Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([C@H:22]4[CH2:26][CH2:25][CH2:24][NH:23]4)[N:19]=[C:18]3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:35])[F:34])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].N1C=CC=CC=1.[C:43](Cl)(=[O:45])[CH3:44]>C1COCC1>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([C@H:22]4[CH2:26][CH2:25][CH2:24][N:23]4[C:43](=[O:45])[CH3:44])[N:19]=[C:18]3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:34])[F:35])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CC(=O)Cl
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-n3cc([C@H]4CCCN4)nc3-c3ccccc3C(F)(F)F)cc2)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)N1CCC[C@@H]1c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(-c2ccccc2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into an 8 mL vial was weighed 26.8 mg (52 μmol) of 1-(3′-(methylsulfonyl)biphenyl-4-yl)-4-((R)-pyrrolidin-2-yl)-2-(2-(trifluoromethyl)phenyl)-1H-imidazole. The vial was charged with 0.5 mL of THF, followed by 15 μL (185 μmol) of pyridine, and 7 μL (98 μmol) of acetyl chloride. After stirring for 30 minutes at ambient temperature, LC/MS analysis of the reaction showed complete conversion to product. The reaction was quenched by addition of a small amount of water. The reaction solution was directly injected into the reverse phase preparative HPLC and eluted with acetonitrile/water. (Phenomenex Axia Gemini C18 30×100 mm 5 μm, A=H2O with 0.1% trifluoroacetic acid, B=acetonitrile with 0.1% trifluoroacetic acid, 17 minute gradient from 10% B to 100% B at 35 mL/minute). Product fractions were combined, made basic by the addition of sat. NaHCO3, and concentrated in vacuo to remove the acetonitrile. The resulting basic aqueous was extracted with CH2Cl2 (3×), and the organics were dried over Na2SO4, filtered and concentrated in vacuo. The resulting 1-((2R)-2-(1-(3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)pyrrolidin-1-yl)ethanone was isolated as a white powder, yield 20.2 mg (70%); 1H NMR (400 MHz, CDCl3): δ 8.10-8.07 (m, 1H), 7.95-7.90 (m, 1H), 7.83-7.79 (m, 1H), 7.77-7.72 (m, 1H), 7.67-7.61 (m, 1H), 7.56-7.42 (m, 4H), 7.38-7.34 (m, 0.6H), 7.30-7.26 (m, 0.4H), 7.20-7.16 (m, 2.4H), 7.05-7.04 (m, 0.6H), 5.34-5.31 (m, 0.4H), 5.08-5.05 (m, 0.6H), 3.78-3.67 (m, 1H), 3.63-3.49 (m, 1H), 3.09 (s, 1.8H), 3.08 (s, 1.2H), 2.52-2.46 (m, 0.4H), 2.36-2.26 (m, 1.6H), 2.14 (s, 1.8H), 2.12 (s, 1.2H), 2.08-1.95 (m, 2H); MS (ES): 554.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][P:4]([O:41][CH2:42][CH3:43])([C:6]([F:40])([F:39])[C@@H:7]([C@H:9]1[O:29][C@H:28]([CH2:30][O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@@H:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:10]1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)O)=[O:5])[CH3:2].C(OP(OCC)(C(F)(F)[C@@H](O)[C@H]1O[C@H](COCC2C=CC=CC=2)[C@@H](OCC2C=CC=CC=2)[C@@H]1OCC1C=CC=CC=1)=O)C.N(C(C)(C)C#N)=NC(C)(C)C#N>C1(C)C=CC=CC=1>[CH2:42]([O:41][P:4]([O:3][CH2:1][CH3:2])([C:6]([F:40])([F:39])[CH2:7][C@H:9]1[O:29][C@H:28]([CH2:30][O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C@@H:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:10]1[O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:5])[CH3:43]
Reactant: CCOP(=O)(OCC)C(F)(F)[C@H](O)[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCOP(=O)(OCC)C(F)(F)[C@@H](O)[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)C(F)(F)C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1

