Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([O:29]CC)=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([OH:29])=[O:28])([CH3:25])[CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Yield: 62.2 %

Procedure:
Racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (2.7 g, 4.5 mmol) was dissolved in THF (20 mL). Then aqueous solution (10 mL) of KOH (0.5 g) was added. The mixture was refluxed for 1 h. After cooled to room temperature, the solution was concentrated and then the residue was acidified to “pH” 2-3 by addition of concentrated aqueous HCl solution. The white solid was collected by filtration to give title compound (1.6 g).
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([C:19]([O:21]CC)=[CH2:20])=[C:13]1[C:12]1[C:7](=[C:8]([Cl:26])[C:9]([O:24][CH3:25])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].Cl>C(O)C.O>[C:19]([C:14]1[C:15](=[O:18])[CH2:16][CH2:17][C:5]2([CH2:1][CH2:2][CH2:3][CH3:4])[C:13]=1[C:12]1[C:7](=[C:8]([Cl:26])[C:9]([O:24][CH3:25])=[CH:10][CH:11]=1)[CH2:6]2)(=[O:21])[CH3:20]
Reactant: C=C(OCC)C1=C2c3ccc(OC)c(Cl)c3CC2(CCCC)CCC1=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCCCC12CCC(=O)C(C(C)=O)=C1c1ccc(OC)c(Cl)c1C2
Temperature: 80 °C

Procedure:
The product from step 1 in ethanol (1.0 mL), water (0.2 mL) and aqueous 2N HCl (0.2 mL) was stirred and heated in an oil bath at 80° C. for 40 minutes. After cooling, the mixture was partitioned between EtOAc (20 mL) and water (20 mL). The organic phase was washed with brine (20 mL), dried over MgSO4, filtered, and evaporated under vacuum to provide 4-acetyl-9a-butyl-8-chloro-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (54 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].Br[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.Cl.C>C1(C)C=CC=CC=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.O>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH:4][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1
Reactant: Nc1c(F)cccc1Cl
Reactant: Cc1ccc(Br)cc1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(Nc2c(F)cccc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
A mixture of 2-chloro-6-fluoroaniline (4.00 g, 27.5 mmol), 4-bromotoluene (4.70 g, 27.5 mmol), sodium tert-butylate (4.75 g, 49.4 mmol), and toluene (55 mL) is stirred at 25° C. under nitrogen for 30 minutes. To this mixture, a solution of palladium-bis-(dibenzylidenacetone) (15.8 mg, 55 mmol) and tri-tert-butylphosphine (1) (8.3 mg, 0.04 mmol) in toluene (5 mL) is added and the resulting suspension is stirred at 110° C. for 14 hours. The mixture is then cooled to 30° C. Water (30 ml), concentrated hydrochloric acid (10 ml), charcoal and cellite (1 g each) are added and stirring is continued for 1 hour. The mixture is filtered and the filtrate is separated into its phases. The organic phase is washed three times with water (10 mL) and concentrated in vacuo to give 6.5 g of crude (2′-chloro-6′-fluorophenyl)-(4-methylphenyl)-amine. The product can be used directly in the next step (Step 1.2). Alternatively, it can be distilled in vacuo by Kugelrohr.
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([NH:12][C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=1.[C:16]([Cu])#[N:17]>CN(C=O)C>[C:16]([C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([NH:12][C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=1)#[N:17]
Reactant: CC(=O)Nc1ccc(Br)c2c1CCCC2
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C#N)c2c1CCCC2
Temperature: 25 °C
Yield: 998.3 %

Procedure:
A suspension of compound 2B (1 g, 3.7 mmol) and CuCN (0.335 g, 0.374 mmol) in anhydrous DMF (8 mL) was refluxed for 5 h. After cooling to rt, the reaction mixture was concentrated under reduced pressure to remove most of the DMF and the remaining residue triturated with EtOAc (5×). The combined EtOAc was washed with water and brine, dried (Na2SO4), and concentrated under reduced pressure to dryness to yield compound 2C (0.8 g) as a yellow solid.
Reaction SMILES: Br[C:2]1[C:3]2[CH2:10][C:9]([CH3:12])([CH3:11])[CH:8]([OH:13])[C:4]=2[CH:5]=[N:6][CH:7]=1.[C:14]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)#[N:15]>>[OH:13][CH:8]1[C:4]2[CH:5]=[N:6][CH:7]=[C:2]([C:19]3[CH:20]=[CH:21][C:16]([C:14]#[N:15])=[CH:17][CH:18]=3)[C:3]=2[CH2:10][C:9]1([CH3:12])[CH3:11]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC1(C)Cc2c(Br)cncc2C1O
Product: CC1(C)Cc2c(-c3ccc(C#N)cc3)cncc2C1O

