Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11]C)=[C:9]2[C:5]([C:6]3[CH:16]=[C:15]([CH3:17])[CH:14]=[N:13][C:7]=3[NH:8]2)=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])[CH:19]=2)[CH:3]=1.C(S(C1C=C(C2C=CC(O)=C3C=2C2C=C(C)C=NC=2N3)C=CC=1)(=O)=O)C>>[Cl:1][C:2]1[C:10]([OH:11])=[C:9]2[C:5]([C:6]3[CH:16]=[C:15]([CH3:17])[CH:14]=[N:13][C:7]=3[NH:8]2)=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH2:27][CH3:28])(=[O:25])=[O:26])[CH:19]=2)[CH:3]=1
Reactant: CCS(=O)(=O)c1cccc(-c2cc(Cl)c(OC)c3[nH]c4ncc(C)cc4c23)c1
Agent: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(C)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2cc(Cl)c(O)c3[nH]c4ncc(C)cc4c23)c1

Procedure:
The title compound was prepared from Compound 246 by using an analogous procedure to that outlined in the preparation of Compound 157. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (t, J=7.33 Hz, 3H) 2.25 (s, 3H) 3.41 (q, J=7.58 Hz, 2H) 4.26 (t, J=6.44 Hz, 2H) 7.23 (s, 1H) 7.46 (s, 1H) 7.87 (t, J=7.71 Hz, 1H) 8.03 (t, J=7.20 Hz, 2H) 8.11 (s, 1H) 8.31 (s, 1H) 12.27 (br. s., 1H); [M+H] calc'd for C20H17ClN2O3S, 401.1; found, 401.3.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][N:26]=[N+:27]=[N-:28])[O:22][C:21]3=[O:29])=[CH:16][C:15]=2[F:30])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31]12CC(CC1)=C[CH:32]=2>O1CCOCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][N:26]4[CH:32]=[CH:31][N:28]=[N:27]4)[O:22][C:21]3=[O:29])=[CH:16][C:15]=2[F:30])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1=C2CCC(=C1)C2
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)C1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)C1
Yield: 73.7 %

Procedure:
(5R)-3-(4-((3R)-3-(t-Butoxycarbonyl)aminopyrrolidin-1-yl)-3-fluorophenyl)-5-azidomethyl-oxazolidin-2-one (695 mg, 1.65 mM) was dissolved in dioxane (30 ml), treated with norbornadiene (760 mg, 8.25 mM) and heated under reflux for 6 hours. After removal of the solvent, the residue was dissolved in the minimum of dichloromethane and purified by chromatography on a 20 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 2.5% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (544 mg).
Reaction SMILES: [C:1]([C:4]1[C:5]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]([Cl:34])[CH:28]=2)=[N:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([NH:15][CH:16]3[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]3)=[O:14])[CH2:9][C:8]=12)(=[O:3])[NH2:2].Cl.O1CCOCC1>CO>[NH:18]1[CH2:17][CH:16]([NH:15][C:13]([N:10]2[CH2:11][CH2:12][N:7]3[N:6]=[C:5]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[C:29]([Cl:34])[CH:28]=4)[C:4]([C:1]([NH2:2])=[O:3])=[C:8]3[CH2:9]2)=[O:14])[CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)N2CCn3nc(-c4ccc(F)c(Cl)c4)c(C(N)=O)c3C2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC(=O)c1c(-c2ccc(F)c(Cl)c2)nn2c1CN(C(=O)NC1CNC1)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.8 %

Procedure:
To a stirred solution of Intermediate 339A (0.25 g, 0.50 mmol) in MeOH (5 mL) was added a 4M solution of HCl in dioxane (5 mL, 20 mmol). The resulting solution was allowed to stir at RT for 4 h. The reaction mixture was then concentrated and triturated with diethyl ether to afford Intermediate 339B (0.2 g, 55%). MS(ES): m/z=393 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.84 (dd, J=7.03, 2.01 Hz, 1H) 7.64-7.70 (m, 1H), 7.45 (q, J=8.70 Hz, 1H), 7.18-7.39 (m, 2H), 6.61 (d, J=7.53 Hz, 1H), 5.53 (s, 1H), 4.73 (s, 2H), 4.13 (m, 1H), 3.97-4.04 (m, 2H), 3.83 (br. s., 2H) 3.05-3.16 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([N+:11]([O-])=O)[CH:5]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([NH2:11])[CH:5]=1
Reactant: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(O)c(N)c1
Reaction time: 2 h