Procedure:
A 440 mg portion of a mixture of 3,6-anhydro-1-deoxy-1-(diethoxyphosphinyl)-1,1-difluoro-4,5,7-tris-O-(phenylmethyl)-D-glycero-D-galacto-heptitol, O-1H-imidazole-1-carbothioate and 2,5-anhydro-7-deoxy-7-(diethoxyphosphinyl)-7,7-difluoro-1,3,4-tris-O-(phenylmethyl)-D-glycero-D-manno-heptitol, O-1H-imidazole-1-carbothioate was dissolved in 12 ml of dry toluene, then treated with 900 μl of n-tributyl stannous hydride and a few crystals of 2,2'-azobisisobutyronitrile and heated in an oil bath under argon for 3 hours. The solution was cooled, then stored in a freezer and finally evaporated. The resulting oil was purified by chromatography giving the desired compound.
Reaction SMILES: [C:1]([C:5](=[O:36])[CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:32]=[CH:33][C:34]=1[Cl:35])[C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:14])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(Cl)[Cl:38]>>[C:1]([C:5](=[O:36])[CH:6]([Cl:38])[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:32]=[CH:33][C:34]=1[Cl:35])[C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:14])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCCCCCCCCCCCCOC(=O)c1ccc(Cl)c(NC(=O)CC(=O)C(C)(C)C)c1
Reactant: ClCCl
Product: CCCCCCCCCCCCCCCCOC(=O)c1ccc(Cl)c(NC(=O)C(Cl)C(=O)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To a suspension of 52.22 g (0.1 mol) of hexadecyl 3-[3-t-butyl-3-oxopropanamido]-4-chlorobenzoate 1 in 350 mL of CH2Cl2 was added 13.52 g (0.1 mol) of SO2Cl2. The mixture was gently refluxed for one hr, then stirred at room temperature for 0.5 hr. The solvent was removed under vacuum to yield a solid that was washed with ligroin and dried. There was thus obtained 52.62 g (94.5% yield) of 2, which was used in the following step.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15](CO)[O:14][CH:12]([OH:13])[C@H:11]([CH2:18][OH:19])[C@H:10]1[OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I([O-])(=O)(=O)=O.[Na+]>CO.O>[CH2:1]([O:8][C@H:9]([CH:15]=[O:14])[C@H:10]([OH:20])[C@@H:11]([CH2:18][OH:19])[CH:12]=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@H]1OC(O)[C@H](CO)[C@@H](O)[C@@H]1OCc1ccccc1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CO
Product: O=C[C@H](CO)[C@@H](O)[C@@H](C=O)OCc1ccccc1
Temperature: 45 °C
Reaction time: 3 h

Procedure:
To a solution of 4-O-benzyl-2-deoxy-2-C-hydroxymethyl-D-gluco-pyranose (1.41 g, 5.0 mmol) in methanol (15 ml), a solution of sodium periodate (5.35 g, 25.0 mmol) in water (50 ml) was added dropwise over 15 minutes. Further, methanol (25 ml) was added. The mixture was stirred at 45° C. for 3 hours. The precipitated iodate was filtered off, and the mixture was concentrated. By resolution of the residue in ethyl acetate/ethanol (1:1; 80 ml), more iodate was precipitated and filtered off. The mother liquour was concentrated and the residue (2.07 g) was flash chromatographed using ethyl acetate as eluent. The purified product was obtained as a yellow sirup in 87% (1.09 g) yield and 9% of unreacted starting material (0.13 g) was isolated. The purified product was used imidiately in the next reaction.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8]CC)=O)C.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>>[CH2:14]([O:13][C:11]([C:5]1[CH:4]=[N:21][C:20]2[C:22]([C:6]=1[OH:8])=[CH:23][C:17]([Cl:16])=[CH:18][CH:19]=2)=[O:12])[CH3:15]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(Cl)cc1
Product: CCOC(=O)c1cnc2ccc(Cl)cc2c1O
Yield: 98.1 %

Procedure:
From a mixture of 216 g of diethyl ethoxymethylenemalonate, 126.6 g of p-chloroaniline, and 800 ml of diphenyl heated first at 150°-160° for 15 min and then at 245° for 20 min there was obtained on cooling the above-named compound as a precipitate. This precipitate was collected, and washed with water and with hexane to give 245 g of crude damp solid, which was used directly in the hydrolysis reaction described below.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4].[H-].[Na+].[C:16]1([C@@H:22]([NH:24][C:25]2[N:30]=[C:29](Cl)[CH:28]=[CH:27][N:26]=2)[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[C:16]1([C@@H:22]([NH:24][C:25]2[N:26]=[C:27]([N:11]3[C:7]4[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:13]=[CH:12][C:8]=4[N:9]=[CH:10]3)[CH:28]=[CH:29][N:30]=2)[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:16]1([C@@H:22]([NH:24][C:25]2[N:26]=[C:27]([N:9]3[C:8]4[CH:12]=[CH:13][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][C:7]=4[N:11]=[CH:10]3)[CH:28]=[CH:29][N:30]=2)[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[C@H](Nc1nccc(Cl)n1)c1ccccc1
Reactant: COC(=O)c1ccc2nc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)ncn2-c1ccnc(N[C@@H](C)c2ccccc2)n1
Product: COC(=O)c1ccc2ncn(-c3ccnc(N[C@@H](C)c4ccccc4)n3)c2c1
Temperature: 80 °C

