Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]([C:14](=O)C)[NH2:13].[OH-].[K+].[CH2:19]([OH:21])[CH3:20].C(=S)=[S:23]>>[C:19]([NH:13][N:12]1[C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[NH:1][C:14]1=[S:23])(=[O:21])[CH3:20]
Reactant: CC(=O)N(N)c1ccc(C(F)(F)F)cc1N
Reactant: S=C=S
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Product: CC(=O)Nn1c(=S)[nH]c2cc(C(F)(F)F)ccc21
Yield: 67 %

Procedure:
After adding 69.96 g of 2-amino-4-trifluoromethyl-N-acetylphenylhydrazine to a solution of 19.07 g of potassium hydroxide in 300 ml of abs. ethanol, 20.5 ml of carbon disulfide were dropped to the mixture under stirring. The red solution obtained was refluxed for 5 hours, the hot solution was clarified by activated carbon and filtered. After adding 370 ml of water and then 70 ml of a mixture of acetic acid and water (1:2) to the filtrate, the crystalline precipitate was filtered by suction, washed with water and dried at 80° C. Thus, 55.5 g (67%) of 1-acetylamino-5-trifluoromethylbenzimidazole-2-thione were obtained, m.p.: 294°-295° C. after recrystallization from 50% of aqueous ethanol.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:44]/[O:45]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)/[C:8]([NH:10][C@@H:11]2[C:42](=[O:43])[N:13]3[C:14]([C:26]([O:28]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:27])=[C:15]([S:18][CH2:19][C:20]4[CH:25]=[CH:24][N:23]=[CH:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.Cl.C(OCC)(=O)C.CC(C)=O>C(O)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:44]/[OH:45])/[C:8]([NH:10][C@@H:11]2[C:42](=[O:43])[N:13]3[C:14]([C:26]([OH:28])=[O:27])=[C:15]([S:18][CH2:19][C:20]4[CH:25]=[CH:24][N:23]=[CH:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(SCc4ccncn4)CS[C@H]23)cs1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O=CO
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(SCc4ccncn4)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.9 %

Procedure:
To a solution of diphenylmethyl 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(trityloxyimino)acetamido]-3-[(pyrimidin-4-yl)methylthio]-3-cephem-4-carboxylate (1.57 g, 1.74 m mol) in formic acid (6.28 ml) was added conc. HCl (0.435 ml, 5.22 m mol) at 5° C. The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into a mixture of ethyl acetate (43 ml) and acetone (22 ml). The precipitates were collected by filtration, and dried in vacuo. The crude product was desalted with HP-20. The eluent was concentrated to give precipitates. The precipitates were collected by filtration and dried in vacuo to give 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(hydroxyimino)acetamido]-3-[(pyrimidin-4-yl)methylthio]-3-cephem-4-carboxylic acid (128 mg, 0.259 m mol).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](O)=[O:5].[CH2:9]([C:12]1[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][C:13]=1[OH:14])[CH2:10][CH3:11]>OS(C(F)(F)F)(=O)=O>[OH:14][C:13]1[CH:15]=[CH:16][C:17]([C:4](=[O:5])[CH2:3][C:2]([CH3:8])([CH3:7])[CH3:1])=[C:18]([OH:19])[C:12]=1[CH2:9][CH2:10][CH3:11]
Reactant: CC(C)(C)CC(=O)O
Reactant: CCCc1c(O)cccc1O
Agent: O=S(=O)(O)C(F)(F)F
Product: CCCc1c(O)ccc(C(=O)CC(C)(C)C)c1O

Procedure:
Using the procedure in Example 51, step 1, 3,3-dimethylbutyric acid and 2-(n-propyl)resorcinol were condensed in triflic acid to form 1,3-dihydroxy-4-(3,3-dimethylbutyryl)-2-(n-propyl)benzene
Reaction SMILES: O.[OH-].[Li+].O.[CH3:5][N:6]1[C:11](=[O:12])[C:10]2[C:13]([CH:27]=[CH:28][C:29]([O:31]C)=[O:30])=[C:14]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]([F:26])([F:25])[F:24])[S:15][C:9]=2[N:8]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:7]1=[O:37]>O1CCCC1>[CH3:5][N:6]1[C:11](=[O:12])[C:10]2[C:13]([CH:27]=[CH:28][C:29]([OH:31])=[O:30])=[C:14]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]([F:26])([F:24])[F:25])[S:15][C:9]=2[N:8]([CH2:33][CH:34]([CH3:35])[CH3:36])[C:7]1=[O:37]
Reactant: COC(=O)C=Cc1c(Cc2ccccc2C(F)(F)F)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C=CC(=O)O)c(Cc3ccccc3C(F)(F)F)sc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 51.5 %

