Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][O:15][C:14]2=[O:18])=[CH:4][CH:3]=1.[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](O)=[O:35])=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.C(N=C=NC(C)(C)CC)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[CH2:19]([O:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:33][C:34]([NH:1][C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[N:7][N:8]3[CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][O:15][C:14]3=[O:18])=[CH:4][CH:3]=2)=[O:35])=[CH:31][CH:32]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: Nc1ccc2cnn(CCN3CCOC3=O)c2c1
Agent: CCN=C=NC(C)(C)CC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(OCc2ccccc2)cc1)Nc1ccc2cnn(CCN3CCOC3=O)c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 51.4 %

Procedure:
A mixture of 3-[2-(6-Amino-indazol-1-yl)-ethyl]-oxazolidin-2-one (58 mg, 0.24 mmol), 4-benzyloxyphenylacetic acid (68 mg, 0.28 mmol), ethyldimethylpropylcarbodiimide hydrochloride (53 mg, 0.28 mmol), N-hydroxybenzotriazole (37 mg, 0.28 mmol) and N-methyl morpholine (60 mg, 0.56 mmol) in 3 mL of DMF was stirred at room temperature for 6 hours. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (silica gel, ethyl acetate/triethylamine, 30/1) to provide the title compound as a pale yellow solid (58 mg, 52%); 1H NMR (300 MHz, DMSO-d6) ppm 3.39 (m, 2H), 3.55 (m, 2H), 3.61 s, 2H0, 4.09 (m, 2H), 4.47 (m, 2H), 5.09 (s, 2H), 6.67 (d, J=8.47, 2H), 7.13 (m, 1H), 7.27 (m, 2H), 7.31–7.45 (m, 5H), 7.65 (m, 1H), 7.97 (m, 1H), 8.13 (s, 1H), 10.30 (s, 1H); MS (DCI/NH3) m/z 471 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[NH:4][N:3]=1.[Br:8][CH:9]([CH:12]=O)[CH:10]=O>>[Br:8][C:9]1[CH:10]=[C:6]2[C:2]([CH3:1])=[N:3][NH:4][C:5]2=[N:7][CH:12]=1
Reactant: O=CC(Br)C=O
Reactant: Cc1cc(N)[nH]n1
Product: Cc1n[nH]c2ncc(Br)cc12
Yield: 10 %

Procedure:
5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine x153 is synthesized according to the method described in example 20.1 using 3-methyl-1H-pyrazol-5-amine b40 and bromomalonaldehyde a9.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:21]([F:22])=[CH:20][C:16]([C:17](O)=[O:18])=[C:15]([F:23])[C:14]=3[Cl:24])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:25][S:26]([NH2:29])(=[O:28])=[O:27]>>[C:1]12([CH2:11][O:12][C:13]3[C:21]([F:22])=[CH:20][C:16]([C:17]([NH:29][S:26]([CH3:25])(=[O:28])=[O:27])=[O:18])=[C:15]([F:23])[C:14]=3[Cl:24])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cc(F)c(OCC23CC4CC(CC(C4)C2)C3)c(Cl)c1F
Product: CS(=O)(=O)NC(=O)c1cc(F)c(OCC23CC4CC(CC(C4)C2)C3)c(Cl)c1F

Procedure:
The compound was prepared in a similar manner to step 2 of Example 412 from 4-(adamantan-1-ylmethoxy)-3-chloro-2,5-difluorobenzoic acid and methanesulfonamide. LCMS (Method D): RT=6.97 min, m/z: 434.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.66 (dd, J=11.6, 6.6 Hz, 1H), 3.82 (d, J=2.0 Hz, 2H), 1.99 (s, 3H), 1.82-1.56 (m, 12H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:11][CH2:12][C:13]1([C:21]2[CH:22]=[CH:23][C:24]([C:27]([OH:30])([CH3:29])[CH3:28])=[N:25][CH:26]=2)[CH2:18][CH2:17][C:16]([F:20])([F:19])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][CH2:12][C:13]1([C:21]2[CH:26]=[N:25][C:24]([C:27]([OH:30])([CH3:28])[CH3:29])=[CH:23][CH:22]=2)[CH2:18][CH2:17][C:16]([F:20])([F:19])[CH2:15][CH2:14]1)=[O:6]
Reactant: CC(C)(O)c1ccc(C2(CN)CCC(F)(F)CC2)cn1
Reactant: O=C(O)c1ccccc1Cl
Product: CC(C)(O)c1ccc(C2(CNC(=O)c3ccccc3Cl)CCC(F)(F)CC2)cn1

