Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=4)=[O:29])=[CH:20][C:19]=3[CH:38]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].Cl.Cl[CH2:41][C:42]1[N:46]([CH3:47])[CH:45]=[N:44][N:43]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([O:37][CH2:41][C:42]5[N:46]([CH3:47])[CH:45]=[N:44][N:43]=5)=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:38]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cn1cnnc1CCl
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(O)cc2)CCN3CCC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(OCc4nncn4C)cc2)CCN3CCC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
To 7-[4-(2-butoxyethoxy)phenyl]-N-(4-hydroxyphenyl)-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.62 g), 3-chloromethyl-4-methyl-4H-1,2,4-triazole hydrochloride (0.24 g) and potassium carbonate (0.5 g), N,N-dimethylformamide (15 ml) was added and the mixture was stirred overnight under nitrogen atmosphere at room temperature. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol/triethylamine), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(4-methyl-4H-1,2,4-triazol-3-yl) methoxy]phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 24) (0.48 g) as yellow amorphous.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:29]=[CH:30][CH:31]=1)[CH2:14][NH:15][C:16]1[C:25]2[C:20](=[C:21]([C:26]([NH2:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][N:17]=1.C(N(CC)CC)C>C(Cl)Cl>[NH:7]([C:8]([NH:10][C:11]1[CH:12]=[C:13]([CH:29]=[CH:30][CH:31]=1)[CH2:14][NH:15][C:16]1[C:25]2[C:20](=[C:21]([C:26]([NH2:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][N:17]=1)=[O:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)c1cccc2c(NCc3cccc(N)c3)ncnc12
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1cccc2c(NCc3cccc(NC(=O)Nc4ccccc4)c3)ncnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
Phenyl isocyanate (240 μL, 0.5 M in anhydrous DCM, 0.11 mmol, 1.1 equiv.) was added to a solution of 4-[(3-aminobenzyl)amino]quinazoline-8-carboxamide (32 mg, 0.1 mmol, 1.0 equiv.) and triethylamine (40 μL, 0.3 mmol, 3.0 equiv.) in anhydrous DCM (2 mL). The resulting mixture was stirred at rt overnight. The title compound was obtained by pre-HPLC in 34% yield. Mass: M+H+: 413.
Reaction SMILES: C(OC(N[C@@H]1CCNC[C@@H]1C(OC)=O)=O)C1C=CC=CC=1.C(N(CC)C(C)C)(C)C.BrCCO.[CH2:35]([O:42][C:43]([NH:45][C@@H:46]1[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][OH:54])[CH2:48][C@@H:47]1[C:55]([O:57][CH3:58])=[O:56])=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([O:42][C:43]([NH:45][C@@H:46]1[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][OH:54])[CH2:48][C@H:47]1[C:55]([O:57][CH3:58])=[O:56])=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COC(=O)[C@H]1CN(CCO)CC[C@H]1NC(=O)OCc1ccccc1
Agent: COC(=O)[C@H]1CNCC[C@H]1NC(=O)OCc1ccccc1
Agent: OCCBr
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1CN(CCO)CC[C@H]1NC(=O)OCc1ccccc1
Yield: 60 %

Procedure:
Methyl (3S,4R)-4-{[(benzyloxy)carbonyl]amino}piperidine-3-carboxylate (WO 2005/066176) (2.0 g, 6.84 mmol), N,N-diisopropylethylamine (1.8 mL, 10.26 mmol) and 2-bromoethanol (0.63 mL, 8.9 mmol) were reacted as described for Intermediate 37 to give 1.38 g (60%) of the product as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([CH:9]([CH3:11])[CH3:10])=[C:6]([OH:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:21][C:22]#[N:23]>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([CH:9]([CH3:11])[CH3:10])=[C:6]([CH:7]=1)[O:8][CH2:21][C:22]#[N:23]
Reactant: COc1cc(C(C)C)c(O)cc1Cl
Reactant: N#CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c(OCC#N)cc1Cl
Temperature: 65 °C
Yield: 96.8 %