Procedure:
Lithium hydroxide monohydrate (0.20 g) and water (6 ml) were added to a solution of 3-[1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxo-6-[[2-(trifluoromethyl)phenyl]methyl]-thieno[2,3-d]pyrimidin-5-yl]-2-propenoic acid, methyl ester (0.20 g) in tetrahydrofuran (7 ml) and stirred at room temperature for 20 hours. The solution was neutralised to pH7 and extracted with dichloromethane. The organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash silica chromatography eluting with a gradient of 0-5% ethanol in dichloromethane to give the title compound as a white solid (0.10 g).
Reaction SMILES: Cl.[C:2]([CH:4]1[CH2:7][NH:6][CH2:5]1)#[N:3].N1CCCC1.[C:13]([NH:20][C@@H:21]([C:26]([OH:28])=O)[CH2:22][CH:23]([CH3:25])[CH3:24])([O:15]C(C)(C)C)=O.C(N[C@@H](C(O)=O)C(C)(C)C)(OC(C)(C)C)=O.[CH3:45][N:46]1[CH:50]=[C:49]([C:51]2[N:56]=[C:55]3[C:57](C(O)=O)=[CH:58][N:59](COCC[Si](C)(C)C)[C:54]3=[N:53][CH:52]=2)[CH:48]=[N:47]1.C1(C2N=C3C(C(O)=O)=CN(COCC[Si](C)(C)C)C3=NC=2)CC1.FC(F)(F)C(O)=O>>[C:2]([CH:4]1[CH2:7][N:6]([C:26]([C@H:21]([NH:20][C:13]([C:57]2[C:55]3[C:54](=[N:53][CH:52]=[C:51]([C:49]4[CH:48]=[N:47][N:46]([CH3:45])[CH:50]=4)[N:56]=3)[NH:59][CH:58]=2)=[O:15])[CH2:22][CH:23]([CH3:24])[CH3:25])=[O:28])[CH2:5]1)#[N:3]
Reactant: N#CC1CNC1
Reactant: Cn1cc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)cn1
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Agent: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(C3CC3)cnc21
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCNC1
Product: CC(C)C[C@@H](NC(=O)c1c[nH]c2ncc(-c3cnn(C)c3)nc12)C(=O)N1CC(C#N)C1

Procedure:
Prepared according to the procedure outlined in Example 1 substituting 3-cyanoazetidine hydrochloride for pyrrolidine, Boc-D-leucine for Boc-D-tert-leucine, and 2-(1-methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid for 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid. Trifluoroacetic acid was used in place of hydrochloric acid for all N-Boc deprotection steps. MS: (M+H)+=421.
Reaction SMILES: [NH2:1][C@:2]([C:6]([NH:8][C@H:9]([C:17]([NH:19][C@H:20]([C:39]([OH:41])=[O:40])[CH2:21][C:22]1[N:26]=[CH:25][N:24](C2C=CC([N+]([O-])=O)=CC=2[N+]([O-])=O)[CH:23]=1)=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH2:4][CH3:5])[CH3:3].C1(C[N-]C[C@@H](O)[CH2:52][CH2:53][OH:54])CCCCC1.C1(S)C=CC=CC=1>>[NH2:1][C@:2]([C:6]([NH:8][C@H:9]([C:17]([NH:19][C@H:20]([C:39]([OH:41])=[O:40])[CH2:21][C:22]1[N:26]=[CH:25][NH:24][CH:23]=1)=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH2:4][CH3:5])[CH3:3].[CH:11]1([CH2:10][C@H:9]([NH-:8])[C@@H:17]([OH:18])[CH2:52][CH2:53][OH:54])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: OCC[C@H](O)C[N-]CC1CCCCC1
Reactant: CC[C@](C)(N)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1cn(-c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cn1)C(=O)O
Agent: Sc1ccccc1
Product: CC[C@](C)(N)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Product: [NH-][C@@H](CC1CCCCC1)[C@@H](O)CCO