Procedure:
From 2-chlorobenzoic acid and 2-[5-(1-aminomethyl-4,4-difluoro-cyclohexyl)-pyridin-2-yl]-propan-2-ol. LCMS (MH+): m/z=423.2, tR (minutes, Method F)=1.78
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[C:4]#[N:5].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[N+:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([O:1][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:3]=1[C:4]#[N:5])([O-:12])=[O:11]
Reactant: BrCc1ccccc1
Reactant: N#Cc1c(O)cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: N#Cc1c(OCc2ccccc2)cccc1[N+](=O)[O-]
Yield: 32.3 %

Procedure:
To a solution of 2-hydroxy-6-nitrobenzonitrile (Example 115) (1.0 g, 6.09 mmol) and Cs2CO3 (2.16 g, 6.64 mmol) in acetone (14 mL) was added benzyl bromide (1.16 g, 6.76 mmol). The reaction was refluxed under N2 for 1.5 hours, then filtered and the filtrate concentrated. The residue was purified by flash chromatography 3:2 Hexane:EtOAc to provide 2-nitro-6-(benzyloxy)benzonitrile (500 mg, 32%). 1H NMR (400 MHz, MeOD) δ 5.40 (s, 2H), 7.34-7.45 (m, 3H), 7.53 (m, 2H), 7.69 (dd, J=8.6, 0.8 Hz, 1H), 7.82 (t, J=8.4 Hz, 1H), 7.91 (t, J=8.2, 0.8 Hz, 1H).
Reaction SMILES: [CH2:1]([NH:8][CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]1[C:15]2[CH:16]=[CH:17][C:18]([CH2:20][CH2:21]Br)=[CH:19][C:14]=2[O:13][C:12]1=[O:23]>>[CH3:10][N:11]1[C:15]2[CH:16]=[CH:17][C:18]([CH2:20][CH2:21][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH3:9])=[CH:19][C:14]=2[O:13][C:12]1=[O:23]
Reactant: Cn1c(=O)oc2cc(CCBr)ccc21
Reactant: CNCc1ccccc1
Product: CN(CCc1ccc2c(c1)oc(=O)n2C)Cc1ccccc1
Yield: 65 %

Procedure:
By following the procedure indicated in Example 6, but starting from 0.04 mol (4.90 g) of N-benzyl-N-methylamine and 0.02 mol (5.10 g) of 3-methyl-6-(2-bromoethyl)-benzoxazolinone, 3.85 g of the title compound having a melting point of 72°-73° C. were obtained after recrystallisation from hexane.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[O:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=3)[CH:19]([CH2:33][OH:34])[CH2:18]2)=[C:13]([CH3:35])[N:12]([CH2:36][C:37]2[C:42]([C:43]([F:46])([F:45])[F:44])=[CH:41][CH:40]=[CH:39][C:38]=2[F:47])[C:11]1=[O:48])(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[NH2:7][C@H:8]([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[O:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=3)[CH:19]([CH2:33][OH:34])[CH2:18]2)=[C:13]([CH3:35])[N:12]([CH2:36][C:37]2[C:42]([C:43]([F:45])([F:46])[F:44])=[CH:41][CH:40]=[CH:39][C:38]=2[F:47])[C:11]1=[O:48]
Reactant: Cc1c(N2CCN(Cc3ccc(C(F)(F)F)o3)C(CO)C2)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(N2CCN(Cc3ccc(C(F)(F)F)o3)C(CO)C2)c(=O)n(C[C@H](N)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a solution of ((R)-2-{3-(2-fluoro-6-trifluoromethyl-benzyl)-5-[3-hydroxymethyl-4-(5-trifluoromethyl-furan-2-ylmethyl)-piperazin-1-yl]-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl}-1-phenyl-ethyl)-carbamic acid tert-butyl ester (17 mg, 0.022 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (100 μl, 1.30 mmol), followed by at room temperature for 1 hr. The solution was neutralized with an aqueous saturated sodium bicarbonate solution. After concentration of the organic layer thus formed, the residue was purified using silica gel chromatography (eluent: dichloromethane/methanol, 10/1) and dried in a vacuum to afford 12 mg of the compound as a white foam (yield 81%). 1H NMR (300 MHz, CDCl3) δ 2.29 (3H, s), 2.50 (3H, m), 2.86 (2H, m), 3.50-3.76 (3H, m), 3.95 (2H, m), 4.04 (2H, m), 4.21 (1H, t), 4.36 (1H, dd), 5.40 (2H, dd), 6.30 (1H, s), 6.73 (1H, s), 7.22 (2H, m), 7.33 (2H, t), 7.40 (3H, m), 7.54 (1H, d) MS (ESI) m/z 684.4 (MH+)
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].Br[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:23][O:22][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][O:11][C:6]1[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=1[CH2:8][CH2:9][CH3:10]
Reactant: COC(=O)CCCCBr
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCC(=O)OC)ccc(C(C)=O)c1O
Yield: 66.7 %