Procedure:
To a solution of 5-methoxycarbonylbenzimidazole (66 mg, 0.375 mmol, 1 eq) in DMF (2 mL) was added NaH (15 mg, 0.375 mmol, 1 eq). The mixture was stirred until gas evolution ceased. To the DMF solution was added 2-[(S)-1-phenylethylamino]-4-chloro-pyrimidine (87.5 mg, 0.375 mmol, 1 eq). The mixture was heated to 80° C. and stirred for several hours. The DMF was removed under reduced pressure and the residue was diluted with ethyl acetate and washed with water. The aqueous layer was back extracted with ethyl acetate. The organic extracts were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified by preparative thin layer chromatography (eluted with 7% MeOH in CH2Cl2) to give 30 mg 2-[(S)-1-phenylethylamino]-4-[6-(methoxycarbonyl)benzimidazol-1-yl]pyrimidine (faster regioisomer) and 26 mg 2-[(S)-1-phenylethylamino]-4-[5-(methoxycarbonyl)benzimidazol-1-yl]pyrimidine (slower regioisomer). 1H NMR (500 MHz, CD3OD): δ 1.58 (3H, d, J=7.5 Hz), 3.94 (3H, s), 4.59 (1H, br s), 5.1 (1H, br s) 6.97 (1H, d, J=5.5 Hz), 7.23 (1H, br t, J=7 Hz), 7.35 (2H, br m), 7.44 (2H, d, J=7.5 Hz), 7.6-8.1 (2H, m), 8.3-8.4 (2H, m), 8.91 (1H, br s). Mass spectrum (ESI) 374.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][CH3:31])=[CH:4][C:5]([O:28][CH3:29])=[C:6]([NH:8][C:9]([CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]([CH2:23][C:24]([OH:26])=O)[C:13]2=[O:27])=[O:10])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:56]([O:60][C:61](=[O:68])[NH:62][C@@H:63]1[CH2:67][CH2:66][NH:65][CH2:64]1)([CH3:59])([CH3:58])[CH3:57].CCN(C(C)C)C(C)C>O.CN(C=O)C>[C:56]([O:60][C:61](=[O:68])[NH:62][C@H:63]1[CH2:67][CH2:66][N:65]([C:24](=[O:26])[CH2:23][N:14]2[C:15](=[O:22])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]([CH2:11][C:9](=[O:10])[NH:8][C:6]3[CH:7]=[C:2]([Cl:1])[C:3]([O:30][CH3:31])=[CH:4][C:5]=3[O:28][CH3:29])[C:13]2=[O:27])[CH2:64]1)([CH3:59])([CH3:57])[CH3:58]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)O)c(=O)c3ccccc32)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)N3CC[C@H](NC(=O)OC(C)(C)C)C3)c(=O)c3ccccc32)cc1Cl
Temperature: 25 °C

Procedure:
To a vial charged with {1-[(5-chloro-2,4-dimethoxy-phenylcarbamoyl)-methyl]-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-acetic acid (50.1 mg, 0.11 mmol), HATU (50.1 mg, 0.12 mmol), and (R)-pyrrolidin-3-yl-carbamic acid tert butyl ester (22.8 mg, 0.12 mmol), DMF (3 ml) was added. The stirring mixture is treated with DIPEA (33 μL, 0.275 mmol) and stirred at RT. Water is added to the mixture with stirring giving rise to a solid. This is filtered off and washed with water to afford the title compound; [M+H]+ 616
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[BrH:1].[N:13]1([C:10]2[CH:9]=[C:8]3[C:7](=[CH:12][CH:11]=2)[NH:6][C:4](=[O:5])[CH2:3][CH2:2]3)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: O=C(CCBr)Nc1ccc(N2CCNCC2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: Br
Product: O=C1CCc2cc(N3CCNCC3)ccc2N1
Temperature: 0 °C
Yield: 40.9 %