Procedure:
To a solution of 5-chloro-2-isopropyl-4-methoxy-phenol (10.36 g, 51.6 mmol) in 40 mL DMF was added K2CO3 (8.55 g, 62.0 mmol) and the mixture was heated to 65° C. After 15 minutes iodoacetonitrile (9.05 g, 54.2 mmol) was added and the mixture was heated to 80° C. for 1 hour. The mixture was cooled, poured into an ice/H2O mixture and extracted with 1:1 toluene/hexane. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by passing through a short plug of silica to afford (5-chloro-2-isopropyl-4-methoxy-phenoxy)-acetonitrile (11.97 g, 97%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.[ClH:18].Cl.[NH2:20][CH2:21][CH2:22][O:23][NH2:24].N1C=CC=CC=1>C(O)C>[ClH:1].[ClH:18].[NH2:20][CH2:21][CH2:22][O:23][N:24]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: NCCON
Reactant: O=C(CCCn1ccnc1)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: NCCON=C(CCCn1ccnc1)c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 77.4 %

Procedure:
A mixture of 1-(4-chlorophenyl)-4-(1-(1H)-imidazolyl)-1-butanone (2.20 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (1.58 g), 3 equivalents of pyridine, and absolute ethanol (75 ml) was heated under reflux, under nitrogen, with stirring, for two hrs. The reaction mixture was partitioned between 10% sodium hydroxide solution and ethyl acetate. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was taken up in toluene and evaporated. The residue was purified by flash chromatography (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and concentrated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. Diethyl ether was added. The precipitate was collected and recrystallized twice from absolute ethanol/ether to give 1.3 g (39%) of product, mp 205°-207° C. (dec).
Reaction SMILES: [N:1]1([CH:16]2[CH2:22][CH:21]3[N:23]([C:24]([O:26][C@@H:27]4[CH2:31][CH2:30][O:29][CH2:28]4)=[O:25])[CH:18]([CH2:19][CH2:20]3)[CH2:17]2)[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][NH:8][CH2:7]2)[CH2:3][CH2:2]1.[CH3:32][N:33]([CH3:37])[C:34](Cl)=[O:35].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:32][N:33]([CH3:37])[C:34]([N:8]1[CH2:7][C:4]2([CH2:3][CH2:2][N:1]([CH:16]3[CH2:22][CH:21]4[N:23]([C:24]([O:26][C@@H:27]5[CH2:31][CH2:30][O:29][CH2:28]5)=[O:25])[CH:18]([CH2:19][CH2:20]4)[CH2:17]3)[CH2:6][CH2:5]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:35]
Reactant: O=C(O[C@@H]1CCOC1)N1C2CCC1CC(N1CCC3(CC1)CNCc1ccccc13)C2
Reactant: CN(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C(=O)N1Cc2ccccc2C2(CCN(C3CC4CCC(C3)N4C(=O)O[C@@H]3CCOC3)CC2)C1
Reaction time: 0.17 h

Procedure:
(R)-tetrahydrofuran-3-yl 3-(2,3-dihydro-1H-spiro[isoquinoline-4,4-piperidine]-1′-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (20 mg, 0.047 mmol) was dissolved in CH2Cl2 (1 mL) and treated with a solution of dimethylcarbamic chloride (20 mg, 0.13 mmol) in CH2Cl2 (100 μL). A solution of diisopropyl ethylamine (20 μL, 14.8 mg, 0.11 mmol) was added. The resulting mixture was allowed to stand at room temperature for 10 min and was then purified by LC/MS (10-99% CH3CN—H2O, with 0.03% TFA, 9 min) to provide (R)-tetrahydrofuran-3-yl 3-(2-(dimethylcarbamoyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate. LC/MS m/z [M+H]+ 497.4, retention time 2.15 min (10-99% CH3CN—H2O gradient, with 0.05% TFA, 5 min).
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.Br[CH:15]([CH3:21])[CH2:16][C:17]([O:19][CH3:20])=[O:18].C(N(CC)CC)C>CN(C=O)C>[CH3:20][O:19][C:17](=[O:18])[CH2:16][CH:15]([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)[CH3:21]
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: COC(=O)CC(C)Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CC(C)N1CCN(c2ccc(O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
To a mixture of 4-piperazin-1-yl-phenol (2 g, 11.2 mmol) and methyl 3-bromo-butyrate (2.03 g, 11.2 mmol) in DMF (5 mL) was added triethylamine (4.5 mL, 11.53 mmol) dropwise and the reaction mixture was stirred at ambient temperature overnight. The mixture was poured onto water and extracted with ethyl acetate (50 ml×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and evaporated under vacuum to dryness. The residue was purified by silica gel flash chromatography (1% methanol in CH2Cl2) to furnish the title compound (1.85 g, 59.3%); MS; m/z 279 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[OH:12].[CH2:13]=[O:14].ClCCl>[OH-].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([CH2:13][OH:14])=[C:7]2[OH:12]
Reactant: C=O
Reactant: Oc1ccnc2c(F)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: OCc1cnc2c(F)cccc2c1O