Procedure:
A mixture of 2.92 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.91 g of methyl 5-bromopentanoate and 3.1 g of anhydrous potassium carbonate in 35 ml of anhydrous dimethyl formamide was stirred and heated at 75° for 16 hours. The usual workup followed by chromatography on 350 g of silica gel and elution with 5% ethyl acetate-toluene gave 3.07 g (66% yield) of 5-(4-Acetyl-3-hydroxy-2-propylphenoxy)pentanoic acid methyl ester, the titled compound, as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:39])[C:12]3[S:19][C:18]([CH2:20][N:21]([CH2:23][C@H:24]([C:26]4[O:27][CH:28]=[CH:29][CH:30]=4)[OH:25])[CH3:22])=[C:17]([CH2:31][O:32]CC[Si](C)(C)C)[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:39])[C:12]3[S:19][C:18]([CH2:20][N:21]([CH2:23][C@H:24]([C:26]4[O:27][CH:28]=[CH:29][CH:30]=4)[OH:25])[CH3:22])=[C:17]([CH2:31][OH:32])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:40][CH:41]=1
Reactant: CN(Cc1sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2c1COCC[Si](C)(C)C)C[C@@H](O)c1ccco1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CN(Cc1sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2c1CO)C[C@@H](O)c1ccco1

Procedure:
A solution of 121 mg of compound N-(4-chlorobenzyl)-2-{[[(2R)-2-(2-furyl)-2-hydroxyethyl](methyl)amino]methyl}-4-methyl-7-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide in 3 mL of 75% TFA in CH2Cl2 is stirred at room temperature for 3 h, then diluted with CHCl3 and added to stirred aq. NaHCO3. The aqueous phase is extracted with 4 portions of CH2Cl2, and the combined organic phases dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography of the residue on silica gel using 3% MeOH in CH2Cl2 provides 19 mg of the title compound as a brown solid. Recrystallization from EtOAc-hexane affords granular brown crystals.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:35])=[C:11]([NH:13][C:14](=[O:34])[C:15]3[CH:20]=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][N:25]([CH:28]5[CH2:30][CH2:29]5)[CH2:24][CH2:23]4)[CH:18]=[CH:17][C:16]=3[N+:31]([O-])=O)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.N[C:37]1C=CC(OC2CCN(C3CC3)CC2)=CC=1C(NC1C=C(C(NC2CC2)=O)C=CC=1C)=O>>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:35])=[C:11]([N:13]3[C:14](=[O:34])[C:15]4[C:16](=[CH:17][CH:18]=[C:19]([O:21][CH:22]5[CH2:27][CH2:26][N:25]([CH:28]6[CH2:30][CH2:29]6)[CH2:24][CH2:23]5)[CH:20]=4)[N:31]=[CH:37]3)[CH:12]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(OC2CCN(C3CC3)CC2)ccc1N
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(OC2CCN(C3CC3)CC2)ccc1[N+](=O)[O-]
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OC3CCN(C4CC4)CC3)cc2c1=O

