Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[N:12][N:11]=[C:10]1[C:14]1[S:23][C:22]2[C:21]3[CH:24]=[C:25]([C:28](O)=[O:29])[CH:26]=[CH:27][C:20]=3[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=1.[CH3:31][NH:32][CH2:33][CH2:34][OH:35]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[N:12][N:11]=[C:10]1[C:14]1[S:23][C:22]2[C:21]3[CH:24]=[C:25]([C:28]([N:32]([CH2:33][CH2:34][OH:35])[CH3:31])=[O:29])[CH:26]=[CH:27][C:20]=3[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=1
Reactant: CNCCO
Reactant: O=C(O)c1ccc2c(c1)-c1sc(-c3nncn3-c3ccc(F)cc3F)cc1CCO2
Product: CN(CCO)C(=O)c1ccc2c(c1)-c1sc(-c3nncn3-c3ccc(F)cc3F)cc1CCO2

Procedure:
2-[4-(2,4-Difluoro-phenyl)-4H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid and 2-(methylamino)ethanol were reacted in the general amide coupling procedure to give 376. NMR: (CDCl3): (400 MHz, CDCl3): 3.13 (3 H, s, Me), 3.13-3.16 (2 H, m), 3.74-3.78 (2 H, m), 3.90-3.95 (2 H, m), 4.31-4.34 (2 H, m), 6.93 (1 H, s, Ar), 7.05 (1 H, d, J 8.3, Ar), 7.12-7.16 (2 H, m, Ar), 7.31-7.33 (1 H, m, Ar), 7.43-7.48 (1 H, m, Ar), 7.69-7.70 (1 H, m, Ar) and 8.24 (1 H, s, Ar). MS: (ESI+) MH+=483.08
Reaction SMILES: Cl([O-])(=O)(=O)=O.[Li+].[CH3:7][Mg]Br.[CH3:10][C:11]1([CH3:23])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Br:21])[CH:19]=2)[S:14]C(=O)[CH2:12]1.CC[O:26][CH2:27][CH3:28]>>[Br:21][C:18]1[CH:17]=[CH:16][C:15]([SH:14])=[C:20]([C:11]([CH3:12])([CH3:23])[CH2:10][C:27]([CH3:28])([OH:26])[CH3:7])[CH:19]=1
Reactant: CCOCC
Reactant: C[Mg]Br
Reactant: CC1(C)CC(=O)Sc2ccc(Br)cc21
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: CC(C)(O)CC(C)(C)c1cc(Br)ccc1S
Temperature: 0 °C

Procedure:
To 3.49 g (32.8 mmol) of lithium perchlorate was added under argon 35 ml of 3.0M (105 mmol) methyl magnesium bromide in ether. The above mixture was treated dropwise with 1stirring with a solution of 2.961 g (10.926 mmol) of 4,4-dimethyl-6-bromo-2-oxo-thiochroman (Compound 31) and the reaction mixture was then heated at reflux for 70 h. The reaction mixture was then allowed to cool and poured onto a mixture of 100 g of ice and 8 ml of conc. H2S04. The organic layer was separated and the aqueous layer was extracted with 2 ×25 ml of ether. The organic layers were combined and washed successively with 2×25 ml of saturated NaHCO3 solution, 25 ml of water and 25 ml of saturated NaCl solution and then dried (MgSO4). The solvent was removed in-vacuo and the residue purified by flash chromatography to give the title compound as a pale yellow oil. PMR (CDCl3 ): & 1.05 (6H, s), 1.52 (6H, s), 2.30 (2H, s), 3.71 (1H, s), 7.22 (1H, dd, J~8.5 Hz, 2.1 Hz), 7.28 (1H, d, J~8.5 Hz), 7.35 (1H, d, J~2 1 Hz)
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([OH:21])=[O:20])=[CH:15][CH:14]=2)=[O:9])[C:4](=[O:22])[CH2:3]1.O[NH:24][C:25]([NH:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:26].S(Cl)(Cl)=O>O1CCOCC1>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([S:19]([NH:24][C:25]([NH:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:26])(=[O:21])=[O:20])=[CH:17][CH:18]=2)=[O:9])[C:4](=[O:22])[CH2:3]1
Reactant: CC1CCN(C(=O)NCCc2ccc(S(=O)O)cc2)C(=O)C1
Reactant: CCCCNC(=O)NO
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: CCCCNC(=O)NS(=O)(=O)c1ccc(CCNC(=O)N2CCC(C)CC2=O)cc1
Temperature: 60 °C