Procedure:
8-Fluoro-4-hydroxyquinoline was reacted with formaldehyde in aqueous sodium hydroxide to give the novel compound 8-fluoro-4-hydroxy-3-hydroxymethylquinoline, m.p. 176°-178° (from dichloromethane).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[S:9]([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)([OH:12])(=[O:11])=[O:10].[CH3:20][NH:21]CCCCC=C>>[S:9]([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)([OH:12])(=[O:11])=[O:10].[CH3:20][NH:21][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH:7][CH3:8]
Reactant: C=CCCCCCBr
Reactant: C=CCCCCNC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC=CCCCCNC

Procedure:
Compound 32b was synthesized from 7-bromo-heptene as a white solid in quantitative yield, following the procedure as described for compound 32a.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[CH2:13][CH:12]1[C:14]1[NH:18][N:17]=[N:16][N:15]=1.I[CH3:20].[OH-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[CH2:13][CH:12]1[C:14]1[N:18]=[N:17][N:16]([CH3:20])[N:15]=1
Reactant: O=C1Nc2ccc(Br)cc2C12CC2c1nnn[nH]1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cn1nnc(C2CC23C(=O)Nc2ccc(Br)cc23)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 34 %

Procedure:
A suspension containing 5′-bromo-2-(tetrazole-5-yl)-spiro[cyclopropane-1,3′-[3H]indol]-2′(1′H)-one (153 mg, 0.5 mmol), iodomethane (85 mg, 0.6 mmol) and sodium hydroxide (20 mg, 0.5 mmol) in 5 mL of DMF was stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness in vacuo. The solid residue was chromatographed using hexane and ethyl acetate (v/v 1:1) as eluent. The chromatographed material gave the title compound in 34% yield (55 mg). MS m/z 320 [M+1]+. 1H NMR (CDCl3): δ 8.52 (s, 1H), 7.27 (m, 1H), 7.04 (br, 1H), 6.80 (m, 1H), 4.34 (s, 3H), 3.35 (t, 1H), 2.48 (m, 1H), 2.05 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][N:7]=1.[C:13]([C:15]([C:21]#[N:22])=[C:16](SC)[S:17][CH3:18])#[N:14]>>[C:13]([C:15]([C:21]#[N:22])=[C:16]([S:17][CH3:18])[NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][N:7]=1)#[N:14]
Reactant: CSC(SC)=C(C#N)C#N
Reactant: NCCSCc1ncccc1Cl
Product: CSC(NCCSCc1ncccc1Cl)=C(C#N)C#N

