Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:26])[C@H:5]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH:6][C:7](=[O:21])[C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH:27]1[CH:31]=[CH:30][N:29]=[C:28]1[CH:32]=O.CC(C[C@H](NC(C1C=CC(NCC2NC=NC=2)=CC=1C1C=CC=CC=1)=O)C(O)=O)C>>[CH3:2][O:3][C:4](=[O:26])[C@H:5]([CH2:22][CH:23]([CH3:24])[CH3:25])[NH:6][C:7](=[O:21])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH2:32][C:28]2[NH:27][CH:31]=[CH:30][N:29]=2)=[CH:10][C:9]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ncc[nH]1
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)c1ccc(N)cc1-c1ccccc1
Agent: CC(C)C[C@H](NC(=O)c1ccc(NCc2cnc[nH]2)cc1-c1ccccc1)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](CC(C)C)NC(=O)c1ccc(NCc2ncc[nH]2)cc1-c1ccccc1

Procedure:
Reductive animation of N-[4-amino-2-phenylbenzoyl]-L-leucine methylester hydrochloride and imidazole-2-carboxaldehyde following similar procedures to those described for GGTI-2132 afforded after purification N-[4-(Imidazol-2-ylmethylamino)-2-phenylbenzoyl]leucine methyl ester as a white solid. 42%. mp=156-160° C. 1H NMR (DMSO-d6) 8.19 (m, 1H, aryl), 7.58 (s, 2H), 7.34-7.22 (m, 6H), 6.67 (d, 1H, J=8.3 Hz), 6.60 (s, 1H), 4.72 (s, 2H, CH2), 4.17 (m, 1H), 3.59 (s, 3H), 1.52-1.35 (m, 3H), 0.80 (d, 3H, J=5.3 Hz), 0.75 (d, 3H, J=5.04 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.CN(C=O)C.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>O>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=[C:4]([Cl:10])[CH:3]=1
Reactant: Oc1c(Cl)cc(Br)cc1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1c(Cl)cc(Br)cc1Cl
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-2,6-dichlorophenol (11.9 g, 49.2 mmol, H. Joyce et al., J. Amer. Chem. Soc., 39, 2644 (1917)) in DMF (100 mL) imidazole (5.0 g, 74 mmol) and tert-butyldimethylsilylchloride (8.9 g, 59 mmol) was added at room temperature and the mixture was stirred for 1 h. The mixture was poured into water (300 mL) and extracted with diethyl ether (100 mL×2) and washed with water (50 mL×2), dried over MgSO4 and concentrated in vacuo gave pale yellow oil. (15.3 g, 87%)
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])=[C:7]([NH:17][CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[CH:6]=1)=[O:4].[OH-].[Na+].C(O)(=O)C>CO>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])=[C:7]([NH:17][CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[CH:6]=1)([OH:4])=[O:2]
Reactant: CCC(CC)Nc1cc(C(=O)OC)ccc1N1CCCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CCC(CC)Nc1cc(C(=O)O)ccc1N1CCCC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.9 %

