Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]C(Br)C.[Mg].[Br:6][C:7]1[C:8]([O:27][CH2:28][CH:29]2[CH2:31][O:30]2)=[CH:9][CH:10]=[C:11]2[C:15]=1[N:14]([CH2:16][CH:17]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH3:18])[N:13]=[CH:12]2>C1COCC1>[Br:1][CH2:31][CH:29]([OH:30])[CH2:28][O:27][C:8]1[C:7]([Br:6])=[C:15]2[C:11]([CH:12]=[N:13][N:14]2[CH2:16][CH:17]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH3:18])=[CH:10][CH:9]=1
Reactant: CC(Br)Br
Reactant: CC(Cn1ncc2ccc(OCC3CO3)c(Br)c21)O[Si](C)(C)C(C)(C)C
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(Cn1ncc2ccc(OCC(O)CBr)c(Br)c21)O[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 86.4 %

Procedure:
Dibromoethane (1.09 mL, 12.6 mmol) was added dropwise to a suspension of magnesium powder (0.81 g, 33.5 mmol) in anhydrous THF (150 mL) under nitrogen. During this period the mixture was heated at about 50° C. until gas evolution was observed and then allowed to cool to 40° C. Additional dibromoethane (0.05 mL) was added and the mixture was heated at reflux for 20 min and placed in an ice bath. To the cooled mixture was added a solution of the product from Step D (3.70 g, 8.38 mmol) in THF (50 mL). After stirring for 20 min at ambient temperature, the reaction was quenched with a saturated aqueous solution of ammonium chloride (200 mL) and the mixture was extracted with EtOAc (2×150 mL). Evaporation of the extracts gave a crude oil (3.78 g, 86%): LC/MS (+APCI) m/z 521, 523, 525 (M+H).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:2]1.[Na].[CH3:15][OH:16]>>[CH3:15][O:16][CH2:2][CH:3]([OH:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCC1CO1
Reactant: CO
Agent: [Na]
Product: CCCCCCCCCCC(O)COC
Yield: 88 %

Procedure:
1,2-Epoxydodecane is reacted with sodium in methanol as in Example 1 to yield 1-methoxy-2-dodecanol as a colourless oil, bp 97° C./0.07 mbar, yield 88%.
Reaction SMILES: [H-].[Na+].[CH2:3]([P:10](=[O:15])([O:13][CH3:14])[O:11][CH3:12])[P:4](=[O:9])([O:7][CH3:8])[O:5][CH3:6].[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)([O-:18])=[O:17]>CN(C=O)C.C1COCC1>[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][CH:3]([P:4](=[O:9])([O:7][CH3:8])[O:5][CH3:6])[P:10](=[O:15])([O:11][CH3:12])[O:13][CH3:14])=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: COP(=O)(CP(=O)(OC)OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COP(=O)(OC)C(Cc1ccc([N+](=O)[O-])cc1)P(=O)(OC)OC
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 30 %