Procedure:
In analogy to the procedure described for the preparation of examples 85 and 86, 4-bromo-6,6-dimethyl-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (intermediate A-17) and 4-cyanophenylboronic acid gave racemic 4-[7-hydroxy-6,6-dimethyl-5,7-dihydrocyclopenta[c]pyridin-4-yl]benzonitrile. SFC separation afforded (+)-4-[(7R or 7S)-7-hydroxy-6,6-dimethyl-5,7-dihydrocyclopenta[c]pyridin-4-yl]benzonitrile (example 87) and (−)-4-[(7S or 7R)-7-hydroxy-6,6-dimethyl-5,7-dihydrocyclopenta[c]pyridin-4-yl]benzonitrile (example 88) as white solids. MS: 264.9 (M+H+).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[C:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CN(C)C=O>[CH2:1]([NH:8][C:9]([C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)C(=Cc2ccc(-c3cccc(C(=O)NCc4ccccc4)c3)cc2)S1
Solvent: CN(C)C=O
Product: O=C1NC(=O)C(Cc2ccc(-c3cccc(C(=O)NCc4ccccc4)c3)cc2)S1
Yield: 24 %

Procedure:
In a manner similar to that of Example 1(g), starting with 430 mg (1 mmol) of N-benzyl-4′-(2,4-dioxothiazolidin-5-ylidenemethyl)biphenyl-3-carboxamide in 7 ml of dimethylformamide, 100 mg (23%) of the desired product, with a melting point of 148° C., are obtained.
Reaction SMILES: O1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([CH2:21][CH:22]([CH:27]([CH3:29])[CH3:28])[C:23]([NH:25][OH:26])=[O:24])(=[O:20])=[O:19])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.CC(C)C(CS([N:40]1CCN(C2C=CC(C3C=NC=CC=3)=CC=2)C[CH2:41]1)(=O)=O)C(O)=O>>[N:40]1[CH:5]=[CH:4][CH:3]=[C:2]([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH2:21][CH:22]([CH:27]([CH3:29])[CH3:28])[C:23]([NH:25][OH:26])=[O:24])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][CH:7]=2)[CH:41]=1
Reactant: CC(C)C(CS(=O)(=O)N1CCN(c2ccc(-c3ccco3)cc2)CC1)C(=O)NO
Reactant: CC(C)C(CS(=O)(=O)N1CCN(c2ccc(-c3cccnc3)cc2)CC1)C(=O)O
Product: CC(C)C(CS(=O)(=O)N1CCN(c2ccc(-c3cccnc3)cc2)CC1)C(=O)NO
Yield: 76 %

Procedure:
Prepared according to the method for the preparation of 2-[4-(4-furan-2-yl-phenyl)piperazine-1-sulfonylmethyl]-N-hydroxy-3-methylbutyramide, from 3-methyl-2-[4-(4-pyridin-3-yl-phenyl)piperazine-1-sulfonylmethyl]butyric acid (0.075 g), to yield the title compound as a white solid (0.059 g, 76%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:20]=[C:19]([N:21]=[C:22]=[O:23])[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:9]=[CH:10][C:11]2[S:15][N:14]=[CH:13][C:12]=2[CH:16]=1>C(OCC)C>[Cl:4][C:5]1[CH:20]=[C:19]([NH:21][C:22]([N:2]([CH3:3])[CH3:1])=[O:23])[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:9]=[CH:10][C:11]2[S:15][N:14]=[CH:13][C:12]=2[CH:16]=1
Reactant: O=C=Nc1ccc(Oc2ccc3sncc3c2)c(Cl)c1
Reactant: CNC
Solvent: CCOCC
Product: CN(C)C(=O)Nc1ccc(Oc2ccc3sncc3c2)c(Cl)c1
Reaction time: 12 h
Yield: 70 %

