3H, CH3), 1.2-2.0 (m, 4H, CH2), 3.3-4.0 (m, 5H, OCH2 and benzylic), 4.4-4.9 (m, 3H, OCOCH2 and benzylic), 5.6 (s, 1H, CH), 6.9-7.5 (m, 8H, aromatic).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.OCC[O:10][C:11]1[N:20]=[C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:32]#[N:33])[CH:17]=2)[N:12]=1.C(N(CC)[CH:38]([CH3:40])[CH3:39])(C)C.[CH2:43]([O:45][C:46](C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:47])[CH3:44]>CS(C)=O.O.C(Cl)Cl>[CH2:43]([O:45][C:46]([CH:40]=[CH:38][CH2:39][O:10][C:11]1[N:20]=[C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:32]#[N:33])[CH:17]=2)[N:12]=1)=[O:47])[CH3:44]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc2nc(OCCO)nc(NCc3ccc4c(c3)OCO4)c2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C=CCOc1nc(NCc2ccc3c(c2)OCO3)c2cc(C#N)ccc2n1
Reaction time: 0.17 h

Procedure:
250 μl of dimethyl sulfoxide was slowly dropped into a mixture comprising 150 μl of oxalyl chloride and 15 ml of methylene chloride which had been preliminarily cooled in a dry ice/acetone bath. After 10 minutes, a solution of 500 mg of 2-(2-hydroxyethyl)oxy-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline in 1 ml of dimethyl sulfoxide was dropped into the mixture prepared above at the same temperature and after 10 minutes, 1.4 ml of N,N-diisopropylethylamine was dropped thereinto at the same temperature. The obtained mixture was stirred at the same temperature for 10 minutes and brought to room temperature. After 20 minutes, 600 mg of ethoxycarbonylmethylenetriphenylphosphorane was added in a crystalline state to the resulting mixture to conduct a reaction for 30 minutes, followed by the addition of water. The obtained mixture was extracted with ethyl acetate and the extract was purified by silica gel column chromatography using an ethyl acetate/benzene mixture to give 400 mg of 2-(3-ethoxycarbonyl-2-propenyl)oxy-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline (cis/trans mixture).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH2:13])C)=[CH:2]1.[C:14](OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:14][C:2]1[NH:1][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH2:10][CH2:11][NH2:13]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C[C@H](N)Cc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1[nH]c2ccccc2c1CCN
Temperature: 25 °C

Procedure:
A mixture of (S)-2-(1H-Indol-3-yl)-1-methylethylamine (0.43 g, 2.5 mmol) and di-t-butyl dicarbonate (0.60 g, 2.75 mmol) in acetone is treated dropwise with aqueous K2CO3 (3.5 g, 25 mmol) at 0° C., allowed to warm to room temperature for 16 h, concentrated to an aqueous residue and extracted with EtOAc. The extracts are combined, dried over MgSO4 and concentrated in vacuo to dryness. This residue is chromatographed (silica gel, 10%-50% EtOAc in hexanes as gradient eluent) to give the protected®-2-methyl tryptamine. A mixture of the protected tryptamine (0.17 g, 0.62 mmol) and 6-chloroimidazo[2,1-b]thiazole-5-sulfonyl chloride (0.16 g, 0.62 mmol) in THF is treated with potassium t-butoxide (77 mg, 0.68 mmol) at room temperature, stirred for 1 H, poured into saturated NaHCO3 and extracted with EtOAc. The extracts are combined, dried over Na2SO4 and concentrated in vacuo. The resultant residue is dispersed in THF and 4N HCl in dioxane, stirred for 16 h, concentrated in vacuo and purified by HPLC1 to afford the title product as a beige solid, 0.62 mg (35% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[C:13]([Br:17])=[C:14](Br)[S:15][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Li]CCCC.[F:23][C:24]([F:34])([F:33])[C:25](C(O)C(F)(F)F)=[O:26]>C1COCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[C:13]([Br:17])=[C:14]([C:25](=[O:26])[C:24]([F:34])([F:33])[F:23])[S:15][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2sc(Br)c(Br)c2CC1
Reactant: O=C(C(O)C(F)(F)F)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)N1CCc2sc(C(=O)C(F)(F)F)c(Br)c2CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 35.1 %

