Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([P:14](=[O:23])([O:19][CH:20]([CH3:22])[CH3:21])[O:15][CH:16]([CH3:18])[CH3:17])[P:4](=[O:13])([O:9][CH:10]([CH3:12])[CH3:11])[O:5][CH:6]([CH3:8])[CH3:7].Br[CH:25]([CH2:31][CH3:32])[C:26]([O:28]CC)=[O:27].[I-].[Na+]>CN(C)C=O.O>[CH:20]([O:19][P:14]([O:15][CH:16]([CH3:18])[CH3:17])([CH:3]([P:4]([O:9][CH:10]([CH3:11])[CH3:12])([O:5][CH:6]([CH3:8])[CH3:7])=[O:13])[CH2:32][CH2:31][CH2:25][C:26]([OH:28])=[O:27])=[O:23])([CH3:22])[CH3:21]
Reactant: CCOC(=O)C(Br)CC
Reactant: CC(C)OP(=O)(CP(=O)(OC(C)C)OC(C)C)OC(C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)OP(=O)(OC(C)C)C(CCCC(=O)O)P(=O)(OC(C)C)OC(C)C
Reaction time: 0.17 h
Yield: 8.7 %

Procedure:
Under a nitrogen atmosphere, 60% sodium hydride (2.56 g) was suspended in dry N,N-dimethylformamide (20 ml), and tetraisopropyl methylenebisphosphonate (20.0 g) was added dropwise thereto at room temperature. After stirring for 10 minutes, ethyl bromobutyrate (8.4 ml) was added dropwise thereto and the resulting mixture was stirred at 100° C. for 1 hour. Then, sodium iodide (0.85 g) was added thereto and stirred for 4 hours. Water was added thereto, followed by extraction (twice) with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in methanol (50 ml), followed by adding thereto a 2N aqueous sodium hydroxide solution (10 ml), and the resulting mixture was stirred with heating under reflux for 3 hours. The mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure, and then the residue was purified by a silica gel column chromatography to obtain 5,5-bis(diisopropoxyphosphinoyl)valeric acid (1.88 g, yield 8.7%). 1H-NMR (CDCl3) δ: ppm; 1.34 (12H, d, J=6.3 Hz), 1.34 (12H, d, J=5.9 Hz), 1.8-2.4 (7H, m), 4.7-4.9 (4H, m).
Reaction SMILES: C([O:5][C:6]([C:8]1([CH2:12][NH:13][C:14]([C:16]2[N:17]=[C:18]([C:35]#[N:36])[C:19]3[C:20](=[O:34])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:22]=[CH:23][C:24]=3[C:25]=2[OH:26])=[O:15])[CH2:11][CH2:10][CH2:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:27]([N:21]1[C:20](=[O:34])[C:19]2[C:18]([C:35]#[N:36])=[N:17][C:16]([C:14]([NH:13][CH2:12][C:8]3([C:6]([OH:7])=[O:5])[CH2:9][CH2:10][CH2:11]3)=[O:15])=[C:25]([OH:26])[C:24]=2[CH:23]=[CH:22]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)C1(CNC(=O)c2nc(C#N)c3c(=O)n(Cc4ccccc4)ccc3c2O)CCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1nc(C(=O)NCC2(C(=O)O)CCC2)c(O)c2ccn(Cc3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
1-{[(7-Benzyl-1-cyano-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carbonyl)-amino]-methyl}-cyclobutanecarboxylic acid tert-butyl ester (32 mg, 0.066 mmol) was dissolved in 2 mL of CH2Cl2. Trifluoroacetic acid (0.4 mL) was added, and the mixture was stirred at r.t. for 2 h. The mixture was concentrated in vacuo, and the residue was dissolved in saturated NaHCO3. The aqueous solution was washed with ether, and then acidified to pH about 1 with 4 M HCl to give a white suspension. The solid was isolated by filtration and dried under vacuum to give 22 mg of the title compound as an off-white solid. MS: (+) m/z 433.35 (M+1).
Reaction SMILES: [CH3:1][C@@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[O:31])[CH:25]=[C:26]([Cl:28])[CH:27]=1.Cl>CN(C)C1C=CN=CC=1.ClCCl>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:31])[CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: CC1(C)C2CC[C@]1(C)C(=O)CC2=O
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@]1(C)C(=O)C(C(=O)Nc1cc(Cl)cc(Cl)c1)C2=O
Temperature: 30 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
To an ice-cooled solution of (1S)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.18 g, 1.0 mmole), triethylamine (0.10 g, 1.0 mmole) and 4-(dimethylamino)pyridine (0.12 g, 1.0 mmole) in dry dichloromethane (25 mL) was added a solution of 3,5dichlorophenyl isocyanate (0.19 g, 1.0 mmole) in dry dichloromethane (5 mL). The resulting mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature, and then was heated at 30° C. for 7 hours. The reaction mixture was treated with 2N aqueous HCl and the layers separated. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield a yellow oil, which was crystallized from 95% ethanol to yield the title compound as a beige solid (0.20 g, 55% yield), mp=112–114° C.; MS (−) ESI m/z=366 (M−H)−; [α]D25=−25.4° (c=1, EtOH).
Reaction SMILES: I[C:2]1[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=1.[S:24]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25]1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH3:22])[N:12]=[CH:11][CH:10]=[C:9]2[O:8][C:7]1[C:2]([C:26]2[CH:27]=[CH:28][S:24][CH:25]=2)=[N:3][C:4]([CH3:23])=[CH:5][CH:6]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: OB(O)c1ccsc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3ccsc3)c2cc1OC
Temperature: 80 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxyquinoline (compound 116) (84 mg), 3-thiopheneboronic acid (128 mg), and tetrakistriphenylphosphine palladium (12 mg) were dissolved in toluene (1 ml) to prepare a solution. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was added to the solution, and the mixture was stirred at 80° C. for 3 hr. The reaction solution was filtered, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using methanol-chloroform to give the title compound (58 mg, yield 77%).
Reaction SMILES: Cl.[CH:2]1([NH:5][C:6](=[NH:8])[CH3:7])[CH2:4][CH2:3]1.Br[C:10](=[CH:13]OC(C)C)[CH:11]=[O:12].C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl.O>[CH:2]1([N:5]2[C:10]([CH:11]=[O:12])=[CH:13][N:8]=[C:6]2[CH3:7])[CH2:4][CH2:3]1
Reactant: CC(C)OC=C(Br)C=O
Reactant: CC(=N)NC1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ncc(C=O)n1C1CC1
Reaction time: 8 h
Yield: 35.8 %