Procedure:
A solution of the above ester (0.150 g, 0.49 mmol) in 1 mL of methanol was treated with 1N sodium hydroxide (2 mL) and the resulting mixture was stirred at ambient temperature for 16 h. The reaction mixture was acidified with glacial acetic acid and a solid precipitated. The solid was collected by filtration, washed with water and dried to give 0.125 g (87%) of the title compound, mp 178-180° C.
Reaction SMILES: [C:1]([N:8]1[CH2:31][CH2:30][C@@:15]23[C:16]4[CH:17]=[C:18]([O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:20][C:21]=4[CH2:22][C@@H:9]1[C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14]3)(OC(C)(C)C)=O.O1CCO[CH2:34][CH2:33]1.Cl.C(Br)C#C.C1(C)C=CC=CC=1>C(Cl)Cl>[CH2:1]([N:8]1[CH2:31][CH2:30][C@@:15]23[C:16]4[CH:17]=[C:18]([O:23][C:24](=[O:29])[C:25]([CH3:27])([CH3:28])[CH3:26])[CH:19]=[CH:20][C:21]=4[CH2:22][C@@H:9]1[C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14]3)[C:33]#[CH:34]
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(OC(=O)C(C)(C)C)cc13
Agent: C#CCBr
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C#CCN1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(OC(=O)C(C)(C)C)cc13
Temperature: 0 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of compound 31 (5 mg, 0.012 mmol) in dry CH2Cl2 (0.2 mL) was added 4 M HCl dioxane solution (0.5 mL) and the mixture stirred for 2 h at 0° C. Solvent was evaporated under reduced pressure. The crude amine salt 32 was dissolved in CH2Cl2 (0.5 mL) and to the mixture was slowly added 80 wt % propargyl bromide solution in toluene (2 μL, 0.020 mmol) and TEA (9 μL, 0.064 mmol) at 0° C. After 4 h stirring, the reaction mixture was concentrated under reduced pressure. The crude product was purified on a silica gel column chromatography (1:1 n-Hexane/EtOAc) to give a colorless oil (3 mg, 68% yield): 1H NMR (300 MHz, CDCl3) 1.15˜1.87 (m, 20H); 2.14˜2.31 (m, 2H); 2.67˜2.74 (m, 2H); 3.02 (d, J=18.6 Hz, 1H); 3.12˜3.14 (m, 1H); 3.36˜3.39 (m, 2H); 6.81˜6.93 (m, 2H); 7.16 (d, J=8.2 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16](O)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.F[B-](F)(F)F.N1(O[C+](N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[NH2:53][CH:54]([C:57]1[CH:58]=[N:59][CH:60]=[CH:61][CH:62]=1)[CH2:55][OH:56]>CN(C=O)C.O>[F:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:2]([F:1])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:53][CH:54]([C:57]3[CH:58]=[N:59][CH:60]=[CH:61][CH:62]=3)[CH2:55][OH:56])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)O
Reactant: NC(CO)c1cccnc1
Agent: CN(C)[C+](On1nnc2ccccc21)N(C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(CO)c1cccnc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
150 mg (0.47 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid, 227 mg (0.71 mmol) of (benzotriazol-1-yloxy)bisdimethylaminomethylium fluoroborate (TBTU) and 238 mg (2.36 mmol) of 4-methylmorpholine were initially charged in 3 ml of DMF. After 10 min at RT, 98 mg (0.71 mmol) of 2-amino-2-(pyridin-3-yl)ethanol were added and the mixture was stirred at room temperature overnight. About 25 ml of water were added to the reaction solution and the precipitate formed was stirred for another 30 min, filtered off, washed thoroughly with water and dried under high vacuum overnight. The crude product was purified by silica gel chromatography (mobile phase: dichloromethane:methanol gradient). The product fractions were concentrated and stirred with acetonitrile. The solid obtained was filtered off and dried. This gave 40 mg of the target compound (20% of theory, purity 100%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]3([C:13]#N)[CH2:12][CH2:11]3)[CH:8]=2)[CH2:3][CH2:2]1.[OH-:15].[Na+].Cl.C[OH:19]>>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]3([C:13]([OH:19])=[O:15])[CH2:12][CH2:11]3)[CH:8]=2)[CH2:3][CH2:2]1
Reactant: N#CC1(c2ccc3c(c2)CCC3)CC1
Reactant: [OH-]
Reactant: CO
Agent: Cl
Agent: [Na+]
Product: O=C(O)C1(c2ccc3c(c2)CCC3)CC1
Temperature: 100 °C
Yield: 47 %

Procedure:
To a stirred 1-(2,3-dihydro-1H-inden-6-yl)cyclopropanecarbonitrile (9.3 g, 50.8 mmol) in methanol (40 mL) was added a solution of 150 mL of sodium hydroxide (25% NaOH w/w in water). The mixture was heated at 100° C. for 8 hours. After cooling to room temperature, the reaction mixture was poured over ice-water (0° C.), the pH was adjusted to pH=4 with hydrogen chloride (1 N) and the mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were dried over Na2SO4 and evaporated under vacuum. The residue that was purified by column chromatography (petroleum ether:ethyl acetate=5:1) to give 1-(2,3-dihydro-1H-inden-6-yl)cyclopropanecarboxylic acid (4.8 g, 47%). 1H NMR (CDCl3, 400 MHz) δ 1.23-1.26 (m, 2H), 1.62-1.65 (m, 2H), 2.03-210 (m, 2H), 2.81-2.91 (m, 4H), 7.11-7.21 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[N:24]=[CH:23][C:22](Br)=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]([F:41])([F:40])[O:29][C:30]1[CH:35]=[CH:34][C:33](OB(O)O)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:26])[C:7]([CH3:9])([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[N:24]=[CH:23][C:22]([C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]([F:27])([F:40])[F:41])=[CH:35][CH:34]=3)=[CH:21][N:20]=2)[N:15]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)Oc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ncc(Br)cn2)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ncc(-c3ccc(OC(F)(F)F)cc3)cn2)cs1
Yield: 85 %

