Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]([C:11]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:13]=2[N:12]=1)[CH3:10])C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:26][C:23]1[CH:24]=[CH:25][C:13]2[N:12]=[C:11]([C@@H:9]([NH:7][CH3:6])[CH3:10])[N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:14]=2[CH:22]=1
Reactant: C[C@@H](c1nc2ccc(F)cc2n1-c1ccccc1)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](C)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.6 %

Procedure:
To a solution of [(S)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]methylcarbamic acid tert-butyl ester (0.264 g, 0.72 mmol) in DCM (8 mL) was added TFA (4 mL) and the mixture stirred at RT for 1.5 h. The volatiles were removed under in vacuo and the resulting residue partitioned between DCM and a saturated aqueous solution of NaHCO3. The two phase system was stirred for 10 minutes and then the aqueous phase extracted with DCM. The combined organic fractions were dried (MgSO4) and concentrated in vacuo to afford the title compound as a colourless oil (102 mg, 53%). LCMS (Method J): RT 1.80 min [M+H]+ 270.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[I:9].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1.CCOC(C)=O>CC1CCCO1>[C:13]([Si:10]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([I:9])[CH:4]=1)([CH3:12])[CH3:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(Cl)c(I)c1
Agent: c1c[nH]cn1
Solvent: CC1CCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Cl)c(I)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
To a solution of 4-chloro-3-iodophenol (2 g. 7.86 mmol) in anhydrous 2-methyltetrahydrofuran (10 mL) was added tert-butyldimethylsilyl chloride (1.25 g, 8.28 mmol) followed by imidazole (642 mg, 68.1 mmol) The resulting mixture was stirred at room temperature for 3 hours. EtOAc (10 mL) was added and the mixture washed with aqueous sodium hydroxide solution (2M, 3×10 mL), water (10 mL), and brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with heptane:EtOAc 90:10 to afford the title compound as colourless oil in 30% yield, 870 mg.
Reaction SMILES: [CH3:1][S:2][C:3](=[S:15])[S:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]([OH:8])=O.[CH2:16]([N+:20]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19].[NH2:33][CH:34]1[CH2:37][N:36]([S:38]([O-:41])(=[O:40])=[O:39])[C:35]1=[O:42].C1(N=C=NC2CCCCC2)CCCCC1.C1(NC(=O)NC2CCCCC2)CCCCC1>C(#N)C>[CH2:29]([N+:20]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:30][CH2:31][CH3:32].[CH3:1][S:2][C:3](=[S:15])[S:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]([NH:33][C@H:34]1[CH2:37][N:36]([S:38]([O-:41])(=[O:40])=[O:39])[C:35]1=[O:42])=[O:8]
Reactant: CSC(=S)SC(C(=O)O)c1ccccc1
Reactant: NC1CN(S(=O)(=O)[O-])C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Solvent: CC#N
Product: CSC(=S)SC(C(=O)N[C@H]1CN(S(=O)(=O)[O-])C1=O)c1ccccc1
Yield: 50.3 %

