Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-:2].[Ca+2].C(#N)C.[CH3:9][N:10]([CH3:32])[CH2:11][CH2:12][C:13]1([C:19]2[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[CH:21]=[CH:22][CH:23]=2)SCCCS1>CCCCCC>[CH3:9][N:10]([CH3:32])[CH2:11][CH2:12][C:13]([C:19]1[N:20]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[CH:21]=[CH:22][CH:23]=1)=[O:2]
Reactant: CN(C)CCC1(c2cccn2Cc2ccccc2F)SCCCS1
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC#N
Solvent: CCCCCC
Product: CN(C)CCC(=O)c1cccn1Cc1ccccc1F

Procedure:
To a solution of 28.1 g of mercuric chloride and 10.3 g of calcium carbonate in 150 ml of aqueous 80% acetonitrile is added under nitrogen a solution of 17.0 g of 2-(2-dimethylaminoethyl)-2-[1-(o-fluorobenzyl)-2-pyrryl]-1,3-dithiane in 100 ml of aqueous 80% acetonitrile. The reaction mixture is stirred at reflux for 4 hours, the mixture is permitted to cool and filtered through celite. The filter cake is washed with a hexane-dichloromethane mixture and the washed solution is washed successively with a 5M aqueous ammonium acetate solution and water, dried and filtered. The solvents are evaporated off leaving a dark oil which solidifies upon trituration with n-hexane to give the solid product of 2-(3-dimethylaminopropionyl)-1-(o-fluorobenzyl)pyrrole.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][C:10]([OH:17])=[CH:11][CH:12]=3)[O:7][C:6]=2[CH:5]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:3]=1.[H-].[Na+].Br[CH2:27][CH2:28][O:29][P:30](=[O:47])([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C.CCOC(C)=O>[OH:1][C:2]1[CH:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[CH:5]=[C:6]2[C:15]=1[C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([O:17][CH2:27][CH2:28][O:29][P:30](=[O:47])([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:9][C:8]=1[O:7]2
Reactant: O=c1c2ccc(O)cc2oc2cc(N3CCOCC3)cc(O)c12
Reactant: O=P(OCCBr)(OCc1ccccc1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1c2ccc(OCCOP(=O)(OCc3ccccc3)OCc3ccccc3)cc2oc2cc(N3CCOCC3)cc(O)c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31 %

Procedure:
A solution of 1,6-dihydroxy-3-morpholin-4-yl-xanthen-9-one in anhydrous DMF (2.0 mL) was treated with sodium hydride (27.7 mg, 0.693 mmol). After 15 minutes, a solution of phosphoric acid dibenzyl ester 2-bromoethyl ester (267.0 mg, 0.693 mmol) in DMF (1.0 mL), was added, and reaction mixture was stirred overnight at room temperature. The reaction mixture then was dissolved in EtOAc (250 mL) and washed with water (6×50 mL) and brine (1×50 mL). The organics were dried. (Na2SO4) and concentrated. The residue then was purified via Biotage chromatography using 80% EtOAc in hexanes as, eluent to yield 132 mg (31%) of phosphoric acid dibenzyl ester 2-(8-hydroxy-6-morpholin-4-yl-9-oxo-9H-xanthen-3-yloxy)-ethyl ester as a white solid. 1H NMR (CDCl3, 400 MHz) δ: 12.82 (s, 1H), 8.12 (d, 1H), 7.34 (m, 10H), 6.82 (d, 1H), 6.73 (s, 1H), 6.24 (s, 1H), 6.22 (s, 1H), 5.04 (m, 4H), 4.38 (m, 2H), 4.18 (m, 2H), 3.83 (m, 4H), 3.38 (m, 4H).
Reaction SMILES: [C:1]([C:5]1[CH:23]=[CH:22][C:8]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]([O:19]CC)=O)[CH2:12][CH2:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:24][NH2:25]>C(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]([NH:24][NH2:25])=[O:19])[CH2:14][CH2:15]2)=[CH:22][CH:23]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)CN1CCN(Cc2ccc(C(C)(C)C)cc2)CC1
Reactant: NN
Solvent: CCO
Product: CC(C)(C)c1ccc(CN2CCN(CC(=O)NN)CC2)cc1

