Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[N:11]=[C:12]([Br:15])[S:13][CH:14]=2)[C:5]([C:16]#[N:17])=[C:4]([SH:18])[N:3]=1.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[S:24][CH:25]=1.C(=O)(O)[O-].[Na+].O>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[N:11]=[C:12]([Br:15])[S:13][CH:14]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:20][C:21]2[N:22]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[S:24][CH:25]=2)[N:3]=1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1csc(Br)n1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1csc(Br)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
4.78 g (purity 77%, 10.882 mmol) of 2-amino-4-(2-bromo-1,3-thiazol-4-yl)-6-sulfanylpyridine-3,5-dicarbonitrile were initially charged in 30 ml of DMF, 2.923 g (11.971 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 2.742 g (32.647 mmol) of sodium bicarbonate were added and the mixture was stirred at room temperature overnight. The reaction mixture was added to water, and the precipitated solid was filtered off with suction, washed with water and dried under high vacuum. The contaminated product was applied to silica gel and purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 2:1). The product-containing fractions were concentrated, the residue was triturated with dichloromethane and the solid was filtered off, washed with dichloromethane and dried under high vacuum. This gave 1.1 g of the target compound in a purity of 91% (yield: 17% of theory).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Cl:19][C:20]1[C:21]([C:48]2[CH:53]=[CH:52][C:51]([N:54]3[CH2:58][CH2:57][CH2:56][CH2:55]3)=[CH:50][CH:49]=2)=[CH:22][C:23]2[N:27]=[C:26]([O:28][C:29]3[CH:30]=[CH:31][C:32]([CH3:38])=[C:33]([CH:37]=3)[C:34]([OH:36])=[O:35])[N:25](COCC[Si](C)(C)C)[C:24]=2[CH:47]=1>O1CCOCC1.CCOC(C)=O>[Cl:19][C:20]1[C:21]([C:48]2[CH:53]=[CH:52][C:51]([N:54]3[CH2:58][CH2:57][CH2:56][CH2:55]3)=[CH:50][CH:49]=2)=[CH:22][C:23]2[N:27]=[C:26]([O:28][C:29]3[CH:30]=[CH:31][C:32]([CH3:38])=[C:33]([CH:37]=3)[C:34]([OH:36])=[O:35])[NH:25][C:24]=2[CH:47]=1
Reactant: Cc1ccc(Oc2nc3cc(-c4ccc(N5CCCC5)cc4)c(Cl)cc3n2COCC[Si](C)(C)C)cc1C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc(Oc2nc3cc(-c4ccc(N5CCCC5)cc4)c(Cl)cc3[nH]2)cc1C(=O)O
Temperature: 80 °C

Procedure:
TBAF (1M in THF) (0.5 mL, 0.5 mmol) was added to a solution of 5-[(6-chloro-5-(4-pyrrolidin-1-ylphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]-2-methylbenzoic acid in dioxane (3 mL). The reaction was heated at 80° C. for 16 h. The mixture was diluted with EtOAc (10 mL) and washed with 2N HCl, followed by water and concentrated. Purification by reverse phase HPLC eluting with 10-90% MeCN:water) afforded the title compound as an off-white solid. LC-MS: calculated for C25H22ClN3O3 447.13, observed m/e 448.04 (M+H)+ (Rt 1.80 min). 1H NMR (500 MHz, CD3OD): δ 1H NMR (500 MHz, CD3OD): δ 7.87 (s, 1H) 7.48 (s, 1H) 7.42 (m, 2H) 7.28 (s, 1H) 7.22 (m, 2H) 6.75 (m, 2H) 3.84 (s, 3H) 3.31 (m, 2H) 2.61 (s, 3H) 2.03 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[OH:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:30]1[CH2:31][CH2:32][N:27]([OH:26])[CH2:28][CH2:29]1)=[O:5])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: ON1CCNCC1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N2CCN(O)CC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, 4-hydroxypiperazine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.80 minutes; C21H21Cl2N5O3 (462.34); mass spectrum: (M−H)−=461/463/465 (chlorine isotope).