Procedure:
5 parts of gaseous dimethylamine were passed into 30.3 parts of 5-(2'-chloro-4'-isocyanatophenoxy)-benzisothiazole and 300 parts of diethyl ether at from 20° to 30° C., the mixture was stirred for 12 hours at this temperature and the resulting precipitate was then isolated and dried. 27.5 parts (70% of theory) of 5-(2'-chloro-4'-dimethylaminocarbonylaminophenoxy)-benzisothiazole of melting point 149° C. were obtained.
Reaction SMILES: [CH3:1][N:2]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=1)[C:3](=[O:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[CH2:33](I)[CH3:34].O>ClCCl>[CH2:33]([N:30]1[CH2:31][CH2:32][N:27]([C:24]2[CH:23]=[CH:22][C:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][N:2]([CH3:1])[C:3](=[O:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:9])[CH3:10])[CH:16]=3)=[CH:26][CH:25]=2)[CH2:28][CH2:29]1)[CH3:34]
Reactant: CCI
Reactant: CN(Cc1cccc(-c2ccc(N3CCNCC3)cc2)c1)C(=O)CNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O
Product: CCN1CCN(c2ccc(-c3cccc(CN(C)C(=O)CNC(=O)OC(C)(C)C)c3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
tert-Butyl (2-{methyl[(4′-piperazin-1-ylbiphenyl-3-yl)methyl]amino}-2-oxoethyl)carbamate (180 mg) was dissolved in dichloromethane (3.6 ml), and TEA (125 mg) was added thereto under ice-cooling. Subsequently, ethyl iodide (128 mg) was added thereto, followed by stirring at room temperature overnight. To the reaction mixture was added water, followed by extraction with CHCl3. The organic layer was dried over MgSO4, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (2% MeOH/CHCl3) to obtain tert-butyl {2-[{[4′-(4-ethylpiperazin-1-yl)biphenyl-3-yl]methyl}(methyl)amino]-2-oxoethyl}carbamate (137 mg).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[O:3].[F:22][C:23]([F:37])([F:36])[C:24]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:25]=1[CH:26]=O>>[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:26][C:25]1[CH:28]=[CH:29][C:30]([C:32]([F:35])([F:34])[F:33])=[CH:31][C:24]=1[C:23]([F:22])([F:36])[F:37]
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: O=Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Product: O=C(C=Cc1ccc(C(F)(F)F)cc1C(F)(F)F)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
The title compound was prepared from a mixture of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (200 mg, 0.633 mmol) and 2,4-bis(trifluoromethyl)benzaldehyde (108 ul, 0.633 mmol) similar to Example 6 as a yellow solid (27 mg, 8%). 1H NMR (CDCl3): 8.03 (dd, J=2.0, 15.5 Hz, 1H), 7.97 (s, 1H), 7.93 (d, J=8.1 Hz, 1H), 7.86 (d, J=7.2 Hz, 1H), 7.50 (d, J=15.6 Hz, 1H), 7.35 (d, J=3.3 Hz, 1H), 7.18 (dd, J=3.3, 9.0 Hz, 1H), 6.95 (d, J=9.3 Hz, 1H), 4.47-4.35 (m, 4H).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]3[S:13][C:14]4[CH2:18][CH2:17][CH2:16][C:15]=4[C:10]3=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:8]=2[CH:26]([CH2:31][CH2:32][CH3:33])[C:27]([O:29]C)=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([C:7]2[N:12]=[C:11]3[S:13][C:14]4[CH2:18][CH2:17][CH2:16][C:15]=4[C:10]3=[C:9]([C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)[C:8]=2[CH:26]([CH2:31][CH2:32][CH3:33])[C:27]([OH:29])=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC(C(=O)OC)c1c(-c2ccccc2)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(-c2ccccc2)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3
Temperature: 60 °C
Yield: 38.8 %