Procedure:
Synthesized according to General Procedure C: 6{20} (4.12 g, 12.9 mmol, 1 equiv.), anhydrous hydrazine (1.2 mL, 38.8 mmol, 3 equiv.), ethanol (26.0 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{20} (3.36 g, 84%) as a beige solid. 1H-NMR (500 MHz, CDCl3): δ 8.17 (br s, 1H), 7.31 (d, 2H, J=8.5 Hz), 7.20 (d, 2H, J=8.5 Hz), 3.85 (br s, 2H), 3.46 (s, 2H), 3.05 (s, 2H), 2.52 (br s, 4H), 2.45 (br s, 4H), 1.30 (s, 9H). 13C-NMR (125 MHz, CDCl3): δ 170.4, 149.9, 134.5, 128.7, 125.0, 62.4, 60.5, 53.5, 52.9, 34.3, 31.3.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[C:14]([Cu])#[N:15]>[Cu]I.CN1C(=O)CCC1>[C:14]([C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1)#[N:15]
Reactant: N#C[Cu]
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Agent: [Cu]I
Solvent: CN1CCCC1=O
Product: CCOC(=O)Cc1ccc(C#N)cc1
Temperature: 160 °C
Reaction time: 0.17 h
Yield: 133.2 %

Procedure:
Combined ethyl 2-(4-bromophenyl)acetate (30 g, 0.123 mol) and NMP (200 mL). Then CuCN (33 g, 0.370 mol) was added in portions and then degassed and refilled with nitrogen three times. Then CuI (4.7 g, 0.0247 mol) was added in one portion. The reaction was degassed and refilled with nitrogen three times and then heated to 160° C. for 4 hours. Then the reaction was heated to 180° C. for another 3 hours. The solution was then cooled to room temperature and diluted with EtOAc (500 mL) and water (500 mL). After stirring for 10 mins, the reaction was filtered and the aqueous layer was extracted with EtOAc (500 mL×2). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to dryness to give the title compound (31 g, 66.5%) as a brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[N:17]1[CH2:21][C:20](=[O:22])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[S:18]1(=[O:30])=[O:29])[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:12][OH:13])[CH:14]=[CH:15][C:16]=1[N:17]1[S:18](=[O:30])(=[O:29])[N:19]([CH2:23][CH2:24][Si:25]([CH3:27])([CH3:26])[CH3:28])[C:20](=[O:22])[CH2:21]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C=O)cc2OCc2ccccc2)S1(=O)=O
Agent: CC[SiH](CC)CC
Solvent: c1ccccc1
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CO)cc2OCc2ccccc2)S1(=O)=O
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of 3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-benzaldehyde (1.6 g, 3.6 mmol) in benzene (20 mL), in a pressure vessel, is added triethylsilane (688 μL, 4.3 mmol) and (PPh3)2Re(O)2I (63 mg, 0.072 mmol). The vessel is sealed and the reaction is stirred at 60° C. for 18 h. The mixture is allowed to cool to ambient temperature and the solvent is removed under reduced pressure. The crude triethylsilyl ether is immediately dissolved in MeOH (20 mL), treated with TFA (approximately 150 μL) and stirred for 1 h. The solvent is removed under reduced pressure and the crude alcohol is purified via silica gel chromatography using a gradient of 0-50% EtOAc/hexanes to afford of 5-(2-benzyloxy-4-hydroxymethylphenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one as a light gray solid: MS (M+H)+=466.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[CH:13]2[N:26]([C:29](=[O:46])[CH:30]([NH:38]C(OC(C)(C)C)=O)[CH:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH3:32])[CH2:27][CH2:28][CH:12]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[CH:13]2[N:26]([C:29](=[O:46])[CH:30]([NH2:38])[CH:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH3:32])[CH2:27][CH2:28][CH:12]12)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(OC(C)(C)C)C(NC(=O)OC(C)(C)C)C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(OC(C)(C)C)C(N)C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
A solution containing crude 43 (340 mg, 0.53 mmol) in DCM (10 mL) was cooled to 0° C. TFA (3 mL) was added. After 2 h, the reaction mixture was quenched by the slow addition of cold, aqueous K2CO3. The reaction mixture was extracted with DCM and the resultant organic phase was washed successively with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 283 mg of 44 as an amber-colored foam which was used without further purification. Mass spectrum, m/z [537.3] (M+H)+.
Reaction SMILES: [CH3:1][S:2]([O-:4])=[O:3].[Na+].Br[C:7]1[N:11]2[CH2:12][CH2:13][N:14]([CH3:31])[C:15]3([CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:17][CH2:16]3)[C:10]2=[CH:9][CH:8]=1>[Cu]I.CS(C)=O>[CH3:31][N:14]1[C:15]2([CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH2:19][CH2:20]2)[C:10]2=[CH:9][CH:8]=[C:7]([S:2]([CH3:1])(=[O:4])=[O:3])[N:11]2[CH2:12][CH2:13]1
Reactant: CN1CCn2c(Br)ccc2C12CCN(C(=O)OCc1ccccc1)CC2
Reactant: CS(=O)[O-]
Agent: [Cu]I
Agent: [Na+]
Solvent: CS(C)=O
Product: CN1CCn2c(ccc2S(C)(=O)=O)C12CCN(C(=O)OCc1ccccc1)CC2
Temperature: 90 °C
Yield: 52.1 %

