Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:16]([OH:18])=O)[C:7]3[CH:12]=[N:11][N:10]([CH2:13][CH2:14][CH3:15])[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.[NH2:19][CH2:20][C:21]1[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=1[CH3:27].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>CS(C)=O>[CH:1]1([C:4]2[CH:5]=[C:6]([C:16]([NH:19][CH2:20][C:21]3[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=3[CH3:27])=[O:18])[C:7]3[CH:12]=[N:11][N:10]([CH2:13][CH2:14][CH3:15])[C:8]=3[N:9]=2)[CH2:2][CH2:3]1
Reactant: CCCn1ncc2c(C(=O)O)cc(C3CC3)nc21
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: On1nnc2cccnc21
Solvent: CS(C)=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CCCn1ncc2c(C(=O)NCc3c(C)cc(C)[nH]c3=O)cc(C3CC3)nc21

Procedure:
The title compound was prepared in the same manner as described for intermediate 56 using 6-cyclopropyl-1-propyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (90 mg, 0.368 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (70 mg, 0.460 mmol), 1-hydroxy-7-azabenzotriazole (100 mg, 0.736 mmol), DMSO(10 mL), EDC (141 mg, 0.736 mmol), and N-methylmorpholine (0.162 mL, 1.472 mmol). The final product was collected as 0.118 g (84%). LCMS E-S (M+H)=380.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.78 (t, 3 H), 0.99-1.16 (m, 4 H), 1.85 (d, J=7.33 Hz, 2 H), 2.13 (s, 3 H), 2.22 (s, 4 H), 4.25-4.43 (m, 4 H), 5.90 (s, 1 H), 7.43 (s, 1 H), 8.21 (s, 1 H), 8.75 (s, 1 H), 11.57 (s, 1 H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10](Cl)[N:9]=2)[N:5]=[CH:4][N:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[NH2:23][CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>O1CCCC1>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]([NH:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[N:9]=3)[N:5]=[CH:4][N:3]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Clc1nccc(-c2ncnc(Cl)n2)n1
Reactant: NC1CCOCC1
Solvent: C1CCOC1
Product: Clc1cccc(Nc2ncnc(-c3ccnc(NC4CCOCC4)n3)n2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-chloro-4-(2-chloro-4-pyrimidinyl)-1,3,5-triazine (i.e., the product of Example 1, Step B) (25 mg, 0.11 mmol) in tetrahydrofuran (1.0 mL) was added 3-chloroaniline (0.1 mL), and the resulting mixture was stirred at room temperature for 3 h to provide a yellow suspension. To this suspension added 4-aminotetrahydropyran (0.2 mL), and the mixture was refluxed for 5 h. The solution was concentrated and purified using column chromatography on silica gel eluted with 70% ethyl acetate in hexanes to give 25 mg of the title compound as a yellow solid.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=1[N+:24]([O-:26])=[O:25].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[ClH:14].[N+:21]([C:18]1[CH:17]=[C:16]([N+:24]([O-:26])=[O:25])[CH:15]=[CH:20][C:19]=1[N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=2)[CH2:6][CH2:5]1)([O-:23])=[O:22]
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cl
Product: O=[N+]([O-])c1ccc(N2CCN(c3ccc(O)cc3)CC2)c([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 37.7 %

Procedure:
A mixture of 4.5 parts of 4-(1-piperazinyl)phenol, 5.5 parts of 1-chloro-2,4-dinitrobenzene, 2.6 parts of sodium carbonate and 90 parts of N,N-dimethylacetamide was stirred overnight at 50° C. After cooling, the mixture was poured into ice water and the product was extracted twice with 4-methyl-2-pentanone. The undissolved product was dissolved in 2-propanol. This solution and the combined organic layers were washed with water, dried, filtered and evaporated. The residue was converted into the hydrochloride salt in 2-propanol. The salt was filtered off and crystallized twice: first from a mixture of 2-propanol and water (10:1 by volume) and then from a mixture of methanol and water (10:1 by volume). The product was filtered off and dried, yielding 3.9 parts (37.7%) of 4-[4-(2,4-dinitrophenyl)-1-piperazinyl]-phenol monohydrochloride, methanol(1:1); mp. 178.0° C. (compound 1.13).
Reaction SMILES: C[O:2][C:3](=[O:27])[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][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH2:28]([O:35][CH2:36][C:37](Cl)=[O:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:35][CH2:36][C:37]([N:24]([CH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:21])([F:22])[F:20])[CH:17]=[CH:18][C:13]=1[C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:27])=[O:2])[CH:6]=1)[CH2:25][CH3:26])=[O:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Reactant: O=C(Cl)COCc1ccccc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)COCc1ccccc1