Procedure:
To a solution of methyl 2-[2-phenyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate (0.194 g; 0.42 mmol) in methanol (4.2 mL) was added a solution of sodium hydroxide 10 N (0.42 ml) and the mixture was heated to 60° C. for 18 h. After cooling, the reaction mixture was concentrated under reduced pressure and the crude solid was suspended in ethyl acetate and the mixture was acidified with 1N HCl (pH˜2). The organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography silica using a mixture ethyl acetate/heptane (1/1)+0.5% acetic acid as eluent to afford 0.072 g (39%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23]O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.P(Br)(Br)[Br:27].C([O-])(O)=O.[Na+].CCOC(C)=O>COCCOC>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][Br:27])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CO)c1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CBr)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To (2′-hydroxymethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (1.855 g, 5.23 mmol) in DME (19 mL) was added phosphorus tribromide (0.74 mL, 7.85 mmol), and the reaction was stirred at room temperature for 1.5 hours. The mixture was cooled to 0° C., and saturated aqueous NaHCO3 and EtOAc were added. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:18])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[C:19](Cl)(=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:19](=[O:28])[CH:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:18])=[CH:21][CH:22]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(C(=O)CCc2ccccc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C(Cc2ccccc2)C(=O)c2ccc(OC)cc2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(4-methoxyphenyl)-3-phenylpropan-1-one (1.0 equiv.) in THF at −78° C. was added dropwise 1.5 equiv. of [(CH3)2Si]2NLi. The solution was stirred for 1 h at −78° C., followed by addition of 1.2 equiv. of p-anisoyl chloride. The reaction mixture was stirred for 10 min at −78° C. and then for 22 h at rt, acidified with 10% citric acid, and extracted with EtOAc. The combined organic layers were washed with water and dried over Na2SO4. Removal of solvent in vacuo provided a crude solid which was purified by flash chromatography (CH2Cl2) to give 1,3-bis(4-methoxyphenyl)-2-benzylpropane-1,3-dione.
Reaction SMILES: I[CH2:2][CH2:3][CH:4]1[CH2:10][CH2:9][C:8]2[C:11]([O:21][CH3:22])=[C:12]([O:19][CH3:20])[C:13]([O:17][CH3:18])=[C:14]([O:15][CH3:16])[C:7]=2[CH2:6][CH2:5]1.[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:16][O:15][C:14]1[C:7]2[CH2:6][CH2:5][CH:4]([CH2:3][CH2:2][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH2:10][CH2:9][C:8]=2[C:11]([O:21][CH3:22])=[C:12]([O:19][CH3:20])[C:13]=1[O:17][CH3:18]
Reactant: Oc1ccccn1
Reactant: COc1c2c(c(OC)c(OC)c1OC)CCC(CCI)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c2c(c(OC)c(OC)c1OC)CCC(CCOc1ccccn1)CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
A mixture of 7-(2-iodoethyl)-1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene (1.50 g), 2-hydroxypyridine (407 mg), and potassium carbonate (987 mg) in DMF (15 ml) was stirred at room temperature for 12 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was diluted with hexane and the resultant crystals were collected by filtration. The crystals were recrystallized from hexane-ethyl acetate to obtain 2-[2-(1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-7-yl)ethoxy]pyridine (830 mg).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:12]O)=[O:6])#[N:2].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.[CH3:47][S:48][C:49]1[CH:54]=[CH:53][C:52]([SH:55])=[CH:51][CH:50]=1>CN(C)C=O>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:12][S:55][C:52]1[CH:53]=[CH:54][C:49]([S:48][CH3:47])=[CH:50][CH:51]=1)=[O:6])#[N:2]
Reactant: CSc1ccc(S)cc1
Reactant: N#CCNC(=O)[C@@H]1CCC[C@H]1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CSc1ccc(SC[C@@H]2CCC[C@H]2C(=O)NCC#N)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
trans-N-(Cyanomethyl)-2-(hydroxymethyl)cyclopentane carboxamide (11 mg, 63 mmol) and triphenylphosphine (19 mg, 72 mmol) were placed in a 1 mL vial and dimethylformamide (0.15 mL) was added. The reaction mixture was cooled to 0° C. and diisopropyl azodicarboxylate (14 μL, 69 μmol) was added. After stirring for 10 min., 4-(methylsulfanyl)thiophenol (11 μL, 72 μmol) was added and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was partitioned between ethyl acetate (10 mL) and 1:1 water:saturated aqueous sodium chloride (10 mL). The product was extracted into ethyl acetate. The combined organic phase was dried with anhydrous sodium sulfate and then concentrated on a rotary evaporator. Chromatography of the residue on silica gel eluting with 2:3 ethyl acetate:hexanes provided the title compound as a colorless solid. 1H NMR (500 MHz, acetone-d6): δ=7.75 (1H, br s), 7.29 (2H, d), 7.21 (2H, d), 4.21 (2H, d), 3.10 (1H, dd), 2.89 (1H, dd), 2.51 (1H, q), 2.46 (3H, s), 2.43 (1H, m), 1.99-1.90 (2H, m), 1.75 (1H, m), 1.70-1.61 (2H, m), 1.40 (1H, m). MS [ESI, (M−H)−] m/z=319.2 amu
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][C:4]#[CH:5].[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](Cl)=[N:10][N:9]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(#N)C>[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:5]#[C:4][CH2:3][N:2]([CH3:6])[CH3:1])=[N:10][N:9]=1
Reactant: Clc1nnc(Cl)c2ccccc12
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Product: CN(C)CC#Cc1nnc(Cl)c2ccccc12
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A resealable pressure bottle was charged with dichlorobis(triphenyl-phosphine)palladium(II) (106 mg, 0.15 mmol), N,N-dimethylprop-2-yn-1-amine (0.13 ml, 1.5 mmol), 1,4-dichlorophthalazine (300 mg, 1.5 mmol), copper(I) iodide (29 mg, 0.15 mmol), TEA (4.2 mL, 30.1 mmol), and ACN (15.0 mL, 0.1M). The vessel was sealed and the mixture was stirred at overnight at 90° C. Next day the reaction was cooled to RT, filtered over celite, and the filtrate was concentrated under reduced pressure to afford a brown residue, which was purified by ISCO silica gel chromatography (5%-7% of 90/10/1 DCM/MeOH/NH4OH to afford 3-(4-chlorophthalazin-1-yl)-N,N-dimethylprop-2-yn-1-amine. MS m/z=246 [M+1]+. Calc'd for C13H12ClN3: 245.7.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:8][CH2:9]C1(O)CCCCC1.COC1CCC(C(O)=O)CC1>>[Br:8][CH2:9][CH:4]1[CH2:5][CH2:6][CH:1]([OH:7])[CH2:2][CH2:3]1
Reactant: OC1CCCCC1
Reactant: OC1(CBr)CCCCC1
Agent: COC1CCC(C(=O)O)CC1
Product: OC1CCC(CBr)CC1