Reaction SMILES: [OH:1][CH:2]([CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([CH2:39][OH:40])[CH:33]=1)[CH2:3][NH:4][CH:5]([CH3:29])[CH2:6][C:7]1[CH:28]=[CH:27][C:10]([CH2:11][P:12]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:18])[O:13]CCCC)=[CH:9][CH:8]=1.Cl>>[OH:1][CH:2]([CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([CH2:39][OH:40])[CH:33]=1)[CH2:3][NH:4][CH:5]([CH3:29])[CH2:6][C:7]1[CH:28]=[CH:27][C:10]([CH2:11][P:12]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:13])[OH:18])=[CH:9][CH:8]=1
Reactant: CCCCOP(=O)(COc1ccccc1)Cc1ccc(CC(C)NCC(O)COc2ccc(O)c(CO)c2)cc1
Agent: Cl
Product: CC(Cc1ccc(CP(=O)(O)COc2ccccc2)cc1)NCC(O)COc1ccc(O)c(CO)c1

Procedure:
The title compound was prepared from (SR)-4-{2-[2-hydroxy-3-(4-hydroxy-3-hydroxymethyl-phenoxy)propylamino]propyl}phenoxymethylbenzylphosphinic acid, n-butyl ester according to the method described in Example 5 followed by acidification to pH 3.5 with 1M hydrochloric acid, as a solid (mp 180°-183° C.) following chromatography on C18 reverse phase silica-gel, eluting with 40% methanol in water.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[CH3:21][CH:22]([OH:24])[CH3:23].[H-].[Na+]>O>[CH:22]([O:24][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1)([CH3:23])[CH3:21]
Reactant: CC(C)O
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)Oc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole and 3 ml of 2-propanol, 52 mg of 60% sodium hydride (in oil) was added while ice-cooling. The mixture was stirred for 1.5 hours and then heated to room temperature and stirred for 1.5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.12 g of 2-(3-isopropoxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 70”).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[H-].[Na+].[CH:14]1(Br)[CH2:18][CH2:17][CH2:16][CH2:15]1>CN(C)C=O>[CH:14]1([O:9][C:8]2[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=2[O:6][CH3:7])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: BrC1CCCC1
Reactant: COc1cc(C=O)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OC1CCCC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of vanillin (50 g) in N,N-dimethylformamide (600 ml) are added 62.5% sodium hydride (13.9 g) and cyclopentyl bromide (38.8 ml) under ice-cooling, and the mixture is stirred at 90° C. overnight. The mixture is concentrated under reduced pressure to remove the N,N-dimethylformamide, and to the residue is added water. The mixture is extracted with ethyl acetate, and the extract is washed, dried, and concentrated under reduced pressure to remove the solvent. The resulting residue is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=3:1) to give 4-cyclopentyloxy-3-methoxybenzaldehyde (65 g).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[C:5]1([NH:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O.Cl>[N:1]([N:11]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3]
Reactant: O=N[O-]
Reactant: CCOC(=O)CNc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CN(N=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of NaNO2 (9.5 g, 0.14 mol) in H2O (27 ml) is added to an ice-cold stirred solution of ethyl phenylamino-acetate (25 g, 0.14 mol) in conc. HCl (20 ml) and H2O (27 ml) within 2 h. The reaction mixture is kept stirring for 1 h and then extracted twice with CH2Cl2. The combined organic layers are washed with H2O and brine, dried over Na2SO4 and filtered. The solvent is evaporated and the crude subtitle compound thus obtained as orange oil is used without further purification. tR (LC-4) 1.02 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([I:11])=[CH:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19]Cl>CN(C)C=O.O1CCCC1.[Cl-].[Na+]>[Cl:1][C:2]1[C:7]2[C:8]([I:11])=[CH:9][N:10]([CH2:19][O:18][CH2:17][CH2:16][Si:15]([CH3:22])([CH3:21])[CH3:14])[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1nccc2[nH]cc(I)c12
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)nccc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a 0° C. solution of C6 (900 mg, 3.2 mmol) in N,N-dimethylformamide (3 mL) and tetrahydrofuran (70 mL) was added sodium hydride (60% in mineral oil, 168 mg, 4.2 mmol). After 5 minutes, 2-(trimethylsilyl)ethoxymethyl chloride (592 mg, 3.55 mmol) was added to the cold mixture. The reaction mixture was stirred at room temperature for 3 hours, then cooled to 0° C. and treated with additional sodium hydride (56 mg, 1.4 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (197 mg, 1.18 mmol). After stirring at room temperature for 18 hours, the reaction mixture was diluted with saturated aqueous sodium chloride solution (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were dried, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 30% ethyl acetate in petroleum ether) provided the product as a yellow oil. Yield: 650 mg, 1.59 mmol, 50%. 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J=6.0 Hz, 1H), 7.39 (d, J=6.0 Hz, 1H), 7.38 (s, 1H), 5.44 (s, 2H), 3.44-3.50 (m, 2H), 0.86-0.92 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:23]=[C:22]([C:24]([O:26]C)=[O:25])[O:21][N:20]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+]>CO>[C:1]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[O:21][N:20]=2)[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)c1cc(OCCCCC2CCN(C(=O)OC(C)(C)C)CC2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CCCCOc2cc(C(=O)O)on2)CC1
Yield: 98.3 %

Procedure:
A solution of 4-4 (2.7 g, 6.9 mmol), CH3OH (50 mL), and 1N NaOH (13.9 mL, 13.9 mmol) was stirred at ambient temperature for 1 h. The CH3OH was evaporated and the resulting aqueous portion acidified with 1M NaHSO4. The solution was extracted with EtOAc (3×) and then the extracts were combined, dried (MgSO4), and concentrated to give 4-5 (2.5 g) as a solid.