Procedure:
(2′-{[(2-Benzyloxy-acetyl)-ethyl-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (Compound 1-92) was prepared by following the procedures outlined in Example 1 and using (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and benzyloxyacetyl chloride.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:20])[NH:10][C:11]3[C:16]=2[CH:15]=[C:14]2[CH:17]=[CH:18][CH:19]=[C:13]2[CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:28][CH3:29].O>CN(C=O)C>[CH2:28]([O:20][C:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[CH2:15][C:14]3=[CH:17][CH:18]=[CH:19][C:13]3=[CH:12][C:11]=2[N:10]=1)[CH3:29]
Reactant: CCI
Reactant: O=c1[nH]c(-c2ccccc2)c2cc3cccc3cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1nc2c(c(-c3ccccc3)n1)CC1=CC=CC1=C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.8 %

Procedure:
To a suspension of 4-phenylcyclopenta[g]quinazolin-2(1H)-one (120 mg, 0.46 mmol) and K2CO3 (76 mg, 0.55 mmol) in 4 mL of DMF was added iodoethane (44 μL, 0.55 mmol) and stirred at rt overnight. Water was then added and the resulting suspension extracted with 2×20 mL of EtOAc. The extract was washed with water twice and brine, then dried over MgSO4 and concentrated in vacuo. The crude solid was then subjected to flash column chromatography eluting with acetone/hexane to give the title compound 2-ethoxy-4-phenyl-cyclopenta[g]quinazoline (25 mg, 19%) followed by the title compound 1-ethyl-4-phenylcyclopenta[g]quinazolin-2(1H)-one (66 mg, 50%). 1H NMR (CDCl3): 7.7 (d, 2H), 7.63 (s, 1H), 7.53 (m, 3H), 7.29 (s, 1H), 4.38 (q, 2H), 3.09 (t, 2H), 2.93 (t, 2H), 2.16 (p, 2H), 1.45 (t, 3H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][N:7]1[C:16]2[NH:15][C:14]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:13]=3[N:12]([C:22]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([N:34]4[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]4)=[O:33])=[C:26]([CH3:40])[CH:25]=3)=[O:23])[CH2:11][C:10]=2[CH:9]=[N:8]1>ClCCl.C(N(CC)CC)C>[CH3:6][N:7]1[C:16]2[NH:15][C:14]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:13]=3[N:12]([C:22]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([N:34]4[CH2:39][CH2:38][N:37]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:36][CH2:35]4)=[O:33])=[C:26]([CH3:40])[CH:25]=3)=[O:23])[CH2:11][C:10]=2[CH:9]=[N:8]1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)c1ccc(CCC(=O)N2CCNCC2)c(C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)c1ccc(CCC(=O)N2CCN(S(C)(=O)=O)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of methanesulfonyl chloride (0.57 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of 3-[4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-phenyl]-1-piperazin-1-yl-propan-1-one (2.36 mg, 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (0.0035 ml). The mixture was stirred at room temperature for 20 h then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=551.3
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26](I)[CH:25]=3)[C:5]2=[CH:4][CH:3]=1.C[Si]([C:36]#[CH:37])(C)C.C(N(CC)CC)C>O1CCCC1.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:36]#[CH:37])[CH:25]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cccc(I)c2)N1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#Cc1cccc(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
A solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-iodophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.56 g, 1 mmol) prepared in example 192b in anhydrous tetrahydrofuran (30 mL) was added trimethylsilyl acetylene (0.1 g, 2.0 mmol) (Aldrich), CuI (0.38 g, 2.0 mmol) (Aldrich) and triethylamine (0.2 g, 2.0 mmol) was degassed under nitrogen for 5 min, then dichlorobis(triphenylphosphine)palladium(0) (140 mg, 0.2 mmol) (Strem) was added and the reaction mixture was heated at 100° C. under nitrogen for 3 h. The reaction mixture was cooled to room temperature and filtered through a short pad of silica gel, the silica gel was washed with ethyl acetate. The filtrate was concentrated. To the residue was added methanol (10 mL) and aqueous NaOH solution (1 N, 2 mL). The mixture was stirred at room temperature for 2 h, then partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4 and concentrated. The residue was purified with chromatography (EtOAc:hexanes=2:1) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-ethynyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 0.24 g, 52%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]4)[C:14]([F:24])=[CH:13][N:12]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.[C:35]([O:39][C:40](=[O:43])CBr)([CH3:38])([CH3:37])[CH3:36].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.[Na+].[Cl-]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][N:20]([C:40]([O:39][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:43])[CH2:19]4)[C:14]([F:24])=[CH:13][N:12]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCNC4)n3)c3cc(Cl)cnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCN(C(=O)OC(C)(C)C)C4)n3)c3cc(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[5,4-b]pyridin-3-yl]-5-fluoro-N-[(3S)-3-piperidyl]pyrimidin-4-amine, 1c, (0.25 g, 0.50 mmol) in DMF was added tert-butylbromoacetate (0.08 mL, 0.55 mmol) and Na2CO3 (0.11 g, 0.99 mmol). The reaction mixture was stirred at room temperature for 6 h. The resulting thick white precipitate was diluted with aqueous saturated NaCl solution and washed with water. The white solid was dissolved in CH2Cl2 and the solution was dried (MgSO4), filtered and concentrated in vacuo. The crude was purified via silica gel chromatography (0%-5% MeOH/CH2Cl2) to afford the desired product, 2a, as a white solid.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.O>C1C=CC=CC=1>[N:8]1([C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C1CCCCC1
Reactant: C1CCNC1
Solvent: c1ccccc1
Solvent: O
Product: C1=C(N2CCCC2)CCCC1
Yield: 95.9 %