Procedure:
Ethyl acetimidate hydrochloride (5.0 g, 40 mmol) and cyclopropylamine (2.3 mL, 40 mL) were dissolved in 45 mL of EtOH and heated to 85° C. in a sealed pressure vessel overnight. The mixture was cooled and concentrated to provide N-cylcopropyl-acetamidine hydrochloride as a viscous oil. N-Cyclopropyl-acetamidine hydrochloride (1.00 g, 7.43 mmol) and 2-bromo-3-isopropoxy-propenal (Shilcrat, S. C. et al. J. Org. Chem., 1997, 62, 8449–8454) (1.45 g, 7.50 mmol) were dissolved in 13 mL of CHCl3 and 1.6 mL of water. Then K2CO3 (1.5 g, 11 mmol) was added and the mixture was stirred overnight. The reaction was partitioned between CH2Cl2 (60 mL) and water (30 mL). The layers were separated and the aqueous portion was extracted with CH2Cl2 (40 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4), filtered, concentrated, and chromatographed to provide 400 mg of 3-cyclopropyl-2-methyl-3H-imidazole-4-carbaldehyde.
Reaction SMILES: [CH2:1]([C:8]1[S:14][CH:13]2[CH:10]([C:11](=[O:29])[N:12]2[C:15](=[C:26]([OH:28])[CH3:27])[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>O1CCCC1.C(N(CC)CC)C>[CH2:1]([C:8]1[S:14][CH:13]2[CH:10]([C:11](=[O:29])[N:12]2[C:15](=[C:26]([O:28][S:31]([CH3:30])(=[O:33])=[O:32])[CH3:27])[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)=C(C(=O)OCc1ccccc1)N1C(=O)C2N=C(Cc3ccccc3)SC21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(OS(C)(=O)=O)=C(C(=O)OCc1ccccc1)N1C(=O)C2N=C(Cc3ccccc3)SC21
Reaction time: 0.92 h