Procedure:
A solution of 1.03 g of (±)-α-[[(methylthio)thioxomethyl]thio]benzeneacetic acid and 1.63 g of 3-amino-2-oxo-1-azetidinesulfonic acid, tetrabutylammonium salt (see Example 6A) in 30 ml of acetonitrile is treated with 0.8 g of dicyclohexylcarbodiimide dissolved in 10 ml of acetonitrile at -5° C. After stirring for about 16 hours the formed dicyclohexyl urea is filtered off and the mother liquor is evaporated. The remaining oily residue is chromatographed on a column of 400 g of silica (ethyl/acetate/methanol/water (8.5:1:0.5) is the eluent), yielding 1.3 g of the title compound.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:33]([O:35][CH3:36])=[O:34])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][C@@H:16]([O:26][CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][NH:29]2)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:37][N:38]([CH2:46][CH:47]=O)[C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42].[BH3-]C#N.[Na+]>CO.C1COCC1.CC(O)=O>[C:41]([O:40][C:39]([N:38]([CH3:37])[CH2:46][CH2:47][N:29]1[CH2:30][CH2:31][CH2:32][CH:28]1[CH2:27][O:26][C@H:16]1[CH2:15][N:14]2[C:13]3[CH:12]=[C:11]([C:33]([O:35][CH3:36])=[O:34])[CH:10]=[CH:9][C:8]=3[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[C:21]2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17]1)=[O:45])([CH3:44])([CH3:43])[CH3:42]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](OCC1CCCN1)COc1ccccc1-3
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](OCC1CCCN1CCN(C)C(=O)OC(C)(C)C)COc1ccccc1-3
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution (0.02 M) of methyl (7S)-14-cyclohexyl-7-(pyrrolidin-2-ylmethoxy)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate in MeOH/THF (2/1), AcOH (cat.) was added followed by tert-butyl methyl(2-oxoethyl)carbamate (2 eq, prepared as described in Tetrahedron 2002, 58, 1719-1737). The reaction was stirred at RT for 30 min at which point NaCNBH3 (2 eq) was added and the mixture was stirred at 40° C. for 1 h. Additional tert-butyl methyl(2-oxoethyl)carbamate (1 eq) and NaCNBH3 (5 eq) were added and the reaction was stirred for further 30 min at 40° C. The reaction was quenched by adding sat. aq. NaHCO3. The aqueous phase was extracted with EtOAc and the combined organics washed with brine before being dried (Na2SO4), filtered and concentrated in vacuo. The product was used in the subsequent step without further purification. (ES+) m/z 646 (M+H)+
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.[CH3:11][NH:12][CH3:13].[CH2:14]=O>C(O)CCC>[CH3:11][N:12]([CH2:14][C:3]1[C:4]2=[N:5][CH:6]=[CH:7][CH:8]=[C:9]2[NH:1][CH:2]=1)[CH3:13]
Reactant: C=O
Reactant: CNC
Reactant: c1cnc2cc[nH]c2c1
Agent: Cl
Solvent: CCCCO
Product: CN(C)Cc1c[nH]c2cccnc12
Yield: 64 %