Procedure:
A solution of 4-hydroxy-3-nitro-benzoic acid methyl ester (5.0 g, 25.4 mmol) in ethanol (120 mL) was treated with 5% palladium on active carbon (0.24 g, 2.3 mmol, 0.1 equiv.) and the flask was evacuated and placed under an hydrogen atmosphere. The mixture was stirred vigorously for 2 h and 45′, the palladium was filtered off, washing extensively with ethanol. The solvent was removed in vacuo to yield 3-amino-4-hydroxy-benzoic acid methyl ester as a white solid, 4.2 g (100%), MS (ISP): m/e=168.3 (M+H+.). This was used crude in the following reaction.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][CH2:19][C:20](O)=O)C1C=CC=CC=1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[CH3:44][O:45][C:46]1[CH:47]=[CH:48][C:49]2[O:54][CH2:53][CH:52]([CH2:55][NH2:56])[O:51][C:50]=2[CH:57]=1.Cl>CN(C=O)C>[CH3:44][O:45][C:46]1[CH:47]=[CH:48][C:49]2[O:54][CH2:53][CH:52]([CH2:55][NH:56][CH2:20][CH2:19][CH2:18][C:12]3[C:11]4[C:15](=[CH:16][CH:17]=[C:9]([OH:8])[CH:10]=4)[NH:14][CH:13]=3)[O:51][C:50]=2[CH:57]=1
Reactant: O=C(O)CCc1c[nH]c2ccc(OCc3ccccc3)cc12
Reactant: COc1ccc2c(c1)OC(CN)CO2
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OC(CNCCCc1c[nH]c3ccc(O)cc13)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
5-Benzyloxyindole-3-propionic acid (1.8 g, 6.0 mmole), 1-hydroxybenzotriazole hydrate (0.97 g, 7.2 mmole) and 1,3-diisopropylcarbodiimide (2.3 ml, 14.4 mmole) were combined in 150 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 7-methoxy-2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.4 g, 6.0 hydrochloride (1.4 g, 6.0 mmole) in 50 ml of DMF and the mixture was further stirred for 48 hours. The solvent was removed and replaced with dichloromethane. The mixture was then washed with H2O. The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel using first dichloromethane and then 2.5% methanol in dichloromethane as eluants to give 2.6 g (90%) of the desired product, (7-methoxy-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-(5-benzyloxy-1H-indol-3-yl)-propanamide, as a light tan solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)[CH:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22]>>[Cl:16][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[F:15])[NH:8][C:4]1[CH:3]=[C:2]([NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[C:19]([O:18][CH3:17])[CH:20]=2)[N:7]=[CH:6][N:5]=1
Reactant: Fc1ccc(Nc2cc(Cl)ncn2)cc1Cl
Reactant: COc1cccc(N)c1
Product: COc1cccc(Nc2cc(Nc3ccc(F)c(Cl)c3)ncn2)c1
Yield: 16 %

Procedure:
Using an analogous reaction procedure to that described in Example 6, 6-chloro-4-(3'-chloro-4'-fluoroanilino)pyrimidine was reacted with 3-methoxyaniline. The reaction product was recrystallised from a mixture of methylene chloride, methanol and hexane, to give 4-(3'-chloro-4'-fluoroanilino)-6-(3'-methoxyanilino)pyrimidine in 16% yield, m.p. 214°-216° C.;
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.FCCN(CCF)C1C=CC(C#N)=C(C(F)(F)F)C=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:43][C:44]([O:46][CH3:47])=[O:45]>C(#N)C>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:3][CH2:2][F:1])[CH2:43][C:44]([O:46][CH3:47])=[O:45])=[CH:6][C:7]=1[C:13]([F:14])([F:15])[F:16])#[N:10]
Reactant: COC(=O)CBr
Reactant: N#Cc1ccc(NCCF)cc1C(F)(F)F
Agent: N#Cc1ccc(N(CCF)CCF)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)CN(CCF)c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 85 °C
Yield: 50 %