Procedure:
Sodium hydride (1.02 g, 25.4 mmol) was added in portions to a stirring solution of tetramethyl methylenebisphosphonate in DMF (40 mL). After 30 min a solution of 4-nitrobenzylbromide (5.00 g, 23.1 mmol) in THF (5 mL) was added and the resulting mixture was stirred at room temperature for 4.5 hr. The reaction was quenched by the addition of saturated aqueous NH4Cl (20 mL). After the addition of water (100 mL) the product was extracted with EtOAc and the combined organics were washed with brine, dried over MgSO4, filtered and concentrated at reduced pressure. The crude product was purified by silica gel chromatography (0% to 10% MeOH in EtOAc) resulting in 12 as a colorless solid (2.55 g, 30%). 1H NMR (400 MHz, CDCl3) δ 2.65 (tt, J=6.5, 23.8, 1H), 3.31 (dt, J=6.5, 16.5, 2H), 3.73 (d, J=7.0, 6H), 3.75 (d, J=7.0, 6H), 7.42 (d, J=8.9, 2H), 8.15 (d, J=8.9, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23](OC)=[O:24])=[N:20][CH:21]=3)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(OC)C=CC=CC=1>C1(C)C=CC=CC=1>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23]([NH:34][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:24])=[N:20][CH:21]=3)=[CH:14][CH:15]=2)[CH2:5][CH2:6]1
Reactant: NCc1ccccc1
Reactant: COC(=O)Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Solvent: Cc1ccccc1
Solvent: COc1ccccc1
Product: O=C(Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
A 1 L single-necked round-bottomed flask was charged with 7 (61.4 g, 0.172 mol), benzyl amine (55.6 g, 0.519 mol, 3 eq), and anhydrous anisole (300 g) and then stirred at reflux until reaction was essentially complete (23 h, 165° C. oil bath temperature; internal temperature was 147° C.) and then allowed to cool to near room temperature. A portion (1 mL) of the reaction mixture was diluted with toluene (1 mL) resulting in the complete crystallization of that portion. This seed was then added to the reaction mixture and allowed to stand until the whole reaction mixture had crystallized to a single block. Toluene (150 mL) was added and the mixture swirled to break up the solid. Heptane/toluene (1:1, 100 mL) was added and the solid mixture broken up further. Finally, heptane (50 mL, then 25 mL) was added and the mixture broken up even further, allowing to stand an additional 30 min before filtering the solid. Filtration of the solid, washing with 2:1 toluene/heptane (300 mL), 1:2 toluene/heptane (300 mL), and then heptane (2×300 mL), and then drying (air, then high vac) gave 60.16 g (yield of 81%) of title product as a white solid (≧98.9% AUC). Another 2.5 g of less pure (97.4%) material was obtained from the mother liquors.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([NH2:13])=[N:9][NH:10][C:11]=1[NH2:12].[N:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH:23]=O)[CH:21]=O)=[CH:16][CH:15]=1>C(O)C.C(O)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([NH2:12])=[N:10][N:9]2[CH:23]=[C:20]([C:17]3[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=3)[CH:21]=[N:13][C:8]=12
Reactant: Nc1n[nH]c(N)c1-c1ccccn1
Reactant: O=CC(C=O)c1ccncc1
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1nn2cc(-c3ccncc3)cnc2c1-c1ccccn1
Yield: 61.6 %

Procedure:
A mixture of 4-pyridin-2-yl-1H-pyrazole-3,5-diamine (290 mg, 1.66 mmol) and 2-pyridin-4-yl-malonaldehyde (247 mg, 1.66 mmol) were placed in ethanol (5 mL) with a catalytic amount of acetic acid (6 drops). The reaction mixture was submitted to microwave irradiations at 140° C. for 15 minutes. The crude mixture was cooled down to room temperature and the resulting precipitate was filtered and washed with more ethanol to provide the title as a golden yellow solid (295 mg, 62%). MS (ES+) 289, (ES−) 287. δH (DMSO-d6) 7.16 (1H, dd), 7.21 (2H, m), 7.84 (1H, m), 7.89 (2H, m), 8.57 (2H, br m), 8.65 (2H, d), 8.98 (1H, d), 9.44(1H, d).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][OH:13])[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[CH3:20][C:21]1[NH:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1>>[CH3:11][N:8]1[C:7]([CH2:12][OH:13])=[N:6][C:5]2[C:9]1=[N:10][C:2]([N:22]1[C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=[C:21]1[CH3:20])=[N:3][C:4]=2[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: Cn1c(CO)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: Cc1nc2ccccc2[nH]1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CO)n(C)c2n1

Procedure:
(2-Chloro-9-methyl-6-morpholino-9H-purin-8-yl)methanol (4.0 g) was reacted with 2-Methylbenzimidazole (1.96 g) via General Procedure I for Buchwald coupling. The solids were filtered from the reaction mixture while still warm. Water was added to the filtered reaction mixture (5 times the volume of DMF) to precipitate the product out of the reaction mixture. The precipitated orange solid was filtered and dried under vacuum for quantitative yield of (9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-9H-purin-8-yl)methanol.
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-])=[C:6]([NH:9][C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[O:11])[CH:5]=[C:4](Cl)[N:3]=1.[NH:18]1[CH2:23][CH2:22][CH:21]=[CH:20][CH2:19]1>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([NH:9][C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[O:11])[CH:5]=[C:4]([N:18]2[CH2:19][CH:20]=[CH:21][CH2:22][CH2:23]2)[N:3]=1
Reactant: C1=CCNCC1
Reactant: COCCOC(=O)Nc1cc(Cl)nc(N)[n+]1[O-]
Solvent: ClC(Cl)Cl
Product: COCCOC(=O)Nc1cc(N2CC=CCC2)nc(N)n1
Temperature: 45 °C
Reaction time: 12 h