Procedure:
310 mg of Iva-Phe-His(DNP)-cyclohexylmethyl-2(S),4-dihydroxybutylamide are reacted with thiophenol to give the title compound in analogy to reference example 1a.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]#N)=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:3][CH:2]=1.N1C=CC=CC=1.C(O)(=[O:28])C>CN(C=O)C.O.[Ni]>[N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[C:17]3[C:12](=[CH:13][C:14]([CH:18]=[O:28])=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:3][CH:2]=1
Reactant: CC(=O)O
Reactant: N#Cc1ccc2c(/C=C/c3ccncc3)n[nH]c2c1
Agent: [Ni]
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=Cc1ccc2c(/C=C/c3ccncc3)n[nH]c2c1
Temperature: 60 °C

Procedure:
The crude (E)-3-(2-(pyridin-4-yl)vinyl)-1H-indazole-6-carbonitrile was dissolved in DMF (10 mL). Pyridine (10 mL) and acetic acid (5 mL) were added, followed by NaH2PO2/H2O (1.76 g, 20 mmol/5 mL) and Raney-Nickel 2400 (slurry in H2O, 1 mL). The resulting mixture was heated at 60° C. for 1 h before cooling to rt. The mixture was diluted with H2O and extracted with EtOAc (50 mL×3). The combined extracts were dried (Na2SO4) and concentrated to give an orange liquid. H2O (50 mL) was added and the resulting suspension was sonicated, suction filtered, rinsed with H2O and dried to give crude (E)-3-(2-(pyridin-4-yl)vinyl)-1H-indazole-6-carbaldehyde (540 mg) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 13.90 (s, 1H), 10.15 (s, 1H), 8.57 (d, 2H, J=4.0 Hz), 8.40 (d, 1H, J=8.0 Hz), 8.20 (s, 1H), 7.89 (d, 1H, J=16.4 Hz), 7.73-7.68 (m, 3H), 7.55 (d, 1H, J=16.8 Hz); MS ESI 249.9 [M+H]+, calcd for [C23H16N4O+H]+ 250.1.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[CH:28][CH:27]=1.[NH2:35][C@H:36]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:37][OH:38]>>[OH:38][CH2:37][C@H:36]([NH:35][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:29]1[CH:28]=[CH:27][C:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH3:19])=[CH:31][CH:30]=1)=[O:7])=[O:18])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1
Product: CON=C1C[C@@H](C(=O)N[C@@H](CO)c2ccccc2)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and (2R)-2-amino-2-phenylethanol, the title compound was obtained in 91% purity by HPLC. MS (ESI+): m/z=472.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][C:12]([O:14][CH2:15]C)=[O:13])[C:6]=2[CH:23]=1.[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)C(C)C)(C)C.[CH3:42][OH:43]>>[NH:30]([C:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:6]=2[CH:23]=1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[NH2:30][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=1[C:42]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:11][C:12]([OH:14])=[O:13])[C:6]=2[CH:23]=1)=[O:43]
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(N)cc21
Reactant: CO
Reactant: O=C=Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC(c1ccccc1)n1cnc2ccc(NC(=O)Nc3ccccc3)cc21
Product: Nc1ccccc1C(=O)Nc1ccc2ncn(C(CC(=O)O)c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of ethyl 3-(6-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate (150 mg, 485 μmol) in methanol (6 mL) was added phenyl isocyanate (50 μL, 460 μmol) and N,N-diisopropylethylamine (80 μL, 459 μmol). The solution was stirred at room temperature for 48 hours, and additional aliquots of phenyl isocyanate (10 μL, 92 μmol) and N,N-diisopropylethylamine (16 μL, 92 μmol) were added. The solution was stirred at room temperature for an additional 24 hours, and was then evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (95:5) to afford the title compound, [LCMS (Method A, Mobile Phase II) RT 5.13 min, MH+ 415].
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[Na].O.C(O)(=O)C.[CH2:23]([O:25][C:26](=O)[O:27]CC)[CH3:24]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([C:26]([O:25][CH2:23][CH3:24])=[O:27])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)OCC
Reactant: CCOC(=O)Cc1ccc2ccccc2c1
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)c1ccc2ccccc2c1
Temperature: 25 °C