Procedure:
Reaction of 2-[(2-aminoethyl)thiomethyl]-3-chloropyridine with 1,1-dicyano-2,2-bis-methylthioethylene by the procedure of Example 1(b)(i) yields 1,1-dicyano-2-methylthio-2-[2-((3-chloro-2-pyridyl)methylthio)ethylamino]ethylene.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]([OH:11])=O)=[CH:5][N:4]=1.CCN(C(C)C)C(C)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.Cl.Cl.[F:40][C:41]1[C:42]([C@H:47]([C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=2)[NH2:48])=[N:43][CH:44]=[CH:45][CH:46]=1>C1(C)C=CC=CC=1>[F:40][C:41]1[C:42]([C@H:47]([C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:57])([F:58])[F:56])=[CH:51][CH:50]=2)[NH:48][C:9]([C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=2)=[O:11])=[N:43][CH:44]=[CH:45][CH:46]=1
Reactant: N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1F
Reactant: COc1ncc(C(=O)O)cn1
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COc1ncc(C(=O)N[C@@H](c2ccc(C(F)(F)F)cc2)c2ncccc2F)cn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methoxypyrimidine-5-carboxylic acid (80 mg, 0.519 mmol), DIPEA (0.25 mL, 1.435 mmol) in toluene (3 mL) was added DPPA (0.19 mL, 0.882 mmol). The reaction was stirred at 80° C. for 2 hours. (S)-(3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methanamine dihydrochloride (167 mg, 0.487 mmol) was then added as a solid in one portion. After 24 hours, the reaction was concentrated in vacuo and the residue was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (12 g), eluting with 0% to 80% EtOAc in hexane, to provide the title compound as an off-white solid. 1H NMR (DMSO-d6, 400 MHz) δ ppm 9.02 (d, J=4.7 Hz, 1H), 8.97 (d, J=8.6 Hz, 1H), 8.30 (d, J=7.8 Hz, 1H), 7.63-7.77 (m, 3H), 7.54 (d, J=8.2 Hz, 2H), 7.39 (s, 1H), 7.01 (s, 1H), 6.66 (d, J=8.6 Hz, 1H), 3.93 (s, 3H) MS (ESI pos. ion) m/z: 407.0 (M+H).
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([C:22]#[N:23])[CH2:10][CH2:9][C:8]([S:11][Si](C(C)C)(C(C)C)C(C)C)=[CH:7][CH2:6]2)[CH2:3][CH2:2]1.Br[CH2:25][CH:26]1[CH2:28][CH2:27]1.[F-].[Cs+]>CN(C)C=O.O>[CH:1]1([CH2:4][C:5]2([C:22]#[N:23])[CH2:10][CH2:9][C:8]([S:11][CH2:25][CH:26]3[CH2:28][CH2:27]3)=[CH:7][CH2:6]2)[CH2:2][CH2:3]1
Reactant: BrCC1CC1
Reactant: CC(C)[Si](SC1=CCC(C#N)(CC2CC2)CC1)(C(C)C)C(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC1(CC2CC2)CC=C(SCC2CC2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.9 %

Procedure:
To a solution of 1-cyclopropylmethyl-4-triisopropylsilanylsulfanylcyclohex-3-enecarbonitrile (20.5 g, 58.5 mmol) and (bromomethyl)cyclopropane (15.8 g, 117 mmol) in anhydrous N,N-dimethylformamide (65 ml) was added cesium fluoride (17.8 g, 117 mmol) and the mixture left to stir at ambient temperature for 15 hours. The mixture was diluted with water (500 ml) and extracted with diethyl ether (3×200 ml). The combined organic layer was washed with water (2×300 ml) and brine (200 ml), dried over anhydrous magnesium sulphate, filtered and evaporated to give an orange oil. The oil was purified by dry flash column chromatography on silica eluting with isohexane on a gradient of dichloromethane (10-40%). Collecting appropriate fractions gave a colourless oil (10.7 g, 74%). 1H NMR δ (ppm) (CDCl3): 5.53 (1H, t, J=1.6 Hz), 2.69-2.51 (4H, m), 2.30-2.11 (3H, m), 1.71-1.67 (1H, m), 1.60-1.45 (2H, m), 1.05-0.99 (1H, m), 0.92-0.88 (1H, m), 0.60-0.56 (4H, m), 0.26-0.18 (4H, m).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH3:42])([CH3:41])[C@H:13]3[C@:30]([CH3:33])([CH2:31][CH:32]=2)[C@@H:29]2[C@:16]([CH3:40])([C@@:17]4([CH3:39])[C:26](=[CH:27][CH2:28]2)[C@H:25]2[C@:20]([C:36]([OH:38])=[O:37])([CH2:21][CH2:22][C@@H:23]([CH3:35])[C@@H:24]2[CH3:34])[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>O1CCOCC1.CO>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([CH3:42])([CH3:41])[C@H:13]3[C@:30]([CH3:33])([CH2:31][CH:32]=2)[C@@H:29]2[C@:16]([CH3:40])([C@@:17]4([CH3:39])[C:26](=[CH:27][CH2:28]2)[C@H:25]2[C@:20]([C:36]([OH:38])=[O:37])([CH2:21][CH2:22][C@@H:23]([CH3:35])[C@@H:24]2[CH3:34])[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:9][CH:10]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(C2=CC[C@]3(C)[C@H]4CC=C5[C@@H]6[C@@H](C)[C@H](C)CC[C@]6(C(=O)O)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: C[C@H]1[C@H](C)CC[C@]2(C(=O)O)CC[C@]3(C)C(=CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@H]12
Temperature: 65 °C
Yield: 61 %