Procedure:
Using an analogous procedure to that described paragraph (B) in the portion of Example 15 which is concerned with the preparation of starting material, N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-[(1-cyclopropylpiperidine-4-yl)oxy]-2-nitrobenzamide was reduced to 2-amino-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-[(1-cyclopropylpiperidine-4-yl)oxy]benzamide; Mass Spectrum: M+H+ 449.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC(C(O)=O)CC(C)C.N[C@H](C(O)=O)CC(C)C.C(OC(N[C@H](C(O)=O)CC(C)C)=O)C1C=CC=CC=1.Cl.[CH3:58][O:59][C:60](=[O:67])[C@H:61]([CH2:63][CH:64]([CH3:66])[CH3:65])[NH2:62].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(N(CC)CC)C.CN(C)C=O>[CH3:58][O:59][C:60](=[O:67])[C@H:61]([CH2:63][CH:64]([CH3:66])[CH3:65])[NH:62][C:17](=[O:19])[C@@H:12]([CH2:13][CH:14]([CH3:15])[CH3:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CC(C)C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)CC(N)C(=O)O
Agent: CC(C)C[C@H](N)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2.65 g. of Nα -benzyloxycarbonyl-D-leucine [This material is prepared by the same procedure as used by Grassman and Wunsch, Ber. 91, 462 (1968) for the DL-leucine and for the L-leucine see Losse and Demuth, Ber. 94, 1762 (1961). The material is an oil as described for the Nα -benzyloxycarbonyl-L-leucine enantiomer. See also Farthing, J. Chem. Soc. 1950, 3213 and Bergmann, J. Biol. Chem., 115, 593 (1936).] in 50 ml. of dimethylformamide is treated with 1.98 g. of L-leucine methyl ester hydrochloride and cooled in an ice bath. The solution is treated with 1.4 ml. of triethylamine, then with 1.5 g. of 1-hydroxybenztriazole, and finally with 2.26 g. of dicyclohexylcarbodiimide. The reaction is stirred overnight with initial ice bath cooling and gradual warming to room temperature, and then an additional 24 hours at room temperature. The mixture is filtered and the filtrate evaporated. The residue is dissolved in ethyl acetate and the solution washed with 1N hydrochloric acid, saturated sodium chloride solution, 5% sodium bicarbonate solution and again with saturated sodium chloride solution. The ethyl acetate solution is separated and dried over magnesium sulfate, filtered and evaporated. The residue crystallizes and is recrystallized from isopropyl ether; [α]D23 -5.3° (c 2.06, methanol), m.p. 80°-82° C.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([NH2:7])[CH:4]=[C:3]2[CH2:8][CH2:9][CH2:10][C:2]=12.N1C=CC=CC=1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>C(#N)C>[N:1]1[CH:6]=[C:5]([NH:7][C:18](=[O:19])[O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:4]=[C:3]2[CH2:8][CH2:9][CH2:10][C:2]=12
Reactant: Nc1cnc2c(c1)CCC2
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C(Nc1cnc2c(c1)CCC2)Oc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6,7-Dihydro-5H-cyclopenta[b]pyridin-3-amine (D) (250 mg, 1.86 mmol) was dissolved in acetonitrile. The reaction mixture was added pyridine (0.18 mL, 2.23 mmol) and phenyl chloroformate (0.26 mL, 2.05 mmol) and stirred at room temperature for 3 h under N2. TLC showed complete consumption of starting material. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic part was washed with water and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude was purified by column chromatography to give phenyl 6,7-dihydro-5H-cyclopenta[b]pyridin-3-ylcarbamate (E). (372 mg, 78%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:21])[C:5]2[NH:6][C:7](=[O:20])[C:8]3[CH:19]=[CH:18][CH:17]=[N:16][C:9]=3[N:10]([CH:13]3[CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>CN(C)C1C=CN=CC=1>[C:22]([N:6]1[C:7](=[O:20])[C:8]2[CH:19]=[CH:18][CH:17]=[N:16][C:9]=2[N:10]([CH:13]2[CH2:15][CH2:14]2)[C:11]2[N:12]=[C:2]([Cl:1])[CH:3]=[C:4]([CH3:21])[C:5]1=2)(=[O:24])[CH3:23]
Reactant: Cc1cc(Cl)nc2c1NC(=O)c1cccnc1N2C1CC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Product: CC(=O)N1C(=O)c2cccnc2N(C2CC2)c2nc(Cl)cc(C)c21
Temperature: 130 °C

