Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C:9]3=2)[NH:4][CH:3]=1.[H-].[Na+].[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:26]=1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>CN(C=O)C>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[O:15][CH2:14][CH2:13][NH:12][CH2:11][C:9]3=2)[N:4]([S:31]([C:27]2[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=2)(=[O:33])=[O:32])[CH:3]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]cc(Cl)c3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1cccnc1)n1cc(Cl)c2c3c(ccc21)OCCNC3
Temperature: 50 °C

Procedure:
Pyridine-3-sulfonyl chloride hydrochloride (20 mg, 0.093 mmol) was dissolved in a mixture of dichloromethane and aqueous saturated NaHCO3 and the organic layer was dried (MgSO4) and evaporated to give pyridine-3-sulfonyl chloride. tert-Butyl 10-chloro-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 20, 10 mg, 0.031 mmol) was dissolved in DMF (1 mL) and sodium hydride (60% in mineral oil, 2.5 mg, 0.062 mmol) was added. The mixture was stirred for 10 minutes before pyridine-3-sulfonyl chloride (0.093 mmol) in DMF (1 mL) was added. The reaction mixture was stirred at room temperature for 10 minutes before TFA (2 mL) was added and the mixture was heated at 50° C. overnight. The reaction mixture was evaporated and the crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH3CN) to give the title compound as a white solid (2.6 mg) in the form of the trifluoroacetate salt. MS m/z 364 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[N+:25]([O-:27])=[O:26])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:20]([S:21](=[O:23])(=[O:24])[NH:22][C:28](=[O:30])[CH3:29])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[N+:25]([O-:27])=[O:26])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Nc2c([N+](=O)[O-])cc(C(=O)O)cc2S(N)(=O)=O)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(Nc2c([N+](=O)[O-])cc(C(=O)O)cc2S(=O)(=O)NC(C)=O)cc1

Procedure:
The starting material is prepared as follows: The mixture of 20 g of 4-(4-acetamidophenylamino)-3-nitro-5-sulfamoylbenzoic acid and 200 ml of acetic anhydride is refluxed for ten minutes while stirring under nitrogen. It is evaporated under reduced pressure, the residue triturated with water and dissolved in 200 ml of 2N aqueous sodium hydroxide. The solution is washed with diethyl ether, filtered and acidified with concentrated hydrochloric acid to pH of 1- and the precipitate filtered off, to yield the 4-(4-acetamidophenylamino)-3-nitro-5-acetylsulfamoylbenzoic acid melting at 175°-185°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][O:8][C:9](=[O:10])[C:2]=12.[Li+].CC([N-]C(C)C)C.CS([C:23]1[N:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[N:24]=1)(=O)=O.Cl>C1COCC1>[CH3:32][O:31][C:25]1[CH:26]=[C:27]([O:29][CH3:30])[N:28]=[C:23]([CH:7]2[C:3]3[C:2](=[N:1][CH:6]=[CH:5][CH:4]=3)[C:9](=[O:10])[O:8]2)[N:24]=1
Reactant: O=C1OCc2cccnc21
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(OC)nc(C2OC(=O)c3ncccc32)n1
Temperature: 25 °C