Procedure:
Cyclohexanone (196.3 g) and pyrrolidine (214 g) in benzene (500 ml) were refluxed under nitrogen with a Dean-Stark apparatus, until no more water separated out. The solvents were then evaporated off under nitrogen, and the residual oil was distilled to give 1-(1-pyrrolidinyl)cyclohexene (290 g).
Reaction SMILES: [O:1]([C:9]1[CH:10]=[C:11]([C@@H:23]([OH:28])[CH2:24][N+:25]([O-])=O)[CH:12]=[CH:13][C:14]=1[O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[H][H]>CO.[Pd]>[O:1]([C:9]1[CH:10]=[C:11]([C@@H:23]([OH:28])[CH2:24][NH2:25])[CH:12]=[CH:13][C:14]=1[O:15][Si:16]([C:19]([CH3:21])([CH3:20])[CH3:22])([CH3:18])[CH3:17])[Si:2]([C:5]([CH3:8])([CH3:6])[CH3:7])([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@@H](O)C[N+](=O)[O-])cc1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@@H](O)CN)cc1O[Si](C)(C)C(C)(C)C
Yield: 96 %

Procedure:
100 mg of optically active 1-(3,4-di(t-butyldimethylsiloxy)phenyl)-2-nitroethanol obtained in example 1 was dissolved in 10 ml of methanol, and 10 mg of 10% Pd/C was added to the solution, after which the mixture was reacted at 20° C. under the hydrogen pressure of 0.1 MPa for 20 hours, so as to obtain 89.3 mg of the intended compound (in a yield of 96%, with an optical purity of 94% e.e.).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][CH:3]1[CH:18]([CH3:20])[CH3:19].C[O-].[Na+].[CH:24]([C:26]([CH3:28])=[O:27])=[CH2:25].C(O)(=O)C>CO.C1C=CC=CC=1>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH:18]([CH3:20])[CH3:19])[CH2:25][CH2:24][C:26](=[O:27])[CH3:28]
Reactant: CC(C)C1Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Reactant: C=CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)CCC1(C(C)C)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A stirred solution of (1-oxo-2-isopropyl-6,7-dichloro-5-indanyloxy)acetic acid (3.17 g., 0.01 mole) and sodium methoxide (3.2 g., 0.05 mole) in methanol (100 ml.) and benzene (100 ml.) in an inert atmosphere is cooled to 0° C. and treated with methyl vinyl ketone (2.0 g., 0.029 mole) in methanol (10 ml.) during a 1/2 hour period then stirred 72 hours at 25° C. The reaction mixture is acidified with acetic acid, evaporated to dryness, extracted with chloroform, washed with water, dried over magnesium sulfate and evaporated to dryness affording [1-oxo-2-isopropyl-2-(3-oxobutyl)-6,7-dichloro-5-indanyloxy]acetic acid which melts at 125°-128° C. after recrystallization from methanol.