Procedure:
A mixture of 2-chloro-11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and acetic anhydride with 4-dimethylaminopyridine was heated at 130° C. until a clear solution was obtained. The solvent was evaporated and the residue was chromatographed over silica gel with ethyl acetate/hexane to give 0.85 g of the title compound, which crystallized from isopropyl ether/ethyl acetate, m.p. 204°-206° C.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C=O)C>[CH2:9]([O:7][C:6]1[CH:5]=[CH:4][C:3]([Br:8])=[CH:2][CH:1]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Br)cc1
Solvent: CN(C)C=O
Product: Brc1ccc(OCc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a solution composed of p-bromophenol (17.3 g, 0.1 mol) and dry DMF (100 mL), anhydride K2CO3 (8.28 g, 0.06 mmol) and benzyl bromide (25.6 g, 0.15 mmol) were added. The mixture was stirred at 80° C. under a nitrogen atmosphere for six hours. Then, the reaction mixture was charged into 500 mL of ice water.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[CH2:10]([O:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[C:20](\[CH3:24])/[CH:21]=[CH:22]/[CH3:23])=[CH:15][CH:14]=1)[CH3:11].I([O-])(=O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[C:5]([O:4][C:3]([N:2]1[CH:22]([CH3:23])[CH:21]=[C:20]([CH3:24])[CH:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:10][CH3:11])=[CH:18][CH:17]=2)[O:1]1)=[O:9])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)NO
Reactant: C/C=C/C(C)=C/c1ccc(OCC)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: ClCCl
Product: CCOc1ccc(C2ON(C(=O)OC(C)(C)C)C(C)C=C2C)cc1
Temperature: 4 °C
Reaction time: 4 h

Procedure:
A solution of t-butyl N-hydroxycarbamate (11.14 g, 84 mmol) in dichloromethane (300 ml) was added dropwise over 25 mins to a stirred mixture of 1-(4-ethoxyphenyl)-2-methyl-pent-1E,3E-diene (8.46 g, 42 mmol) and tetrabutylammonium periodate (32.6 g, 75 mmol) in dichloromethane (300 ml) cooled to 4° C. under nitrogen atmosphere. After stirring for 4 h at 3-4° C. the reaction mixture was washed with 2M aqueous sodium carbonate containing sodium metabisulphite and then twice with water. The dichloromethane solution was dried over magnesium sulphate, filtered and evaporated to an oil (33.1 g). This was purified by chromatography twice on silica eluting with n-hexane: diethyl ether 4:1 to give 2-t-butoxycarbonyl-3,6-dihydro-3,5-dimethyl-6-(4-ethoxyphenyl)-2H-1,2-oxazine as a yellow oil.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C([N-]C(C)C)(C)C.[Li+].[CH3:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br>O1CCCC1>[CH3:18][C:19]1[CH:20]=[C:21]([CH2:22][CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])[CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1cccc(CBr)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CCc1cccc(C)c1
Reaction time: 0.5 h

