Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].[CH3:14][C:15]([CH:22]1[CH2:26][CH:25]=[C:24]([CH3:27])[C:23]1([CH3:29])[CH3:28])([CH2:18][C:19]([CH3:21])=[CH2:20])[CH:16]=[O:17]>C(O)(C)C>[CH3:28][C:23]1([CH3:29])[C:24]([CH3:27])=[CH:25][CH2:26][CH:22]1[C:15]([CH3:14])([CH2:18][C:19]([CH3:21])=[CH2:20])[CH2:16][OH:17]
Reactant: C=C(C)CC(C)(C=O)C1CC=C(C)C1(C)C
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CC(C)O
Product: C=C(C)CC(C)(CO)C1CC=C(C)C1(C)C
Yield: 95.9 %

Procedure:
A 4 neck 1 liter round bottomed flask was charged with 400 g of dry isopropanol and 100 g of aluminum isopropoxide (0.48 mole). The contents of the flask were refluxed (80° C.) and 200 g of 2,4-dimethyl-2-(2,2,3-trimethylcyclopent-3-en-1-yl)-4-pentenal at 95.2% (0.865 mole) were added dropwise under nitrogen over 80 minutes. The reaction was refluxed for 2 hours. Then the lights were distilled off to a pot temperature of 110° C. After cooling the batch was extracted with 150 ml of 10% sulfuric acid and 300 ml of hexane. The hexane extract was washed with 150 ml of water, 100 ml of 5% sodium carbonate, and 100 ml of brine. After drying with magnesium sulfate, the batch was filtered, concentrated in vacuo and the crude alcohol, 201.1 g, was distilled from 1 g of soda ash to afford 193.6 g of purified product (88% yield). BP 94° C./0.10 mmHg; 1H-NMR (300 MHz), δ1.007 (3H, s), 1.02 (3H, s), 1.42 (3H, s), 1.54 (3H, s), 1.83 (4H, br s), 2.0-2.4 (5H, br m), 3.60 (2H, AB quartet, JAB =11.1 Hz), 4.75 (1H, s), 4.88 (1H, s), 5.27 (1H, s); 13C-NMR (75 MHz), δ12.35, 20.07, 22.31, 25.48, 28.38, 30.96, 42.11, 45.10, 48.27, 54.77, 68.48, 114.81, 121.38, 144.22, 148.28; IR (Neat), 3400 br, 2980, 1040 cm-1 ; MS (m/e), 207 (M+ -15), 191, 109 (Base).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)=[N:7][CH:8]=1>[Pd].CO.CC(=O)OCC>[CH3:1][O:2][C:3]1[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[N:7][CH:8]=1
Reactant: COc1cnc(-c2ccc([N+](=O)[O-])cc2)nc1N1CCOCC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cnc(-c2ccc(N)cc2)nc1N1CCOCC1
Yield: 82.9 %

Procedure:
4-[5-methoxy-2-(4-nitro-phenyl)-pyrimidin-4-yl]-morpholine (0.2 g, 1 eq) was stirred under hydrogen balloon with palladium on carbon (10 percent, 0.1 g, 0.15 eq) in a mixture of MeOH and EA (1:1, 8 mL) at room temperature overnight. The reaction mixture was then filtered through Celite, volatiles were removed in vacuo, and the residue was purified by flash chromatography to give a white solid (0.15 g, 83%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Br[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>C1C=CC=CC=1>[N:1]1([CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)CCCn1ccnc1
Temperature: 25 °C
Yield: 30.2 %

Procedure:
Part A. A solution of imidazole (17.0 g, 0.25 mole) in benzene (200 mL) at room temperature was treated with sodium hydride (60% w/w oil dispersion; 8.0 g, 0.20 mole) and heated at reflux for 1 hour. After cooling to room temperature, a solution of ethyl 4-bromobutyrate (30.0 g, 0.20 mole) in benzene (50 mL) was added. The resulting mixture was again heated at reflux for 20 hours. After cooling to room temperature, the solution was washed with water, dried (MgSO4) and concentrated under reduced pressure. The residual yellow oil was subjected to kugelrohr distillation at 125°-135° under rotary vacuum pump pressure to provide ethyl 4-(1-imidazolyl)butyrate as a colorless liquid (11.0 g, 30% yield). NMR(CDCl3) 7.44(1H,s) 7.04(1H,s) 6.90(1H,s) 4.12(2H,q,J=7 Hz) 4.02(2H,t,J=8 Hz) 2.24(2H,t,J=8 Hz) 2.08(2H,m) 1.31(3H,t,J=7 Hz).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[C:18]1[C:22]([CH3:23])=[CH:21][S:20][CH:19]=1)[C:12]([OH:14])=O.O[N:25]=[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35])[NH2:27].CCN(C(C)C)C(C)C>>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:12]2[O:14][N:27]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])[N:25]=2)[CH:15]=[CH:16][C:17]=1[C:18]1[C:22]([CH3:23])=[CH:21][S:20][CH:19]=1
Reactant: COc1ccccc1C(N)=NO
Reactant: COc1cc(C(=O)O)ccc1-c1cscc1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1noc(-c2ccc(-c3cscc3C)c(OC)c2)n1