Procedure:
A mixture of sodium methanesulfinate (293 mg, 2.87 mmol), benzyl 6-bromo-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (1.00 g, 2.39 mmol), CuI (296 mg, 1.55 mmol) and DMSO (5 mL) was heated at 90° C. in a pressure vessel for 20 hours. The mixture was cooled and was partitioned between ether (10 mL) and water (10 mL). The organic layer was separated and the aqueous layer was extracted with ether (3×5 mL). The combined organic layers were washed with brine (2×10 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography utilizing a gradient of 0-50% ethyl acetate in CH2Cl2 to yield benzyl 2-methyl-6-methylsulfonyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (520 mg, 52%) as a white solid. ESI-MS m/z calc. 417.2, found 418.3 (M+1)+; Retention time: 1.27 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.45-7.30 (m, 5H), 6.88 (d, J=4.1 Hz, 1H), 6.01 (d, J=3.9 Hz, 1H), 5.15 (s, 2H), 4.28-4.15 (m, 2H), 4.09-3.89 (m, 2H), 3.40-3.16 (m, 4H), 3.10 (s, 3H), 2.37 (s, 3H), 2.20-2.02 (m, 2H), 1.89-1.66 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:25][CH:26]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCBr
Reactant: Cc1ccc(-c2ccc(OCc3ccccc3)cc2)n1-c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCOc1ccc(-n2c(C)ccc2-c2ccc(OCc3ccccc3)cc2)cc1
Yield: 78 %

Procedure:
A solution of 4-[2-(4-benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]phenol (1.00 g, 2.82 mmol), 1-bromooctane (0.584 ml, 3.38 mmol) and potassium carbonate (466 mg, 3.38 mmol) in DMF (20 ml) was stirred at 80° C. for 4 hours. The reaction solution was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate anhydride, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to give the object compound as an oily substance. 1.03 g (yield: 78.0%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH:19]=[CH:18][C:12]=2[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+].Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:21]=[C:20]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[CH:19]=[CH:18][C:12]=2[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)c1ccc(-c2ccc(F)cc2)cc1-c1ccc(OC)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2cc(-c3ccc(F)cc3)ccc2C(=O)O)cc1OC
Yield: 81 %