Procedure:
One adds to a solution of benzyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hydroxyethylidene)acetate (1.424 g) in tetrahydrofuran (15 ml), triethylamine (0.96 ml), and methanesulfonyl chloride (0.28 ml) at -30° to -20° C., stirs for 55 minutes to give benzyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-methanesulfonyloxyethylidene)acetate, adds morpholine (0.40 ml) and stirs for 5 hours at -10° C. to +3° C. to give benzyl α-[3-benzyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-morpholinoethylidene)-acetate, cools to -35° C. to -30° C., adds pyridine (0.27 ml) and bromine in carbon tetrachloride (1 mmole/ml: 3.2 ml), and stirs for 20 minutes to give benzyl α-[3-benzyl- 7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]hept-2-en-6-yl]-α-(1-morpholino-2-bromoethylidene)acetate, adds 5% hydrochloric acid (13 ml) and methanol (50 ml), and kept at 0° C. overnight to hydrolyze and cyclize giving the cephem product. The solvent is removed under reduced pressure, and the residual solution is extracted with ethyl acetate. The extract solution is washed with saturated saline and water, dried over sodium sulfate, and purified by chromatography over silica gel containing 10% water. The fractions containing the product are combined and evaporated. Recrystallization of the residue from a mixture of methanol, ether, and hexane gives benzyl 7-phenylacetamido-3-hydroxy-3-cephem-4-carboxylate. m.p. 149°-162° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[C:13]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:16]([C:19](Cl)=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C>C1COCC1>[O:12]=[C:8]1[CH2:7][CH2:6][CH2:5][C:4]2[CH:3]=[C:2]([NH:1][C:19]([C:16]3[CH:17]=[CH:18][C:13]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:14][CH:15]=3)=[O:20])[CH:11]=[CH:10][C:9]1=2
Reactant: Nc1ccc2c(c1)CCCC2=O
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2c(c1)CCCC2=O)c1ccc(-c2ccccc2)cc1
Yield: 86 %

Procedure:
Reaction of 6-Amino-3,4-dihydro-2H-naphthalen-1-one (80 mg, 0.50 mmol) in THF (6 mL) with 4-biphenylcarbonyl chloride (143 mg, 0.65 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave biphenyl-4-carboxylic acid (5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl)-amide (150 mg, 0.43 mmol, 86% yield) as a white powder after purification by flash chromatography on silica gel (EtOAc/DCM 1/9 to 2/8).
Reaction SMILES: [CH2:1]([NH:4][S:5]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[Cl:17])[C:11]([OH:13])=[O:12])(=[O:7])=[O:6])[CH:2]=[CH2:3].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.Cl>CN(C)C=O>[ClH:17].[CH2:1]([NH:4][S:5]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[N:22]1[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]1)[C:11]([OH:13])=[O:12])(=[O:7])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCNS(=O)(=O)c1cc(C(=O)O)ccc1Cl
Reactant: CN1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Product: C=CCNS(=O)(=O)c1cc(C(=O)O)ccc1N1CCN(C)CC1
Temperature: 140 °C

Procedure:
A mixture of 28 g of 3-allylsulfamoyl-4-chlorobenzoic acid, 30 g of N-methylpiperazine and 20 ml of dimethylformamide was heated for 4 hours at 140° C. When the reaction solution was subsequently introduced into 0.3 l of 2N HCl, the monohydrochloride crystallized immediately. The product was then purified by recrystallization from water.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:7][C:8]=1[Cl:9].[CH2:14]1[CH2:19][CH2:18][CH:17]([N:20]=[C:21]=[N:22][CH:23]2[CH2:28]CCCC2)CC1.CCN(CC)CC>>[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([N:22]2[CH2:23][CH2:28][N:20]3[CH2:17][CH2:18][CH2:19][CH2:14][C@H:21]23)=[O:13])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Br
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCN2CCCC[C@@H]21
Yield: 63.5 %

Procedure:
The HBr salt of the title product of Example 4 (1.00 g, 3.3 mmol) and 3,4-dichlorophenylacetic acid (1.07 g, 5.2 mmol, 1.5 eq) and DCC (1.43 g, 6.9 mmol, 2.0 eq) were reacted by addition of Et3N (2.4 mL, 5.0 eq) to give the title -compound (0.84 g, 92%) as a colorless crystalline solid. The reaction was-conducted as follows. To a stirred solution of the dichlorophenylacetic acid in CH2Cl2 (100 mL) was added a solution of the DCC in CH2Cl2 (100 mL) and the solution was stirred for 10 min at rt. To the precipitated complex was added the salt of the title compound of Example 4 followed by the Et3N and stirring was continued until TLC (solvent system A) indicated the reaction to -be complete. The precipitated DCU was removed by filtration and the filter cake was washed with Et20 (50 mL). The filtrate was diluted with enough Et20 to render the organic layer less dense than the aqueous layer, and the organic extract was then extracted with 10% aqueous -citric acid (200 mL) and discarded. The aqueous layer was washed with Et20 (2×200 mL) and the combined washings were discarded. The aqueous layer was basified by addition of excess concentrated aqueous NH3 solution and extracted with CH2Cl2 (2×200 mL). The combined organic layer was washed with water, dried (Na2SO4) and evaporated to give the desired product: mp 102.5-103.5° C. 2-propanol);
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([OH:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:16]([N:23]1[CH2:28][CH2:27][CH:26](O)[CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:1]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:15][CH:26]2[CH2:27][CH2:28][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:24][CH2:25]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(C(C)(C)C)cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)(C)C)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 72 h