Procedure:
To a solution of a 6:1 mixture of 4-[(2-fluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-[bis(2-fluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (0.100 g) in acetonitrile (3 mL) was added Cs2CO3 (0.169 g, 0.52 mmol) and methyl bromoacetate (0.080 g, 0.52 mmol). The mixture was heated at 85° C. for 2 h. Upon cooling, additional methyl bromoacetate (0.080 g, 0.52 mmol) was added and heated at 85° C. for 8 h. Upon cooling, the mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by radial chromatography (10-80% EtOAc-hexanes gradient) to give 0.052 g (50% yield) of the desired product as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J=8.9 Hz, 1H), 6.92 (d, J=2.7 Hz, 1H), 6.76 (dd, J=8.9, 2.7 Hz, 1H), 4.68 (dt, J=47.0, 4.8 Hz, 2H), 4.21 (s, 2H), 3.81 (dt, J=25.6, 4.8 Hz, 2H), 3.78 (s, 3H).
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:10](Br)=[CH:9][C:8]=1[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[B:28](OC)([O:31]C)[O:29]C.Cl.[K+].[Br-]>CCOCC>[Br:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:10]([B:28]([OH:31])[OH:29])=[CH:9][C:8]=1[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: COB(OC)OC
Reactant: CCCCCCOc1cc(Br)c(OCCCCCC)cc1Br
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Product: CCCCCCOc1cc(B(O)O)c(OCCCCCC)cc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Butyllithium (48.2 mmol, 30.2 ml, 15% in hexane) was added into a solution of 1,4-dibromo-2,5-dihexyloxybenzene (48.2 mmol, 21.0 g) in ether (195 ml) under argon at between -10° to -30° C. over 15 min. The mixture was allowed to warm to room temperature and was stirred for further 2 h. It was then transferred into a solution of freshly distilled trimethyl borate (145 mmol, 16.4 ml) in ether (390 ml) under argon at -60° C. The mixture was allowed to warm to room temperature and was stirred for further 15 h. Aqueous hydrochloric acid (2M, 300ml) was added into the mixture, and the aqueous layer was separated and extracted with ether (100 ml×2). The combined organic layer was evaporated and 40/60 petroleum ether (200 ml) was added. A colourless solid was recovered by filtration and dried under vacuum. Further purification was carried out by column chromatography over silica (60 g), with toluene (200 ml) as an eluent to remove by-products. Elution with ether (300 ml) produced a pure product. (8.9 g, 46%); m.p. 102°-103° C.; Rf (ether), 0.71; γmax (KBr, cm-1) 3360 (OH), 2940 (C--H), 1200 (Ph), 1040 (C--O), 810 (Ph); δH (400 MHz, CDCl3) 0.91 (67H, m, Me), 1.33 (8H, m), 1.44 (4H, m) 1.80 (4H, m) 4.00 (4H, m), 6.48 (2H, s, OH), 7.09 (1H, s, Ph), 7.36 (ill, s, Ph); t δc (100 MHz, CDCl3) 13.9, 22.5, 25.5, 29.1, 31.4, 69.6, 116.3, 116.4 (PhC--H), 118 (br, C--B), 120.5 (PhC--H), 149.6 (PhC--O), 158.0 (PhC--O).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([C:16]3[N:20]([C:21]4[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=4)[N:19]=[C:18]([C:28]([F:31])([F:30])[F:29])[CH:17]=3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(Cl)Cl>[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][O:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([N:20]2[C:16]([C:14]3[S:15][C:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=4)=[CH:12][CH:13]=3)=[CH:17][C:18]([C:28]([F:31])([F:29])[F:30])=[N:19]2)[CH:22]=1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(F)(F)F)nn3-c3cccc(O)c3)s2)c1
Reactant: CN(C)CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)CCOc1cccc(-n2nc(C(F)(F)F)cc2-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)c1
Temperature: 0 °C
Yield: 43.8 %