Procedure:
A solution of 1.3 g (0.0096 mols) of furo [3,4-b]pyridine-7(5H)-one in 50 ml of dry THF is cooled to -75° C. and 8 ml (0.0192 mols) of 2.5M LDA added dropwise over 5 minutes. The mixture is allowed to react for 1 hr at -750° C. and 2.1 g (0.0096 mol) of 2-methylsulfonyl-4,6-dimethoxypyrimidine in 30 ml of dry THF added dropwise over 10 minutes. The mixture is allowed to warm to RT, 1.6 ml of HCl added and the THF evaporated off. The residue is dissolved in 75 ml of CH2Cl2, washed with water (2×50 ml) and the organic phase concentrated to give a yellowish white gummy solid. This is chromatographed on a silica gel column using 50/50 hexane/ethyl acetate (500 ml), ethyl acetate (500 ml) and 80/20 acetone/methanol (1000 ml) (30 fractions). The crystalline residue (fractions 18-21) of the title product has m.p. of 167°-168° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:30][C:31]1[NH:32][C:33]2[C:38]([C:39]=1[CH3:40])=[CH:37][C:36]([OH:41])=[CH:35][CH:34]=2>CN(C=O)C>[CH3:30][C:31]1[NH:32][C:33]2[C:38]([C:39]=1[CH3:40])=[CH:37][C:36]([O:41][C:2]1[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=1)=[CH:35][CH:34]=2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN(C)S(C)(=O)=O
Reactant: Cc1[nH]c2ccc(O)cc2c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)c(C)c4c3)ncnc2cc1OCCCN(C)S(C)(=O)=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 41.5 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazoline (360 mg, 1.00 mmol), (prepared as described for the starting material in Example 152), potassium carbonate (215 mg, 1.56 mmol) and 2,3-dimethyl-5-hydroxyindole (177 mg, 1.10 mmol), (Arch. Pharm. 1972, 305, 159), in DMF (8.0 ml) was stirred at 100° C. for 5 hours and allowed to cool to ambient temperature. The solvent was removed by evaporation and the residue purified by silica column chromatography eluting with methanol (2.5%) in dichloromethane. The resulting solid was recrystallised from tertbutyl methyl ether/acetonitrile, filtered and washed with diethyl ether to give 4-(2,3-dimethylindol-5yloxy)-6-methoxy-7-(3-(N-methyl-N-methylsulphonylamino)propoxy)quinazoline (201 mg, 42%).
Reaction SMILES: [ClH:1].[O:2]([CH2:4][C:5]1[NH:6][CH:7]=[CH:8][N:9]=1)[NH2:3].[NH2:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=O)[C:17]([OH:19])=[O:18])[N:15]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O>[ClH:1].[NH2:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=[N:3][O:2][CH2:4][C:5]2[NH:6][CH:7]=[CH:8][N:9]=2)[C:17]([OH:19])=[O:18])[N:15]=1
Reactant: NOCc1ncc[nH]1
Reactant: Nc1nc(C(=O)C(=O)O)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Nc1nc(C(=NOCc2ncc[nH]2)C(=O)O)cs1
Reaction time: 12 h

Procedure:
2 g of 2-[(aminoxy)methyl]-1H-imidazolehydrochloride (1:2) from example 1(b) and 2.24 g 2-amino-thiazol-4-glyoxylic acid are suspended with stirring in 50 ml H2O. The pH is adjusted with potassium carbonate to 6 and stirring is continued for 12 hours. The pH is then adjusted to 6.4 with hydrochloric acid. After 2 hours 0.8 of crystalline 2-amino-α-[(1H-imidazol-2-yl-methoxy)imino]-4-thiazole acetic acid hydrochloride (1:2) is filtered off with a melting point of 158°-160° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([B:8]([OH:10])[OH:9])[CH:5]=[CH:6][CH:7]=1.COC(N1[C:19](=[O:20])[CH:18]=[CH:17][C:16]1=[O:21])=O.OS(O)(=O)=O>C([O-])(O)=O.[Na+].O>[C:16]1(=[O:21])[N:1]([C:2]2[CH:3]=[C:4]([B:8]([OH:10])[OH:9])[CH:5]=[CH:6][CH:7]=2)[C:19](=[O:20])[CH:18]=[CH:17]1
Reactant: Nc1cccc(B(O)O)c1
Reactant: COC(=O)N1C(=O)C=CC1=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C1C=CC(=O)N1c1cccc(B(O)O)c1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 64.1 %