Procedure:
A solution of 4-azaindole (0.880 g, 7.45 mmol), dimethylamine hydrochloride (0.67 g, 8.19 mmol) and paraformaldehyde (0.25 g, 8.19 mmol eq.) in 1-butanol is heated at reflux temperature for 3 h, cooled, concentrated in vacuo, treated with water and saturated aqueous NaHCO3 and extracted with 4:1 CH2Cl2:ethanol. The combined extracts are dried over MgSO4 and concentrated in vacuo. The resultant residue is chromatographed (silica gel, ethyl acetate, followed by 5:95 triethylamine:ethanol as eluent) to afford the title compound as a tan solid, 0.838 g (64% yield), identified by NMR analysis.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH:15]=[C:14]([CH2:16][O:17][CH3:18])[O:13][N:12]=2)=[C:9]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:23]1(=O)[CH2:28][CH2:27][CH2:26][CH2:25][C:24]1=[O:29].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[Cl:1][C:2]1[C:10]([C:11]2[CH:15]=[C:14]([CH2:16][O:17][CH3:18])[O:13][N:12]=2)=[C:9]([S:19]([CH3:22])(=[O:20])=[O:21])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:28]1[CH2:27][CH2:26][CH2:25][C:24](=[O:29])[CH:23]=1)=[O:5]
Reactant: O=C1CCCCC1=O
Reactant: COCc1cc(-c2c(S(C)(=O)=O)ccc(C(=O)O)c2Cl)no1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COCc1cc(-c2c(S(C)(=O)=O)ccc(C(=O)OC3=CC(=O)CCC3)c2Cl)no1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.04 g (3.0 mmol) of 2-chloro-3-(5-methoxymethylisoxazol-3-yl)-4-methylsulfonylbenzoic acid are introduced into 50 ml of dichloromethane together with 0.37 g (3.3 mmol) of cyclohexanedione and treated with 0.68 g (3.3 mmol) of dicyclohexylcarbodiimide. After stirring at room temperature for 16 hours, the precipitate is filtered off with suction and the filtrate is washed with water. After the removal of the solvent, 1.22 g (92% of theory) of 3-oxo-1-cyclohexenyl 2-chloro-3-(5-methoxymethylisoxazol-3 yl)-4-methyl-sulfonylbenzoate are obtained as a yellowish, partly crystalline oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[F:26][C:27]1[CH:28]=[C:29]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:30]=[CH:31][CH:32]=1>C1(C)C=CC=CC=1>[F:26][C:27]1[CH:28]=[C:29]([N:33]2[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:35][CH2:34]2)[CH:30]=[CH:31][CH:32]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: Fc1cccc(N2CCNCC2)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCN(c2cccc(F)c2)CC1
Temperature: 20 °C
Yield: 37.6 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (8.4 g), triethylamine (4.2 cc) and 4-(3-fluorophenyl)piperazine (5.3 g) in toluene (100 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on a silica column, under a I current of argon at medium pressure (0.5-1.5 bar) with dichloromethane and then a mixture of dichloromethane and ethyl acetate (50-50 vol) as eluant, and recrystallization from boiling acetonitrile (20 cc), 2-{3-[4-(3-fluorophenyl)-1-piperazinyl]propyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (4.7 g) is obtained, m.p. 103° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH:10](OCC)OCC)=[CH:4][C:3]=1[F:17]>ClC1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[S:8][CH:9]=[CH:10][C:4]=2[C:3]=1[F:17].[Br:1][C:2]1[C:3]([F:17])=[CH:4][C:5]2[S:8][CH:9]=[CH:10][C:6]=2[CH:7]=1
Reactant: CCOC(CSc1ccc(Br)c(F)c1)OCC
Solvent: Clc1ccccc1
Product: Fc1c(Br)ccc2sccc12
Product: Fc1cc2sccc2cc1Br
Temperature: 130 °C
Reaction time: 10 h

Procedure:
Polyphosphoric acid (13.9 g) was stirred in chlorobenzene (50 mL) at 130° C. (4-bromo-3-fluorophenyl)(2,2-diethoxyethyl)sulfane (7.7 g, 0.0238 mol) in chlorobenzene (15.4 mL) was added dropwise at 130° C. The mixture was then stirred at 130° C. for 10 h. The solvent was removed and the residue was extracted with toluene, hexane, and then water. The organic phase was combined and washed with saturated NaHCO3 solution and brine, and then dried over Na2SO4. The products 5-bromo-4-fluorobenzo[b]thiophene and 5-bromo-6-fluorobenzo[b]thiophene were obtained after purification via column chromatography (3.6 g, 65.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[S:8][C:9]3[N:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N:12]=2)=[CH:4][CH:3]=1.[H-].[Li+].[Cl:22][C:23]1[S:27][C:26]([CH2:28]Cl)=[CH:25][CH:24]=1>CN(C=O)C>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]=[C:7]2[N:12]([CH2:28][C:26]3[S:27][C:23]([Cl:22])=[CH:24][CH:25]=3)[C:11](=[O:13])[C:10]3[CH:14]=[CH:15][CH:16]=[N:17][C:9]=3[S:8]2)=[CH:4][CH:3]=1.[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]([C:7]2[S:8][C:9]3[N:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N:12]=2)[CH2:28][C:26]2[S:27][C:23]([Cl:22])=[CH:24][CH:25]=2)=[CH:4][CH:3]=1
Reactant: ClCc1ccc(Cl)s1
Reactant: O=c1nc(Nc2ccc(Cl)cc2)sc2ncccc12
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=c1c2cccnc2sc(=Nc2ccc(Cl)cc2)n1Cc1ccc(Cl)s1
Product: O=c1nc(N(Cc2ccc(Cl)s2)c2ccc(Cl)cc2)sc2ncccc12
Yield: 14.3 %