Procedure:
Ethyl acetoacetate (74.5 ml) was added dropwise to a solution of lithium diisopropylamide (2.0M solution in heptane/tetrahydrofuran/ethylbenzene, 600 ml) in tetrahydrofuran (2.5 L) at 0° C. The mixture was stirred for 30 min then 3-methylbenzylbromide (79 ml) was added dropwise. The mixture was stirred for 1 hour at 0° C. then quenched with 2M HCl. The mixture was extracted with ethyl acetate, the extracts washed with water, dried (MgSO4) and evaporated to give an oil which was purified by chromatography eluting with 5-10% ethyl acetate in isohexane.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>C(O)C>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Sc1ccc(Br)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)CSc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
1.36 g of potassium hydroxide was dissolved in 38 ml ethanol by heating, allowed to cool, mixed with 3.8 g of 4-bromobenzenethiol, further with 3.8 g of silica gel and 2.96 ml of t-butyl bromoacetate, followed by stirring at room temperature for 4 hours. Silica gel was filtered off and the filtrate was concentrated and purified via column chromatography on silica gel (ethyl acetate:hexane=1:20) to give t-butyl [(4-bromophenyl)thio]acetate (5.98 g, 98.6%).
Reaction SMILES: [O:1]([CH2:8][CH2:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[NH2:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:24](OC)(OC)[CH2:25][CH2:26][CH2:27][CH3:28]>>[CH2:25]([C:24]1[N:10]([CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:21]=1)[CH2:26][CH2:27][CH3:28]
Reactant: Nc1cnc2ccccc2c1NCCOc1ccccc1
Reactant: CCCCC(OC)(OC)OC
Product: CCCCc1nc2cnc3ccccc3c2n1CCOc1ccccc1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
N4-(2-Phenoxyethyl)quinoline-3,4-diamine (2.0 g, 7.2 mmol), xylenes (150 ml), and trimethylorthovalerate (2.5 ml, 14.3 mmol) were combined under an atmosphere of nitrogen and heated at reflux temperature for 4 days. The external heat was increased and approximately 35 ml of xylenes was removed by distillation. The reaction was slowly cooled to room temperature and a precipitate formed. The solid was recovered by vacuum filtration to yield 2.4 g of 2-butyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinoline as a light tan crystalline solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].Cl>N1CCCCC1.N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:11][C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cccc(Br)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cccc(Br)c1
Temperature: 25 °C
Yield: 94.4 %

Procedure:
3-Bromobenzaldehyde (10.0 g, 54 mmol), malonic acid (10.1 g, 97 mmol) and piperidine (0.267 mL, 2.7 mmol) are treated with pyridine (30 mL) and treated at 100° C. for 3.5 hours. The reaction mixture is cooled to room temperature, poured into 200 ml of 20% hydrochloric acid at 0° C.; the resultant precipitate is collected, washed with copious amounts of water and dried in a vacuum dessicator overnight to afford the title compound (11.64 g, 51 mmol).
Reaction SMILES: Cl([O-])(=O)(=O)=O.C1(CCN=CC2C=CC=CN=2)C=CC=CC=1.[OH-].[K+].[C:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])[CH3:25]>C(O)(C)C>[C:27]1([CH:24]([OH:26])[CH3:25])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(=O)c1ccccc1
Agent: C(=NCCc1ccccc1)c1ccccn1
Agent: [K+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(C)O
Product: CC(O)c1ccccc1
Reaction time: 4 h

Procedure:
24.4 mg of [Ir(PPEI)COD]+ClO4- (+) (4×10-5 moles) (PPEI=2-pyridinal-phenylethylimine; COD=cis cis 1-5 cyclooctadiene), suspended in 1 ml of isopropanol were oxidized with air for 4 hours. The resulting yellow solution was degasified for 20 minutes at reflux in a nitrogen stream and treated with 3.75 ml of a deaerated isopropanol solution of KOH (8 mg of KOH). After a 30-minutes reduction in a nitrogen stream, 4.8 ml of deaerated acetophenone were added. After a 120-minute reaction, a conversion to 1-phenylethanol (+) of 91.2% and an e.e. of 13.6% were obtained. The polarimetric determination was effected on the hydrogenation product distilled at reduced pressure. Ratios:
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].O=S(Cl)Cl.N1C=CC=CC=1.[C:32]([C:34]1[CH:41]=[CH:40][C:37]([CH2:38]O)=[CH:36][CH:35]=1)#[N:33]>C1(C)C=CC=CC=1>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:38][C:37]3[CH:40]=[CH:41][C:34]([C:32]#[N:33])=[CH:35][CH:36]=3)=[O:20])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: N#Cc1ccc(CO)cc1
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(CC(=O)O)cc2)CC1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCCCC[C@H]1CC[C@H](c2ccc(CC(=O)OCc3ccc(C#N)cc3)cc2)CC1
Reaction time: 2 h

Procedure:
28.8 g of p-(trans-4-pentylcyclohexyl)-phenylacetic acid is boiled for 1 hour with 24 g of SOCl2 ; the mixture is evaporated; the crude acid chloride obtained is dissolved in 150 ml of toluene, 8 ml of pyridine and 13.3 g of p-cyanobenzyl alcohol are added; and the mixture is boiled for 2 hours. Cooling and working up in a customary manner give p-cyanobenzyl p-(trans-4-pentylcyclohexyl)-phenylacetate, m.p. 85°, c.p. 30°.