Procedure:
0.6 g of 4-[2-(4-methyl-2-oxo-piperidine-1-carboxamido)-ethyl]-benzenesulfinic acid (crude product m.p. 113°-115° C., prepared by reaction of 4-[2-(4-methyl-2-oxo-piperidine-1-carboxamido)-ethyl]-benzenesulfochloride with sodium sulfite) and 0.3 g of N-hydroxy-N'-butyl urea are dissolved in 50 ml of dioxan. 0.4 g of thionyl chloride in 10 ml of dioxan is added dropwise to this solution, and the batch is heated for 2 hours at 60° C. Subsequently, the solvent is evaporated under reduced pressure, water is added dropwise to the residue, the oily substance is separated and reprecipitated from ammonia. The N-(4-[2-(4-methyl-2-oxo-piperidine-1-carboxamido)-ethyl]-benzenesulfonyl)-N'-butyl urea obtained has a melting point of 155°-157° C., and, with the substance obtained according to Example 8, shows no depression.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[CH:21]([NH:22][CH3:23])[CH2:20][CH2:19][CH2:18][N:13]3[C:14](=[O:17])[C:15]=2[OH:16])=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C>CC1C=CC=CC=1C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:21]([NH:22][CH3:23])=[CH:20][CH:19]=[CH:18][N:13]3[C:14](=[O:17])[C:15]=2[OH:16])=[O:9])=[CH:24][CH:25]=1
Reactant: CNC1CCCn2c1nc(C(=O)NCc1ccc(F)cc1)c(O)c2=O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1C
Product: CNc1cccn2c(=O)c(O)c(C(=O)NCc3ccc(F)cc3)nc12
Temperature: 156 °C

Procedure:
To a solution of N-(4-fluorobenzyl)-3-hydroxy-9-(methylamino)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide hydrotrifluoroacetate and diisopropylethylamine (4 eqs.) in o-xylene was added Pd(C) (10%). The suspension was stirred and heated to 156° C. for 7 hours. The suspension was left cooling to room temperature and the catalyst was filtered off. The catalyst was washed with methanol and dichloromethane and the filtrate and catalyst washes were combined and the combined organic solutions were concentrated to dryness. The product was purified by preparative RP-HPLC, using water (0.1% TFA) and acetonitrile (0.1% TFA) as eluants (column: C18). After lyophilization of the pooled product fractions the product was obtained as bright yellow fluffy material.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][NH:5][C:6]=1[CH3:7].[H-].[Na+].[H][H].IC.[C:15](=O)([O-])O.[Na+]>CN(C)C=O>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][N:5]([CH3:15])[C:6]=1[CH3:7]
Reactant: [H][H]
Reactant: O=C([O-])O
Reactant: Cc1n[nH]c(C)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1nn(C)c(C)c1Br

Procedure:
4-Bromo-3,5-dimethylpyrazole (10 g) in dry dimethylformamide (50 ml) was added to a stirred suspension of sodium hydride (1.8 g) in dry dimethylformamide at 0° C. When the evolution of hydrogen was complete, iodomethane (8.9 g) was added dropwise. The mixture was allowed to warm to room temperature and after 30 minutes saturated aqueous sodium hydrogen carbonate (5 ml) was added. Following evaporation under high vacuum, the residue was purified by column chromatography to give the title compound.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([S:14]([NH2:16])=[O:15])([CH3:13])[CH3:12]>ClC(Cl)C.ClCCl.O.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[N:16]/[S:14]([C:11]([CH3:13])([CH3:12])[CH3:10])=[O:15])=[CH:4][CH:3]=1
Reactant: CC(C)(C)S(N)=O
Reactant: O=Cc1ccc(Br)nc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: O
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CC(C)(C)S(=O)/N=C/c1ccc(Br)nc1
Temperature: 110 °C
Reaction time: 0.17 h