Reaction SMILES: C(O[C:4](=[O:16])[C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[CH2:14]Br)C.[CH3:17][O:18][C:19](=[O:29])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1.NC1C=CC=CC=1>>[CH3:17][O:18][C:19](=[O:29])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:14][C:6]3[C:5](=[CH:10][C:9]([N+:11]([O-:13])=[O:12])=[CH:8][CH:7]=3)[C:4]2=[O:16])=[CH:24][CH:23]=1
Reactant: COC(=O)COc1ccc(N)cc1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1CBr
Solvent: Nc1ccccc1
Product: COC(=O)COc1ccc(N2Cc3ccc([N+](=O)[O-])cc3C2=O)cc1

Procedure:
By using 2-bromomethyl-5-nitrobenzoic acid ethyl ester and (4-amino-phenoxy)-acetic acid methyl ester instead of 2-bromomethyl-6-nitro-benzoic acid methyl ester and aniline used in Example 25, synthesis was performed in the same manner as that of Example 25 to obtain [4-(6-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-phenoxy]-acetic acid methyl ester (Compound 25) as a yellow green powdery substance.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].F[C:9](F)(F)[C:10](O)=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][C@H:40]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]1.C(Cl)(=O)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:10]([N:42]1[CH2:43][CH2:44][CH2:45][C@H:40]([CH2:39][C:38]([NH:37][C:29]2[CH:30]=[CH:31][C:32]3[NH:33][C:34]4[N:35]=[C:19]([NH:20][C:21]5[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=5)[CH2:26][CH2:27][C:28]=2[CH:36]=3)[N:18]=[CH:17][C:16]=4[Cl:15])=[O:46])[CH2:41]1)(=[O:11])[CH3:9]
Reactant: O=C(C[C@H]1CCCNC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: CC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCC[C@H](CC(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)C1
Yield: 78 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3R)-piperidin-3-yl]acetamide bis(trifluoroacetate) and acetyl chloride as the starting materials in 78% yield. LCMS for C27H30ClN6O2 (M+H)+: m/z=505.0.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.[OH:23][C:24]([C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([S:36]([F:41])([F:40])([F:39])([F:38])[F:37])[CH:35]=1)[C:30](O)=[O:31])([CH3:26])[CH3:25]>>[OH:23][C:24]([C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([S:36]([F:41])([F:37])([F:38])([F:39])[F:40])[CH:35]=1)[C:30]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[CH:4]=1)=[O:31])([CH3:25])[CH3:26]
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Reactant: CC(C)(O)c1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Product: Cc1ccc(NC(=O)c2cc(C(C)(C)O)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12

Procedure:
50 mg (0.17 mmol) of the compound of Example 6A and 52.9 mg (0.17 mmol) of the compound of Example 19A were reacted and worked up analogously to the procedure of Example 19. This gave 49 mg (49% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH:16]=[CH:15][CH:14]=[CH:13]2)[C:9]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:8][C:3]=1[C:4](OC)=[O:5].[NH2:21][C:22]([NH2:24])=[NH:23]>>[NH2:23][C:22]([NH2:24])=[N:21][C:4](=[O:5])[C:3]1[CH:8]=[C:9]([S:17]([CH3:20])(=[O:19])=[O:18])[C:10]([N:12]2[CH:16]=[CH:15][CH:14]=[CH:13]2)=[CH:11][C:2]=1[CH3:1]
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(-n2cccc2)cc1C
Reactant: N=C(N)N
