Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=C(C=C([N+]([O-])=O)C=1OC)C(Cl)=NC.N1NN=NC=1[C:23]1[C:24]([C:29]([F:32])([F:31])[F:30])=[N:25][CH:26]=[CH:27][CH:28]=1>N1C=CC=CC=1>[F:30][C:29]([F:32])([F:31])[C:24]1[CH:23]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: FC(F)(F)c1ncccc1-c1nn[nH]n1
Agent: CN=C(Cl)c1cc(OC)c(OC)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Product: FC(F)(F)c1ccccn1
Temperature: 82.5 °C

Procedure:
3,4-Dimethoxy-N-methyl-5-nitro-benzimidoyl chloride (0.28 g, 1.08 mmol) was added to a stirred solution of 3-(2H-tetrazol-5-yl)-2-(trifluoromethyl)pyridine (0.215 g, 1 mmol) in dry pyridine (3 mL), preheated to 50° C. The resulting mixture was cautiously heated to 75-90° C. and maintained at this temperature until nitrogen evolution ceased. The mixture was then poured onto water (30 mL) and extracted with dichloromethane (25 mL). The organic phase was separated, dried over anhydrous magnesium sulphate, filtered and evaporated to dryness. The resulting residue was purified by chromatography to afford 345-(3,4-dimethoxy-5-nitrophenyl)-4-methyl-4H-1,2,4-triazol-3-yl)-2-(trifluoromethyl)pyridine, 0.241 g (59%).
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][C:15]1[C:16]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:17]=2[S:18][CH:19]=1.[CH3:25][C:26]1[N:27]=[C:28]([N:36]2[CH2:40][CH2:39][NH:38][C:37]2=[O:41])[S:29][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[Cl:24][C:22]1[CH:21]=[CH:20][C:17]2[S:18][CH:19]=[C:15]([CH2:14][N:38]3[CH2:39][CH2:40][N:36]([C:28]4[S:29][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:26]([CH3:25])[N:27]=4)[C:37]3=[O:41])[C:16]=2[CH:23]=1
Reactant: Clc1ccc2scc(CBr)c2c1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)nc1C
Yield: 65 %

Procedure:
Following the procedure as described in Example 13, making variations as required to replace 4-(trifluoromethyl)benzyl bromide with 3-(bromomethyl)-5-chlorobenzo[b]thiophene to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in 65% yield: MS (ES+) m/z 436.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:18])[C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.O1CCOCC1>[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=1[C:9]([NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:29][CH:30]=2)[CH:7]=1)=[O:18]
Reactant: O=C(Nc1ccnc(Br)c1)c1c(Cl)cccc1Cl
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(Nc2cc(NC(=O)c3c(Cl)cccc3Cl)ccn2)cc1
Temperature: 120 °C
Yield: 83 %

Procedure:
A 25 mL microwave tube containing N-(2-bromopyridin-4-yl)-2,6-dichlorobenzamide (0.50 g, 1.40 mmol), ethyl 4-aminobenzoate (0.31 g, 1.92 mmol), Pd2(dba)3 (40 mg, 0.043 mmol), Cs2CO3 (0.94 g, 2.91 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 17 mg, 0.029 mmol), and dioxane (20 mL) was degassed and then charged by N2 (3×). The mixture was then heated at 120° C. for 30 min and then diluted with dioxane (20 mL). The reaction was filtered through Celite and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (Gemini, 200 mm×25 mm, gradient: CH3CN/0.05% NH3.H2O, 50-80%, 10 min) to afford ethyl 4-(4-(2,6-dichlorobenzamido)pyridin-2-ylamino)benzoate (500 mg, yield: 80%). 1H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 9.60 (s, 1H), 8.15 (d, J=5.6, 1H), 7.96-7.76 (m, 4H), 7.57 (ddd, J=16.0, 9.0, 4.2, 4H), 6.92 (dd, J=5.6, 1.6, 1H), 4.27 (q, J=7.1, 2H), 1.31 (t, J=7.1, 3H). LCMS (ESI) m/z: 431.4 [M+H+].
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[O:40]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[N:53]=[C:54]=[O:55])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[O:40]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[NH:53][C:54]([O:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:29][CH2:30]4)(=[O:26])=[O:27])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1)=[O:55])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: O=C=Nc1ccccc1Oc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1COCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Product: CC(C)(C)OC(=O)NC1COCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)Nc3ccccc3Oc3ccccc3)CN2C1=O
Yield: 15.3 %