Procedure:
Under nitrogen atmosphere, 2-[(4-{2-[(5-bromopyrimidin-2-yl)oxy]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (600 mg) synthesized in Example 110-1 and 4-trifluoromethoxyphenylboric acid (400 mg) were dissolved in dioxane (6 mL) and aqueous sodium carbonate solution (2 mol/L, 3 mL), tetrakis(triphenylphosphine)palladium (75 mg) was added, and the mixture was refluxed for 4 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=3:1) to give the title compound (600 mg) as a colorless oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].[Cl:23][C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=1)[C:27](=O)[CH2:28]Br>O>[Cl:23][C:24]1[CH:25]=[C:26]([C:27]2[N:12]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=3)[S:13][CH:28]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Reactant: O=C(CBr)c1cccc(Cl)c1
Solvent: O
Product: O=C(O)c1cc(-c2nc(-c3cccc(Cl)c3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 30 %

Procedure:
4-[4-(3-Chloro-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (82 mg, 30%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 3-chlorophenacyl bromide (available from Oakwood Products, Inc.) using the procedure described for the preparation of Example 18 except that the entire 4 mL of water was added at the beginning of the hydrolysis step rather than being added in two portions. 1H NMR (300 MHz, DMSO-d6) δ 13.12 (br s, 1H), 8.56 (d, J=1.7 Hz, 1H), 8.42 (s, 1H), 8.28 (dd, J=8.0, 1.9 Hz, 1H), 8.12-8.16 (m, 2H), 8.03-8.07 (m, 1H), 7.76-7.81 (m, 1H), 7.62-7.68 (m, 1H), 7.41-7.55 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][N:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[CH:6]1[CH2:10][CH2:9][NH:8][CH2:7]1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:31][CH2:32][CH:33]=[C:34]1[C:40]2[CH:41]=[CH:42][CH:43]=[N:44][C:39]=2[CH2:38][O:37][C:36]2[CH:45]=[CH:46][C:47]([C:49]([OH:52])([CH3:51])[CH3:50])=[CH:48][C:35]1=2>C(O)(C)C>[CH3:1][O:2][C:3](=[O:19])[CH2:4][N:5]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[CH:6]1[CH2:10][CH2:9][N:8]([CH2:31][CH2:32][CH:33]=[C:34]2[C:40]3[CH:41]=[CH:42][CH:43]=[N:44][C:39]=3[CH2:38][O:37][C:36]3[CH:45]=[CH:46][C:47]([C:49]([OH:52])([CH3:51])[CH3:50])=[CH:48][C:35]2=3)[CH2:7]1
Reactant: COC(=O)CN(Cc1ccc(Cl)cc1)C1CCNC1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: [I-]
Agent: [K+]
Solvent: Cc1cccc(C)n1
Solvent: CC(C)O
Product: COC(=O)CN(Cc1ccc(Cl)cc1)C1CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)C1

Procedure:
To a solution of [(4-Chloro-benzyl)-pyrrolidin-3-yl-amino]-acetic acid methyl ester (188 mg, 0.67 mmol) in isopropanol (5 mL) was added 2,6-lutidine (186 uL, 1.6 mmol), and a catalytic amount of potassium iodide. The resultant solution was heated at 80° C. and to it was added 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (149 mg, 0.4 mmol) portionwise over 0.5 h. The reaction solution was heated overnight then partitioned between water and ethyl acetate. The product was purified on SiO2 (ethyl acetate:Methanol:triethylamine 95:4.5:0.4) and isolated as a film. LCMS (retention time=1.84, ES+; 576); 1H NMR (CD3OD): δ 8.46 (1H,d), 7.76 (1H, d), 7.45 (2H, m), 7.23 (5H, m), 6.74 (1H, d), 6.15 (1H, m), 3.72 (2H, m), 3.60 (4H, s), 3.30 (6H, m), 2.78 (4H, m), 2.42 (2H, m), 2.05 (1H, m), 1.82 (1H, m), 1.50 (6H, s).
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Br:22][C:23]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>CN(C)C=O.O.ClCCl>[Br:22][C:23]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:24]=1[C:25]([N:10]1[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[NH:7][C:6]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:11]1)=[O:26]
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Reactant: O=C(Cl)c1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1Br)N1Cc2cccnc2Nc2ccccc21
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 59.5 %