Procedure:
A mixture of 6-bromo-pyridine-3-carbaldehyde (1.0 g, 5.38 mmol), 2-methylpropane-2-sulfinamide (715 mg, 5.90 mmol) and titanium (IV) isopropoxide (2.5 mL, 8.53 mmol) in dichloroethane (10 mL) was warmed at 110° C. in the microwave for 15 minutes. The reaction was monitored by TLC (ethyl acetate-hexanes 2:8). The mixture was diluted with dichloromethane (100 mL) and water (5 mL) was added. The mixture was stirred for 10 minutes and then dried over magnesium sulfate. The crude material was purified by silica gel chromatography eluting with a gradient of 0-20% ethyl acetate in hexanes to afford 2-methyl-propane-2-sulfinic acid 1-(6-bromo-pyridin-3-yl)-meth-(E)-ylideneamide
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([S:16]Cl)[C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=1>CCOCC>[Cl:3][C:4]1[CH:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[CH:18][C:5]=1[O:6][C:7]1[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=1.[CH3:1][NH:2][SH:16]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1SCl
Reactant: CN
Solvent: CCOCC
Product: CNS
Product: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Reaction time: 2 h
Yield: 95 %

Procedure:
3.1 g of methylamine in the form of a 40% strength aqueous solution were added to a solution of 19.2 parts by weight of 3-(2'-chloro-4'-trifluoromethylphenoxy)-6-nitrobenzenesulfenyl chloride in 100 parts by volume of ether, and stirring was continued for a further 2 hours at room temperature. The organic phase was separated off, dried with magnesium sulfate, filtered, and evaporated down under reduced pressure. 17.5 parts by weight (95% yield) of 3-(2'-chloro-4'-trifluoromethylphenoxy)-6-nitrobenzene-N-methylsulfenamide of refractive index nD25 : 1.6109 were obtained (compound No. 5).
Reaction SMILES: [NH4+].[Cl-].[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18](=[O:22])[C:17]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])([CH2:23][C:24]([F:27])([F:26])[F:25])[CH2:16][CH2:15]3)=[N:10][CH:11]=1)([O-])=O>C(O)C.O.[Fe]>[NH2:3][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18](=[O:22])[C:17]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])([CH2:23][C:24]([F:27])([F:25])[F:26])[CH2:16][CH2:15]3)=[N:10][CH:11]=1
Reactant: CCOC(=O)CC1(CC(F)(F)F)CCc2cc(-c3ccc([N+](=O)[O-])cn3)ccc2C1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC1(CC(F)(F)F)CCc2cc(-c3ccc(N)cn3)ccc2C1=O
Yield: 75.7 %