Product: Cc1cc(-n2cccc2)c(S(C)(=O)=O)cc1C(=O)N=C(N)N

Procedure:
in stage g) by reaction of methyl 2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzoate with guanidine to give the end-product N-diaminomethylene-2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzamide, the guanidino group is introduced.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][S:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:2]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[N:28]=[C:29]([NH2:32])[S:30][CH:31]=1>>[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[N:28]=[C:29]([NH:32][C:15](=[O:17])[C:14]2[CH:13]=[CH:12][C:11]([S:8](=[O:9])(=[O:10])[NH:7][C:3]3[CH:2]=[C:1]([CH3:20])[CH:6]=[CH:5][CH:4]=3)=[CH:19][CH:18]=2)[S:30][CH:31]=1
Reactant: Nc1nc(-c2ccccn2)cs1
Reactant: Cc1cccc(NS(=O)(=O)c2ccc(C(=O)O)cc2)c1
Product: Cc1cccc(NS(=O)(=O)c2ccc(C(=O)Nc3nc(-c4ccccn4)cs3)cc2)c1

Procedure:
4-(N-m-tolylsulfamoyl)benzoic acid (14) (99 mg, 0.34 mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (50 mg, 0.28 mmol) using method C. The residue was purified using flash chromatography eluting with 75-100% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give N-(4-(pyridin-2-yl)thiazol-2-yl)-4-(N-m-tolylsulfamoyl)benzamide as an off white solid. Yield: 24 mg (19%). 1H-NMR: 8.64-8.62 (m, 1H), 8.28 (d, J=8.5 Hz, 2H), 8.02 (d, J=8.0 Hz, 1H), 7.95-7.89 (m, 2H), 7.69 (d, J=8.5 Hz, 2H), 7.36 (ddd, J=7.5, 5.0, 1.0 Hz, 1H), 7.24 (t, J=8.0 Hz, 1H), 7.13 (d, J=7.5 Hz, 1H), 6.98-6.96 (m, 1H), 6.88 (d, J=8.0 Hz, 1H), 3.18 (s, 3H).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][CH:18]([CH3:22])[CH2:19][CH2:20][NH2:21]>>[CH3:17][CH:18]([CH3:22])[CH2:19][CH2:20][NH:21][C:8](=[O:9])[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)CCN
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: CC(C)CCNC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 128° C. and MS: m/e=281 (M+) was prepared in accordance with the general method of example 1 from diphenylacetyl chloride and 3-methyl-butylamine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C@H:10]([CH2:25]O)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:35][S:36](Cl)(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:27])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C@H:10]([CH2:25][S:36][CH3:35])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CO)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
(1R,3R,4S)-(4-Benzyloxycarbonylamino-3-hydroxymethylcyclohexyl)carbamic acid tert-butyl ester (1.0 g) was dissolved in CH2Cl2 (120 ml) and cooled to 0° C. prior to the addition of Et3N (0.5 mL) and methanesulfonyl chloride (0.55 mL). This mixture was warmed to RT and was stirred for 3 h. The CH2Cl2 was removed and EtOAc was added along with water. The organic layer was dried, filtered, and concentrated. This solid was dissolved in DMF (15 mL) and HMPA (2 mL) prior to the addition of NaSMe (1.1 g) and 18-crown-6 (500 mg). After 18 h, additional HMPA (0.5 mL) was added. After another 3 h, water was added and the solution was extracted with EtOAc. The organic layer was dried, filtered, and concentrated. Flash chromatography of the resulting residue gave (1R,3R,4S)-(4-benzyloxycarbonylamino-3-(methyl)thiomethylcyclohexyl)carbamic acid tert-butyl ester (1.1 g). MS found: (M+H)+=409.2.