Procedure:
(3-Aminophenyl)boronic acid (1.26 grams, 0.01 mole) is dissolved in saturated NaHCO3 (50 ml) by briefly heating the mixture on a hot plate. The solution is cooled in an ice bath to approximately 0° C., and N-methoxycarbonylmaleimide (1.55 grams, 0.01 mole) added with vigorous stirring. After 10 min. the solution is diluted with water (200 ml) and then stirred at room temperature for 30 to 40 min. The pH is adjusted to approximately 5.5 by addition of 1M H2SO4, and the precipitate collected by filtration. The precipitate is washed with 1M H2SO4 (2×50 ml), and then dried overnight in vacuo over NaOH pellets to afford 1.39 grams (64% yield) of (3-maleimidophenyl)boronic acid. The structure was confirmed by 300 MHz, 1H NMR spectrometry in d6 -DMSO.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([C:7](O)=[O:8])[N:6]=1.CN(C=O)C.C(Cl)(=O)C([Cl:24])=O>C(Cl)Cl>[CH3:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([C:7]([Cl:24])=[O:8])[N:6]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)s1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc(C(=O)Cl)c(-c2ccccc2)s1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a suspension of 2-methyl-5-phenyl-1,3-thiazole-4-carboxylic acid (1.47 g, 6.70 mmol) in CH2Cl2 (30 mL) cooled at 0° C. was added DMF (26 μL, 0.34 mmol) and oxalyl chloride (0.73 mL, 8.38 mmol). The reaction was allowed to warm to ambient temperature and stirred for 4 h. The solution was concentrated in vacuo to provide 2-methyl-5-phenyl-1,3-thiazole-4-carbonyl chloride as a yellow-orange oil which gave a mass ion (ES+) of 236.3. 1H NMR δ (ppm) (CDCl3): 7.42-7.46 (5H, m), 2.78 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)=[CH:4][CH:3]=1.[CH2:14]1[CH2:20][S:17](=[O:19])(=[O:18])[O:16][CH2:15]1>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([CH2:15][CH2:14][CH2:20][S:17]([OH:19])(=[O:18])=[O:16])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCCO1
Reactant: Fc1ccc(C2=CCNCC2)cc1
Solvent: CC(C)=O
Product: O=S(=O)(O)CCCN1CC=C(c2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
To a solution of 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine (1.96 g, 13.7 mmol) in acetone (30 mL) was added 1,3-propane sultone (1.74 g, 14.5 mmol). The mixture was stirred at reflux overnight. Only a small amount of compound precipitated. The resulting suspension was cooled to room temperature with stiffing and a larger amount of solid precipitated. The suspension was heated with the addition of a small amount of MeOH until complete dissolution of the solid. The resulting solution was stirred at reflux for a few minutes and was cooled to room temperature with stiffing. The solid was collected by filtration, washed with MeOH and dried in vacuo. This allowed the isolation of compound F, 1.33 g (32%).
Reaction SMILES: O1CCOCC1.[Cl:7][C:8]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:16]([Cl:24])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:25]([C:27]3[O:31][N:30]=[C:29]([CH3:32])[CH:28]=3)[OH:26])[CH:14]=2)[N:9]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:7][C:8]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:16]([Cl:24])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:25]([C:27]3[O:31][N:30]=[C:29]([CH3:32])[CH:28]=3)=[O:26])[CH:14]=2)[N:9]=1
Reactant: Cc1cc(C(O)c2ccc3nc(Cl)c(-c4ccccc4)c(Cl)c3c2)on1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(C(=O)c2ccc3nc(Cl)c(-c4ccccc4)c(Cl)c3c2)on1
Temperature: 100 °C

Procedure:
1,4-dioxane (7.5 mL) and manganese (IV) dioxide (447 mg, 5.14 mmol) were added to crude (2,4-dichloro-3-phenylquinolin-6-yl)(3-methylisoxazol-5-yl)methanol (Intermediate 3: step a, 1.03 mmol assuming theoretical yield in prior step). The resulting black suspension was heated in a 100° C. oil bath in a sealed tube for 3 hours then cooled to room temperature. The mixture was then diluted with DCM, and filtered through Celite®. The filtrate was concentrated and the residue was purified by flash column chromatography (silica gel, 3-15% EtOAc-heptane) to afford slightly impure title compound which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH:29]1([CH2:32][C:33]2[NH:34][C:35]3[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=3[N:37]=2)[CH2:31][CH2:30]1>>[CH:29]1([CH2:32][C:33]2[N:34]([C:2]3[N:10]=[C:9]4[C:5]([N:6]=[C:7]([CH2:12][N:13]5[CH2:14][CH2:15][CH:16]([C:19]([OH:22])([CH3:20])[CH3:21])[CH2:17][CH2:18]5)[N:8]4[CH3:11])=[C:4]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)[N:3]=3)[C:35]3[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=3[N:37]=2)[CH2:30][CH2:31]1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: c1ccc2[nH]c(CC3CC3)nc2c1
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(CC4CC4)nc4ccccc43)nc21

Procedure:
Following General Procedure I for Buchwald coupling, 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and 2-(cyclopropylmethyl)-benzimidazole were reacted to give 308. LCMS m/z: 545.3 (MH+)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([O:14]CC)=[O:13])=[CH:7]2.[OH-].[Na+]>O1CCOCC1>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([OH:14])=[O:13])=[CH:7]2
Reactant: CCOC(=O)c1ccc2c(N)cccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1cccc2cc(C(=O)O)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.8 %