Reaction SMILES: C1C=NC2N(O)N=NC=2C=1.[F:11][C:12]1[CH:20]=[CH:19][C:15]([CH2:16][CH2:17][NH2:18])=[CH:14][CH:13]=1.[C:21](O)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(Cl)CCl>C(Cl)Cl>[F:11][C:12]1[CH:20]=[CH:19][C:15]([CH2:16][CH2:17][NH:18][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:14][CH:13]=1
Reactant: NCCc1ccc(F)cc1
Reactant: O=C(O)c1ccccc1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(NCCc1ccc(F)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
1.5 g (10.8 mmol) of HOAt were added to a solution of 15.0 g (108.0 mmol) of 4-fluorophenethylamine and 13.2 g (108.0 mmol) of benzoic acid in DCM and the mixture was then cooled to 0° C. 22.8 g (119.0 mmol) of EDC were then added at this temperature and the mixture was then stirred for 16 h at RT. The reaction solution was then washed successively with a 1M aqueous hydrochloric acid (2×300 ml), a 2M aqueous NaOH solution (300 ml) and brine (200 ml). The organic phase was dried over Na2SO4, filtered and concentrated to small volume under vacuum. 20.5 g (84.2 mmol, 78%) of N-(4-fluorophenethyl)benzamide were obtained as the residue.
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:15]=[C:16]([CH:20]3[CH:29]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([N:38]5[CH2:43][CH2:42][N:41]([C:44](=[O:48])[CH:45]([CH3:47])[CH3:46])[CH2:40][CH2:39]5)=[O:37])[CH:31]=4)[C:28](=O)[C:27]4[C:26]([C:50](OC)=[O:51])=[CH:25][CH:24]=[CH:23][C:22]=4[NH:21]3)[CH:17]=[CH:18][CH:19]=2)=[O:13])[CH2:8][CH2:7]1)(=O)[CH:2]([CH3:4])[CH3:3].[OH2:54].[NH2:55][NH2:56]>CO>[C:1]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:15]=[C:16]([CH:20]3[NH:21][C:22]4[C:27]5[C:28](=[N:55][NH:56][C:50](=[O:51])[C:26]=5[CH:25]=[CH:24][CH:23]=4)[CH:29]3[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([N:38]4[CH2:43][CH2:42][N:41]([C:44](=[O:48])[CH:45]([CH3:47])[CH3:46])[CH2:40][CH2:39]4)=[O:37])[CH:31]=3)[CH:17]=[CH:18][CH:19]=2)=[O:13])[CH2:8][CH2:7]1)(=[O:54])[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1cccc2c1C(=O)C(c1cccc(C(=O)N3CCN(C(=O)C(C)C)CC3)c1)C(c1cccc(C(=O)N3CCN(C(=O)C(C)C)CC3)c1)N2
Reactant: O
Reactant: NN
Solvent: CO
Product: CC(C)C(=O)N1CCN(C(=O)c2cccc(C3Nc4cccc5c(=O)[nH]nc(c45)C3c3cccc(C(=O)N4CCN(C(=O)C(C)C)CC4)c3)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 4 %