Procedure:
Oxalyl chloride (120 μL; 1.45 mmol; 3 eq.), Intermediate 29 (120 mg; 0.48 mmol; 1 eq.), Intermediate 1 (80 mg; 0.48 mmol, 1 eq.) and DIEA (250 μL; 1.45 mmol; 3 eq.) were reacted according to general procedure 2. Purification by precipitation from DCM/n-pentane afforded the title compound as a white solid.
Reaction SMILES: [C:1]([O:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:21])[C:16]([O:18]CC)=[O:17])[N:14]=1)=[O:8])([CH2:4][CH3:5])([CH3:3])[CH3:2].[OH-].[Na+]>O>[C:1]([O:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:21])[C:16]([OH:18])=[O:17])[N:14]=1)=[O:8])([CH2:4][CH3:5])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)OC(C)(C)CC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(C)(C)OC(=O)Nc1nc(C(=O)C(=O)O)cs1
Yield: 68.6 %

Procedure:
Ethyl 2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylate (2.8 g.) and a solution of sodium hydroxide (0.54 g.) in water (20 ml.) were treated according to a similar manner to that of Preparation 6-5) to give brown powder of 2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylic acid (1.75 g.).
Reaction SMILES: C[O-].[Na+].Br[CH2:5][C:6]1[O:10][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[C:17]([F:20])([F:19])[F:18])=[N:8][CH:7]=1.[CH2:21]([SH:24])[CH2:22][CH3:23].O>CO>[CH2:21]([S:24][CH2:5][C:6]1[O:10][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[C:17]([F:20])([F:19])[F:18])=[N:8][CH:7]=1)[CH2:22][CH3:23]
Reactant: FC(F)(F)c1ccncc1-c1ncc(CBr)o1
Reactant: CCCS
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCSCc1cnc(-c2cnccc2C(F)(F)F)o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium methoxide (130 μl, 30% in methanol) was added to a solution of 5-bromomethyl-2-(4-trifluoromethyl-3-pyridyl)-oxazole (160 mg) and n-propanethiol (60 μl), in methanol (7 ml), and the mixture was stirred at room temperature for 4 hours. Water (50 ml) was then added, and the mixture was extracted with ethyl acetate. The organic phase was washed with water, dried (MgSO4), filtered and concentrated. This gave the desired product in pure form as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([N+:16]([O-:18])=[O:17])=[N:11][CH:12]=[C:13](Br)[N:14]=1.[NH2:19][CH2:20][CH2:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25]N=1.[CH:32](N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([NH:19][CH2:20][CH2:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:32]=2)[CH:12]=[N:11][C:10]=1[N+:16]([O-:18])=[O:17]
Reactant: CCN(C(C)C)C(C)C
Reactant: NCCNc1ccc([N+](=O)[O-])cn1
Reactant: O=[N+]([O-])c1ncc(Br)nc1-c1ccc(Cl)cc1Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(NCCNc2cnc([N+](=O)[O-])c(-c3ccc(Cl)cc3Cl)n2)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of 3-(2,4-dichlorophenyl)-5-bromo-2-nitropyrazine (20 mg, 0.057 mmol) in DMF (1 ml), (2-aminoethyl)(5-nitro(2-pyridyl))amine (11.3 mg, 0.06 mmol) and diisopropylethyl amine (40 μl, 0.228 mmol) were added. The reaction mixture was stirred for 12 hours at 80° C. The crude mixture was concentrated in vacuo and subjected to column chromatography (5% methanol in methylene chloride) to afford the title compound as bright yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[C:15](\[CH3:18])/[CH2:16]O)=[CH:10][CH:9]=2)[CH:2]=1.S(Cl)([Cl:21])=O>C(Cl)Cl>[ClH:21].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[C:15](\[CH3:18])/[CH2:16][Cl:21])=[CH:10][CH:9]=2)[CH:2]=1
Reactant: C/C(=C\c1ccc(Cc2cccnc2)cc1)CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: C/C(=C\c1ccc(Cc2cccnc2)cc1)CCl
Product: Cl