Procedure:
2.5 G. of 2-methoxyethyl 2-amino-6-chloro-4-pyrimidinecarbamate-3-oxide are mixed under argon with 3 ml. of 1,2,5,6-tetrahydropyridine and 25 ml. of chloroform. The mixture is stirred at 45° C. for 12 hours, then cooled and washed with 15 ml. of water. The product is extracted with chloroform, the organic phase is dried over sodium sulfate and the solvent is distilled off under reduced pressure. The residue obtained is crystallized from methylene chloride/ether, there being obtained pure 2-methoxyethyl 2-amino-6-[3,6-dihydro-1(2H)-pyridyl]-4-pyrimidinecarbamate having a melting point of 136° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[N:15]1([C:21]2[CH:29]=[C:28]3[C:24]([CH2:25][C:26](=[O:30])[NH:27]3)=[CH:23][CH:22]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.N1CCCCC1>C(O)C>[CH3:14][C:7]1[NH:8][C:9]([CH:12]=[C:25]2[C:24]3[C:28](=[CH:29][C:21]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:22][CH:23]=3)[NH:27][C:26]2=[O:30])=[C:10]([CH3:11])[C:6]=1[CH2:5][CH2:4][C:1]([OH:3])=[O:2]
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Reactant: O=C1Cc2ccc(N3CCOCC3)cc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cc(N4CCOCC4)ccc32)c(C)c1CCC(=O)O
Yield: 41.6 %

Procedure:
3-(2-Carboxyethyl)-2,4-dimethyl-5-formylpyrrole (3.3 g), 4 g 6-(morpholin-4-yl)-2-oxindole and 1.8 mL piperidine in 60 mL of ethanol were heated at 90° C. for 7 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight. The resulting solid was purified by chromatography on a silica gel column eluting with ethyl acetate-hexane-acetic acid to give 2.78 g (38% yield) of the title compound as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[C:15]([CH3:16])=[CH:14][C:13]([O:17][C@H:18]2[CH2:22][CH2:21][O:20][CH2:19]2)=[CH:12][C:11]=1[CH3:23].O[C:25]1[CH:38]=[CH:37][C:28]2[C@H:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:30][O:31][C:27]=2[CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH3:1][C:2]1[C:7]([CH2:8][O:9][C:25]2[CH:38]=[CH:37][C:28]3[C@H:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:30][O:31][C:27]=3[CH:26]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[C:11]([CH3:23])=[CH:12][C:13]([O:17][C@H:18]2[CH2:22][CH2:21][O:20][CH2:19]2)=[CH:14][C:15]=1[CH3:16]
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Reactant: Cc1cc(O[C@H]2CCOC2)cc(C)c1-c1cccc(CO)c1C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(O[C@H]5CCOC5)cc4C)c3C)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
(S)-(2,2′,6′-Trimethyl-4′-((tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methanol 12e (75 mg, 0.24 mmol), methyl (S)-2-(6-hydroxyl-2,3-dihydrobenzofuran-3-yl)acetate (50 mg, 0.24 mmol) and triphenylphosphine (94 mg, 0.36 mmol) were dissolved in 20 mL of dichloromethane. The reaction solution was cooled down to 0° C., followed by addition of diisopropyl azodicarboxylate (73 mg, 0.36 mmol), then warmed up to room temperature and stirred for 2 hours. The resulting solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system B to obtain the title compound methyl 2-((S)-6-((2,2′,6′-trimethyl-4′-(((S)-tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 12f (100 mg, yield 83.0%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:13])[C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:26]([NH:28][C:29]1[C:30]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[N:31][CH:32]=[CH:33][CH:34]=1)[CH3:27].C(=O)(O)[O-].[Na+]>O1CCCC1.ClCCl>[CH3:12][O:11][C:10]1[C:9]([CH3:13])=[CH:8][C:4]([C:5]([N:38]2[CH2:39][CH2:40][N:35]([C:30]3[C:29]([NH:28][CH2:26][CH3:27])=[CH:34][CH:33]=[CH:32][N:31]=3)[CH2:36][CH2:37]2)=[O:7])=[CH:3][C:2]=1[CH3:1]
Reactant: COc1c(C)cc(C(=O)O)cc1C
Reactant: CCNc1cccnc1N1CCNCC1
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCNc1cccnc1N1CCN(C(=O)c2cc(C)c(OC)c(C)c2)CC1
Reaction time: 1 h