Procedure:
Prepared by way of method III using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-12-oxatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and 2-phenoxyphenyl isocyanate (94 mg, 0.53 mmol). The final trituration (diethyl ether/hexane) and filtration gave 21 mg (15%) of 18-(2-phenoxyphenylaminocarbonyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-12-oxatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 99.2% pure (HPLC), MS m/z 780 (M−H)−, HRMS: calcd. 799.3337 and found 799.3325 (M+NH4)−, mp 151-153° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[H-].[Na+].Cl[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.CO.C(Cl)Cl>CN(C)C=O>[N:16]1([CH2:15][CH2:14][NH:1][C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][N:3]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: Nc1noc2ccccc12
Reactant: ClCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: c1ccc2c(NCCN3CCOCC3)noc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.7 %

Procedure:
To a solution of 3-amino-1,2-benzisoxazole (3.5 g) in N,N-dimethylformamide (DMF) (100 ml) was added sodium hydride (0.8 g) under nitrogen. The reaction was stirred one hour at ambient temperature. A solution of 4-(2-chloroethyl)morpholine (4.0 g) in DMF (50 ml) was added followed by heating to 120° C. for one hour. TLC (5% MeOH/DCM) analysis revealed the absence of starting material. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with water, dried (MgSO4), and concentrated in vacuo. Flash column chromatography (silica gel) eluting with 1.5-2.5% MeOH/DCM afforded the product (2.5 g), m.p. 79-80° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([C:9]1[N:10]([CH2:23][CH2:24]O)[C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[C:13]([NH2:21])[C:12]=2[N:22]=1)[CH2:6][CH2:7][CH3:8].CN(C)C=O>C1(C)C=CC=CC=1>[CH2:5]([C:9]1[N:10]([CH2:23][CH2:24][Cl:3])[C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[C:13]([NH2:21])[C:12]=2[N:22]=1)[CH2:6][CH2:7][CH3:8]
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCO
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCl
Yield: 76.5 %