Procedure:
A suspension of 2.2 g of N-(β-bromopropionyl)-p-piperazinylaniline and 28 g of pulverized anhydrous aluminum chloride in 50 ml of carbon disulfide was stirred under reflux for 4 hours. The reaction mixture was poured into ice water and the precipitations were collected by filtration, washed with water and then with ether and converted to hydrobromic acid salt followed by recrystallization from methanol-water to give 0.9 g of 6-(1-piperazinyl)-3,4-dihydrocarbostyril monohydrobromide, m.p. 289°-293° C. (decomp.) (methanol-water), colorless needles.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:13]1C=CN=CN=1)[C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[Cl:12])=O.O.[NH2:21]N.C([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])C>C(O)C>[Cl:12][C:11]1[CH:10]=[CH:9][S:8][C:7]=1[C:5]1[C:4]([C:13]2[CH:27]=[CH:26][N:25]=[CH:28][CH:29]=2)=[CH:3][NH:2][N:21]=1
Reactant: CN(C)C=C(C(=O)c1sccc1Cl)c1ccncn1
Reactant: NN
Reactant: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: Clc1ccsc1-c1n[nH]cc1-c1ccncc1
Yield: 55.4 %

Procedure:
To a solution of 3-(dimethylamino)-1-(3-chloro-2-thienyl)-2-(pyrimidin-4-yl)prop-2-en-1-one (1 eq, 20 mmol) in ethanol (60 mL) was added hydrazine hydrate (1.5 eq, 30 mmol) and triethylamine (1.5 eq, 30 mmol). The reaction mixture was stirred at reflux for 2 h. The mixture was evaporated under reduced pressure. The obtained residue was dissolved in dichloromethane (100 mL) and methanol (10 mL), washed with brine (3×50 mL), dried over Na2SO4 and concentrated. The crude product was suspended in ethylacetate, filtered and dried to afford 2.9 g of 4-(3-(3-chloro-2-thienyl)-1H-pyrazol-4-yl)pyridine (55% yield).
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[Cl:7][C:8]1[CH:34]=[CH:33][C:11]2[CH:12]=[C:13]([S:16]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[C:21](=[O:32])[CH2:20]3)(=[O:18])=[O:17])[CH2:14][O:15][C:10]=2[CH:9]=1.Cl.Cl[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1>>[Cl:7][C:8]1[CH:34]=[CH:33][C:11]2[CH:12]=[C:13]([S:16]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH:26]4[CH2:27][CH2:28][N:29]([C:41]5[CH:40]=[CH:39][N:38]=[CH:37][CH:42]=5)[CH2:30][CH2:31]4)[C:21](=[O:32])[CH2:20]3)(=[O:17])=[O:18])[CH2:14][O:15][C:10]=2[CH:9]=1
Reactant: O=C1CN(S(=O)(=O)C2=Cc3ccc(Cl)cc3OC2)CCN1CC1CCNCC1
Reactant: Clc1ccccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C1CN(S(=O)(=O)C2=Cc3ccc(Cl)cc3OC2)CCN1CC1CCN(c2ccncc2)CC1
Yield: 39.9 %

Procedure:
To sodium bicarbonate solution were added 4-(7-chloro-2H-benzopyran-3-sulfonyl)-1-(piperidin-4-ylmethyl)-2-piperazinone hydrochloride (1.4 g) and chloropyridine hydrochloride (1.02 g), and the mixture was extracted with dichloromethane (twice), dried and concentrated. To the residue was added isoamylalcohol (50 ml), and the mixture was allowed to react at 130° C. for 15 hours. The reaction solution was concentrated, and the residue was dissolved in dichloromethane. The solution was washed with 1N sodium hydroxide solution, dried and concentrated, and the residue was purified with silica gel column chromatography (dichloromethane:methanol containing 10% ammonia solution=20:1) to give colorless solid@ 4-(7-chloro-2H-benzopyran-3-sulfonyl)-1-[1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone (608 mg).
Reaction SMILES: N[C@@H:2]([CH2:6][C:7]1[N:8]=[CH:9][NH:10][CH:11]=1)[C:3]([OH:5])=O.[CH:12]1([NH:19][C:20]([NH2:22])=[S:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([NH:19][C:20]2[S:21][CH:2]([CH2:6][C:7]3[N:8]=[CH:9][NH:10][CH:11]=3)[C:3](=[O:5])[N:22]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: NC(=S)NC1CCCCCC1
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Product: O=C1N=C(NC2CCCCCC2)SC1Cc1c[nH]cn1