Procedure:
Ethyl 2-(3,4-dimethoxyphenyl)-4-(4-fluorophenyl)benzoate (2.8 g; 0.074 mole), absolute ethanol (50 ml) and 10N sodium hydroxide (2 ml) are introduced into a 100 ml flask. The mixture is taken to reflux temperature for two hours, then poured over 1N hydrochloric acid (150 ml). The precipitate is filtered on fritted glass, washed with water, then dried in the air. 2-(3,4-dimethoxyphenyl)-4-(4-fluorophenyl)benzoic acid (2-1 g; yield: 81%) is thus obtained in the form of a white solid of m.p. 210° C.
Reaction SMILES: [Li+].[OH-].IC1C=C(C=CC=1)C[O:8][C:9](=[O:29])[CH2:10][CH2:11][C:12]1[CH:17]=[C:16]([I:18])[C:15]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([I:27])[CH:22]=2)=[C:14]([I:28])[CH:13]=1.Cl.CO>C1COCC1>[I:18][C:16]1[CH:17]=[C:12]([CH2:11][CH2:10][C:9]([OH:29])=[O:8])[CH:13]=[C:14]([I:28])[C:15]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([I:27])[CH:22]=1
Reactant: O=C(CCc1cc(I)c(OCc2cccc(I)c2)c(I)c1)OCc1cccc(I)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCc1cc(I)c(OCc2cccc(I)c2)c(I)c1
Reaction time: 14 h
Yield: 94.6 %

Procedure:
A 1.2 M solution of LiOH (275 μL, 0.33 mmol) was added to a solution of 3-(3,5-diiodo-4-(3-iodobenzyloxy)phenyl)propionic acid 3-iodobenzyl ester (Example 3)(213 mg, 0.25 mmol) in 2 mL THF. The biphasic solution was stirred for 14 hours, then 6 mL 0.5 M HCl was added and an oil formed. Methanol (0.5 mL) was added and the oil formed a solid, which was removed by filtration, yielding the title compound as an off-white powder (150 mg, 95%); 1H NMR (DMSO) δ 12.15 (s, 1H), 7.96 (s, 1H), 7.76-7.75 (m, 3H), 7.62 (d, J=7.6 Hz, 1H), 7.26 (t, J=7.6 Hz, 1H), 4.87 (s, 2H), 2.75 (t, J=7.2 Hz, 2H), 2.54 (t, J=7.4 Hz).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[CH:22][C:21]=1O.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)C>[CH2:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][C:21]2[CH:22]=[C:23]([Cl:27])[C:24]([Cl:26])=[CH:25][C:20]=2[Cl:19])=[O:15])=[CH:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Reactant: CCCCCCCCOc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Product: CCCCCCCCOc1ccc(C(=O)Oc2cc(Cl)c(Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32 %

Procedure:
To a solution of 4-octyloxybenzoic acid (13.8 g) in diethyl ether (552 ml) were added 2,4,5-trichlorophenol (10.87 g) and N,N'-dicyclohexylcarbodiimide (11.37 g). The solution was stirred under a nitrogen atmosphere for 18 hours at room temperature. The precipitate was removed by filtration, and the filtrate was concentrated in vacuo. The residue was dissolved in petroleum ether and was allowed to stand on ice-water. The resulting crystals (15.2 g) were filtered and dissolved in warm n-hexane (150 ml). After standing overnight at room temperature, the resulting crystals were removed by filtration. The filtrate was concentrated to an oil which was purified by a column chromatography (silica gel) using a mixture of ethyl acetate and n-hexane to give 2,4,5-trichlorophenyl 4-octyloxybenzoate (7.58 g) (m.p. 53° C., Anal: Calcd. for C21H23O3Cl3 :Cl24.75, Found: Cl 24.05).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:13]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)=[CH2:14])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.CO.[H][H]>[Pd].CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH:13]([C:15]3[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=3)[CH3:14])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: C=C(c1ccc([N+](=O)[O-])cc1)c1ccnc2cc(OC)ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc2c(C(C)c3ccc(N)cc3)ccnc2c1
Reaction time: 3 h