Procedure:
The reaction procedure of Example 11 was followed except that 2.536 g (8.75 mmol) of 2-(4-chloroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 154 mg of lithium hydride, 1.462 g of 5-chloro-2-thenyl chloride and 40 ml of DMF were used. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform). As a result, 2.643 of 2-(4-chlorophenylimino)-3-(5-chloro-2-thenyl)-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one (recrystallized from ethanol) was obtained as a low polarity substance, and 263 mg of 2-[N-(4-chlorophenyl)-N-(5-chloro-2-thenyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (recrystallized from a mixture of ethyl acetate and diisopropyl ether) was obtained as a high polarity substance.
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[OH-:21].[Na+].[K+].[Br-]>CO>[OH:21][C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:3](=[O:4])[CH:2]=[CH:17][C:16]1[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1
Reactant: O=C(CO)c1ccccc1
Reactant: COc1ccc(C=O)cc1
Reactant: [OH-]
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C=CC(=O)c2ccccc2O)cc1

Procedure:
2-Hydroxy acetophenone, 3 (6 mL, 50 mmol), 4-methoxy benzaldehyde, 4 (6 mL, 50 mmol) and 50% aqueous sodium hydroxide (50 mL) in methanol (100 mL) were reacted as in 7 to yield 9. Yield 11.7 g (92%); mp 81-83° C. (lit. 93-94);227 MS (FAB) 255 (M++1); IR (KBr) 3450, 1639; 1H NMR (200 MHz, CDCl3) δ 7.92 (dd, J=8.7 Hz, 1.4 Hz, 1H), 7.90 (d, J=15.4 Hz, 1H), 7.62 (d, J=8.7 Hz, 2H), 7.53 (d, J=15.5 Hz, 1H), 7.49 (t, J=7.4 Hz, 1H), 6.95 (d, J=8.6 Hz, 2H), 7.03-6.89 (m, 2H), 3.86 (s, 3H).
Reaction SMILES: BrC1C=CC(C(CCCCl)C(O)=O)=CC=1.[CH3:16][O:17][C:18](=[O:31])[CH:19]([C:24]1[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=1)[CH2:20][CH2:21][CH2:22][Cl:23].[C:32]([O:36][C:37](=[O:50])[NH:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[NH:45][C:46](=[O:49])[CH:47]=[CH2:48])([CH3:35])([CH3:34])[CH3:33]>>[CH3:16][O:17][C:18](=[O:31])[CH:19]([C:24]1[CH:29]=[CH:28][C:27](/[CH:48]=[CH:47]/[C:46](=[O:49])[NH:45][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[NH:38][C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:50])=[CH:26][CH:25]=1)[CH2:20][CH2:21][CH2:22][Cl:23]
Reactant: C=CC(=O)Nc1ccccc1NC(=O)OC(C)(C)C
Reactant: COC(=O)C(CCCCl)c1ccc(Br)cc1
Agent: O=C(O)C(CCCCl)c1ccc(Br)cc1
Product: COC(=O)C(CCCCl)c1ccc(/C=C/C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1

Procedure:
Key building block (E)-2-{4-[2-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-vinyl]-phenyl}-5-chloro-pentanoic acid methyl ester (VIII) can be prepared according to Scheme 7. Starting with commercially available 4-(bromo-phenyl)-acetonitrile (XVI), deprotonation with strong base followed by alkylation using 1-bromo-3-chloropropane gives 2-(4-bromo-phenyl)-5-chloro-pentanenitrile (XXXII). Hydrolysis of XXXII under acidic conditions furnishes 2-(4-bromo-phenyl)-5-chloro-pentanoic acid (XXXIII). Nucleophilic acyl substitution converts XXXIII to 2-(4-bromo-phenyl)-5-chloro-pentanoic acid methyl ester (XXXIV), which undergoes Heck reaction with (2-acryloylamino-phenyl)-carbamic acid tert-butyl ester to give key building block (E)-2-{4-[2-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-vinyl]-phenyl}-5-chloro-pentanoic acid methyl ester (VIII).
Reaction SMILES: N[CH2:2][CH2:3][CH2:4][C:5]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:9]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[S:6]1.[CH2:28]=O.[C:30]([BH3-])#[N:31].[Na+]>CO.[Na+].[Cl-]>[CH3:28][N:31]([CH3:30])[CH2:2][CH2:3][CH2:4][C:5]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:9]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[S:6]1
Reactant: [BH3-]C#N
Reactant: CC(C)C(=O)N1N=C(c2cccc(F)c2)SC1(CCCN)c1ccccc1
Reactant: C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC(C)C(=O)N1N=C(c2cccc(F)c2)SC1(CCCN(C)C)c1ccccc1
Temperature: 70 °C
Reaction time: 0.67 h
Yield: 36.3 %