Procedure:
3,5-Dimethyl-4-methoxybenzoic acid (I, PREPARATION 3, 0.36 g) is added to a solution of 1,1'-carbonyldiimidazole (0.33 g) in tetrahydrofuran (4 ml) at 20°-25°. After one hour of stirring, 4-[3-(ethylamino)-2-pyridinyl]piperazine (II, International Publication No WO 87/01706 based on International Patent application No PCT/US86/01797, PREPARATION A-47, 0.42 g) in tetrahydrofuran (6 ml) is added and the solution is stirred for 18 hours. The mixture is diluted with dichloromethane and a saturated aqueous sodium bicarbonate solution. The phases are separated, the organic phase is washed with water, then with saline and the phases are separated. The organic phase is dried over sodium sulfate and concentrated under reduced pressure to give an oil. The oil is flash chromatographed on silica gel (230-400 mesh), the product eluted with chloroform, the appropriate fractions are pooled and concentrated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20](=O)[O:21]C3C=CC([N+]([O-])=O)=CC=3)=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:33][O:34][C:35]([C@H:37]1[CH2:42][CH2:41][C@@H:40]([NH2:43])[CH2:39][CH2:38]1)=[O:36]>>[CH3:33][O:34][C:35]([CH:37]1[CH2:42][CH2:41][CH:40]([NH:43][C:20]([NH:19][CH2:18][C:7]2[C:6](=[O:32])[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=2)=[O:21])[CH2:39][CH2:38]1)=[O:36]
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)[C@H]1CC[C@@H](N)CC1
Product: COC(=O)C1CCC(NC(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)CC1

Procedure:
4-[3-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-ureido]-cyclohexane-carboxylic acid methyl ester was prepared starting from intermediate M and cis-4-amino-cyclohexane carboxylic acid methyl ester. MS calcd. for C25H27ClN3O4 [(M+H)+] 468.2, obsd. 468.0.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:16][O:17][CH:18]=2)=[CH:10][CH:11]=1)=[O:5])C.[NH2:26][CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[O:30]1[CH2:31][CH2:32][CH:27]([NH:26][C:4]([C:6]2[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]3[C:15]([C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)=[N:16][O:17][CH:18]=3)=[CH:10][CH:11]=2)=[O:5])[CH2:28][CH2:29]1
Reactant: CCOC(=O)c1ccc(OCc2conc2-c2ccc(F)cc2)nn1
Reactant: NC1CCOCC1
Product: O=C(NC1CCOCC1)c1ccc(OCc2conc2-c2ccc(F)cc2)nn1
Yield: 82 %

Procedure:
As described for example 121, 6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid ethyl ester (200 mg, 0.58 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (190 mg, 82%) which was obtained as a white solid. MS: m/e=399.1 [M+H]+.
Reaction SMILES: [C:1]1([C:7](=[CH:11][CH3:12])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C@@H:14]1[C:25](=[O:26])[N:16]2[C@@H:17]([C:22]([OH:24])=[O:23])[C:18]([CH3:21])([CH3:20])[S:19][C@H:15]12>>[C:1]1([C:7](=[CH:11][CH3:12])[C:8]([NH:13][CH:14]2[C:25](=[O:26])[N:16]3[CH:17]([C:22]([OH:24])=[O:23])[C:18]([CH3:21])([CH3:20])[S:19][C@H:15]23)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Reactant: CC=C(C(=O)O)c1ccccc1
Product: CC=C(C(=O)NC1C(=O)N2C(C(=O)O)C(C)(C)S[C@H]12)c1ccccc1