Procedure:
Synthesis was performed from (2S)-2-amino-3-(1H-imidazol-4-yl)propanoic acid and N-cycloheptylthiourea according to Method E and C.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11](Br)[N:10]=2)=[O:8])=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CCCC)CCCC)CCC.[C:49]([O:53][CH2:54][CH3:55])(=[O:52])[CH:50]=[CH2:51]>CCOC(C)=O.O>[C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([C:7]([C:9]2[N:10]=[C:11](/[CH:51]=[CH:50]/[C:49]([O:53][CH2:54][CH3:55])=[O:52])[CH:12]=[CH:13][CH:14]=2)=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(C(=O)c2cccc(Br)n2)cc1
Reactant: C=CC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)/C=C/c1cccc(C(=O)c2ccc(C)cc2)n1
Temperature: 130 °C

Procedure:
A mixture of ketone 3 (16.90 g, 61.2 mmol), triphenylphosphine (1.64 g, 6.25 mmol), tributylamine (15 mL), and ethyl acrylate (16 mL) was stirred and heated (hot bath at 125-135° C.) for 7 h. Two additional aliquots of ethyl acrylate (7 mL each) were added at 4 h and 6 h. After the reaction was cooled to room temperature, the reaction mixture was poured over water (300 mL) and EtOAc (300 mL). The aqueous layer was extracted further with EtOAc. The combined organics were dried with Na2SO4, filtered, and evaporated to dryness. Chromatography over silica gel using heptane/EtOAc (starting at 8:1) gave 15.49 g of 5c as a yellow crystalline solid. The structure was confirmed by 1H NMR. (Keto-acrylates 5e and 5f were similarly prepared using isobutyl acrylate and cyclopentyl acrylate, respectively.)
Reaction SMILES: [CH2:1]([N:8]1C(=O)C2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([N:24]([CH2:33][CH:34](OC)OC)[C:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39]([O-:42])(=O)[CH3:40].[NH4+:43]>C(O)(=O)C>[CH2:1]([N:8]1[C:39](=[O:42])[C:40]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([N:24]1[CH:33]=[CH:34][N:43]=[C:25]1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: COC(CN(C(=O)c1ccccc1)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)C(C)C)OC
Reactant: CC(=O)[O-]
Solvent: CC(=O)O
Product: CC(C)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)n1ccnc1-c1ccccc1
Yield: 22.6 %

Procedure:
A solution of N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propyl]-N-(2,2-dimethoxy-ethyl)-benzamide (288 mg, 0.539 mmol) and ammonium acetate (374 mg, 4.85 mmol) in acetic acid (4.0 mL) was refluxed for 2.0 h. The reaction was concentrated in vacuo and the residue was dissolved in ethyl acetate and washed sequentially with saturated sodium carbonate, water, and brine. The organic layer was dried (Na2SO4), concentrated in vacuo, and recrystallized from ethanol to give the title compound as tan crystals (57.1 mg, 23%). MS(ES+) m/e 469 [M+H]+.
Reaction SMILES: C([C:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:9](Cl)=[O:10])[C:6](Cl)=[O:7])(C)(C)C.C(C(C1SC=CC=1)(C(Cl)=O)C(Cl)=[O:24])(C)(C)C.C(=O)(O)[O-].[Na+].[NH2:39][CH:40]1[C:55](=[O:56])[N:42]2[C:43]([C:48]([O:50]C(C)(C)C)=[O:49])=[C:44]([Cl:47])[CH2:45][S:46][C@H:41]12>CC(C)=O>[C:9]([CH:5]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:6]([NH:39][CH:40]1[C:55](=[O:56])[N:42]2[C:43]([C:48]([OH:50])=[O:49])=[C:44]([Cl:47])[CH2:45][S:46][C@H:41]12)=[O:7])([OH:10])=[O:24]
Reactant: CC(C)(C)C(C(=O)Cl)(C(=O)Cl)c1cccs1
Reactant: CC(C)(C)C(C(=O)Cl)(C(=O)Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)C1=C(Cl)CS[C@@H]2C(N)C(=O)N12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(O)C1=C(Cl)CS[C@@H]2C(NC(=O)C(C(=O)O)c3ccccc3)C(=O)N12