Procedure:
To a solution of 1-(2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methylpropan-1-one (9.0 mg, 0.02 mmol) in MeOH (1 mL) was added paraformaldehyde (10 mg, 0.40 mmol). The mixture was heated to 70° C. for 2 hours. The mixture was allowed to cool to room temperature and sodium cyanoborohydride (0.07 mL, 0.07 mmol, 1M solution in THF) was added. After stirring for 40 minutes, the mixture was diluted with half saturated NaCl (50 mL) and extracted with ethyl acetate (3×25 mL). The combined organics were washed with saturated NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (2% triethylamine, 40% ethyl acetate in hexanes) to provide the final product (3.0 mg, 30%) as pale yellow film. MS ESI (+) m/z 414 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.44 (m, 3H), 7.36 (m, 5H), 7.14 (m, 1H), 3.51 (m, 1H), 3.17 (m, 1H), 2.40 (m, 3H), 2.23 (s, 6H), 1.92 (m, 1H), 1.53 (m, 1H), 1.20 (d, 3H, J=7 Hz), 1.18 (d, 3H, J=7 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[F:18])[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[C:27](OC1C=CC=CC=1)=[O:28].[N:36]1([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>O1CCCC1.CN(C)C=O>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH:1][C:27]([N:45]3[CH2:46][CH2:47][CH:42]([N:36]4[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]4)[CH2:43][CH2:44]3)=[O:28])[CH:7]=2)=[C:10]([F:18])[CH:11]=1)([O-:17])=[O:16]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1)N1CCC(N2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.7 %

Procedure:
4-Amino-6-(2-fluoro-4-nitrophenoxy)pyrimidine (40 mg) was dissolved in tetrahydrofuran (2 ml) under a nitrogen atmosphere, and then triethylamine (0.045 ml) and phenyl chloroformate (0.040 ml) were added dropwise thereto, followed by stirring at room temperature for 1 hr. The reaction mixture was concentrated under a reduced pressure to give a residue, which was then dissolved in N,N-dimethylformamide (2 ml). 4-(Piperidin-1-yl)piperidine (108 mg) was added thereto, followed by stirring for 10 min. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of ammonium chloride. The organic layer was washed with a saturated aqueous solution of ammonium chloride, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; hexane:ethyl acetate=1:1 to 1:2). Fractions containing the target compound were concentrated under a reduced pressure, and dried in vacuum to provide the titled compound (43.9 mg, 61.7%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([CH2:15][C:16]([OH:18])=[O:17])=[CH:10][C:11]=3[CH2:12]2)=[CH:4][CH:3]=1.CO.[N+](=[CH2:23])=[N-]>CCOCC.C(O)(=O)C>[CH3:23][C:10]1[C:11]2[CH2:12][C:13]3[C:5](=[CH:4][CH:3]=[C:2]([OH:1])[CH:14]=3)[C:6]=2[CH:7]=[CH:8][C:9]=1[CH2:15][C:16]([OH:18])=[O:17]
Reactant: O=C(O)Cc1ccc2c(c1)Cc1cc(O)ccc1-2
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CO
Product: Cc1c(CC(=O)O)ccc2c1Cc1cc(O)ccc1-2
Reaction time: 0.33 h