Procedure:
Iron powder (0.218 g, 3.9 mmol) and NH4Cl (0.208 g, 3.9 mmol) was added to a solution of 1I (1.7 g, 3.9 mmol) in 15 mL of ethanol-water (2:1) mixture. The reaction mixture was refluxed for 3 h, and solvent was removed under reduced pressure. The crude product was purified by flash chromatography using 25% ethyl acetate in hexane to afford the title compound (1.2 g, 53%) as a solid. 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J=2.8 Hz, 1H), 8.09 (d, J=8.2 Hz, 1H), 7.88-7.78 (m, 2H), 7.60 (d, J=8.4 Hz, 1H), 7.06 (dd, J1=2.9 Hz, J2=8.5 Hz, 1H), 4.13 (q, J=7.2 Hz, 2H), 3.86 (s, 2H), 3.20-3.02 (m, 2H), 2.98-2.81 (m, 2H), 2.72-2.53 (m, 2H), 2.51-2.28 (m, 2H), 1.24 (t, J=7.6 Hz, 3H). ESI-MS m/z: 407 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: OCCCCCc1ccc2c(ccn2-c2ccc(F)cc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCCc1ccc2c(ccn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
300 mg (1 mmol) 5-[1-(4-Fluoro-phenyl)-1H-indol-5-yl]-pentan-1-ol in 10 ml CH2Cl2 were treated with 0.1 ml (1.2 mmol) methane sulfonyl chloride and 0.41 ml (3 mmol) triethyl amine at 0° C. The solution was stirred at RT for 2 h, was diluted with CH2Cl2 and extracted with 1M HCl and water, and dried over Na2SO4. Evaporation yielded 310 mg (83%) Methanesulfonic acid 5-[1-(4-fluoro-phenyl)-1H-indol-5-yl]-pentyl ester as light brown oil, MS: 376 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9](Cl)=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1.[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20][NH2:21].C(N(CC)CC)C>O1CCOCC1>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:21][CH2:20][CH2:19][N:18]([CH3:22])[CH3:17])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1
Reactant: CN(C)CCN
Reactant: COC(=O)C=Cc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)C=Cc1ccc(NCCN(C)C)c([N+](=O)[O-])c1
Temperature: 80 °C
Yield: 84.2 %