Procedure:
To a stirring solution of methyl 4-tert-butyl-2-hydroxybenzoate (9.45 g, 45.4 mmol), 1-Boc-piperidin-4-ol (9.6 g, 47.7 mmol) and triphenylphosphine (12.5 g, 47.7 mmol) in THF (125 mL) was added, dropwise via an addition funnel, a solution of diisopropyl azodicarboxylate (9.4 mL, 47.7 mmol) in THF (25 mL). After 72 h, the solvent was removed in vacuo and the residue was dissolved in a minimal amount of chloroform and vacuum filtered through a pad of silica gel, eluting with a solution of 20% ethyl acetate in hexanes. The filtrate was then concentrated in vacuo and the residue was chromatographed over silica gel, eluting with a gradient of 5% ethyl acetate in hexanes through 20% ethyl acetate in hexanes. The product containing fractions were combined and concentrated in vacuo to give the ether (12.9 g, 73%) as a thick colorless oil.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].[H-].[Na+]>CN(C)C=O>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:17]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Oc1ccc(OCCCCCn2ccnc2)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(OCCCCCn2ccnc2)cc1

Procedure:
To a solution of 2.46 g p-[5-(1-imidazolyl)pentyloxy]phenol and 1.2 ml ethyl bromoacetate in 25 ml anhydrous N,N-dimethylformamide, was added under ice cooling and with stirring 440 mg of 60% sodium hydride in oil, and stirring was continued at room temperature for ten minutes. The solvent was distilled off, the residue was dissolved in chloroform, and the solution was washed with water and dried over anhydrous sodium sulfate. After distilling off the chloroform, the residue was purified by silical gel column chromatography, affording 2.7 g of ethyl p-[5-(1-imidazol-yl)pentyloxy]phenoxyacetate as oil.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]2[N:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1.Br[C:17]1[CH:18]=[CH:19][C:20]2[C:21]3[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28][CH2:27][C:22]=3[N:23]([CH3:26])[C:24]=2[CH:25]=1>>[CH3:26][N:23]1[C:24]2[CH:25]=[C:17]([N:4]3[CH:5]=[CH:6][C:7]([C:9]4[N:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=4)=[CH:8][C:3]3=[O:2])[CH:18]=[CH:19][C:20]=2[C:21]2[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28][CH2:27][C:22]1=2
Reactant: COc1cc(-c2ccc(C)nn2)ccn1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Product: Cc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CCN(C(=O)OC(C)(C)C)C5)c(=O)c2)nn1
Yield: 59.7 %

Procedure:
3-(2-Methoxypyridin-4-yl)-6-methylpyridazine (133 mg, 0.710 mmol) and tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (259 mg, 0.71 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (200 mg, 59%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J=8.7 Hz, 1H), 7.60 (d, J=7.2 Hz, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.39 (d, J=1.6 Hz, 1H), 7.29 (overlapping ddd, J=7.3, 1.8 Hz, 1H), 7.17 (d, J=1.8 Hz, 1H), 7.11 (d, J=7.6 Hz, 1H), 4.67 (br s, 2H), 3.91-3.83 (br m, 2H), 3.67 (s, 3H), 2.89-2.83 (br m, 2H), 2.53 (s, 3H), 1.52 (s, 9H).
Reaction SMILES: [CH2:1]1[C:3]2([CH2:11][NH:10][CH2:9][C:4]32[O:8][CH2:7][CH2:6][O:5]3)[CH2:2]1.Br[CH2:13][CH2:14][OH:15].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[OH:15][CH2:14][CH2:13][N:10]1[CH2:11][C:3]2([CH2:1][CH2:2]2)[C:4]2([O:5][CH2:6][CH2:7][O:8]2)[CH2:9]1
Reactant: C1COC2(CNCC23CC3)O1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCN1CC2(CC2)C2(C1)OCCO2