Procedure:
Thionyl chloride (3.8 g, 32 mmol) was added to a solution of 2-butyl-1-(2-hydroxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (3.7 g, 13 mmol) in toluene containing a catalytic amount of N,N-dimethylformamide. The reaction mixture was heated to reflux and then capped. When analysis by high performance liquid chromatography indicated that the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in warm methanol and then combined with concentrated ammonium hydroxide (5 mL). The mixture was chilled. The resulting precipitate was isolated by filtration, washed with cold methanol and then dried under vacuum overnight to provide 3.01 g of 2-butyl-1-(2-chloroethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([O:16][CH:17]([F:19])[F:18])=[CH:14][NH:13][C:12](=[O:20])[CH:11]=2)[CH:3]=1.CC(C)([O-])C.CC(C)([O-])C.[Mg+2].CC(C)([O-])C.[K+].Br[CH:39]([CH3:43])[C:40]([OH:42])=[O:41]>O1CCCC1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([O:16][CH:17]([F:18])[F:19])=[CH:14][N:13]([CH:39]([CH3:43])[C:40]([OH:42])=[O:41])[C:12](=[O:20])[CH:11]=2)[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1-c1cc(=O)[nH]cc1OC(F)F
Reactant: CC(Br)C(=O)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CC(C(=O)O)n1cc(OC(F)F)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
163 mg (0.55 mmol) of 4-chloro-2-[5-(difluoromethoxy)-2-oxo-1,2-dihydropyridin-4-yl]benzonitrile, 2.0 eq. of magnesium di-tert-butoxide, 1.05 eq. of potassium tert-butoxide and 1.5 eq. of 2-bromopropanoic acid (racemate) were reacted at 45° C. and worked up according to General Method 4A. Owing to incomplete conversion, the crude product was then once more reacted as described above with 1.2 eq. of magnesium di-tert-butoxide, 0.65 eq. of potassium tert-butoxide and 0.8 eq. of 2-bromopropionic acid (racemate) in 3.5 ml of tetrahydrofuran and worked up analogously. Yield: 270 mg (purity 63%, 84% of theory)
Reaction SMILES: [CH3:1][C:2]1[C:3]([Br:26])=[CH:4][C:5](C(C)(C)C)=[C:6]([C:9]2[C:10]([OH:21])=[C:11]([CH3:20])[C:12]([Br:19])=[CH:13][C:14]=2C(C)(C)C)[C:7]=1[OH:8].C1(C)C=CC=CC=1.FC(F)(F)S(O)(=O)=O.O>C(Cl)(Cl)Cl>[CH3:20][C:11]1[C:12]([Br:19])=[CH:13][CH:14]=[C:9]([C:6]2[C:7]([OH:8])=[C:2]([CH3:1])[C:3]([Br:26])=[CH:4][CH:5]=2)[C:10]=1[OH:21]
Reactant: Cc1c(Br)cc(C(C)(C)C)c(-c2c(C(C)(C)C)cc(Br)c(C)c2O)c1O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(Br)ccc(-c2ccc(Br)c(C)c2O)c1O
Temperature: 5 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
The optically active 6,6′-dimethyl-5,5′-dibromo-3,3′-di(t-butyl)-2,2′-biphenol obtained in Example 1 (1.06 g, optical purity: >99% ee, 2.2 mmol), toluene (5 ml) and trifluoromethanesulfonic acid (750 mg, 5 mmol) were mixed followed by stirring the entire volume for 1 hour at 5° C. Water (10 ml) and chloroform (20 ml) were then added to the reaction mixture followed by extraction and liquid separation. The organic phase was then washed with water and dried with anhydrous magnesium sulfate followed by distilling off the solvent under reduced pressure. N-hexane (10 ml) was added to the remaining slurry followed by stirring at room temperature, washing and filtering to obtain optically active 6,6′-dimethyl-5,5′-dibromo-2,2′-biphenol (761 mg, yield: 93%, optical purity: >99% ee).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13](B4OC(C)(C)C(C)(C)O4)[CH:12]=3)=[CH:9][N:10]=[C:4]2[N:3]=1.Br[C:27]1[C:28]([C:33]#[N:34])=[N:29][CH:30]=[CH:31][CH:32]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13]([C:27]4[C:28]([C:33]#[N:34])=[N:29][CH:30]=[CH:31][CH:32]=4)[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[N:3]=1
Reactant: N#Cc1ncccc1Br
Reactant: Cc1ccn2c(-c3cccc(B4OC(C)(C)C(C)(C)O4)c3)cnc2n1
Product: Cc1ccn2c(-c3cccc(-c4cccnc4C#N)c3)cnc2n1
Yield: 34.3 %

Procedure:
7-Methyl-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-imidazo[1,2-a]pyrimidine (0.1 g, 0.29 mmol) was coupled to 3-bromopyridine-2-carbonitrile (0.11 g, 0.59 mmol) as described in Example 24. The crude product was applied to two preparative plates (silica gel) and eluted with 5% methanol in dichloromethane. The appropriate band was collected and processed, affording a solid which was recrystallised from dichloromethane/ethyl acetate/isohexane to give 3-[3-(7-methylimidazo[1,2-a]pyrimidin-3-yl)phenyl]pyridine-2-carbonitrile as a white solid (31 mg): δH (400 MHz, CDCl3) 2.67 (3H, s), 6.80 (1H, d, J 7), 7.55 (1H, td, J 8 and 1), 7.63-7.73 (3H, m), 7.77 (1H, m), 7.86 (1H, s), 7.94 (1H, dd, J 8 and 1.6), 8.75 (1H, d, J 1.6), 8.80 (1H, d, J 7); m/z (ES+) 312 (M++H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[Br:9]Br>C(Cl)(Cl)Cl>[Br:9][C:5]1[S:4][C:3]([CH:7]=[O:8])=[C:2]([CH3:1])[CH:6]=1
Reactant: BrBr
Reactant: Cc1ccsc1C=O
Solvent: ClC(Cl)Cl
Product: Cc1cc(Br)sc1C=O
Temperature: 100 °C