Procedure:
To a solution of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine of Example 1, Step B (5.15 g, 26.1 mmol) in dimethylformamide (70 mL) under nitrogen was added potassium carbonate (7.95 g, 57.51 mmol). The mixture was cooled and treated dropwise with a solution of crude 2-bromo-4-fluorobenzoyl chloride of Step A (31.37 mmol) in dimethylformamide (30 mL). After stirring at room temperature for 75 minutes the mixture was diluted with water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate and evaporated to dryness to give a brown solid foam. The crude material was dissolved in dichloromethane and absorbed onto a silica Merck-60 flash column. Elution with a hexane-ethyl acetate gradient (from 95:5 to 75:25) provided the pure title compound (6.18 g) along with some impure material (1.2 g). The pure material was triturated with hexane to provide an off-white solid foam, which was used as such in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:31])=[C:24]([CH2:27][C:28]([OH:30])=O)[CH:25]=2)[NH:20][C:19](=[O:32])[C:18]=1[C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[C:35]([CH3:40])[CH:34]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:41]([NH:44][CH:45]([CH3:47])[CH3:46])([CH3:43])[CH3:42].Cl.CN(C)CCCN=C=NCC.CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:31])=[C:24]([CH2:27][C:28](=[O:30])[N:44]([CH:45]([CH3:47])[CH3:46])[CH:41]([CH3:43])[CH3:42])[CH:25]=2)[NH:20][C:19](=[O:32])[C:18]=1[C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[C:35]([CH3:40])[CH:34]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)NC(C)C
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(CC(=O)O)c(Cl)cc3[nH]c2=O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(CC(=O)N(C(C)C)C(C)C)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
To a solution of 2-{2-[6-carboxymethyl-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (57 mg in 0.50 mL methylene chloride) was added 0.042 mL diisopropylamine followed by 98 mg 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 6.1 mg dimethylaminopyridine, and the mixture stirred at room temperature. After 42 hours, the mixture was diluted with methylene chloride and washed with water and brine. The organics were dried over sodium sulfate and the concentrate purified by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 97:2:1) to give the title compound (41 mg).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:11]2[N:10]=[CH:9][N:8](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:7]=2[CH2:6][CH2:5][CH2:4]1.[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1O>>[ClH:31].[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:1][CH2:2][CH:3]1[C:11]2[N:10]=[CH:9][NH:8][C:7]=2[CH2:6][CH2:5][CH2:4]1
Reactant: OCC1CCCc2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Oc1ccccc1Cl
Product: Cl
Product: Clc1ccccc1OCC1CCCc2[nH]cnc21

Procedure:
Using a procedure similar to that described in Example 22 and starting from 4-hydroxymethyl-1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazole (0.19 g, 0.48 mmol) and 2-chlorophenol (0.1 ml, 1 mmol) 20 mg (14%) of the title compound was obtained as a solid.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]=12.[CH2:22]([OH:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]=12)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1c(C)n(CC=Cc2ccccc2)c2c(Cl)nncc12
Reactant: OCc1ccccc1
Product: Cc1c(C)n(CC=Cc2ccccc2)c2c(OCc3ccccc3)nncc12
Yield: 85.4 %

Procedure:
The title compound (trans) was prepared as pale brown crystals in 85.4% yield in a similar procedure to that described in Example 1 by using 7-chloro-2,3-dimethyl-1-(3-phenyl-2-propenyl)pyrrolo[2,3-d]pyridazine (trans) and benzyl alcohol.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:9]=[C:10]([CH:14]3OCC[O:15]3)[CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+]>C(O)C.O.O1CCCC1.S(=O)(=O)(O)O>[C:1]1([S:7][C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[CH:14]=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(Sc2cccc(C3OCCO3)c2)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: O=Cc1cccc(Sc2ccccc2)c1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 98 %

Procedure:
2-(3-Phenylsulfanyl-phenyl)-[1,3]dioxolane described in Preparation Example 91 (396 mg, 1.53 mmol) was dissolved in a mixture solution of ethanol (5 mL), water (5 mL), tetrahydrofuran (5 mL) and sulfuric acid (1 mL), and the solution was stirred for 2.5 hours under reflux. The reaction solution was cooled to 0° C., an aqueous solution of saturated sodium bicarbonate was added thereto, the solution was extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1), and the title compound (323 mg, 1.51 mmol, 98%) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[N:9]=[CH:8][N:7]=[C:6]2[NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]2[O:30][CH2:31][O:32][C:25]=12.Cl[CH2:34][C:35]#[N:36]>>[C:35]([CH2:34][N:20]1[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][CH2:14][O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]5[O:30][CH2:31][O:32][C:25]=45)=[N:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2][CH3:1])[CH2:18][CH2:19]1)#[N:36]
Reactant: COc1cc2c(Nc3cccc4c3OCO4)ncnc2cc1OCCCN1CCNCC1
Reactant: N#CCCl
Product: COc1cc2c(Nc3cccc4c3OCO4)ncnc2cc1OCCCN1CCN(CC#N)CC1