Procedure:
In 24 ml of methylene chloride was dissolved 1.2 g of (E)-3-[4-(pyridin-3-ylmethyl)phenyl]-2-methylallyl alcohol, and 1.8 ml of thionyl chloride was dropped into the resulting solution with ice-cooling, after which the resulting mixture was subjected to reaction under reflux for 30 minutes. The solvent and the excessive thionyl chloride were removed by distillation under reduced pressure, to obtain as the residue (E)-3-[4-(pyridin-3-ylmethyl)phenyl]-2-methylallyl chloride hydrochloride. This was crystallized from a mixed solvent of 2-propanol and ethyl acetate to obtain colorless, needle-like crystals having a melting point of 118°-120° C.
Reaction SMILES: [CH2:1](I)[CH3:2].[C:4]1([C:10]2[NH:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CI.CN1C=C(C(F)(F)F)N=C1C1C=CC=CC=1>>[CH2:1]([N:11]1[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=[C:10]1[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: FC(F)(F)c1c[nH]c(-c2ccccc2)n1
Reactant: CCI
Agent: Cn1cc(C(F)(F)F)nc1-c1ccccc1
Solvent: CI
Product: CCn1cc(C(F)(F)F)nc1-c1ccccc1

Procedure:
By substituting equivalent amounts of ethyl iodide and 2-phenyl-4-trifluoromethylimidazole for the methyl iodide and 2-(2-pyridyl)-4(5)-trifluoromethylimidazole of Example 57 and following substantially the procedure described therein there is obtained 1-ethyl-2-phenyl-4-trifluoromethylimidazole, b.p., 160°-165° C. at 0.5 mm.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[S:9](Cl)([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10]>C(N(CC)CC)C>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:3][CH2:2]1
Reactant: OCC1CCOCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2CCOCC2)cc1

Procedure:
Commercially available (tetrahydro-2H-pyran-4-yl) methanol (Maybridge), tosyl chloride and triethylamine were processed using the method described in Example 184B to afford the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 1.05-1.25 (m, 2 H), 1.40-1.53 (m, 2 H), 1.73-1.94 (m, 1 H), 2.43 (s, 3 H), 3.14-3.28 (m, 2 H), 3.71-3.84 (m, 2 H), 3.88 (d, J=6.4 Hz, 2 H), 7.48 (d, J=8.5 Hz, 2 H), 7.79 (d, J=8.5 Hz, 2 H).
Reaction SMILES: [OH:1][N:2]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:23]([O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([CH2:37][NH:38][CH2:39][CH:40]([N:44]2[CH2:49][CH2:48][N:47]([S:50]([CH3:53])(=[O:52])=[O:51])[CH2:46][CH2:45]2)[C:41](O)=[O:42])(=[O:36])=[O:35])=[CH:30][CH:29]=1)[C:24]#[C:25][CH3:26].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH2:23]([O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([CH2:37][NH:38][CH2:39][CH:40]([N:44]2[CH2:45][CH2:46][N:47]([S:50]([CH3:53])(=[O:51])=[O:52])[CH2:48][CH2:49]2)[C:41]([NH:2][OH:1])=[O:42])(=[O:36])=[O:35])=[CH:30][CH:29]=1)[C:24]#[C:25][CH3:26]
Reactant: On1nnc2ccccc21
Reactant: CC#CCOc1ccc(S(=O)(=O)CNCC(C(=O)O)N2CCN(S(C)(=O)=O)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)CNCC(C(=O)NO)N2CCN(S(C)(=O)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.2 %