Procedure:
Modified polyvinylbutryal containing a pendant group with cyclohexanol was prepared by the reaction of PVB with tetrahydropyranyl (THP) protected bromomethylcyclohexanol, followed by acid hydrolysis of the THP protection group. The THP-protected cyclohexanol-containing moiety was prepared by the following reaction sequence: 4-Methoxycyclohexanoic acid was reduced with borane-tetrahydrofuran complex to obtain 4-bromomethyl-cyclohexanol. This compound was treated with phosphorus tribromide to obtain the corresponding bromo compound. This bromo compound was reacted with trimethylsilyliodide to cleave the methoxy group to obtain 4-bromomethyl-cyclohexanol, which in turn was treated with dihyhdropyran to obtain the tetrahydropyranyl-protected bromomethylcyclohexanol. This preparation is represented by the following reaction scheme and further described in paragraphs a-d below. ##STR15## a) Preparation of 4-bromomethylcyclohexanol (C-3): 4-Methoxycyclohexanoic acid (13.0 g) was dissolved in THF (20 g), and cooled with ice. Then, borane-tetrahydrofuran complex (80 ml of 1M solution) was added and stirred overnight. Excess borane was destroyed by adding 15 ml of water dropwise until no effervescence was observed. The solution was then neutralized with potassium carbonate. The THF layer was dried over anhydrous magnesium sulfate and filtered. The solvent from the filtrate was removed under vacuum to obtain the desired 4-methoxycyclohexylmethanol (12.0 g).
Reaction SMILES: [NH2:1][CH:2]([CH3:11])[C:3]([CH3:10])([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14]>C(O)C>[CH2:17]([O:16][C:12]([CH2:13][CH2:14][NH:1][CH:2]([CH3:11])[C:3]([CH3:9])([CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:15])[CH3:18]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)C(C)(C)C(C)N
Solvent: CCO
Product: CCOC(=O)CCNC(C)C(C)(C)C(=O)OCC

Procedure:
In order to carry out this Michael addition, the ethyl 3-amino-2,2-dimethylbutanoate derivative 4 is dissolved with ethyl acrylate in a reaction medium which is inert under the reaction conditions chosen, preferably in a straight-chained or branched C1-4 -alkanol, most preferably ethanol, and heated, preferably to reflux temperature. After the reaction has taken place the solvent is eliminated in vacuo and the resulting ethyl 3-(2-ethoxycarbonylethyl)amino-2,2-dimethylbutanoate 5 is isolated.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH3:9])/[CH:3]=[CH:4]/[CH:5]=[CH:6]/[CH:7]=[O:8].[BH4-].[Na+]>C(O)C>[CH3:1][C:2]([CH3:10])([CH3:9])/[CH:3]=[CH:4]/[CH:5]=[CH:6]/[CH2:7][OH:8]
Reactant: CC(C)(C)/C=C/C=C/C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)/C=C/C=C/CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2 g Trans,trans-6,6-dimethyl-2,4-heptadienal are dissolved in ethanol and reacted at room temperature with 275 mg NaBH4 in successive portions. After stirring for ca. 1 hour at room temperature the mixture is concentrated on a rotary evaporator, the residue partitioned between ethyl acetate and saturated aqueous NaHCO3 and the organic phase dried and concentrated under vacuum. The oily crude product is further reacted directly.