Procedure:
A solution of 3-methyl-thiophene-2-carboxaldehyde (12.0 g) in chloroform (50 ml) was added drop-wise to bromine (5.1 ml) in chloroform over 30 minutes and then heated to 100° C. for 140 minutes. The reaction mixture was diluted with chloroform and washed with 10% aqueous sodium thiosulfate solution, saturated aqueous bicarbonate solution and water. The organic solution was dried over magnesium sulfate and concentrated. The product isolated after evaporation of the solvent was further purified by vacuum distillation (122° C., 4 mbar) to give the title compound as a green oil.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:16])[CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:17][CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:19]([NH:21][CH3:22])=[O:20]>>[Cl:15][C:7]1[CH:8]=[C:9]2[C:4](=[C:5]([Cl:16])[CH:6]=1)[N:3]=[C:2]([NH:17][CH:18]([C:19](=[O:20])[NH:21][CH3:22])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:11]([C:12]([OH:14])=[O:13])=[CH:10]2
Reactant: O=C(O)c1cc2cc(Cl)cc(Cl)c2nc1Cl
Reactant: CNC(=O)C(N)Cc1ccccc1
Product: CNC(=O)C(Cc1ccccc1)Nc1nc2c(Cl)cc(Cl)cc2cc1C(=O)O

Procedure:
In close analogy to the procedure described in Example 32, 2,6,8-trichloroquinoline-3-carboxylic acid is reacted with 2-amino-N-methyl-3-phenyl-propionamide to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:18]=[C:17]([NH:19][C@@H:20]2[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@@H:22]([C:32]([O:34]C)=[O:33])[CH2:21]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.O.[OH-].[Li+].O1CCOCC1.Cl>O>[C:28]([O:27][C:25]([N:23]1[CH2:24][C@@H:20]([NH:19][C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[N:18]=2)[CH2:21][C@@H:22]1[C:32]([OH:34])=[O:33])=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: COC(=O)[C@H]1C[C@H](Nc2nc(-c3ccccc3OC)nc3ccccc23)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccccc1-c1nc(N[C@H]2C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)c2ccccc2n1
Yield: 96.6 %

Procedure:
(2R,4S)-1-tert-Butyl 2-methyl 4-(2-(2-methoxyphenyl)quinazolin-4-ylamino)pyrrolidine-1,2-dicarboxylate (0.415 g, 0.851 mmol) and lithium hydroxide monohydrate (0.089 g, 2.128 mmol) were dissolved in water (8 mL) and dioxane (8 mL) and stirred for 1 hour. Water (30 mL) was added and the mixture was acidified to pH 4 with 1M HCl. The aqueous layer was extracted with ethyl acetate (4×30 mL). The combined organic extracts were dried (MgSO4) and concentrated to give the title compound as a solid (0.382 g, 95%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([CH3:33])([CH:10]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[N:21]=[CH:20]2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=O)(=[O:3])[CH3:2].[S:34]1[CH:38]=[N:37][N:36]=[C:35]1[NH2:39]>>[C:1]([O:4][CH2:5][C:6]([CH:10]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)[N:21]=[CH:20]2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([CH3:33])[C:7]([NH:39][C:35]1[S:34][CH:38]=[N:37][N:36]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(C)(C(=O)O)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: Nc1nncs1
Product: CC(=O)OCC(C)(C(=O)Nc1nncs1)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Yield: 39 %