Procedure:
3-(5-(5-(3-(methylsulfonyl)phenyl)thiophen-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenol (120 mg, 0.26 mmol), 2-(dimethylamino)ethanol (46 mg, 0.52 mmol) and triphenylphosphine (138 mg, 0.52 mmol) were dissolved in a mixture solvent of anhydrous THF (2.5 mL) and DCM (2.5 mL) and cooled off at 0° C. under nitrogen atmosphere. To this solution was added diisopropyl azodicarboxylate (111 mg, 0.52 mmol). The reaction mixture was stirred vigorously and warmed up to mom temperature overnight. The solvent was evaporated in vacuo and the residue was purified by HPLC, providing the product (61 mg, 44%). 1H-NMR (Acetone-d6): δ 8.13 (m, 1H), 7.93 (m, 1H), 7.90 (m, 1H), 7.71 (m, 1H), 7.60 (m, 1H), 7.47 (m, 1H), 7.17-7.09 (br, 5H), 4.12 (t, J=5.8 Hz, 2H), 3.18 (s, 3H), 2.65 (t, J=5.8 Hz, 2H), 2.21 (s, 6H). MS (ES): 536 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13](F)[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:19]1([CH2:25][NH2:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.CCN(C(C)C)C(C)C.Cl>CN(C=O)C>[CH:19]1([CH2:25][NH:26][C:13]2[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][C:3]([NH:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[C:2]([F:1])[CH:14]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NCC1CCCCC1
Reactant: O=[N+]([O-])c1cc(Nc2ccccc2)c(F)cc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Nc2ccccc2)c(F)cc1NCC1CCCCC1
Yield: 34.9 %

Procedure:
A solution of 2,4-difluoro-5-nitro-N-phenylaniline (1.00 g, 4.00 mmol), cyclohexanemethylamine (0.57 mL, 4.40 mmol) and N,N′-diisopropylethylamine (0.77, 4.40 mmol) in DMF (40 mL) was stirred at room temperature under an inert atmosphere for 18.5 h. The reaction mixture was transferred to a separatory funnel containing 2 N HCl. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water, brine and dried over MgSO4. The solution was filtered through diatomaceous earth and the solvent was evaporated. The resulting dark red residue was flash chromatographed (10% EtOAc/hexanes) to give N4-cyclohexylmethyl-2-fluoro-5-nitro-N1-phenyl-benzene-1,4-diamine as a dark red solid (0.48 g, 34.9% yield). M+, 344
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH2:5][S:6][C@@H:7]2[CH:14]([NH:15][C:16](=[O:46])[C:17]([C:21]3[N:22]=[C:23]([NH:26]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:24][CH:25]=3)=[N:18][O:19][CH3:20])[C:13](=[O:47])[N:8]2[C:9]=1[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O>>[CH3:1][S:2][CH2:3][C:4]1[CH2:5][S:6][C@@H:7]2[CH:14]([NH:15][C:16](=[O:46])[C:17]([C:21]3[N:22]=[C:23]([NH2:26])[S:24][CH:25]=3)=[N:18][O:19][CH3:20])[C:13](=[O:47])[N:8]2[C:9]=1[C:10]([OH:12])=[O:11]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSC)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSC)CS[C@H]12)c1csc(N)n1
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
A mixture of 6.15 g of the product of Step A and 61 ml of trifluoroacetic acid was stirred at 20° C. for 20 minutes and the mixture was evaporated under reduced pressure at 30° C. to a volume of 15 ml. 150 ml of ispropyl ether were added at 10° C. to the mixture which was then stirred at 20° C. for 15 minutes and was vacuum filtered. The 3.2 g of raw product were chromatographed over silica gel and were eluted with aqueous 2M sodium chloride solution containing 4% of 1M sodium bicarbonate solution. The raw product was dissolved in a mixture of 10 ml of eluant, 1.4 ml of aqueous 1M sodium bicarbonate solution, 1 ml of triethylamine and 1 ml of aqueous saturated sodium chloride solution and the solution was acidified to a pH of 3 by addition of 50% aqueous formic acid. The mixture was vacuum filtered and the product was washed with water and then with ether to obtain 0.99 g of syn isomer of 3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]1.[CH3:27][O:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[CH:31][C:30]=1[OH:44]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([N:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]2)=[CH:3][C:2]([C:33]2[CH:32]=[CH:31][C:30]([OH:44])=[C:29]([O:28][CH3:27])[CH:34]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: CN(C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N[C@H]4CC[C@H](N(C)C)CC4)c3c2)ccc1O