Procedure:
The compounds of the Formula I wherein Q is a carboxylic acid group can be prepared for example, by the acylation of a 3-halo-3-cephem nucleus with tert-butyl phenylmalonic acid chloride, or with tert-butyl 2-thienylmalonic acid chloride in the presence of a hydrogen halide acceptor such as sodium bicarbonate. For example, tert-butyl 7-amino-3-chloro-3-cephem-4-carboxylate is reacted with 2 equivalents of tert-butyl phenylmalonyl chloride in acetone at a temperature of about 5° C. and in the presence of excess sodium bicarbonate to provide, tert-butyl 7-(α-tert-butyloxycarboxylphenylacetamido)-3-chloro-3-cephem-4-carboxylate. Removal of both tert-butyl ester groups with 90% formic acid provides the diacid, 7-(α-carboxyphenylacetamido)-3-chloro-3-cephem-4-carboxylic acid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:22])[CH2:13][CH2:14][NH:15][S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17].[H-].[Na+]>>[CH3:11][N:12]([CH3:22])[CH2:13][CH2:14][N:15]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[S:16]([CH:19]([CH3:20])[CH3:21])(=[O:18])=[O:17]
Reactant: CC(C)S(=O)(=O)NCCN(C)C
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)S(=O)(=O)N(CCN(C)C)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 1-fluoro-4-nitro-benzene, N-(2-dimethylamino-ethyl)-isopropylsulphonamide and sodium hydride as base
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[NH:23][C:22]2=[O:35])[CH2:17][CH2:16]1.Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[N:23]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:22]2=[O:35])[CH2:17][CH2:16]1
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Reactant: CCOC(=O)CBr
Product: CCOC(=O)Cn1c(=O)n(C2CCN(c3ncnc4cc(OC)c(OC)cc34)CC2)c(=O)c2cc([N+](=O)[O-])ccc21
Yield: 17 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 300 mg (0.63 mmol) of Compound 24 was used and ethyl bromoacetate was used in place of methyl iodide. As a result, 61.3 mg (yield: 17%) of Compound 6 was obtained as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([C:19](OC)=[O:20])=[CH:15][CH:14]=2)=[N:3]1.[H-].[Li+].[Al+3].[H-].[H-].[H-].O>O1CCCC1>[CH3:1][C:2]1([CH3:23])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:14]=[CH:15][C:16]([CH2:19][OH:20])=[CH:17][CH:18]=2)=[N:3]1
Reactant: COC(=O)c1ccc(-c2ccccc2C2=NC(C)(C)CO2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)COC(c2ccccc2-c2ccc(CO)cc2)=N1
Yield: 93 %

Procedure:
2.0 g (6.46 mmol) of 4,4-dimethyl-2-(4'-methoxycarbonylbiphenyl-2-yl)oxazoline was dissolved in tetrahydrofuran (20 ml). 0.49 g (12.9 mmol) of aluminum lithium hydride was gradually added thereto under cooling with ice, followed by the stirring for 2 hours as such. Water (50 ml) was added thereto to conduct hydrolysis, followed by the extraction with chloroform. After washing with water and drying, vacuum concentration was conducted. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 1.69 g of the title compound (yield 93%).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][O:14][C:15]1[CH:23]=[C:22]2[C:18]([CH2:19][CH2:20][CH:21]2[NH2:24])=[CH:17][CH:16]=1.[CH3:25][S:26]([C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32])(=[O:28])=[O:27]>>[CH3:25][S:26]([C:29]1[CH:30]=[C:31]([NH:32][C:2]2[C:3]3[CH:4]=[CH:5][C:6]([NH:24][CH:21]4[C:22]5[C:18](=[CH:17][CH:16]=[C:15]([O:14][CH3:13])[CH:23]=5)[CH2:19][CH2:20]4)=[N:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH:33]=[CH:34][CH:35]=1)(=[O:27])=[O:28]
Reactant: Clc1ccc2c(I)cccc2n1
Reactant: COc1ccc2c(c1)C(N)CC2
Reactant: CS(=O)(=O)c1cccc(N)c1
Product: COc1ccc2c(c1)C(Nc1ccc3c(Nc4cccc(S(C)(=O)=O)c4)cccc3n1)CC2

Procedure:
The title compound, MS: m/e=460.4 (M+H+), was prepared in accordance with the general method of example 6 from 5-iodo-2-chloroquinoline, 6-methoxyindan-1-ylamine (CAS 103028-81-5) and 3-methylsulfonylaniline.