Procedure:
Using an analogous procedure to that described in Example 12, 6-methoxy-4-(2,3-methylenedioxyanilino)-7-(3-piperazin-1-ylpropoxy)quinazoline was reacted with 2-chloroacetonitrile to give the title compound as a solid; NMR Spectrum: (DMSOd6) 2.1 (m, 2H), 2.45–2.7 (m, 11H), 3.5 (s, 2H), 4.0 (s, 3H), 4.25 (t, 2H), 6.0 (s, 2H), 6.7 (d, 1H), 6.9 (t, 1H), 7.0 (m, 2H), 7.75 (d, 1H), 8.7 (s, 1H); Mass Spectrum: M+H+ 477.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:12](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([O:7][CH3:12])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(F)cc(C(=O)O)c1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1cc(C)cc(F)c1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To a solution of 3-fluoro-5-methylbenzoic acid (1.50 g, 9.73 mmol, Oakwood) in Acetone (40 mL) was added Potassium carbonate (1.34 g, 9.73 mmol) followed by Methyl iodide (0.73 mL, 12 mmol). The reaction mixture was heated to 65° C. for 1 hour, heating discontinued and stirred overnight, then heating resumed at that temperature for a further 2 hours. Additional Methyl iodide (0.5 mL, 8 mmol) was added and heating was continued for 6 hours. Solids were removed by filtration and acetone was removed in vacuo. The residue was partitioned between 1N NaOH and ethyl acetate. The aqueous portion was extracted with a further two portions of ethyl acetate. The combined extracts were washed with brine, then dried over sodium sulfate, decanted and concentrated. The product so obtained was used without further purification (1.64 g, 100%). 1H NMR (300 MHz, CDCl3): δ 7.66-7.63 (m, 1H), 7.51 (d, 1H), 7.10-7.04 (m, 1H), 3.91 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[C:19]1[C:23]([NH2:24])=[CH:22][NH:21][N:20]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH:12]1[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:10]=[C:11]1[C:19]1[C:23]([NH:24][C:1](=[O:9])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:22][NH:21][N:20]=1
Reactant: Nc1c[nH]nc1-c1nc2ccccc2[nH]1
Reactant: O=C(O)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1c[nH]nc1-c1nc2ccccc2[nH]1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.3 %

Procedure:
A mixture of benzoic acid (34 mg, 0.28 mmol), 3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (50 mg, 0.25 mmol), EDC (58 mg, 0.30 mmol) and HOBt (40.5 mg, 0.30 mmol) in DMF (5 ml) was stirred at room temperature for 24 h. The solvent was removed in vacuo, the crude product purified by preparative LC/MS and following reduction of the product-containing fractions N-[3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide was obtained as a brown solid (23 mg, 30%). (LC/MS: Rt 3.66, [M+H]+ 303.67).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][N:13]([C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[C:19](=[O:28])[N:20]([CH3:27])[C:21]2=[O:26])[C:14](Cl)=[O:15].N1C=CC=CC=1>C(#N)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][NH:11][C:14]([N:13]([CH3:12])[C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[C:19](=[O:28])[N:20]([CH3:27])[C:21]3=[O:26])=[O:15])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: CN1C(=O)c2cccc(N(C)C(=O)Cl)c2C1=O
Solvent: c1ccncc1
Solvent: CC#N
Product: CN1C(=O)c2cccc(N(C)C(=O)NNc3ccc([N+](=O)[O-])cc3)c2C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.4 %

Procedure:
p-Nitrophenylhydrazine (1.5 g, 10 mmole), N-methyl-N-(2-methyl-1,3-dioxoisoindolin-4-yl) carbamoyl chloride (2.5 g, 10 mmole) and 2 ml pyridine were combined in 25 ml dry acetonitrile, heated to reflux, then stirred at room temperature for 4 hours. The solid formed was collected and washed with ether to give 2.6 g of product, m.p. 194°-196° C.