Procedure:
Following general procedure F, {6-bromo-4-[trans-4-(dimethylamino)cyclohexylamino]quinolin-3-yl}(cyclopropyl)methanone (52 mg, 0.120 mmol) was reacted with 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (45 mg, 0.180 mmol) to afford the desired product (17 mg, 31%) as a yellow-green solid: 1H NMR (300 MHz, CD3OD) δ 9.19 (s, 1H), 8.36 (s, 1H), 8.10 (dd, J=8.8, 1.9 Hz, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.30 (d, J=2.1 Hz, 1H), 7.21 (dd, J=8.2, 2.1 Hz, 1H), 6.95 (d, J=8.2 Hz, 1H), 4.22 (s, 1H), 3.97 (s, 3H), 2.84 (s, 7H), 2.43 (s, 2H), 2.21 (s, 2H), 1.68 (s, 3H), 1.27-1.18 (m, 2H), 1.18-1.07 (m, 2H); ESI MS m/z 460 [C28H33N3O3+H]+; HPLC>99% (AUC), tR=10.86 min.
Reaction SMILES: ClC1SN=C(SC)N=1.N1CCCC1.CS[C:16]1[N:20]=[C:19]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[S:18][N:17]=1.Cl[C:27]1C=CC=[C:29]([C:33](OO)=[O:34])[CH:28]=1.CS(C1N=C(N2CCCC2)SN=1)=O.CS(C1N=C(N2CCCC2)SN=1)(=O)=O.C(O)C#CC.[H-].[Na+]>CN(C)C=O.COC(C)(C)C.C(Cl)(Cl)Cl>[CH2:33]([O:34][C:16]1[N:20]=[C:19]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[S:18][N:17]=1)[C:29]#[C:28][CH3:27]
Reactant: CSc1nsc(N2CCCC2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: CC#CCO
Agent: CS(=O)(=O)c1nsc(N2CCCC2)n1
Agent: CS(=O)c1nsc(N2CCCC2)n1
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC#CCOc1nsc(N2CCCC2)n1
Reaction time: 6 h