Procedure:
63 mg (0.5 mmol) of 1-hydroxybenzotriazole and then 88 mg (0.5 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride are added to a solution of 200 mg (0.4 mmol) of 3-[(4-but-2-ynyloxybenzenesulfonyl)methylamino]-2-(4-methanesulfonylpiperazin-1-yl)propanoic acid in 6 ml of dimethylformamide. The reaction medium is stirred for 10 min at ambient temperature and then 68 mg (0.5 mmol) of O-tert-butyldimethysilylhydroxylamine are added. The reaction medium is then stirred at ambient temperature for 24 h, hydrolyzed by adding 2 ml of a 5% aqueous citric acid solution, and stirred for a further 30 minutes. After extraction with ethyl acetate, the organic phase is washed with water, dried over magnesium sulfate, filtered and concentrated. The crude residue is purified by chromatography on silica gel, elution being carried out with a 95/5 dichloromethane/methanol mixture. 100 mg (50%) of 3-[(4-but-2-ynyloxybenzenesulfonyl) methylamino]-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)propionamide are obtained in the form of a white solid with a melting point of 86° C.
Reaction SMILES: [NH2:1][CH:2]([CH3:28])[CH2:3][N:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[O:7][CH2:6][CH:5]1[CH2:12][NH:13][C:14]1[CH:15]=[C:16]([Cl:27])[CH:17]=[C:18]2[C:26]=1[NH:25][C:24]1[CH:23]=[N:22][CH:21]=[CH:20][C:19]2=1.[CH3:29][C:30]1[O:34][N:33]=[C:32]([C:35](Cl)=[O:36])[CH:31]=1.C([O-])(=[O:40])C.[NH4+]>>[Cl:27][C:16]1[CH:17]=[C:18]2[C:26](=[C:14]([NH:13][C:12]([CH:5]3[CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH2:9][N:4]3[CH2:3][CH:2]([NH:1][C:35]([C:32]3[CH:31]=[C:30]([CH3:29])[O:34][N:33]=3)=[O:36])[CH3:28])=[O:40])[CH:15]=1)[NH:25][C:24]1[CH:23]=[N:22][CH:21]=[CH:20][C:19]2=1
Reactant: CC(N)CN1CC(C)(C)OCC1CNc1cc(Cl)cc2c1[nH]c1cnccc12
Reactant: CC(=O)[O-]
Reactant: Cc1cc(C(=O)Cl)no1
Agent: [NH4+]
Product: Cc1cc(C(=O)NC(C)CN2CC(C)(C)OCC2C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)no1
Yield: 61 %

Procedure:
The desired compound was prepared using [4-(2-Amino-propyl)-6,6-dimethyl-morpholin-3-ylmethyl]-(6-chloro-9H-beta-carbolin-8-yl)-amine and 5-methylisoxazole carbonyl chloride following Method E in 61% yield. 1H-NMR (300 MHz, DMSO): δ 11.2 (1H, s), 9.98 (1H, s), 9.0 (1H, s), 8.7 (1H, d), 8.6 (1H, d), 8.2 (2H, m), 7.9 (1H, s). 6.47 (1H, s), 3.87 (2H, m), 3.17 (2H,m), 2.9 (1H, d), 2.7 (1H, m), 2.3 (4H), 2.1 (1H, d), 1.29 (3H, s), 1.15 (6H, m). Retention time (LC, method: ammonium acetate standard): 1.81 min. MS (M+H+): 526
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1.[F:18][C:19]1[C:24](F)=[C:23]([F:26])[C:22]([F:27])=[C:21]([F:28])[C:20]=1[F:29].O>CN(C)C=O>[CH3:17][C:14]1[CH:13]=[CH:12][C:11]([C:4]2([O:3][C:24]3[C:23]([F:26])=[C:22]([F:27])[C:21]([F:28])=[C:20]([F:29])[C:19]=3[F:18])[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]2)=[CH:16][CH:15]=1
Reactant: Cc1ccc(C2(O)CCN(C)CC2)cc1
Reactant: Fc1c(F)c(F)c(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C2(Oc3c(F)c(F)c(F)c(F)c3F)CCN(C)CC2)cc1
Temperature: 85 °C

Procedure:
To a suspension of sodium hydride (2.2 g, 60% in oil) in 20 ml of dimethylformamide, was added a solution of 11.0 g of 4-hydroxy-4-(4-methylphenyl)-1-methylpiperidine in 50 ml of dimethylformamide. After heating to 85° C. for thirty minutes, the mixture was cooled with an ice-bath, and treated over a period of ten minutes with a solution of 7 ml of hexafluorobenzene in 20 ml of dimethylformamide. After stirring at ambient temperature for twenty hours, the mixture was poured into 200 ml water, stirred for five minutes, then extracted with ethyl acetate (2×). The organic layer was washed with water (2×), followed by a saturated solution of sodium chloride, and dried over anhydrous magnesium sulfate. After filtering, evaporation of the solvent afforded a residue which was purified by means of high pressure liquid chromatography (silica gel; elution with 10% methanol/dichlormethane). The desired fractions were combined, and evaporated to yield 13 g of (4-(4-methylphenyl)-1-methyl-4-(2,3,4,5,6-pentafluorophenoxy) piperidine as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:33][C:32]([C:34](O)=[O:35])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1>C1COCC1>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:33][C:32]([C:34]([NH:1][C:2]3[CH:7]=[C:6]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]5[CH2:20][CH2:19]5)=[O:15])=[CH:10][CH:9]=4)[C:5]([CH3:21])=[CH:4][CH:3]=3)=[O:35])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)o1
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2ccc(-c3ccc(Cl)cc3)o2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 10.9 %