Procedure:
A mixture of 7-methoxy-4-(1-(4-nitrophenyl)vinyl)quinoline (0.146 g, 0.477 mmol) and Palladium on carbon, 10% (0.152 g, 1.43 mmol) in EtOAc (10 mL) and MeOH (1 mL) at RT was exposed to an atmosphere of Hydrogen (balloon). After 3 hrs, the mixture was filtered through celite and concentrated in vacuo to afford 4-(1-(7-methoxyquinolin-4-yl)ethyl)benzenamine as a white foam. MH+=279.1.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:17][C:18]([F:32])([F:31])[C:19]1[CH:20]=[C:21]([C:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=2)[CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([N:28]2[CH2:27][CH:26]=[C:25]([C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:17])([F:31])[F:32])[CH:20]=3)[CH2:30][CH2:29]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: FC(F)(F)c1cccc(C2=CCNCC2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C(c1ccccc1)c1ccccc1)N1CC=C(c2cccc(C(F)(F)F)c2)CC1
Reaction time: 1 h
Yield: 34.2 %

Procedure:
8 g of α,α-diphenylacetyl chloride in 50 ml of methylene chloride were added dropwise to a mixture of 8 g (0.035 mole) of 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine, 50 ml of methylene chloride and 4.96 ml of triethylamine at the temperature of 0/+5° C. Stirring is effected for one hour at room temperature, the solvent is evaporated off under reduced pressure, the residue is taken up into ethyl ether, washing is effected with a 0.2M aqueous solution of hydrochloric acid, with water, with an aqueous solution of sodium carbonate and then with water. Drying is effected over sodium sulphate, the solvent is evaporated off under reduced pressure. 5 g of the title compound are obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][CH2:10][CH2:11][OH:12].Cl[C:14]1[N:19]=[CH:18][C:17]([C:20]2[S:21][C:22]([C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:27])=[C:23]([CH3:25])[N:24]=2)=[CH:16][CH:15]=1>CN(C)C=O>[CH3:25][C:23]1[N:24]=[C:20]([C:17]2[CH:18]=[N:19][C:14]([O:12][CH2:11][CH2:10][CH2:9][N:5]3[CH2:6][CH2:7][CH2:8][CH:4]3[CH3:3])=[CH:15][CH:16]=2)[S:21][C:22]=1[C:26]([N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[O:27]
Reactant: Cc1nc(-c2ccc(Cl)nc2)sc1C(=O)N1CCOCC1
Reactant: CC1CCCN1CCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(OCCCN3CCCC3C)nc2)sc1C(=O)N1CCOCC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 8 %

Procedure:
Sodium hydride 60% in oil (0.11 g, 2.2 eq, 2.82 mmol) is added to a mixture of 3-(2-methyl-1-pyrrolidinyl)-1-propanol (0.31 g, 2.2 eq, 2.18 mmol) in dimethylformamide (15 ml) cooled to 0° C. The mixture is stirred at 22° C. for 20 min, and cooled again to 0° C. 4-{[2-(6-chloropyridin-3-yl)-4-methyl-1,3-thiazol-5-yl]carbonyl}morpholine i99 (0.415 g, 1 eq, 1.28 mmol) is then added to the solution and the mixture is stirred 48 h at room temperature. The solvent is evaporated, and the residue is taken up in ethyl acetate and washed two times with an aqueous solution of sodium hydrogenocarbonate. The organic layer is dried over magnesium sulfate, filtered and concentrated under vacuum. Purification by chromatography over silicagel (eluent: dichloromethane/methanol/ammonia 97/2.7/0.3) affords 0.047 g of 4-[(4-methyl-2-{6-[3-(2-methylpyrrolidin-1-yl)propoxy]pyridin-3-yl}-1,3-thiazol-5-yl)carbonyl]morpholine 147.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][S:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23](O)=[O:24])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[N:27]=[C:28]([CH:30]1[CH2:32][CH2:31]1)[NH2:29]>>[CH:30]1([C:28]2[N:29]=[C:23]([CH:11]3[CH2:10][CH:9]([C:6]4[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=4)[CH2:14][N:13]([C:15]([N:17]4[CH2:22][CH2:21][S:20][CH2:19][CH2:18]4)=[O:16])[CH2:12]3)[O:24][N:27]=2)[CH2:32][CH2:31]1
Reactant: NC(=NO)C1CC1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCSCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(C4CC4)no3)CN(C(=O)N3CCSCC3)C2)cc1