Procedure:
To a solution of ethyl 2-naphtylacetate (2 g) in 23.3 ml of diethylcarbonate, kept under stirring and at room temperature, are added portionwise 0.232 g of sodium. The reaction mixture is refluxed for 2 hours 30 minutes, then it is concentrated in order to eliminate the not reacted diethylcarbonate and it is added with 20 ml of cold water. The resulting mixture is acidified with acetic acid until weak acidity is reached, then it is extracted three times with diethyl ether. The pooled organic extracts are dried over sodium sulfate and the solvent is evaporated off, to give, after recrystallization from diethyl ether (19 ml), 1.015 g of the product as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([NH:8][CH3:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(CC)CC.[CH2:19]([O:26][CH2:27][C:28](Cl)=[O:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl.CCOC(C)=O>[CH2:19]([O:26][CH2:27][C:28]([N:8]([CH3:9])[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=1)=[O:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: CNc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(C(=O)COCc1ccccc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 70 %

Procedure:
To a suspension of 4-nitro-N-methylaniline in DCM (10 mL) was added at 0° C. was added Et3N (0.63 mL, 4.5 mmol) and 2-benzoxyacetyl chloride (0.513 mL, 3.3 mmol). After stirring for 15 h at room temperature, the reaction mixture was diluted with EtOAc, washed with Sat. NaHCO3, brine, dried and concentrated to give 2-benzoxy-N-methyl-N-(4-nitrophenyl)acetamide (0.63 g, 70%).
Reaction SMILES: [F:1][C:2]1[C:3]2[O:11][CH2:10][O:9][C:6]([C:7]=1[F:8])=[CH:5][C:4]=2[CH3:12].[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[C:3]2[O:11][CH2:10][O:9][CH:12]([Br:13])[C:4]=2[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc2c(F)c(F)c1OCO2
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc2c(c1F)OCOC2Br

Procedure:
172 g of 3,4-difluoromethylenedioxytoluene, 180 g of N-bromosuccinimide and a pinch of azobisisobutyronitrile were mixed with 1,000 ml of CCl4 and the mixture was heated to the boil for 5 hours. After cooling, it was filtered, the material on the filter was rinsed with a little CCl4 and the filtrate was distilled. 3,4-Difluoromethylenedioxybenzyl bromide of boiling point 108°-111° C./15 mm Hg was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[CH3:8].[NH:11]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[C:13]([C:20](O)=O)=[N:12]1.C(OCC)(=O)C>CCCCCC>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[NH:9][C:20]([C:13]3[C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=4[NH:11][N:12]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Cc1cc(N)c(N)cc1C
Reactant: O=C(O)c1n[nH]c2c1CCCC2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc2nc(-c3n[nH]c4c3CCCC4)[nH]c2cc1C
Reaction time: 0.03 h
Yield: 17 %

Procedure:
4,5-Dimethylbenzene-1,2-diamine (90 mg) and 4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid [110 mg, Reference Example 17(a)] were mixed in a glass vial then subjected to microwave radiation (900 W, domestic oven) twice for two minutes. The resulting solid was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (85:15, v/v) to give 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-4,5,6,7-tetrahydro-1H-indazole (30 mg) as a pale brown solid. LC-MS (METHOD B): RT=2.28 minutes; 267 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Br:12][CH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([F:21])[CH:15]=1.C(OCC)(=O)C>CN(C=O)C>[BrH:12].[Cl:11][C:8]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2](=[NH:1])[N:10]([CH2:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([F:21])[CH:15]=2)[CH:9]=1
Reactant: Cc1cc(F)cc(CBr)c1
Reactant: NC(=O)c1cc(Cl)cnc1N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Br
Product: Cc1cc(F)cc(Cn2cc(Cl)cc(C(N)=O)c2=N)c1
Temperature: 25 °C
Yield: 42.4 %