Procedure:
Example 154 was prepared from 2-(acetoxymethyl)-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-3-phenylpropanoic acid (75 mg, 0.168 mmol) and 1,3,4-thiadiazol-2-amine using General Coupling Method B to give 35 mg (39% yield). MS found: (M+H)+=530.
Reaction SMILES: Cl.[CH2:2]([O:5][N:6]=[C:7]([C:35]1[N:36]=[C:37]([NH:40]C=O)[S:38][CH:39]=1)[C:8]([NH:10][CH:11]1[C:33](=[O:34])[N:13]2[C:14]([C:30]([OH:32])=[O:31])=[C:15]([CH2:18][S:19][C:20]3[N:24]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[N:23]=[N:22][N:21]=3)[CH2:16][S:17][C@H:12]12)=[O:9])[CH:3]=[CH2:4]>CO>[CH2:2]([O:5][N:6]=[C:7]([C:35]1[N:36]=[C:37]([NH2:40])[S:38][CH:39]=1)[C:8]([NH:10][CH:11]1[C:33](=[O:34])[N:13]2[C:14]([C:30]([OH:32])=[O:31])=[C:15]([CH2:18][S:19][C:20]3[N:24]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[N:23]=[N:22][N:21]=3)[CH2:16][S:17][C@H:12]12)=[O:9])[CH:3]=[CH2:4]
Reactant: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCC(=O)O)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCC(=O)O)CS[C@H]12)c1csc(N)n1
Reaction time: 0.5 h
Yield: 18.8 %

Procedure:
Conc. hydrochloric acid (572 mg) was added to a solution of 7-[2-allyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-[1-(2-carboxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.28 g) in methanol (16 ml) at ambient temperature and the mixture was stirred for 30 minutes. The reaction mixture was post-treated according to a conventional manner to give 7-[2-allyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[1-(2-carboxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(410 mg).
Reaction SMILES: [CH3:1][C@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[O:31])[CH:25]=[C:26]([Cl:28])[CH:27]=1.Cl>CN(C)C1C=CN=CC=1.ClCCl>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:31])[CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: CC1(C)C2CC[C@@]1(C)C(=O)CC2=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@@]1(C)C(=O)C(C(=O)Nc1cc(Cl)cc(Cl)c1)C2=O
Temperature: 30 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To an ice-cooled solution of (1R)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.18 g, 1.0 mmole), triethylamine (0.10 g, 1.0 mmole) and 4-(dimethylamino)pyridine (0.12 g, 1.0 mmole) in dry dichloromethane (25 mL) was added a solution of 3,5-dichlorophenyl isocyanate (0.19 g, 1.0 mmole) in dry dichloromethane (5 mL). The resulting mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature, and then was heated at 30° C. for 24 hours. The reaction mixture was treated with 2N aqueous HCl and the layers separated. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield a yellow oil, which was crystallized from 95% ethanol to yield the title compound as a white solid (0.25 g, 67% yield), mp=115–117° C.; MS (−) ESI m/z=366 (M−H)−; [α]D25=+24.9° (c=1, EtOH).
Reaction SMILES: [CH2:1]([C:3]1[N:7](S(N(C)C)(=O)=O)[N:6]=[CH:5][C:4]=1[C:14]1[S:22][C:21]2[C:20](=[O:23])[NH:19][C:18]([CH3:25])([CH3:24])[N:17]([CH3:26])[C:16]=2[CH:15]=1)[CH3:2].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+].CC(C)=O.[O-]S([O-])(=O)=O.[Mg+2].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C>[CH2:1]([C:3]1[NH:7][N:6]=[CH:5][C:4]=1[C:14]1[S:22][C:21]2[C:20](=[O:23])[NH:19][C:18]([CH3:25])([CH3:24])[N:17]([CH3:26])[C:16]=2[CH:15]=1)[CH3:2]
Reactant: CCc1c(-c2cc3c(s2)C(=O)NC(C)(C)N3C)cnn1S(=O)(=O)N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCc1[nH]ncc1-c1cc2c(s1)C(=O)NC(C)(C)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.7 %