Procedure:
Saponification of the intermediates A6 was conducted as followed: to a solution of (1S,2R,4aS,6aS,6bR,8aR,12aS,12bR,14bS)-10-(4-(methoxycarbonyl)phenyl)-1,2,6a,6b,9,9,12a-heptamethyl-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,12,12a,12b,13,14b-octadecahydropicene-4-a-carboxylic acid (intermediate A6) (20 mg, 0.035 mmol) in a mixture of dioxane (1 mL) and methanol (0.5 mL) was added a 1N solution of NaOH (0.5 mL, 0.5 mmol). The mixture was warmed to 65° C. for 2 h. The crude product was further purified by preparative HPLC(YMC Combiprep ODS 30×50 mm S5 column) eluted with gradient mixture of MeOH/water/TFA. The desired fractions were combined, evaporated to afford the title compound (12 mg, 61%).
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[C:15](I)[C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:4]1.[C-:23]#[N:24].[K+]>C1COCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([C:23]#[N:24])[C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:4]1
Reactant: O=C(N1CC(CCl)c2c1ccc1c(I)cccc21)C(F)(F)F
Reactant: [C-]#N
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1cccc2c3c(ccc12)N(C(=O)C(F)(F)F)CC3CCl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
A mixture of 125 (148 mg, 0.34 mmol), KCN (120 mg, 1.9 mmol), Pd(PPh3)4 (10 mg, 0.01 mmol), and CuI (50 mg, 0.26 mmol) in dry THF (30 mL) was heated to reflux under N2 with vigorous stirring for 30 min. The mixture was cooled to room temperature, diluted with EtOAc (50 mL), and then filtered through Celite. The filtrate was washed with water and brine, dried and concentrated under reduced pressure. Chromatography of the residue on silica gel eluting with EtOAc/petroleum ether (from 1:5 to 1:2) gave 1-(chloromethyl)-3-(trifluoroacetyl)-1,2-dihydro-3H-benzo[e]indole-6-carbonitrile (126) (97 mg, 85%): mp (EtOAc/petroleum ether) 158-160° C.; 1H NMR (CDCl3) δ 8.63 (d, J=9.1 Hz, 1H), 8.26 (d, J=9.2 Hz, 1H), 8.05 (d, J=8.5 Hz, 1H), 7.90 (dd, J=7.2, 1.0 Hz, 1H), 7.64 (dd, J=8.2, 7.2 Hz, 1H), 4.70-4.63 (m, 1H), 4.51-4.43 (m, 1H), 4.28-4.20 (m, 1H), 3.95-3.89 (m, 1H), 3.64-3.55 (m, 1H); 13C NMR S 154.7 (q, JC-F 38.3 Hz), 141.5, 132.0, 130.7, 129.0, 127.7, 127.5, 126.7, 119.7, 117.2, 115.9 (q, JC-F 288 Hz), 111.7, 52.7, 45.4, 42.6. Anal. (C16H10ClF3N2O.⅓H2O) C, H, N.
Reaction SMILES: NC1C=CC=CC=1[C:4](O)=[O:5].[NH2:11][C:12]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:13]=1[C:14]([OH:16])=[O:15].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[Cl:21][C:18]1[CH:17]=[C:13]2[C:14]([O:16][C:4](=[O:5])[NH:11][C:12]2=[CH:20][CH:19]=1)=[O:15]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: Nc1ccccc1C(=O)O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Yield: 89 %

Procedure:
Isatoic anhydrides were prepared from 2-aminobenzoic acid derivatives using the following procedure. A solution of 2-amino-5-chlorobenzoic acid (1.56 g, 9.7 mmol) in 25 mL of dry THF and triphosgene (1.00 g, 3.3 mmol) was stirred at room temperature for 18 h. The resultant solid was filtered, washed with cold acetone, and dried under vacuum to give 1.56 g (89%) of 5-chloroisatoic anhydride.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[N:12]=1)[C:6]([NH:8][OH:9])=[NH:7])[CH3:2].[CH2:14]([C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([CH3:26])[C:24]=1[OH:25])[C:19](O)=O)[CH3:15]>>[CH2:14]([C:16]1[CH:17]=[C:18]([C:19]2[O:9][N:8]=[C:6]([C:5]3[CH:10]=[C:11]([CH3:13])[N:12]=[C:3]([CH2:1][CH3:2])[CH:4]=3)[N:7]=2)[CH:22]=[C:23]([CH3:26])[C:24]=1[OH:25])[CH3:15]
Reactant: CCc1cc(C(=O)O)cc(C)c1O
Reactant: CCc1cc(C(=N)NO)cc(C)n1
Product: CCc1cc(-c2noc(-c3cc(C)c(O)c(CC)c3)n2)cc(C)n1