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide (53 mg, 0.189 mmol) and 5-(4-chlorophenyl)-2-furoic acid (84.2 mg, 0.378 mmol) were mixed in THF (5 ml) and the mixture shaken in a varian tube for 15 min at room temperature. Carbodiimde resin (500 mg) was added and shaking continued for 18 h. The solution was filtered off and concentrated under vacuum. The residue was dissolved in methanol, filtered through an SCX SPE and the solvent evaporated under vacuum to give 5-(4-chlorophenyl)-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2- furamide (10 mg, 11%). NMR; δH CDCl3 8.07,(1H, b), 7.85,(2H, d), 7.69-7.65,(3H, m), 7.52,(1H, d), 7.44-7.41,(4H, m), 7.31-7.29,(2H, m), 6.98,(1H, b), 6.79,(1H, d), 3.36,(2H, m), 2.25,(3H, s), 1.10,(1H, m), 0.60,(2H, m), 0.31,(2H, m). LCMS: retention time 3.92 min, MH+485.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11](=[O:18])[NH:10][C:9]2[CH:19]=[CH:20][CH:21]=[N:22][C:8]1=2)=[O:6].[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O1CCOCC1>[N:23]1([CH2:2][CH2:3][CH2:4][C:5]([N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[NH:10][C:9]3[CH:19]=[CH:20][CH:21]=[N:22][C:8]2=3)=[O:6])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C1CCNC1
Reactant: O=C1Nc2cccnc2N(C(=O)CCCCl)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: O=C1Nc2cccnc2N(C(=O)CCCN2CCCC2)c2ccccc21

Procedure:
5.5 gm of 11-(4-chlorobutyryl)-5,11-dihydro-6H-pyrido [2,3-b][1,4]-benzodiazepin-6-one, 1.4 gm of pyrrolidine and 2.1 gm of sodium carbonate were refluxed in a mixture of 80 ml of absolute ethanol and 20 ml of absolute dioxane for 10 hours. Then the hot mixture was suction-filtered, the filtrate was evaporated in vacuo to dryness, and the residue was purified on a silica gel column. The eluate was evaporated in vacuo to dryness, and the residue was recrystallized from acetonitrile.
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[CH3:3].C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[N:18]=1>C1(C)C=CC=CC=1.C(OCC)C>[Cl:23][C:19]1[N:18]=[C:17]([C:2]([CH3:4])([CH3:3])[C:1]#[N:5])[CH:22]=[CH:21][CH:20]=1
Reactant: Clc1cccc(Cl)n1
Reactant: CC(C)C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)(C#N)c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of isobutyronitrile (T) (830 mg, 12 mmol, 1 equiv.) in toluene (16 mL) at 0° C., a solution of KHMDS 0.5 M in toluene (26 mL, 13 mmol, 1.05 equiv.) was added. The resulting mixture was warmed to room temperature and stirred for 15 min. This mixture was then added to a solution of 2,6-dichloropyridine (S)(4.39 g, 29.7 mmol, 2.5 equiv.) in toluene (10 mL) and the resulting solution was stirred at room temperature for 1 h. The reaction was quenched with a saturated solution of NH4Cl, followed by aqueous NaHCO3. The crude reaction was diluted in diethyl ether, washed with brine, dried over anhydrous Na2SO4 and the solvent was then removed under reduced pressure. The resulting material was purified by flash chromatography on silica gel, eluting with mixtures of dichloromethane/hexanes (2:1). The title compound U was isolated as a white solid (1.1 g, 51%). 1-(6-chloropyridin-2-yl)cyclopropanecarbonitrile (V), 1-(6-chloropyridin-2-yl)cyclopentanecarbonitrile (W), 1-(6-chloropyridin-2-yl)cyclohexanecarbonitrile (X), and ethyl 2-(6-chloropyridin-2-yl)-2-methylpropanoate (Y) were made following the procedure for 2-(6-chloropyridin-2-yl)-2-methylpropanenitrile (U).
Reaction SMILES: [OH-].[Al+3:2].[OH-].[OH-].[S:5](=[O:9])(=[O:8])([OH:7])[OH:6]>>[S:5]([O-:9])([O-:8])(=[O:7])=[O:6].[Al+3:2].[S:5]([O-:9])([O-:8])(=[O:7])=[O:6].[S:5]([O-:9])([O-:8])(=[O:7])=[O:6].[Al+3:2]
Reactant: O=S(=O)(O)O
Agent: [Al+3]
Agent: [OH-]
Product: O=S(=O)([O-])[O-]