Procedure:
The compound (B) (100 mg) was mixed with 2-Bromoethanol (100 mg) and K2CO3 (120 mg) in Acetonitrile. The reaction was refluxed overnight and filtered, the filtrate was evaporated and purified on silica gel column to give the titled product. Mass: (M+1), 200
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH3:4].[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[O:15][C:14](=[O:16])[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:12]([OH:23])[C:11]=2[CH:24]=1.O>CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[O:15][C:14](=[O:16])[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:12]([O:23][CH2:1][CH2:2][CH2:3][CH3:4])[C:11]=2[CH:24]=1
Reactant: O=c1oc2ccc(Br)cc2c(O)c1-c1ccccc1
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1c(-c2ccccc2)c(=O)oc2ccc(Br)cc12
Reaction time: 48 h

Procedure:
Butyl bromide (0.05 ml) was added with stirring to a mixture of a solution of 6-bromo-4-hydroxy-3-phenyl-2H-1-benzopyran-2-one (80 mg) (Synthesis 1993, 99), in dry dimethylformamide (0.5 ml) and potassium carbonate (70 mg). The mixture was stirred for 48 hours and water (5 ml) was added. The mixture was extracted with diethyl ether and the extract washed with water, dried and evaporated under reduced pressure. The residue was washed with water and dried to give 6-bromo-4-butoxy-3-phenyl-2H-1-benzopyran-2-one, m.p. 87-9° C. (compound 29)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[Cl:27])[C:21](Cl)=[O:22]>CCOCC>[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[Cl:27])[C:21]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[N:9]1)=[O:22]
Reactant: CN1CCC(c2n[nH]c3ccccc23)CC1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: CCOCC
Product: CN1CCC(c2nn(C(=O)c3ccc(Cl)c(Cl)c3)c3ccccc23)CC1
Temperature: 100 °C
Yield: 57 %

Procedure:
A mixture of 3.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole and 8 ml of 3,4-dichlorobenzoyl chloride was heated at 100° C. in a steam bath for 4 hrs. After the reaction mixture cooled to ambient temperature, ether was added and the salt was collected. The salt was mixed with water and ammonium hydroxide solution was added until the mixture was basic. The mixture was warmed on the steam bath for about 5 mins, cooled and extracted with dichloromethane. Evaporation of the dichloromethane in vacuo provided the free base. The base was recrystallized from methanol-trichloromethane (with concentration of the mother liquor) to yield 3.0 g (57%) of product, mp 187°-189° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1)[C:4]([OH:6])=O.[NH2:20][CH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>>[C:21]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:4](=[O:6])[CH:3]([O:2][CH3:1])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=2)=[CH:24][CH:23]=1)#[N:20]
Reactant: N#Cc1ccc(CN)cc1
Reactant: COC(C(=O)O)c1cccc(Oc2ccccc2)c1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1cccc(Oc2ccccc2)c1

Procedure:
(RS)-Methoxy-(3-phenoxy-phenyl)-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-methoxy-2-(3-phenoxy-phenyl)-acetamide. Light yellow oil. MS 373.3 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.N12CCCN=C1CCCCC2.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[C:34]([O:42][CH2:43][C@@H:44]1[C@@:48]([O:50][C:51](=[O:53])[CH3:52])([CH3:49])[C@:47]([F:55])([CH3:54])[CH:46](OC(=O)C)[O:45]1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(#N)C>[C:34]([O:42][CH2:43][C@@H:44]1[C@@:48]([O:50][C:51](=[O:53])[CH3:52])([CH3:49])[C@:47]([F:55])([CH3:54])[CH:46]([N:6]2[CH:5]=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[Cl:1])[O:45]1)(=[O:41])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: CC(=O)OC1O[C@H](COC(=O)c2ccccc2)[C@](C)(OC(C)=O)[C@@]1(C)F
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)O[C@@]1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Reaction time: 0.25 h
Yield: 57 %

Procedure:
To a stirred solution of 6-chloropurine (about 0.87 g, 5.7 mmol) in acetonitrile (about 20 ml) was added 1,8-Diazabicyclo[5.4.0]undec-7-ene (about 1.7 ml, 11.4 mmol) and Trimethylsilyl trifluoromethanesulfonate (about 2.76 ml, 15.2 mmol) at about 0° C., stirred for about 15 minutes then ((2R,3S,4R)-3,5-diacetoxy-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 1.4 g, 3.8 mmol) dissolved in Acetonitrile (about 20 ml) was added and reaction continued stirring at about 65° C. for about 8 hours. Completion of reaction monitored by thin-layer chromatography and quenched with saturated sodium bicarbonate. Aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with saturated sodium bicarbonate solution, brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 20% ethyl acetate: hexane as eluent furnished title compounds Isomer A and B (0.7 g) as a colorless liquid. Yield: 57%;