Procedure:
2-Ethyl-4-[3-(2-ethyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-5-yl]-6-methyl-phenol is prepared in analogy to Example 10 by coupling and cyclising 2-ethyl-N-hydroxy-6-methyl-isonicotinamidine with 3-ethyl-4-hydroxy-5-methyl-benzoic acid; LC-MS: tR=0.83 min; [M+1]+=324.15.
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[Si:12]([O:19][CH2:20][C:21]1[S:25][C:24]([NH2:26])=[N:23][CH:22]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>>[Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:26][C:24]2[S:25][C:21]([CH2:20][O:19][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:14])=[CH:22][N:23]=2)=[N:4][CH:3]=1
Reactant: Brc1ncc(Br)n2ccnc12
Reactant: CC(C)(C)[Si](C)(C)OCc1cnc(N)s1
Product: CC(C)(C)[Si](C)(C)OCc1cnc(Nc2ncc(Br)n3ccnc23)s1

Procedure:
Prepared from Intermediate 2 and Intermediate 7 using the procedure described in Example 1, Step 1. MS (MH+, m/z) 440.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[O:9][CH2:8][N:7]([C:10]([CH3:20])([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)[CH3:11])[C:6](=[O:21])[C:5]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[C:28](O)(=[O:30])[CH3:29]>O>[C:28]([O:1][N:2]=[CH:3][C:4]1[O:9][CH2:8][N:7]([C:10]([CH3:11])([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)[CH3:20])[C:6](=[O:21])[C:5]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)O
Reactant: CC(C)(c1cc(Cl)cc(Cl)c1)N1COC(C=NO)=C(c2ccccc2)C1=O
Solvent: O
Product: CC(=O)ON=CC1=C(c2ccccc2)C(=O)N(C(C)(C)c2cc(Cl)cc(Cl)c2)CO1
Yield: 94 %

Procedure:
A mixture of 6-hydroxyiminomethyl-3-[1-methyl-1-(3,5-dichlorophenyl)ethyl]-5-phenyl-2,3-dihydro-4H-1,3-oxazin-4-one (Compound No. 135, 0.60 g) and anhydrous acetic acid (2 ml) was stirred at room temperature for 4 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was rinsed with saturated saline solution, and dried with magnesium sulfate. The solvent was removed by evaporation, and the crude product was purified by silica gel chromatography to afford the captioned compound (0.54 g, yield 94%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH:3]1C(OCC)=O.[Cl-].[Na+].O>CS(C)=O>[O:1]=[C:2]1[CH2:3][CH2:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:6][CH2:7]1
Reactant: CCOC(=O)C1CC(C(=O)OCC)(C(=O)OCC)CCC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C1(C(=O)OCC)CCC(=O)CC1
Temperature: 160 °C
Reaction time: 3.5 h
Yield: 99 %

Procedure:
The procedure in Sanchez et al., Synth. Comm., 1985, 15, 141 was followed. A mixture of triethyl 4-oxocyclohexane-1,1,3-tricarboxylate, Intermediate 1, (135.2 g, 400 mmol), sodium chloride (70.1 g, 1200 mmol), and H2O (17.30 mL, 960 mmol) in DMSO (530 mL) was stirred at 160° C. (oil bath) under N2 for 3.5 h. The cooled mixture was poured into ice-water (3 L) and extracted with EtOAc (400 mL×3). The combined extracts were washed with brine, dried (Na2SO4) then concentrated to provide the title compound (103.4 g, 397 mmol, 99% yield) as an amber oil. HPLC: 2.04 min (AP 45% at 220 nm). LCMS: m/z 243 (M+H). 1H NMR (500 MHz, CDCl3) δ ppm 1.27 (6H, t, J=7.0 Hz, 9,12-CH3), 2.37 (4H, t, J=6.9 Hz, 3,5-CH2), 2.43 (4H, t, J=6.7 Hz, 2,6-CH2), 4.23 (4H, q, J=7.2 Hz, 8,11-OCH2). 13C NMR (126 MHz, CDCl3) δ ppm 14.1 (9,12-CH3), 31.0 (3,5-CH2), 37.8 (2,6-CH2), 53.6 (4-C), 61.9 (8,11-OCH2), 170.7 (7,10-OC═O), 209.4 (1-C═O).