Procedure:
In a similar manner to that of Example 17, 2-phenylbut-2-enoic acid (cis isomer) was converted into its acid chloride and coupled with (3S, 5R, 6R)-6-amino-2,2-dimethylpenam-3-carboxylic acid to give the title compound, λmax. (pH 6 phosphate buffer) 234, 345 nm (ε7,200; 4,260), νmax. (nujol) 1770 (β-lactam), τ (d6 -DMSO) values include 0.92 (d, NH), 3.83 (q, 6Hz vinylic proton), 4.3-4.5 (m, 5 and 6 H), 8.42 and 8.52 (gem dimethyl).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][C:10]2[N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[CH3:16][C:17]([CH3:25])([C:19]1[N:23]=[C:22]([CH3:24])[O:21][N:20]=1)[NH2:18]>>[CH3:15][C:2]1([CH3:1])[CH2:11][C:10]2[N:9]=[C:8]([C:12]([NH:18][C:17]([C:19]3[N:23]=[C:22]([CH3:24])[O:21][N:20]=3)([CH3:25])[CH3:16])=[O:14])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: CC1(C)CCc2ccc(C(=O)O)nc2C1
Reactant: Cc1nc(C(C)(C)N)no1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc3c(n2)CC(C)(C)CC3)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 7,7-dimethyl-5,6,7,8-tetrahydro-quinoline-2-carboxylic acid (Example 143 d) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, LC-MS (UV peak area/EIC) 100%, 329.1977 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=O.[C:14]([N:17]1[CH2:22][CH2:21][CH:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]1)(=[S:16])[NH2:15]>C(O)C>[N+:11]([C:7]1[CH:6]=[C:5]([C:3]2[N:15]=[C:14]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]3)[S:16][CH:2]=2)[CH:10]=[CH:9][CH:8]=1)([O-:13])=[O:12]
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)C1CCN(C(N)=S)CC1
Solvent: CCO
Product: CCOC(=O)C1CCN(c2nc(-c3cccc([N+](=O)[O-])c3)cs2)CC1
Temperature: 25 °C
Yield: 54.5 %

Procedure:
A solution of 2-bromo-1-(3-nitrophenyl)ethanone (621 mg, 2.54 mmol) and ethyl 1-carbamothioylpiperidine-4-carboxylate (500 mg, 2.31 mmol) in ethanol (7.7 mL) was heated to reflux for 16 hours, and then cooled to room temperature. The mixture was concentrated under reduced pressure and the resulting residue purified directly by CombiFlash (0-70% ethyl acetate/hexanes) to provide 457 mg (1.26 mmol, 49% yield) of ethyl 1-[4-(3-nitrophenyl)-1,3-thiazol-2-yl]piperidine-4-carboxylate as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:5]=1)[CH3:2].[Br:15][C:16]1[CH:17]=[CH:18][C:19]([F:24])=[C:20]([CH:23]=1)[CH:21]=O>>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([F:24])=[C:20]([CH2:21][C:12]2[S:11][C:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=3)=[CH:14][CH:13]=2)[CH:23]=1
Reactant: CCOc1ccc(-c2cccs2)cc1
Reactant: O=Cc1cc(Br)ccc1F
Product: CCOc1ccc(-c2ccc(Cc3cc(Br)ccc3F)s2)cc1

Procedure:
2-(4-Ethoxyphenyl)thiophene obtained in Reference Example 68-(1) and 5-bromo-2-fluorobenzaldehyde were treated in a manner similar to Reference Example 7 to give the target compound. APCI-Mass m/Z 391/393 (M+H).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1.[C:22](=[O:24])=[O:23].Cl>C1COCC1>[F:9][C:10]1[C:15]([C:22]([OH:24])=[O:23])=[CH:14][CH:13]=[C:12]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:11]=1
Reactant: Fc1cccc(-c2ccccc2)n1
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccccc2)nc1F
Reaction time: 0.5 h
Yield: 65 %