Reaction SMILES: F[C:2]1[CH:10]=[N:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=[O:5].[F:12][C:13]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:14]=1[NH2:15].C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>C1COCC1>[F:11][C:7]1[CH:8]=[N:9][CH:10]=[C:2]([NH:15][C:14]2[CH:16]=[CH:17][C:18]([I:20])=[CH:19][C:13]=2[F:12])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1c(F)cncc1F
Reactant: Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1c(F)cncc1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
25 g 3,5-difluoroisonicotinic acid (157.141 mmol, 1 eq.) and 37,245 g 2-fluoro-4-iodoaniline (157.141 mmol. 1 eq.) were dissolved in 1275.5 mL of dry THF and put under a nitrogen atmosphere. The mixture was cooled with an ice bath to +3° C., upon which 471.422 mL lithium hexamethyldisilazide (LiHMDS) solution (1M in THF; 471.422 mmol, 3. eq.) were added slowly. Upon completion of addition of the base, the reaction mixtures was allowed to warm to rt and stirring was continued for 18 h. The reaction mixture was concentrated in Vacuo and then partitioned between aq. sodium hydroxide solution (2N, 800 ml) and dichloromethane. The separated organic phase was washed twice with sodium hydroxide solution (2N, 300 ml each). The combined aqueouse layers were cooled to 0° C. and treated with HCl (conc., 222 ml) until ph=2 was reached. The resulting yellow suspension was stirred for 18 h at room temperature and then the precipitate was filtered off to yield 5.15 g (13.01 mmol, 8%) of the analytically pure target compound as a tanish solid. The organic filtrate formed a suspension as well. This precipitate was filtered off as well and rinsed twice with dichloromethane. The precipitate was suspended in water (400 ml), cooled to 0° C. and treated with HCl (conc., 20 ml) until ph=1 was reached. The resulting yellow suspension was stirred for 18 h at room temperature and then the precipitate was filtered off to yield 28.27 g (71.41 mmol, 45%) of the analytically pure target compound as a yellowish solid.
Reaction SMILES: CC(C)=O.[OH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[NH:13][C:14]([CH2:16][O:17][N:18]=[C:19]([C:43]1[N:44]=[C:45]([NH:48]C=O)[S:46][CH:47]=1)[C:20]([NH:22][CH:23]1[C:41](=[O:42])[N:25]2[C:26]([C:38]([OH:40])=[O:39])=[C:27]([CH2:30][S:31][C:32]3[N:36]([CH3:37])[N:35]=[N:34][N:33]=3)[CH2:28][S:29][C@H:24]12)=[O:21])=[O:15].Cl>CO>[OH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[NH:13][C:14]([CH2:16][O:17][N:18]=[C:19]([C:43]1[N:44]=[C:45]([NH2:48])[S:46][CH:47]=1)[C:20]([NH:22][CH:23]1[C:41](=[O:42])[N:25]2[C:26]([C:38]([OH:40])=[O:39])=[C:27]([CH2:30][S:31][C:32]3[N:36]([CH3:37])[N:35]=[N:34][N:33]=3)[CH2:28][S:29][C@H:24]12)=[O:21])=[O:15]
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)Nc3cc(Cl)ccc3O)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: CC(C)=O
Solvent: CO
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)Nc3cc(Cl)ccc3O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
To a mixture of acetone (1 ml.), methanol (4 ml.) and 7-[2-{N-(2-hydroxy-5-chlorophenyl)carbamoylmethoxyimino}-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.55 g.) was added conc. hydrochloric acid (0.11 ml.) followed by stirring for 3 hours at room temperature. The reaction mixture was concentrated and then to the residue were added water (3 ml.) and an aqueous solution of sodium bicarbonate whereby the pH was adjusted to about 2. The resulting mixture was stirred at room temperature and the precipitates were collected by filtration, washed with water and then dried to give the title compound (0.40 g.), mp. 165° to 175° C. (dec.).
Reaction SMILES: [H-].[Na+].[CH2:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN(C)[CH:13]=[O:14]>>[CH2:3]([O:14][CH2:13][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ClCc1ccccc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
This residue (non-purified) was added to a solution of 3.8 g of sodium hydride in 150 ml of dimethylformamide. The mixture was stirred at 60° C. for 30 min and the reaction mixture was cooled to room temperature. 13.7 g of benzyl chloride was added dropwise thereto and the reaction was conducted at 60° C. again for 1 h. The reaction mixture was poured into ice/water. After extraction with ethyl acetate, the extract was dried over magnesium sulfate and concentrated under reduced pressure to obtain crude benzyl ether. After purification according to silica gel column chromatography (ethylacetate/hexane=3:97), 12.0 g of the intended compound was obtained in the form of a faint yellow oil.