Procedure:
A solution of 83mg. of 7-hydroxyfluorene-2-acetic acid in 2ml. of methanol and 5ml. of ether is treated with an excess of diazomethane in ether. After 20 min. at room temperature, the mixture is treated with several drops of acetic acid and evaporated. The residue is plate chromatographed on silica gel using chloroform as the developing solvent. The major band (UV) is eluted with ethyl acetate, evaporated, and the residue crystallized from acetone-isopropyl ether to give 36mg. of the title compound, mp 135.5°-136.5°. The analytical sample is prepared by recrystallization from acetone-isopropyl ether, mp 136-137°; λ KBr 5.85μ; τCDCl3 TMS 6.31 (S, 2-CH2CO2CH3).
Reaction SMILES: [Br-].[N:2]1([CH2:7][CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[C:28]1([CH3:49])[CH:33]=[CH:32][C:31]([C:34]([C:36]2[N:41]=[C:40](/C=C/C(OCC)=O)[CH:39]=[CH:38][CH:37]=2)=O)=[CH:30][CH:29]=1>C1COCC1>[CH3:49][C:28]1[CH:33]=[CH:32][C:31](/[C:34](/[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][N:41]=2)=[CH:8]\[CH2:7][N:2]2[CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:30][CH:29]=1
Reactant: CCOC(=O)/C=C/c1cccc(C(=O)c2ccc(C)cc2)n1
Reactant: c1ccc([P+](CCN2CCCC2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1ccc(/C(=C\CN2CCCC2)c2ccccn2)cc1

Procedure:
A solution of 25 mL of 1.6 M n-BuLi/hexanes was added to a stirred and cooled (0° C.) suspension of (2-pyrrolidinoethyl)triphenylphosphonium bromide (17.24 g, 39.18 mmol) in dry THF (250 mL) over a period of ˜4 min. The ylide-forming reaction mixture was stirred an additional 10 min at 0° C., followed by the addition of one aliquot of a solution of 5c (4.52 g, 15.3 mmol) in dry THF (75 mL). After stirring at 0° C. for only 2 min, the reaction mixture was quenched by the addition of water (100 mL). The reaction mixture was then extracted twice with EtOAc and the combined organics were dried with Na2SO4, filtered, and evaporated to dryness. Chromatography over silica gel using MeOH/EtOAc (starting at 5% MeOH) gave 1.42 g (25%) of E,E-7c as a yellow crystalline solid and 2.42 g (42%) of E,E-7c. The structure of the products were confirmed by 1H NMR and MS. (Triprolidine ester E,E-7e was similarly prepared.)
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]([NH:10][CH:11]1[C:39](=[O:40])[N:13]2[CH:14]([C:23]([O:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[C:15]([CH2:19][O:20]C=O)=[C:16]([CH3:18])[S:17][C@H:12]12)=[O:9].CCOC(C)=O.O>CN(C=O)C>[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]([NH:10][CH:11]1[C:39](=[O:40])[N:13]2[CH:14]([C:23]([O:25][CH:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:24])[C:15]([CH2:19][OH:20])=[C:16]([CH3:18])[S:17][C@H:12]12)=[O:9]
Reactant: CC1=C(COC=O)C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC1=C(CO)C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S1
Temperature: 25 °C
Reaction time: 20 h
Yield: 51.2 %

Procedure:
A 22.8 ml portion of 2N HCl was added to a solution of 30 g of diphenylmethyl 7-(2-thienylacetamido)-2-methyl-3-formyloxymethylceph-2-em-4-carboxylate in 100 ml of DMF, and the mixture was stirred at room temperature for 20 hours. AcOEt and H2O were added to the reaction solution to separate out the AcOEt layer. The AcOEt layer was washed with 5% aqueous NaHCO3 solution and with saturated aqueous NaCl solution, and dried over Na2SO4, followed by distilling off the AcOEt under reduced pressure. The residue was added on a column of silica gel and washed with CH2Cl2.AcOEt (10:1). Then, the fractions eluted with acetone were collected, and the solvent was distilled off under reduced pressure, resulting 14.6 g (62%) of diphenylmethyl 7-(2-thienylacetamido)-2-methyl-3-hydroxymethylceph-2-em-4-carboxylate.