Procedure:
According to a further method, the aluminum hydroxide obtained above as an intermediate product or a highly aluminous clay mineral is reacted with sulfuric acid to obtain aluminum sulfate. Then, aluminum hydroxide is precipitated by neutralization with alkali, followed by filtration and water-washing. Thereafter, the resulting slurry is subjected to wet pulverization using a beads mill or a pot mill and subsequent spray drying into a spherical alumina.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]([CH3:19])=[C:11]([Cl:18])[C:12]([F:17])=[CH:13]2)=[C:8]([CH:20]2[CH2:22][CH2:21]2)[CH:7]=1)=[O:5])C.C(=O)(O)[O-].[Na+].C(OC([NH:35][C@@H:36]([C@@H:38]1[CH2:42][CH2:41][NH:40][CH2:39]1)[CH3:37])=O)(C)(C)C>C(#N)C>[ClH:18].[NH2:35][CH:36]([CH:38]1[CH2:42][CH2:41][N:40]([C:7]2[C:8]([CH:20]3[CH2:22][CH2:21]3)=[C:9]3[N:14]([C:15](=[O:16])[C:6]=2[C:4]([OH:3])=[O:5])[CH:13]=[C:12]([F:17])[CH:11]=[C:10]3[CH3:19])[CH2:39]1)[CH3:37]
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Reactant: C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Cc1cc(F)cn2c(=O)c(C(=O)O)c(N3CCC(C(C)N)C3)c(C3CC3)c12
Product: Cl

Procedure:
A 0.35 g sample of 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester, from Example 253i above, and 0.73 g of sodium bicarbonate were dissolved in 24 mL of anhydrous acetonitrile, reacted with (3R,1R)-3-(1-(t-butoxycarbonylamino)ethyl)-pyrrolidine (0.51 g, prepared as described by Schroeder et al., J. Heterocyclic Chem., 29:1481-1498 (1992)), and carried forward as described in Example 253k-l to give the title product. mp 220°-222° C. MS 374 (M+H)+ ; 1H NMR (D6 -DMSO) ∂: 0.61 (m, 2H), 0.94 (m, 1H), 1.07 (m, 1H), 1.28 (d, 3H, J=6 Hz), 1.82 (m, 1H), 2.27 (m, 2H), 2.46 (m, 1H), 2.62 (s, 3H), 3.57 (s, 1H), 3.92 (m, 1H), 7.90 (s, 1H), 8.17 (br s, 3H), 9.07 (d, 1H, J=l 1 Hz), 13.84 (brs, 1H).
Reaction SMILES: O[Li].O.[CH3:4][C:5]1[CH:6]=[CH:7][C:8]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:9]([CH:20]=1)[C:10]([O:12]CC1C=CC=CC=1)=[O:11].C1COCC1.Cl>C(OCC)(=O)C.O>[CH3:4][C:5]1[CH:6]=[CH:7][C:8]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:9]([CH:20]=1)[C:10]([OH:12])=[O:11]
Reactant: Cc1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(OCc2ccccc2)c(C(=O)O)c1

Procedure:
LiOH.H2O (0.379 g, 9.03 mmol) was added to a stirred solution of phenylmethyl 5-methyl-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 8; 1.0 g, 3.01 mmol) in a 3:1 mixture of THF:H2O (40 ml). The mixture was refluxed for 12 h and then diluted with ethyl acetate (50 ml). 10% aqueous HCl was added to the mixture to adjust the pH to 2. The organic phase was isolated, washed with brine, dried over MgSO4, and concentrated to yield the title compound as a yellow solid. 500 mg.