Procedure:
A mixture of 3-(4-chloro-3-nitro-phenyl)-acrylic acid methyl ester (Ia, 0.658 g, 2.72 mmol), N,N-dimethylethylenediamine (0.90 mL, 8.20 mmol) and triethylamine (1.2 mL, 8.6 mmol) in dioxane (20 mL) was heated at 80° C. for 5 h. The solution was evaporated and the residue was added DCM and aqueous Na2CO3. The DCM (×3) extracts were concentrated and the residue was added EtOAc-hexane. The resulting red solid was filtered to give the titled compound (0.672 g, 84.2%). HPLC purity at 254 nm: 99.2%, tR=1.59 min. LCMS (ESI) m/z: 294 ([M+H]+). 1H NMR (CDCl3+CD3OD) δ 8.21 (1H, d, J=2.1 Hz), 7.56 (1H, dd, J=9.0, 2.1 Hz), 7.48 (1H, d, J=16.0 Hz), 6.81 (1H, d, J=9.0 Hz), 6.20 (1H, d, J=15.9 Hz), 3.70 (3H, s), 3.34 (2H, t, J=6.5 Hz), 2.56 (2H, t, J=6.4 Hz), 2.23 (6H, s); 13C NMR (CDCl3+CD3OD) δ 167.3, 145.4, 142.6, 134.0, 131.1, 127.1, 121.3, 114.8, 114.0, 56.7, 51.1, 44.6, 40.1.
Reaction SMILES: [C:1]1(B(O)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[C:15]1[CH:16]=[C:17]([C:22]2[N:27]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:25]=[C:24]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:23]=2)[CH:18]=[C:19](Br)[CH:20]=1.C([O-])([O-])=O.[K+].[K+].[N:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:52]1[CH:57]=[CH:56][C:55](B(O)O)=[CH:54][CH:53]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C.C1(C)C=CC=CC=1>[C:28]1([C:26]2[N:25]=[C:24]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:23]=[C:22]([C:17]3[CH:16]=[C:15]([C:55]4[CH:54]=[CH:53][C:52]([C:47]5[CH:48]=[CH:49][CH:50]=[CH:51][N:46]=5)=[CH:57][CH:56]=4)[CH:20]=[C:19]([C:1]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH:4]=[CH:3][CH:2]=4)[CH:18]=3)[N:27]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Brc1cc(Br)cc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c1
Reactant: OB(O)c1cccc2ccccc12
Reactant: OB(O)c1ccc(-c2ccccn2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc(-c2nc(-c3ccccc3)nc(-c3cc(-c4ccc(-c5ccccn5)cc4)cc(-c4cccc5ccccc45)c3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
In a stream of argon, 0.37 g (2.14 mmol) of 1-naphthaleneboronic acid, 1.00 g (2.14 mmol) of 2-(3,5-dibromophenyl)-4,6-diphenyl-1,3,5-triazine and 24.7 mg (0.021 mmol) of tetrakis(triphenylphosphine)palladium were suspended in a mixed solvent composed of 80 mL of toluene and 10 mL of ethanol, and the resultant suspension was heated to 60° C. To the suspension, 8.56 mL (8.56 mmol) of an aqueous 1M K2CO3 solution was gradually added dropwise, and the mixture was stirred for 3 hours. Then the mixture was cooled to room temperature, and 0.64 g (3.21 mmol) of 4-(2-pyridyl)phenylboronic acid wad added. Then the mixture was heated to 70° C. and maintained at that temperature for 3 hours while being stirred. Then the reaction mixture was cooled to room temperature, and was then distilled under a reduced pressure to remove all volatile materials. Methanol was added to the concentrate, and the thus-deposited solid was collected by filtration. The obtained crude product was purified by silica gel chromatography using a hexane/chloroform (1:2) mixed solvent as an eluent to give 0.61 g of the target 4,6-diphenyl-2-[5-(1-naphthyl)-4′-(2-pyridyl)biphenyl-3-yl]-1,3,5-triazine as a white solid (yield: 49%).
Reaction SMILES: C1(C2(CCC3C=CC(C(C)(C)C#N)=C(F)C=3)CC(O)=C(CC3NC(CC)=NC=3C)C(=O)O2)CCCC1.[CH:37]1([C:42]2([CH2:50][CH2:51][C:52]3[CH:57]=[CH:56][C:55]([C:58]4([C:63]#[N:64])[CH2:62][CH2:61][CH2:60][CH2:59]4)=[C:54]([F:65])[CH:53]=3)[CH2:47][C:46](=[O:48])[CH2:45][C:44](=[O:49])[O:43]2)[CH2:41][CH2:40][CH2:39][CH2:38]1.C1(C2(CCC3C=CC(C(C)(C)C#N)=C(F)C=3)CC(O)=CC(=O)O2)CCCC1.[CH3:93][C:94]1[CH:99]=[C:98]([CH3:100])[N:97]2[N:101]=[C:102]([CH:104]=O)[N:103]=[C:96]2[N:95]=1.C(C1NC(C=O)=C(C)N=1)C>>[CH:37]1([C:42]2([CH2:50][CH2:51][C:52]3[CH:57]=[CH:56][C:55]([C:58]4([C:63]#[N:64])[CH2:59][CH2:60][CH2:61][CH2:62]4)=[C:54]([F:65])[CH:53]=3)[CH2:47][C:46]([OH:48])=[C:45]([CH2:104][C:102]3[N:103]=[C:96]4[N:95]=[C:94]([CH3:93])[CH:99]=[C:98]([CH3:100])[N:97]4[N:101]=3)[C:44](=[O:49])[O:43]2)[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: N#CC1(c2ccc(CCC3(C4CCCC4)CC(=O)CC(=O)O3)cc2F)CCCC1
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Agent: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(O)=CC(=O)O2)cc1F
Agent: CCc1nc(C)c(C=O)[nH]1
Agent: CCc1nc(C)c(CC2=C(O)CC(CCc3ccc(C(C)(C)C#N)c(F)c3)(C3CCCC3)OC2=O)[nH]1
Product: Cc1cc(C)n2nc(CC3=C(O)CC(CCc4ccc(C5(C#N)CCCC5)c(F)c4)(C4CCCC4)OC3=O)nc2n1