Procedure:
In 4 ml of N,N-dimethylformamide was dissolved 333 mg of 5-chloro-3-methylthio-1,2,4-thiadiazole, and 142 mg of pyrrolidine was added dropwise at room temperature. The mixture was stirred for 6 hours. The reaction mixture was diluted with tert-butyl methyl ether, and extracted with tert-butyl methyl ether after the addition of 10% hydrochloric acid. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude 3-methylthio-5-(pyrrolidin-1-yl)-1,2,4-thiadiazole. In 4 ml of chloroform was added the crude 3-methylthio-5-(pyrrolidin-1-yl)-1,2,4-thiadiazole, and 1.52 g of 3-chloroperbenzoic acid (content: 65 weight %) was added under ice-cooling. The mixture was stirred at room temperature for 6 hours. The reaction mixture was washed with 10%-sodium sulfite aqueous solution and saturated sodium bicarbonate aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude mixture of 3-methylsulfinyl-5-(pyrrolidin-1-yl)-1,2,4-thiadiazole and 3-methylsulfonyl-5-(pyrrolidin-1-yl)-1,2,4-thiadiazole. The crude mixture of 3-methylsulfinyl-5-(pyrrolidin-1-yl)-1,2,4-thiadiazole and 3-methylsulfonyl-5-(pyrrolidin-1-yl)-1,2,4-thiadiazole was mixed with 4 ml of N,N-dimethylformamide and 140 mg of 2-butyn-1-ol, and 120 mg sodium hydride (oil suspension; content: 60 weight %) under ice-cooling. The mixture was stirred for 15 minutes and at room temperature for 6 hours. The reaction mixture was extracted with tert-butyl methyl ether after the addition of saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 158 mg of 3-(2-butynyloxy)-5-(pyrrolidin-1-yl)-1,2,4-thiadiazole (hereinafter, referred to as the present compound (1)).
Reaction SMILES: C1COCC1.[H-].[Na+].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[N:18]1[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]1)[CH:13]=O.[C:24]([O:27][CH2:28][CH3:29])(=[O:26])[CH3:25]>O>[CH2:28]([O:27][C:24](=[O:26])/[CH:25]=[CH:13]/[C:12]1[CH:15]=[CH:16][C:17]([N:18]2[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]2)=[C:10]([O:9][CH3:8])[CH:11]=1)[CH3:29]
Reactant: CCOC(C)=O
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc(-n2cnc(C)c2)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a THF (15 mL) solution of sodium hydride (814 mg) triethylphosphonoacetic acid (4.1 mL) was added at 0° C., and the reaction solution was agitated at 0° C. for 30 minutes and at room temperature for 1 hour. After cooling the reaction solution at 0° C., the THF (5 mL) solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (4.0 g) synthesized in Example 1 was added dropwise to the reaction solution. The reaction solution was further agitated at 0° C. for 30 minutes and then at room temperature for 2 hours. Ethyl acetate and water was added to the reaction solution, and the organic layer was separated and washed with a saturated ammonium chloride solution. After drying with anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. By re-crystallizing the obtained solid using a mixed solution of hexane and ethyl acetate, the 4.55 g (86%) title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:16][C:17]1[CH:42]=[CH:41][C:20]([CH2:21][NH:22][C:23]([C:25]2[CH:26]=[N:27][C:28]3[C:33]([C:34]=2[OH:35])=[CH:32][C:31]([CH2:36][CH2:37][CH2:38]O)=[CH:30][C:29]=3[F:40])=[O:24])=[CH:19][CH:18]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:4]([O:3][C:1]([NH:8][CH:9]([CH:10]([CH3:11])[CH3:12])[C:13]([O:15][CH2:38][CH2:37][CH2:36][C:31]1[CH:32]=[C:33]2[C:28](=[C:29]([F:40])[CH:30]=1)[N:27]=[CH:26][C:25]([C:23]([NH:22][CH2:21][C:20]1[CH:19]=[CH:18][C:17]([Cl:16])=[CH:42][CH:41]=1)=[O:24])=[C:34]2[OH:35])=[O:14])=[O:2])([CH3:5])([CH3:7])[CH3:6]
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(CCCO)cc2c1O
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OCCCc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Boc-valine (0.13 g) is added to a solution of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxypropyl)-3-quinolinecarboxamide from example 110 (0.15 g), EDC hydrochloride (0.11 g), and DMAP (0.016 g) in 4 mL pyridine. The reaction is stirred at room temperature overnight. The solvent is removed in vacuo and the residue partitioned between CH2Cl2 and H2O. The organic layer is washed once with water, and once with brine. The organic layer is then dried over Na2SO4, filtered, and concentrated in vacuo to give a yellow liquid. The residue is adsorbed onto silica and purified by chromatography on a Biotage Flash 40S column (eluent 1% MeOH:CH2Cl2 (1 L) followed by 2% MeOH:CH2Cl2 (2 L)). The product is obtained as a white solid which is further purified by recrystallization with CH2Cl2 /hexanes (0.17 g, 74%).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.Cl[CH2:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17]>>[CH3:11][C:10]1[C:4]2[N:3]=[C:2]([S:1][CH2:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[NH2:17])[NH:6][C:5]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1ccccc1CCl
Reactant: Cc1cccc2nc(S)[nH]c12
Agent: Cl
Product: Cc1cccc2[nH]c(SCc3ccccc3N)nc12
Yield: 23.1 %

Procedure:
The title compound was prepared by the method of Example 1 using 3.52 g of 2-mercapto-4-methylbenzimidazole instead of 2-mercaptobenzimidazole and 3.52 g of 2-(chloromethyl) aniline hydrochloride instead of 2-(chloromethyl)-N,N-dimethylaniline. Recrystallization from diethyl ether gave 1.23 g of the title compound: m.p. 125-127° C. Anal. Calc'd. for C15H15N3S: C, 66.89; H, 5.61; N,15.60; S, 11.90. Found: C, 66.76; H, 5.62; N, 15.41; S, 11.87.