Procedure:
A mixture of ethyl 5-amino-2-naphthoate (7.0 g, 0.0325 mol), dioxane (40 ml), and 1 N NaOH (39 mL) was stirred at room temperature for 16 hours. The dioxane was removed under reduced pressure, H2O (50 mL) was added, and the mixture was neutralized with acetic acid (2.23 mL). The resulting brown solid precipitate was collected by filtration to give the desired product (5.4 g, 89%), m.p. 231°-234° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([CH2:11][CH3:12])([CH3:10])[CH2:8][CH3:9])=[N:5][N:6]=1.[CH2:13]([C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH3:25])[C:16]=1[C:17](Cl)=[O:18])[CH3:14]>C1(C)C=CC=CC=1>[CH2:8]([C:7]([C:4]1[S:3][C:2]([NH:1][C:17](=[O:18])[C:16]2[C:20]([CH2:24][CH3:25])=[CH:21][CH:22]=[CH:23][C:15]=2[CH2:13][CH3:14])=[N:6][N:5]=1)([CH3:10])[CH2:11][CH3:12])[CH3:9]
Reactant: CCC(C)(CC)c1nnc(N)s1
Reactant: CCc1cccc(CC)c1C(=O)Cl
Solvent: Cc1ccccc1
Product: CCc1cccc(CC)c1C(=O)Nc1nnc(C(C)(CC)CC)s1
Yield: 36.2 %

Procedure:
A solution of 1.85 g of 2-amino-5-(1- ethyl-1-methylproyl)-1,3,4-thiadiazole and 2.21 g of 2,6-diethylbenzoyl chloride in 50 ml of toluene was heated at reflux for sixteen hours and then cooled and the solvent was removed by evaporation under reduced pressure to provide a solid residue. The solid was crystallized from 2B ethanol to give 1.25 g of N-[5-(1-ethyl-1-methylpropyl)-1,3,4-thiadiazol-2-yl]-2,6-diethylbenzamide.
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]=[C:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12]3[N:20]=[CH:21][CH:22]=[CH:23][C:11]=3[N:10]2[CH:24]=1.[Br:26]N1C(=O)CCC1=O>C1COCC1>[Br:26][C:24]1[N:10]2[C:11]3[CH:23]=[CH:22][CH:21]=[N:20][C:12]=3[NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:9]2=[N:8][C:7]=1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:25]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1-c1cn2c(n1)-c1ccccc1Nc1ncccc1-2
Solvent: C1CCOC1
Product: Cc1ccccc1-c1nc2n(c1Br)-c1cccnc1Nc1ccccc1-2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.4 %