Procedure:
The product of Example 1, step (e) (200 mg, 0.52 mmol) was dissolved in 5 mL THF, cooled to −78° C. and treated with BuLi (0.33 mL of 1.6 M). After stirring for 15 minutes at −78° C., trifluoroacetyl 2,2,2-trifluoroethanol (132 uL, 0.68 mmol) was added and the reaction was allowed to warm to room temperature. The reaction was quenched with water (50 uL) and concentrated. The residue was purified by silica gel chromatography to give 73 mg of the sub-title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[SH:10].[H-].[Na+].[CH2:13]([N:20]1[C:24]2[N:25]=[C:26]([NH2:30])[N:27]=[C:28](Cl)[C:23]=2[CH:22]=[CH:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:20]1[C:24]2[N:25]=[C:26]([NH2:30])[N:27]=[C:28]([S:10][C:3]3[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])[C:23]=2[CH:22]=[CH:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1cc(C)c(S)c(C)c1
Reactant: Nc1nc(Cl)c2ccn(Cc3ccccc3)c2n1
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(C)c(Sc2nc(N)nc3c2ccn3Cc2ccccc2)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.2 %

Procedure:
To a solution of 2,4,6-trimethylbenzene-1-thiol (231 mg, 1.52 mmol) in 1-methyl-2-pyrridone (2 mL) was added NaH (58 mg, 1.52 mmol). The reaction mixture was stirred at room temperature for 15 min and a solution of 7-benzyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (131 mg, 0.51 mmol) in 1-methyl-2-pyrridone (2 mL) was added to the mixture. The mixture was heated at 60° C. for 16 h and cooled to room temperature. The reaction was poured into ice water and extracted with EtOAc (2×20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=75:25) yielded 180 mg (94%) of 7-benzyl-4-(2,4,6-trimethyl-phenylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3](=[O:20])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2([C:18]#N)[CH2:17][CH2:16][CH2:15]2)=[CH:9][CH:8]=1.[N:22]([C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([C:33]([F:36])([F:35])[F:34])[CH:26]=1)=[C:23]=[S:24].C[OH:38].Cl>CN(C=O)C.O>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([N:22]2[C:18](=[O:38])[C:14]3([CH2:17][CH2:16][CH2:15]3)[N:13]([C:10]3[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][CH2:4][C:3]([N:2]([CH3:21])[CH3:1])=[O:20])=[CH:8][CH:9]=3)[C:23]2=[S:24])=[CH:26][C:27]=1[C:33]([F:34])([F:36])[F:35])#[N:30]
Reactant: CN(C)C(=O)CCCc1ccc(NC2(C#N)CCC2)cc1
Reactant: CO
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)CCCc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Temperature: 25 °C

Procedure:
A mixture of N,N-Dimethyl 4-[4-(1-cyanocyclobutylamino)phenyl]butanamide (Formula 48) (58 mg. 0.20 mmol) and 4-isothiocyanato-2-trifluoromethyl benzonitrile (74 mg, 0.32 mmol) in DMF (3 mL) was heated under reflux for 2 hours. To this mixture was added methanol (20 mL) and aq. 1 N HCl (5 mL). The second mixture was refluxed for 1.5 h. After being cooled to room temperature, the reaction mixture was poured into cold water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over MgSO4, concentrated and the residue was purified with silica gel column chromatography (dichloromethane:acetone, 95:5) to give 4-(4-(7-(4-Cyano-3-(trifluoromethyl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenyl)-N,N-dimethylbutanamide, NC56 (Formula 49) (44 mg, 42%) as a pale yellowish solid. 1H NMR δ 7.98 (s, 1H), 7.97 (d. 1H, J=8.2 Hz), 7.86 (d, 1H, J=8.2 Hz), 7.42 (d, 2H, J=8.3 Hz), 7.22 (d, 2H, J=8.3 Hz), 2.99 (s, 3H), 2.96 (s, 3H), 2.78 (t, 2H, J=7.5 Hz), 2.62-2.70 (m, 2H), 2.52-2.63 (m, 2H), 2.40 (t, 2H, J=7.5 Hz), 2.15-2.30 (m, 11H), 2.04 (p, 2H, J=7.5 Hz), 1.62-1.73 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[N:4][C:3]=1O.P(Br)(Br)([Br:15])=O.O.C(=O)([O-])O.[Na+]>ClCCl>[Br:15][C:3]1[N:4]=[N:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=1[Br:1]
Reactant: Oc1nnc(C(F)(F)F)cc1Br
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: FC(F)(F)c1cc(Br)c(Br)nn1
Temperature: 60 °C
Reaction time: 4 h
Yield: 45.5 %