Procedure:
A mixture of 5-ethyl-N,N-dimethyl-4-(1,2,2-trimethyl-4-oxo-1,2,3,4-tetrahydrothieno[3,2-d]pyrimidin-6-yl)-1H-pyrazole-1-sulfonamide (129 mg, 0.325 mmol) and TFA (2.00 mL, 26.0 mmol) was stirred for 1 h at room temperature. The mixture was poured into saturated aqueous NaHCO3 and extracted with EtOAc, and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was mixed with acetone (5 mL, 68.1 mmol), MgSO4 (78 mg, 0.649 mmol), PTSA (6.2 mg, 0.032 mmol) and DMF (1 mL). This mixture was stirred at 60° C. for 1 h. The mixture was poured into saturated aqueous NaHCO3 and extracted with 3:1 EtOAc/THF, and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, hexane to EtOAc then to 80:20 EtOAc/MeOH). The obtained solid was triturated with EtOAc and collected by filtration to afford the title compound (41.2 mg, 44%) as a pale yellow solid:
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:7]([S:26]([CH3:29])(=[O:28])=[O:27])[N:6]=1)(=O)=O.C([Li])CCC.[CH:35]1([CH2:41][OH:42])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH:35]1([CH2:41][O:42][C:5]2[N:6]=[C:7]([S:26]([CH3:29])(=[O:27])=[O:28])[C:8]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])[N:10]=2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: OCC1CCCCC1
Reactant: CS(=O)(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c(S(C)(=O)=O)n1
Agent: [Li]CCCC
Product: CS(=O)(=O)c1nc(OCC2CCCCC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
2,4-bis(Methylsulfonyl)-5-[4-chlorophenyl]-6-[2,4-dichlorophenyl]pyrimidine (Reference Example 5) (98 mg, 0.2 mmol) was reacted with 1 equivalent each of n-butyl lithium and cyclohexyl methanol by the procedure described in Reference Examples 6 and 7. Workup and flash column chromatography on silica gel eluted with 85/15 hexanes/ethyl acetate afforded 2-(cyclohexylmethoxy)-4-(methyl-sulfonyl)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (HRf product): 1H-NMR 500 MHz (CDCl3): δ 0.9-1.1 (m, 1H), 1.10-1.2 (m, 2H), 1.2-1.4 (m, 3H); 1.67-1.88 (m, 3H), 1.9-2.0 (m, 2H), 3.38 (s, 3H), 4.29 (d, J=6 Hz, 2H), 7.0 (d, J=7 Hz, 1H), 7.18-7.22 (m, 3H), 7.24-7.28 (m, 2H), 7.36 (d, J=2 Hz, 1H) and 28 mg of 2-(methylsulfonyl)-4-(cyclohexylmethyloxy)-5-(4-chlorophenyl)-6-(2,4-dichloro-phenyl)pyrimidine (LRf product): 1H-NMR 500 MHz (CDCl3): δ 0.87-0.9 (m, 1H), 0.95-1.07 (m, 2H), 1.1-1.3 (m, 2H), 1.33 (m, 2H), 1.7-1.82 (m, 4H), 3.40 (s, 3H), 4.37 (d, J=6 Hz, 2H), 7.08-7.12 (m, 2H), 7.22-7.30 (m, 4H), 7.36 (d, J=2 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:26]=[CH:25][C:16]([O:17][CH2:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:15]([CH3:27])[CH:14]=2)([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:28].[CH2:29]([S:31](Cl)(=[O:33])=[O:32])[CH3:30]>>[CH3:21][C:20]([CH3:22])([CH3:23])[C:19](=[O:24])[CH2:18][O:17][C:16]1[CH:25]=[CH:26][C:13]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:31]([CH2:29][CH3:30])(=[O:33])=[O:32])=[C:3]([CH3:28])[CH:4]=2)([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:14][C:15]=1[CH3:27]
Reactant: CCS(=O)(=O)Cl
Reactant: CCC(CC)(c1ccc(N)c(C)c1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Product: CCC(CC)(c1ccc(NS(=O)(=O)CC)c(C)c1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Yield: 45.7 %

Procedure:
Using a procedure analogous to Example 17, 1-{4-[1-(4-amino-3-methyl-phenyl)-1-ethyl-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-one (229 mg, 0.6 mmol), ethanesulfonyl chloride (0.080 mL, 0.9 mmol) gives N-(4-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-N,N-bis-ethanesulfonamide (Example 22) (120 mg, 35%), and N-(4-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-ethanesulfonamide (Example 23) (130 mg, 46%).