Procedure:
The title compound was prepared analogously to Example A(97) 2-[4-(2-{2-cyclopentyl-5-[(2-ethyl-4-methyl-1H-imidazol-5-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile where 1-{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-cyclopentanecarbonitrile Example A(189) was substituted in place of 2-{4-[2-(2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl]-2-fluorophenyl}-2-methylpropanenitrile and 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substituted in place of 2-ethyl-4-methyl-1H-imidazole-5-carbaldehyde. 1H NMR (400 MHz, CDCl3) δ: 1.44–1.96 (m, 17 H), 2.14–2.22 (m, 2H), 2.56–2.62 (m, 8 H), 2.70–2.74 (m, 2 H), 3.79 (d, J=16 Hz, 1 H), 3.92 (d, J=16 Hz, 1 H), 7.12 (s, 1 H), 7.24 (s, 1 H), 7.26 (d, J=5 Hz, 1 H), 7.42–7.47 (m, 1 H), 10.9 (s, 1 H). Anal. Calcd. For C32H36FN5O3: C, 68.92; H, 6.51; N, 12.56. Found: C, 68.74; H, 6.60; N, 12.47. MS (ESI): 558 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[O:4]1[C:8]2([CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]2)[O:7][CH2:6][CH2:5]1.[C-:16]#[N:17].[K+].Cl>CO>[CH3:1][N:2]([CH:14]([CH:11]1[CH2:10][CH2:9][C:8]2([O:4][CH2:5][CH2:6][O:7]2)[CH2:13][CH2:12]1)[C:16]#[N:17])[CH3:3]
Reactant: O=CC1CCC2(CC1)OCCO2
Reactant: CNC
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CN(C)C(C#N)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 96 h

Procedure:
40% aqueous dimethylamine solution (85 ml, 0.67 mole), 1,4-dioxa-spiro-[4.5]decane-8-carbaldehyde 5 (240 g, 0.141 mole) and potassium cyanide (22.05 g, 0.338 mole) were added while cooling with ice to a mixture of 4N hydrochloric acid (37 ml) and methanol (22 ml). The mixture was stirred for four days at room temperature and then extracted, after adding water (80 ml), with diethyl ether (4×100 ml). The organic phase was dried over sodium sulfate, concentrated by evaporation in vacuo, and the product was obtained as a white solid.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([OH:28])=[O:27])=[C:15]([CH2:18]OC(=O)CC(=O)C)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH:31][C:32]1[N:36]([CH3:37])[N:35]=[N:34][N:33]=1.C(=O)(O)[O-].[Na+]>O>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([OH:28])=[O:27])=[C:15]([CH2:18][S:31][C:32]4[N:36]([CH3:37])[N:35]=[N:34][N:33]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Reactant: Cn1nnnc1S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Yield: 96.2 %

Procedure:
In 50 ml of water was dissolved 4.32 g of 7-phenylacetamido-3-(3-oxobutyryloxy)methyl-3-cephem-4-carboxylic acid, together with 1.50 g of 5-mercapto-1-methyl-1H-tetrazole and 1.68 g of sodium bicarbonate and the reaction was conducted at 60° C. for 50 minutes. After cooling, the reaction mixture was adjusted to pH 5.0 and washed with ethyl acetate. It was then brought down to pH 2.0 and extracted three times with ethyl acetate. The ethyl acetate solution was washed with a saturated aqueous solution of sodium chloride, treated with magnesium sulfate, filtered and distilled under reduced pressure to remove the solvent. The residue was recrystallized from ethyl acetate-ether. The procedure provided 4.29 g (yield 96.2%) of 7-phenylacetamido-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C@H:12]([C@H:14]([C@@H:16]([C@@H:18]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][CH:23]=2)[OH:19])[OH:17])[OH:15])[OH:13])=[CH:6][CH:5]=1)([OH:3])=[O:2].C(O[C:35](=[O:37])[CH3:36])(=O)C.C(Cl)Cl>N1C=CC=CC=1>[C:1]([O:19][C@@H:18]([C@H:16]([C@@H:14]([C@@H:12]([CH2:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([C:1]([OH:3])=[O:2])=[CH:9][CH:8]=1)[O:13][C:35](=[O:37])[CH3:36])[O:15][C:12](=[O:13])[CH3:11])[O:17][C:7](=[O:10])[CH3:6])[CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([OH:30])=[O:29])=[CH:26][CH:27]=1)(=[O:2])[CH3:4]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccc(OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)COc2ccc(C(=O)O)cc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O[C@@H]([C@H](OC(C)=O)[C@@H](COc1ccc(C(=O)O)cc1)OC(C)=O)[C@@H](COc1ccc(C(=O)O)cc1)OC(C)=O
Temperature: 0 °C