Procedure:
A mixture of methyl 2,3-bis(3-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (90 mg, 0.12 mmol) in hydrazine monohydrate (5 mL) and methanol (2 mL) was stirred at 25° C. for 4 hr. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by prep-HPLC to give 8,9-bis(3-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (3.2 mg, yield: 4%) as a white solid. 1H-NMR (400 MHz, CD3OD) δ: 0.95-0.97 (q, 12H), 2.80-2.88 (m, 2H), 2.98-3.08 (m, 3H), 3.33-3.53 (m, 13H), 4.23-4.26 (d, J=10.4 Hz, 1H), 4.62-4.64 (d, J=10.0 Hz, 1H), 7.02-7.46 (m, 11H); LC-MS (ESI) m/z: 704(M+1)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[NH2:9][C:10]1[C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[C:19]([CH3:20])[C:14]=2[O:13][C:12](=[O:22])[CH:11]=1>C(Cl)Cl.N1C=CC=CC=1.O>[NH2:9][C:10]1[C:15]2[CH:16]=[CH:17][C:18]([O:21][C:6]([C:2]3[NH:1][CH:5]=[CH:4][CH:3]=3)=[O:7])=[C:19]([CH3:20])[C:14]=2[O:13][C:12](=[O:22])[CH:11]=1
Reactant: O=C(Cl)c1ccc[nH]1
Reactant: Cc1c(O)ccc2c(N)cc(=O)oc12
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Cc1c(OC(=O)c2ccc[nH]2)ccc2c(N)cc(=O)oc12

Procedure:
A solution of pyrrole-2-carboxylic acid chloride (0.065 gm) in methylene chloride (0.5 ml) was added to a suspension of 4-amino-7-hydroxy-8-methyl-benzopyran-2-one (0.095 gm) in pyridine (2 ml). The suspension was heated at 70 for 10 mins. to obtain a homogeneous solution. The reaction mixture was then diluted with water, filtered and the solid was crystallized form dimethylformamide/water to afford the title compound. MS: m/e 284 (M+).
Reaction SMILES: [CH3:1][N:2]([CH:21]1[CH:28]2[CH2:29][C:24]3([C:31]([O-:33])=[O:32])[CH2:25][CH:26]([CH2:30][CH:22]1[CH2:23]3)[CH2:27]2)[C:3](=[O:20])[C:4]([N:7]([CH2:18][CH3:19])[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])(=[O:10])=[O:9])([CH3:6])[CH3:5].C1COCC1.CO.O[Li].O>O>[CH3:1][N:2]([CH:21]1[CH:22]2[CH2:23][C:24]3([C:31]([OH:33])=[O:32])[CH2:25][CH:26]([CH2:27][CH:28]1[CH2:29]3)[CH2:30]2)[C:3](=[O:20])[C:4]([N:7]([CH2:18][CH3:19])[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])(=[O:9])=[O:10])([CH3:5])[CH3:6]
Reactant: CCN(C(C)(C)C(=O)N(C)C1C2CC3CC1CC(C(=O)[O-])(C3)C2)S(=O)(=O)c1ccccc1C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCN(C(C)(C)C(=O)N(C)C1C2CC3CC1CC(C(=O)O)(C3)C2)S(=O)(=O)c1ccccc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.6 %