Procedure:
A solution of 2-amino-5-chloronicotinamide (150 mg) and 1-(bromomethyl)-3-fluoro-5-methylbenzene (270 mg) in DMF (3 ml) was stirred at 100° C. for 24 hr. After cooling to room temperature, ethyl acetate was added, and the precipitated crystals were filtered and recrystallized to give the title compound (139 mg).
Reaction SMILES: [NH2:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][CH2:14][OH:15])=[CH:9][CH:10]=2)[C:5](=[O:16])[C:4]([C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[O:18])=[CH:3]1.C(O)(=O)C>CO.CN(C=O)C.[Pt]>[NH2:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][CH2:13][CH2:14][OH:15])=[CH:9][CH:10]=2)[C:5](=[O:16])[C:4]([C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[O:18])=[CH:3]1
Reactant: Nn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21
Agent: [Pt]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CO
Product: Nn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCCO)ccc21
Reaction time: 4.5 h
Yield: 47.1 %

Procedure:
1-Amino-N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.21 g) from Example No. 118 is dissolved in a 1:1 mixture of methanol/DMF. To the solution is added 5% platinum on carbon (0.11 g) and acetic acid (0.5 mL). The reaction is shaken under a hydrogen atmosphere (35 psi) for 4.5 hours. The catalyst is removed by filtration through Celite. The filtrate is concentrated in vacuo, and the resulting white solid is triturated with dichloromethane. The crude product is then purified by column chromatography (MeOH/CH2Cl2: 3%, 5%) yielding 0.10 g of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:28])[C:7]=1[NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18]C(=O)C2C=CC=CC=2)[CH:11]=1.O.C(=O)([O-])[O-].[K+].[K+].Cl>CO>[Cl:28][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([OH:18])[CH:11]=1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1OC(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-(3,5-dichloropyrid-4-yl)-3-benzoyloxy-4-methoxybenzamide (13.4 g; that is prepared as described in Reference Example 11) in methanol (160 mL) and water (60 mL) is treated with anhydrous potassium carbonate (18 g), and stirred overnight at room temperature. It is then brought to pH 7 by treatment with dilute hydrochloric acid (2N), and concentrated. The residue is treated with water (100 mL) and filtered, and the resulting solid is dried, to give N-(3,5-dichloropyrid-4-yl)-3-hydroxy-4-methoxybenzamide (8.8 g), m.p. 227°-228° C.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:35])[NH:9][C:10]2[CH:34]=[CH:33][C:13]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=4)[C:26]([O:28]C)=[O:27])[CH2:18][CH2:17]3)=[O:15])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCOCC1.O.[OH-].[Li+]>O>[C:1]1([NH:7][C:8](=[O:35])[NH:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=4)[C:26]([OH:28])=[O:27])[CH2:18][CH2:17]3)=[O:15])=[CH:33][CH:34]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc(CN2CCN(C(=O)c3ccc(NC(=O)Nc4ccccc4)cc3)CC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccccc1)Nc1ccc(C(=O)N2CCN(Cc3cccc(C(=O)O)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 102.5 %

Procedure:
Methyl 3-((4-(4-(3-phenylureido)benzoyl)piperazin-1-yl)methyl)benzoate (0.47 g, 1 mmol) was suspended in a mixture of water (5 mL)/1,4-dioxane (15 mL) and treated with lithium hydroxide mono-hydrate (0.168 g, 4 mmol). The mixture was stirred at room temperature for 60 hours and was filtered over fluted paper. The filtrate was concentrated under vacuum and then acidified with 1M hydrochloric acid. The mixture was extracted with ethyl acetate (×4) and the combined organic layers were dried on magnesium sulfate, filtered and concentrated under vacuum to give the title compound (0.47 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[N:6][CH:7]=1.[NH2:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[N:11]12[CH2:16][CH2:15][CH:14]([CH2:13][CH2:12]1)[CH:9]([O:8][C:5]1[N:6]=[CH:7][C:2]([C:22]3[CH:23]=[C:18]([CH:19]=[CH:20][CH:21]=3)[NH2:17])=[CH:3][CH:4]=1)[CH2:10]2
Reactant: Nc1cccc(B(O)O)c1
Reactant: Brc1ccc(OC2CN3CCC2CC3)nc1
Product: Nc1cccc(-c2ccc(OC3CN4CCC3CC4)nc2)c1