Procedure:
A mixture of 4-bromo-6-trifluoromethyl-pyridazin-3-ol (D3) (4.0 g, 16.4 mmol) and phosphorus oxybromide (28.2 g, 98.4 mmol) was stirred at 60° C. for 4 h. After this period, the reaction mixture was poured into a mixture of ice and water, diluted with dichloromethane and neutralized with a saturated solution of sodium hydrogen carbonate. The organic layer was separated, dried (MgSO4) and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; 3% ammonia in methanol (7M)/dichloromethane). The desired fractions were collected and evaporated in vacuo. to yield D5 (2.28 g, 46%) as a solid. C5HBr2F3N2 requires 305; Found 306 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[NH:13]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14]1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([N:13]2[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14]2)=[CH:3][C:4]=1[C:9]([F:12])([F:11])[F:10]
Reactant: CCOC(=O)CCC1CCNC1
Reactant: FC(F)(F)c1cc(Br)ccc1Cl
Product: CCOC(=O)CCC1CCN(c2ccc(Cl)c(C(F)(F)F)c2)C1
Yield: 61 %

Procedure:
The title compound (5.0 g, yield 61%) was obtained from 4-bromo-1-chloro-2-(trifluoromethyl)benzene and ethyl 3-(pyrrolidin-3-yl)propanoate obtained in Reference Example 12 by a method similar to that in Reference Example 1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10]OC(=O)OC2C=CC([N+]([O-])=O)=CC=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:24][C@H:25]([C:27]([OH:29])=[O:28])[CH3:26].C(N(CC)CC)C.[CH2:37]([OH:39])C.O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:37]([NH:24][C@H:25]([C:27]([OH:29])=[O:28])[CH3:26])=[O:39])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCO
Reactant: C[C@H](N)C(=O)O
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@H](NC(=O)Cc1ccc([N+](=O)[O-])cc1)C(=O)O

Procedure:
The title compound is prepared by the procedure of Example 255 using 5.3 g of product from Example 254, 1.48 g of L-alanine, 4.6 ml of triethylamine, and 200 ml of 80/20 ethyl alcohol/water. The resulting oil is purified by chromatography (3X, silica gel: 50% ethyl acetate/hexane) to give 3.39 g of the desired product.
Reaction SMILES: C([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)C.[CH:13]1([C:18](O)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.[OH-].[Na+]>C(O)C>[CH:13]1([C:18]([NH:11][C:8]2[CH:7]=[CH:6][C:5]([C:4]([OH:3])=[O:12])=[CH:10][CH:9]=2)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C(O)C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(NC(=O)C2CCCC2)cc1

Procedure:
4-Aminobenzoic acid ethyl ester was reacted with cyclopentanecarboxylic acid by method E, and the resulting ester was hydrolyzed by boiling with sodium hydroxide in aqueous ethanol. The product with the molecular weight of 233.27 (C13H15NO3); MS (ESI): 234 (M+H+) was obtained in this way.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][C:15]=1[CH3:21].C(N(C(C)C)CC)(C)C>C(O)C>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=3)[N:3]=2)=[CH:16][C:15]=1[CH3:21]
Reactant: Cc1cc(N)ccc1Br
Reactant: Oc1ccc2nc(Cl)ccc2c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2ccc3cc(O)ccc3n2)ccc1Br

Procedure:
The mixture containing 2-chloroquinolin-6-ol (1eq), 4-bromo3-methylaniline (2 eq) and diisopropylethylamine in ethanol (1 M) was refluxed overnight. The resultant mixture was concentrated and purified on silica gel to provide the desired product. The mixture containing 2-chloroquinolin-6-ol (1 eq), 4-bromo3-methylaniline (2 eq) and diisopropylethylamine in ethanol (1M) was refluxed overnight. The resultant mixture was concentrated and purified on silica gel to provide the desired product.
Reaction SMILES: [NH2:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:16][N:15]=[N:14][N:13]=3)[CH3:10])[CH2:7][S:8][C@H:3]12.C(OC([NH:29][CH:30]([C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41]([NH2:43])=[O:42])=[CH:36][CH:35]=1)[C:31](O)=[O:32])=O)(C)(C)C>>[CH3:10][CH:9]([S:11][C:12]1[NH:13][N:14]=[N:15][N:16]=1)[C:6]1[CH2:7][S:8][C@@H:3]2[CH:2]([NH:1][C:31](=[O:32])[CH:30]([C:34]3[CH:35]=[CH:36][C:37]([NH:40][C:41]([NH2:43])=[O:42])=[CH:38][CH:39]=3)[NH2:29])[C:20](=[O:21])[N:4]2[C:5]=1[C:17]([OH:19])=[O:18]
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccc(NC(N)=O)cc1
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)C(N)c3ccc(NC(N)=O)cc3)[C@H]2SC1

Procedure:
When 7-amino-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (3.28 g, 0.01 mol) was acylated with the product of Example 1 (3.1 g, 0.01 mol) according to the procedure of Example 2, the title compound was obtained: mp>300°.