Procedure:
N-methyl-4-(2-(N-ethyl-2-methylphenylsulfonamido)-2-methylpropanamido)adamantane-1-carboxylate (400 mg, 0.84 mmol) was charged, and dissolved through addition of THF (5 ml), and methanol (5 ml). LiOH.H2O dissolved in H2O (4 ml) was added thereto, followed by stirring for 12 hours at room temperature. After stirring for 12 hours, the resultant solution was vacuum-evaporated, acidified with 2N—HCl to pH 2˜3, and extracted with EA (×2). The organic layer was dried with MgSO4, and filtered. Through vacuum distillation, the solvent was removed so as to obtain N-methyl-4-(2-(N-ethyl-2-methylphenylsulfonamido)-2-methylpropanamido)adamantane-1-carboxylic acid (380 mg, 0.82 mmol, 98%).
Reaction SMILES: [Si](C=[N+:6]=[N-])(C)(C)C.[CH3:8][C:9]1[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=1/[CH:11]=[CH:12]/[C:13]([O:15]C)=[O:14].C(OC)(=O)[C@H](C1C=CC=CC=1)O>C(Cl)(Cl)Cl>[C:9]([NH2:6])([CH3:20])([CH3:10])[CH3:8].[CH3:8][C:9]1[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=1/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COC(=O)/C=C/c1ccccc1C
Agent: COC(=O)[C@@H](O)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)N
Product: Cc1ccccc1/C=C/C(=O)O
Reaction time: 0.08 h

Procedure:
(R)-2-Methyl-3-phenylpropionic acid tert-butylamine salt, reaction time 40 minutes, conversion 100%. The free acid was liberated by partitioning between dichloromethane and 2M HCl. The organic layer was dried (Na2SO4), filtered and the solvent was evaporated, then the product was distilled (kugelrohr, 150° C., 0.5 mbar) to give (R)-2-Methyl-3-phenylpropionic acid as a colorless liquid. [α]D25-22.7, c=1.02, CHCl3. Lit. (E. Tyrell, M. W. H. Tang, G. A. Skinner and J. Fawcett, Tetrahedron, 1996, 52, 9841-9852, [α]D20-23.1 c=1, CHCl3). ee 85% (derivatised using TMS-diazomethane, Chirasil Dex CB column, 25 m×0.25 mm, injector/detector 200° C., helium 20 psi, 100° C. for 21 minutes then ramp at 15° C./min to 200° C., hold for 5 minutes, retention times R 30.40 minutes, S 31.06 minutes, (E)-methyl 2-methylcinnamate, 34.79 minutes). 1H NMR analysis of the (S)-methyl mandelate (E. Tyrell, M. W. H. Tang, G. A. Skinner and J. Fawcett, Tetrahedron, 1996, 52, 9841-9852) confirmed assignment of (R)-configuration.
Reaction SMILES: Br[CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:11]([F:22])[CH:10]=2)[CH2:5][CH2:4]1.[Mg].Br[CH2:25][C@H:26]1[CH2:31][CH2:30][Si@H:29]([CH2:32][CH2:33][CH3:34])[CH2:28][CH2:27]1>[Cu]I.P(OCC)(OCC)(OCC)=O.C1COCC1>[CH2:32]([Si@H:29]1[CH2:30][CH2:31][C@H:26]([CH2:25][CH2:2][C@H:3]2[CH2:8][CH2:7][C@H:6]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)=[C:11]([F:22])[CH:10]=3)[CH2:5][CH2:4]2)[CH2:27][CH2:28]1)[CH2:33][CH3:34]
Reactant: Fc1ccc(-c2ccc([C@H]3CC[C@H](CBr)CC3)cc2F)cc1
Reactant: CCC[Si@H]1CC[C@H](CBr)CC1
Agent: [Cu]I
Agent: [Mg]
Solvent: CCOP(=O)(OCC)OCC
Solvent: C1CCOC1
Product: CCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(-c4ccc(F)cc4)c(F)c3)CC2)CC1

Procedure:
38.3 g (0.1 mol) of 4-(trans-4-bromomethylcyclohexyl)-2,4'-difluorobiphenyl was dripped into a mixture of 2.5 g (0.11 mol) of magnesium and 300 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 500 ml THF solution of 0.5 g of triethyl phosphate, 0.1 g of copper (I) iodide and 22.1 g (0.1 mol) of trans-1-bromomethyl-4-n-propyl-4-silacyclohexane. After a conventional after treatment, purification was conducted by means of chromatography to obtain 37.6 g (yield 81.3%) of 4-(trans-4-(2-(trans-4-n-propyl-4-silacyclohexyl)ethyl)cyclohexyl)-2,4'-difluorobiphenyl.