Procedure:
The product of Example 12A (283 mg, 1 mmol) was treated with 3-amino-phenylboronic acid (Lancaster, 274 mg, 2.0 mmol) according to the procedure of Example 1B. The title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.10) as solid (180 mg, yield, 61%). 1H NMR (MeOH-d4, 300 MHz) δ 1.42-1.56 (m, 1H), 1.62-1.88 (m, 2H), 1.99-2.12 (m, 1H), 2.16-2.28 (m, 1H), 2.73-3.04 (m, 5H), 3.40-3.50 (m, 1H), 5.01-5.10 (m, 1H), 6.70 (ddd, J=7.8, 2.7, 0.7 Hz, 1H), 6.84-6.94 (m, 3H), 7.16 (t, J=7.8 Hz, 1H), 7.88 (dd, J=8.5, 2.4 Hz, 1H), 8.29 (d, J=2.6 Hz, 1H) ppm. MS (DCl/NH3) m/z 296 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[Br:12][C:13]1[C:14]([CH3:21])=[C:15]([CH:19]=O)[NH:16][C:17]=1[CH3:18]>C(O)(=O)C.CCO>[Br:12][C:13]1[C:14]([CH3:21])=[C:15]([CH:19]=[N:9][NH:8][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)[NH:16][C:17]=1[CH3:18]
Reactant: Cc1[nH]c(C=O)c(C)c1Br
Reactant: NNC(=O)c1ccc(O)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1[nH]c(C=NNC(=O)c2ccc(O)cc2)c(C)c1Br
Temperature: 25 °C
Yield: 74.4 %

Procedure:
To a solution of 4-hydroxy-benzoic acid hydrazide (0.06 g, 0.0004 mol) and 4-bromo-3,5-dimethyl-pyrrole-2-carboxaldehyde (0.08 g, 0.0004 mol) in abs. EtOH (5 mL), was added 1 drop of acetic acid. The reaction mixture was refluxed for 5 hours. The reaction mixture was cooling to room temperature and concentrated to remove solvent. The resulting residue was solidified by EtOAc to give red solid 0.1 g, in 77% yield, mp: 235.4° C. 1H NMR (DMSO-d6) δ 11.46 (s, 1H), 11.21 (s, 1H), 9.99 (s, 1H), 8.26 (s, 1H), 7.76 (d, 2H), 6.82 (d, 2H), 2.15 (s, 3H), 2.03 (s, 3H). 13C NMR (DMSO-d6) δ 163.9, 162.2, 140.2, 131.6, 131.3, 126.1, 124.0, 124.3, 116.8, 13.4, 11.8. Anal. Calcd for C14H14BrN3O2.¼H2O: C, 49.35; H, 4.14; N, 12.33; Br, 23.69. Found: C, 49.21; H, 3.95; N, 11.96; Br, 23.37.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].C(N([CH2:10][CH3:11])CC)C.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C(Cl)Cl>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:3][CH2:2][CH2:1][NH:4][S:20]([C:11]2[CH:10]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)(=[O:22])=[O:21])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: NCCN
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)NCCNS(=O)(=O)c2ccc(OC)cc2)cc1
Reaction time: 8 h

Procedure:
Combine ethylenediamine (0.9 g, 15 mmol) in CH2Cl2 (50 mL) and mix with triethylamine (3.03 g, 30 mmol). Cool the mixture on a ice-water bath and add dropwise 4-methoxybenzenesulfonyl chloride (6.2 g, 30 mmol) in CH2Cl2 (50 mL). Warm the reaction to room temperature and stir overnight. Wash the reaction with 1N HCl (100 mL), sat. NaHCO3, brine, dry over Na2SO4, and concentrate the crude product in vacuo. Purification by flash chromatography (CH2Cl2/EtOAc=5:1) gives the title compound: Mass spectrum (electrospray): (m/z)=401.1 (M+1); 1H NMR (CDCl3): δ7.77–7.74 (m, 4H), 6.99–6.96 (m, 4H), 4.95 (br, 2H), 3.87 (s, 6H), 3.06–3.04 (m, 4H).