Procedure:
To a solution of 2-(o-tolyl)-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine (0.2 g, 1 eq.) in THF (5 mL) was added N-bromosuccinimide (0.11 g, 1 eq.). The reaction was stirred at room temperature for 15 minutes, poured onto water (30 mL) and extracted with ethyl acetate (2×30 mL). The organic extracts were combined, washed with saturated sodium bicarbonate (1×50 mL), water (1×50 mL), brine (1×50 mL) and dried over sodium sulfate. After filtration and concentration under reduced pressure, the crude product was purified by column chromatography (20% ethyl acetate in hexanes). The 3-bromo-2-(o-tolyl)-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine (0.19 g, 77%) was obtained as an off-white solid. M.p.: 220-222° C.; 1H NMR (DMSO-d6) 400 MHz δ 8.64 (s, 1H), 8.27 (dd, JA=3.6 Hz, JB=1.6 Hz, 1H), 8.03 (dd, JA=7.2 Hz, JB=1.6 Hz, 1H), 7.78 (dd, JA=7.6 Hz, JB=1.2 Hz, 1H), 7.44 (d, J=6.8 Hz, 1H), 7.38-7.23 (m, 6H), 7.09 (t, J=7.6 Hz, 1H), 2.37 (s, 3H); LCMS: 403 [M+H].
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:52])[C:19]([C:27]3[N:28]=[C:29]([NH:32]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:30][CH:31]=3)=[N:20][O:21][CH2:22][CH2:23][N:24]=[N+:25]=[N-:26])[C:15](=[O:53])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].C(NCC)C>C(O)=O>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:52])[C:19]([C:27]3[N:28]=[C:29]([NH2:32])[S:30][CH:31]=3)=[N:20][O:21][CH2:22][CH2:23][N:24]=[N+:25]=[N-:26])[C:15](=[O:53])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCN=[N+]=[N-])c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Solvent: O=CO
Solvent: CCNCC
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCN=[N+]=[N-])c3csc(N)n3)[C@H]2SC1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
A mixture of 1.238 g of the product of Step C and 6 ml of 70% aqueous formic acid was stirred at 50° C. for 15 minutes and was the vacuum filtered to remove triphenylcarbinol. The filtrate was evaporated to dryness under reduced pressure and the residue was taken up in water with efflorescence. The mixture was vacuum filtered and the recovered product was dried to obtain 0.358 g of the syn isomer of 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-(2-azidoethoxyimino)-acetamido]-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=2)[C:9]2[C:14]([CH3:15])=[CH:13][C:12]([C:16]3[CH:32]=[C:31]([CH3:33])[C:19]([N:20]([C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=4)[C:21](=O)[CH3:22])=[C:18]([CH3:34])[CH:17]=3)=[CH:11][C:10]=2[CH3:35])=[CH:4][CH:3]=1.I[C:44]1[C:57]2[C:58]3=[C:59]4[C:54](=[CH:55][CH:56]=2)C=C[CH:51]=[C:50]4[CH:49]=[CH:48][C:47]3=[CH:46][CH:45]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=2)[C:9]2[C:14]([CH3:15])=[CH:13][C:12]([C:16]3[CH:32]=[C:31]([CH3:33])[C:19]([N:20]([C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=4)[C:21]4[C:54]5[C:59]6=[C:58]7[C:57](=[CH:56][CH:55]=5)[CH:44]=[CH:45][CH:46]=[C:47]7[CH:48]=[CH:49][C:50]6=[CH:51][CH:22]=4)=[C:18]([CH3:34])[CH:17]=3)=[CH:11][C:10]=2[CH3:35])=[CH:4][CH:3]=1
Reactant: Ic1ccc2ccc3cccc4ccc1c2c34
Reactant: CC(=O)N(c1ccc(C)cc1)c1c(C)cc(-c2cc(C)c(N(c3ccc(C)cc3)c3ccc(C)cc3)c(C)c2)cc1C
Product: Cc1ccc(N(c2ccc(C)cc2)c2c(C)cc(-c3cc(C)c(N(c4ccc(C)cc4)c4ccc5ccc6cccc7ccc4c5c67)c(C)c3)cc2C)cc1

Procedure:
The thus obtained N,N,N'-tris(4-methylphenyl)-N'-acetyl-3,3',5,5'-tetramethylbenzidine was hydrolyzed, and the hydrolyzed product and 1-iodo-pyrene were subjected to the same Ullmann reaction as in Preparation Example 1-6, whereby N,N,N'-tris(4-methylphenyl)-N'-(1-pyrenyl)-3,3',5,5'-tetramethylbenzidine (m.p. 198.0°-199.0° C.) was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22](=[O:31])(=[O:30])[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:17]=1.[OH-].[Na+]>CO.O1CCCC1>[CH3:1][C:2]1([CH3:32])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22](=[O:31])(=[O:30])[NH:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:17]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)Nc3ccccc3)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(S(=O)(=O)Nc2ccccc2)c1
Yield: 31.6 %

Procedure:
To a stirred solution of methyl 3,3-dimethyl-2-(3-(N-phenylsulfamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (130 mg, 0.29 mmol) in methanol/tetrahydrofuran (5 mL/5 mL) was added 1N sodium hydroxide (4.33 mL). The resultant mixture was heated to reflux for 2.5 h. Organic solvent was removed and the residue was dissolved in water. The aqueous layer was acidified to pH=4. The precipitates were filtered, and dissolved in tetrahydrofuran, dried over anhydrous magnesium sulfate. anhydrous magnesium sulfate was removed, and after evaporation, the residue was purified on preparative Thin layer chromatography to afford 80 mg of crude product, which was recrystallized from dichloromethane and ether to afford 40 mg of 3,3-dimethyl-2-(3-(N-phenylsulfamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid. (Yield: 32%). MS (ESI+APCI) M+1=437.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:43])([CH2:37][N:38]1[CH:42]=[N:41][CH:40]=[N:39]1)[C@H:10]([N:12]1[C:16](=[O:17])[N:15]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27](CC4C=CC=CC=4)[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH:14]=[N:13]1)[CH3:11].[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:43])([CH2:37][N:38]1[CH:42]=[N:41][CH:40]=[N:39]1)[C@H:10]([N:12]1[C:16](=[O:17])[N:15]([C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:22][CH:23]=2)[CH:14]=[N:13]1)[CH3:11]
Reactant: C[C@@H](n1ncn(-c2ccc(N3CCN(Cc4ccccc4)CC3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: C[C@@H](n1ncn(-c2ccc(N3CCNCC3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 100.1 %