Procedure:
2.10 g of 1,6-bis-O-(4-carboxy-phenyl)-D-mannitol were stirred at room temperature for 20 hours in 30 ml of pyridine with 5.1 ml of acetic anhydride. The reaction mixture was worked up extractively with ice-water and methylene chloride. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was recrystallized from methanol and methylene chloride. There was obtained 2,3,4,5-tetra-O-acetyl-1,6-bis-O-(4-carboxy-phenyl)-D-mannitol, MS: m/z 589 ([M-H]-).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.Cl.Cl.[CH3:28][C:29]1[C:30]2[CH:44]=[CH:43][CH:42]=[CH:41][C:31]=2[S:32][C:33]=1[CH2:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.CCN(C(C)C)C(C)C>CN(C=O)C>[O:22]1[CH:23]=[CH:24][CH:25]=[C:21]1[C:19]1[N:20]=[C:12]2[N:13]([C:14]([NH2:17])=[N:15][C:16]3[N:8]([CH2:7][CH2:6][N:38]4[CH2:39][CH2:40][N:35]([CH2:34][C:33]5[S:32][C:31]6[CH:41]=[CH:42][CH:43]=[CH:44][C:30]=6[C:29]=5[CH3:28])[CH2:36][CH2:37]4)[CH:9]=[CH:10][C:11]=32)[N:18]=1
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Reactant: Cc1c(CN2CCNCC2)sc2ccccc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(CN2CCN(CCn3ccc4c3nc(N)n3nc(-c5ccco5)nc43)CC2)sc2ccccc12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound of Example 1, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), the title B compound, 1-[(3-methylbenzo[b]thiophen-2-yl)methyl]piperazine dihydrochloride (0.33 mmol) and 0.06 mL of DIEA are added, and the solution is stirred at 100° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. To the residue, acetonitrile is added and the solution is stirred at 60° C. for 0.5 h. The solution is then cooled to RT, and the resulting solids are collected by filtration to give 2-(furan-2-yl)-7-(2-(4-((3-methylbenzo[b]thiophen-2-yl)methyl)piperazin-1-yl)ethyl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine: LC/MS (M+1=513.2). 1H NMR (DMSO-d6, 400 MHz) δ 2.32 (s, 3H), 2.50 (m, 8H), 2.69 (t, 2H, J=6.4 Hz), 3.72 (s, 2H), 4.23 (t, 2H, J=6.4 Hz), 6.58 (d, 1H, J=3.2 Hz), 6.71 (m, 1H), 7.15 (d, 1H, J=3.6 Hz), 7.18 (d, 1H, J=3.2 Hz), 7.28-7.38 (m, 2H), 7.50 (br s, 2H), 7.68 (d, 1H, J=7.6 Hz), 7.85 (d, 1H, J=7.6 Hz), 7.92 (d, 1H, J=0.8 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:3]=1.[Br:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1>>[Br:22][C:23]1[N:24]=[CH:25][N:26]([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[N:3]=2)[CH:27]=1
Reactant: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)nc(Cl)n2)c1
Reactant: Brc1c[nH]cn1
Product: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)nc(-n3cnc(Br)c3)n2)c1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(3-trifluoromethyl-phenyl)-pyrimidine (example A.42) (0.65 g, 2.0 mmol) and commercially available 4-bromo-imidazole (0.44 g, 3.0 mmol) according to the general procedure IVa. Obtained as a light yellow solid (0.64 g, 73%). MS (ISP) 439.1 [(M+H)+]; mp 158.5° C.