Procedure:
Cool a solution of LDA (3.46 mmol) in anhydrous THF (6 mL) to −78° C. Cannulate the 2-fluoro-6-phenylpyridine in anhydrous THF (6 mL) to the cooled LDA solution. Stir at −78 (C for 30 minutes then bubble carbon dioxide gas through the solution for 10 minutes. Allow the reaction to come to room temperature and purge with argon. Extract the reaction with 1 M NaOH and discard the organics. Acidify the aqueous layer with conc. HCl and extract with ethyl acetate. Dry the organic layer over MgSO4, filter and evaporate to yield the title compound as a light yellow solid (405 mg, 65%). MS (m/e): 216.1 (M−).
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH:12]=O)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:14](=O)[CH2:15][CH3:16].N1CCCCC1>CO>[CH3:16][C:15]1[CH:14]=[N:1][C:2]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5]
Reactant: CCC=O
Reactant: COC(=O)c1cccc(C=O)c1N
Solvent: CO
Solvent: C1CCNCC1
Product: COC(=O)c1cccc2cc(C)cnc12
Yield: 66 %

Procedure:
Under nitrogen atmosphere, to a solution of methyl 2-amino-3-formylbenzoate (3.00 g) in methanol (80 ml) were added propanal (1.50 mL) and piperidine (800 μL), and the mixture was heated under reflux. To the mixture were further added propanal (700 μL) and piperidine (400 μL), and the mixture was further heated under reflux for total 4 hours. The solvent in the reaction solution was evaporated under reduced pressure, and water was added to the residue. The mixture was extracted with ethyl acetate, and the extract was washed twice with water, and washed with a saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure, and the residue was purified twice by silica gel column (hexane/ethyl acetate=3/1→2/1→1/1) and silica gel column (hexane/ethyl acetate=3/1→2/1) to give 3-methyl-8-methoxycarbonylquinoline (2.21 g, 66%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]=[C:9]2[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.C([Li])CCC.CN([CH:23]=[O:24])C>C1COCC1>[CH:12]([C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([CH:23]=[O:24])[CH:11]=2)[CH2:6][CH2:7][N:8]=1)([CH3:14])[CH3:13]
Reactant: CN(C)C=O
Reactant: CC(C)C1=NCCc2ccc(Br)cc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)C1=NCCc2ccc(C=O)cc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of Example 1I (4.7 g, 18.7 mmol) in THF (80 mL) at −78° C. was treated dropwise with 2.5M n-butyllithium in hexanes (9.0 mL, 22.4 mmol), stirred for 20 minutes, treated dropwise with DMF (2.2 mL, 28.0 mmol), stirred for 20 minutes, quenched with saturated NH4Cl, warmed to room temperature, and extracted with diethyl ether. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated to provide the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[F:27])[C:21](Cl)=[O:22]>>[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[F:27])[C:21]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:22]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccc(F)c(F)c3)c2)CC1

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and 3,4-difluorobenzoyl chloride (29 μL, 0.229 mmol) and mixing for 24 h, 45.6 mg (>100%) of the title compound were recovered.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=1)=O.[CH:18]1([C:23](=O)[CH2:24][C:25]#[N:26])[CH2:22][CH2:21][CH2:20][CH2:19]1>>[Cl:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:23]([CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:24]([C:25]#[N:26])=[C:9]2[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=1
Reactant: N#CCC(=O)C1CCCC1
Reactant: Cc1cc(C(=O)c2cc(Cl)ccc2N)ccn1
Product: Cc1cc(-c2c(C#N)c(C3CCCC3)nc3ccc(Cl)cc23)ccn1

Procedure:
The title compound was prepared in analogy to example 101 step B from (2-amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone (prepared in analogy to example 126 step B) and 3-cyclopentyl-3-oxo-propionitrile (prepared as described in example 105 step A). White solid. MS (ESI): 348.4 (M+H)+.