Procedure:
To a solution of 170 mg of compound 21 in 20 ml of ethanol was added 20 mg of 10% Pd-C and the mixture was stirred at room temperature in a hydrogen stream for 9 hours. The catalyst was filtered off and washed with 5 ml of ethanol. The filtrate and the washing were combined and concentrated under reduced pressure to give 144 mg of 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(1-piperazinyl)phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 22) as a pale yellow oil.
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([C:11]1[CH:12]=[CH:13][C:14]([C:17]#[C:18][C:19]2[CH:33]=[CH:32][C:22]([CH2:23][N:24]3[CH2:27][CH:26]([C:28]([O:30]C)=[O:29])[CH2:25]3)=[CH:21][C:20]=2[F:34])=[N:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1COCC1.O>[CH2:4]([C:11]1[CH:12]=[CH:13][C:14]([C:17]#[C:18][C:19]2[CH:33]=[CH:32][C:22]([CH2:23][N:24]3[CH2:27][CH:26]([C:28]([OH:30])=[O:29])[CH2:25]3)=[CH:21][C:20]=2[F:34])=[N:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)C1CN(Cc2ccc(C#Cc3ccc(Cc4ccccc4)cn3)c(F)c2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CN(Cc2ccc(C#Cc3ccc(Cc4ccccc4)cn3)c(F)c2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of lithium hydroxide hydrate (28.4 mg, 677 μmol) and methyl 1-(4-(2-(5-benzylpyridin-2-yl)ethynyl)-3-fluorobenzyl)azetidine-3-carboxylate (77.9 mg, 188 μmol) in THF (2.7 mL) and water (0.69 mL) was stirred at 25° C. for 3 h. The reaction mixture was then partially concentrated in vacuo (to remove THF), water (1.5 mL) was added, and the resulting solution was sonicated for 1 min. The reaction solution was subsequently acidified with 1.0N HCl (670 μL), brought to pH 6 with 1M Na2HPO4/NaH2PO4 phosphate buffer (1.0 mL), and sonicated. The resulting precipitate was collected by vacuum filtration, washed with water (3.0 mL), and dried in vacuo to provide 1-(4-(2-(5-benzylpyridin-2-yl)ethynyl)-3-fluorobenzyl)azetidine-3-carboxylic acid as a light yellow solid. MS (ESI) m/z: Calculated: 400.2; Observed: 401.1 (M++1).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([N:17]([CH2:21][CH3:22])[CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:23][C:24]1[C:33]([O:34][CH3:35])=[CH:32][C:27]2[NH:28][C:29](=[O:31])[S:30][C:26]=2[CH:25]=1>>[CH2:21]([N:17]([CH:18]([CH3:20])[CH3:19])[C:15]([CH:13]1[CH2:12][CH2:11][C:10]2[C:3]3[C:2]([NH:23][C:24]4[C:33]([O:34][CH3:35])=[CH:32][C:27]5[NH:28][C:29](=[O:31])[S:30][C:26]=5[CH:25]=4)=[N:7][CH:6]=[N:5][C:4]=3[S:8][C:9]=2[CH2:14]1)=[O:16])[CH3:22]
Reactant: COc1cc2[nH]c(=O)sc2cc1N
Reactant: CCN(C(=O)C1CCc2c(sc3ncnc(Cl)c23)C1)C(C)C
Product: CCN(C(=O)C1CCc2c(sc3ncnc(Nc4cc5sc(=O)[nH]c5cc4OC)c23)C1)C(C)C

Procedure:
40 mg (118 μmol) (RS)-4-chloro-N-ethyl-N-isopropyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxamide (prepared according to intermediate example 86a) were transformed in analogy to example 1 using 6-amino-5-methoxy-1,3-benzothiazol-2(3H)-one to give after working up and purification 10.9 mg (18%) of the title compound.