Procedure:
According to General Method 6A, 300 mg (0.828 mmol) of the compound from Example 7A and 91 mg (0.91 mmol) of N′-hydroxycyclopropanecarboximidamide were reacted Yield: 141 mg (40% of theory)
Reaction SMILES: CS[C:3]1[C:4]2[C:5](=[CH:14][S:15][CH:16]=2)[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(O)(=O)C>[N:17]1([C:3]2[C:4]3[C:5](=[CH:14][S:15][CH:16]=3)[NH:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[N:9]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: C1CNCCN1
Reactant: CSC1=Nc2ccccc2Nc2cscc21
Solvent: CC(=O)O
Product: c1ccc2c(c1)N=C(N1CCNCC1)c1cscc1N2

Procedure:
A bomb charged with 2.5 g. of 10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine, 8.6 g. of piperazine, and three drops of acetic acid is placed in an oil bath and heated at 155°-160° C. for 4 days. The bomb is then cooled and the contents are dissolved in 2N acetic acid. The solution is filtered and the filtrate is made alkaline with ammonium hydroxide and extracted with chloroform. The extracts are dried, filtered and evaporated to give a yellow solid. Recrystallization from ethanol gives the product as light tan crystals which melt at 228°-231° C. (dec.).
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:38][O:39][CH2:40][C:41]#[N:42])[C:10]([NH:12][CH:13]2[C:36](=[O:37])[N:15]3[C:16]([C:33]([OH:35])=[O:34])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>CO.O1CCCC1>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:38][O:39][CH2:40][C:41]#[N:42])[C:10]([NH:12][CH:13]2[C:36](=[O:37])[N:15]3[C:16]([C:33]([OH:35])=[O:34])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CCCCCCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC#N)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC#N)c3csc(N)n3)[C@H]2SC1
Yield: 70.7 %

Procedure:
A solution of 7-[2-(2-formamidothiazol-4-yl)-2-cyanomethoxyiminoacetamido]-3-(1-n-hexyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.11 g.) and conc. hydrochloric acid (0.73 g.) in methanol (11 ml.) and tetrahydrofuran (5 ml.) was treated in a similar manner to that of Example 9-(2) to give 7-[2-(2-aminothiazol-4-yl)-2-cyanomethoxyiminoacetamido]-3-(1-n-hexyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 0.75 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([S:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:47]1[NH:52][CH2:51][CH2:50][N:49]2[CH2:53][CH2:54][CH2:55][C@H:48]12>CN(C)C(=O)C.CC1CCCO1>[Cl:1][C:2]1[C:3]([C:4]([N:52]2[CH2:51][CH2:50][N:49]3[CH2:53][CH2:54][CH2:55][C@@H:48]3[CH2:47]2)=[O:6])=[CH:7][C:8]([S:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])(=[O:14])=[O:13])=[C:9]([F:11])[CH:10]=1
Reactant: C1C[C@@H]2CNCCN2C1
Reactant: O=C(O)c1cc(S(=O)(=O)Nc2ccccc2F)c(F)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CC1CCCO1
Product: O=C(c1cc(S(=O)(=O)Nc2ccccc2F)c(F)cc1Cl)N1CCN2CCC[C@@H]2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-chloro-4-fluoro-5-{[(2-fluorophenyl)amino]sulfonyl}benzoic acid (0.9 g, 2.59 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (1.08 g, 2.85 mmol) in N,N-dimethylacetamide (6.4 mL) and 2-methyltetrahydrofuran (15 mL) was added (R)-octahydropyrrolo[1,2-a]pyrazine (0.46 g, 3.68 mmol) in 2-methyltetrahydrofuran (4 mL). The reaction was stirred at ambient temperature overnight and diluted with 2-methyltetrahydrofuran (15 mL). The organic solution was washed with 6% NaHCO3/6% NaCl (10 mL), and the aqueous layer was extracted with 2-methyltetrahydrofuran (15 mL). The combined organic layers were washed with 6% NaHCO3/6% NaCl (10 mL) and saturated NaCl (2×10 mL), and then concentrated. The residue was concentrated from ethanol (2×10 mL) to give the title compound.