Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrCCCCCCCCCCCCCCCC[C:18]1[C:35]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:34][C:33]2[C:32]3[C:27](=[CH:28][C:29]([O:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])=[C:30]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH:31]=3)[C:26]3[C:21](=[CH:22][C:23]([O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])=[C:24]([O:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH:25]=3)[C:20]=2[CH:19]=1.[P:71]([O:78][CH2:79][CH3:80])([O:75][CH2:76][CH3:77])[O:72]CC>>[CH2:79]([O:78][P:71]([CH2:23][CH2:22][CH2:21][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][O:43][C:30]1[C:29]([O:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])=[CH:28][C:27]2[C:26]3[C:21](=[CH:22][C:23]([O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])=[C:24]([O:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH:25]=3)[C:20]3[C:33](=[CH:34][C:35]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[C:18]([O:36][CH2:35][CH2:34][CH2:33][CH2:20][CH2:19][CH3:18])[CH:19]=3)[C:32]=2[CH:31]=1)(=[O:72])[O:75][CH2:76][CH3:77])[CH3:80]
Reactant: CCOP(OCC)OCC
Reactant: CCCCCCOc1cc2c(cc1CCCCCCCCCCCCCCCCBr)c1cc(OCCCCCC)c(OCCCCCC)cc1c1cc(OCCCCCC)c(OCCCCCC)cc21
Product: CCCCCCOc1cc2c3cc(OCCCCCC)c(OCCCCCC)cc3c3cc(OCCCCCCCCCCCCCCCCP(=O)(OCC)OCC)c(OCCCCCC)cc3c2cc1OCCCCCC
Temperature: 150 °C
Reaction time: 27 h

Procedure:
Under argon, 20 mL of triethyl phosphite was added to 6.1 g (5.8 mmol) of 2-(16-bromohexadecyl)-3,6,7,10,11-pentakishexyloxytriphenylene, and the mixture was stirred at 150° C. for 27 hours. Excess triethyl phosphite was evaporated from the mixture and the residue was purified by silica-gel column chromatography. As a result, 5.4 g of a white solid was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(Cl)Cl.CN1CCOCC1.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([S:28]([NH:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)c1cccc(N)c1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)c1cccc(NS(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 906.3 %

Procedure:
To 4.6 g (3.03 mmol) of the methyl 3-aminobenzoate prepared in Example 1 in 30 mL of methylene chloride containing 4.0 mL (36 mmol) of N-methylmorpholine was added 4.0 mL (33 mmol) of benzenesulfonyl chloride. After stirring at room temperature for 1 hr the reaction mixture was quenched with water (100 mL). The suspension was dissolved in ethyl acetate/ether combination. The organic phase was washed sequentially with 2N HCl and then sodium bicarbonate. The organic phase was dried (MgSO4), and concentrated and triturated from ethyl acetate/hexane ether to give 8.0 g (90%) of the title compound as a colorless solid: NMR (DMSO-d6 ; 300 MHz) δ 10.58 (s, 1H), 7.75-7.84 (m, 3H), 7.52-7.72 (m, 4H), 7.35-7.45 (m, 2H), and 3.82 ppm (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:8]([N+:15]([O-:17])=[O:16])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:23]O>>[CH3:23][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([N+:15]([O-:17])=[O:16])[C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:2]=1[NH2:1]
Reactant: Nc1cc(C(F)(F)F)c([N+](=O)[O-])cc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(C(F)(F)F)cc1N
Temperature: 25 °C
Yield: 90 %

Procedure:
A solution of 28 g (112 mmol) of 2-amino-5-nitro-4-trifluoromethyl-benzoic acid in 550 ml of methanol is cooled to 0° C. under nitrogen and concentrated H2SO4 is added dropwise in order to keep the temperature around 20° C. Upon completion of the addition, the mixture is heated to reflux for 24 hours. It is then allowed to cool to room temperature and the mixture is concentrated in vacuo to about 50 ml. This residue is poured onto ice and extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product is recrystallized in toluene to give 26.7 g (90%) of 2-amino-5-nitro-4-trifluoromethyl-benzoic acid methyl ester as yellow crystals, m.p. 174-175° C.
Reaction SMILES: [OH:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.I[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1>>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([O:1][CH:2]2[CH:7]3[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]3)[CH2:3]2)=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: OC1CN2CCC1CC2
Reactant: O=[N+]([O-])c1ccc(I)cc1
Product: O=[N+]([O-])c1ccc(OC2CN3CCC2CC3)cc1

Procedure:
3-Hydroxy quinuclidine (Aldrich, 2.54 g, 10 mmol) was treated with 1-iodo-4-nitro-benzene (5 g, 20 mmol) according to the procedure of Example 14A. The title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.20) (1.02 g, yield, 21%). 1H NMR (MeOH-d4, 300 MHz) δ 1.40–1.56 (m, 1H), 1.65–1.90 (m, 2H), 1.90–2.08 (m, 1H), 2.15–2.25 (m, 1H), 2.75–3.00 (m, 5H), 3.34–3.40 (m, 1H), 4.69 (m, 1H), 7.07 (d, J=9.5 Hz, 2H), 8.21 (d, J=9.2, Hz, 2H) ppm. MS (DCl/NH3) m/z 249 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[O:13]1)[CH:8]=[CH:7]2.[NH:19]1[CH2:24][CH2:23][CH:22]([CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21][CH2:20]1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:17][C:14]1([CH3:18])[O:13][CH:12]([C:9]2[CH:8]=[CH:7][C:6]3[C:11](=[C:2]([N:19]4[CH2:24][CH2:23][CH:22]([CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:21][CH2:20]4)[CH:3]=[CH:4][CH:5]=3)[N:10]=2)[CH2:16][O:15]1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: CC1(C)OCC(c2ccc3cccc(Br)c3n2)O1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCC1CCN(c2cccc3ccc(C4COC(C)(C)O4)nc23)CC1
Temperature: 25 °C

Procedure:
To 8-bromo-2-(2,2-dimethyl-1,3-dioxolan-4-yl)quinoline (101 mg, 0.328 mmol) in toluene (1.3 mL) was added tert-butyl piperidin-4-ylmethylcarbamate (84.3 mg, 0.393 mmol), Pd(OAc)2 (7.3 mg, 0.033 mmol), Binap-rac (25 mg, 0.039 mmol) and Cs2CO3 (235 mg, 0.721 mmol). The reaction was purged twice with nitrogen and heated at reflux overnight. The reaction mixture was cooled to ambient temperature and filtered through Celite, and the solids were washed with EtOAc (20 mL). The filtrate was concentrated, and the crude material was purified by silica gel chromatography (EtOAc/Hexane 1:6) provided final product.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([C:15]1[C:16]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[N:17][CH:18]=[CH:19][CH:20]=1)#[CH:14].Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C1COCC1.O.CO.CCOC(C)=O.CCCCCC>[C:22]([C:21]([C:16]1[C:15]([C:13]#[C:14][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:20][CH:19]=[CH:18][N:17]=1)([CH3:25])[CH3:24])#[N:23]
Reactant: CCOC(=O)Cl
Reactant: C#Cc1cccnc1C(C)(C)C#N
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)C#Cc1cccnc1C(C)(C)C#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.5 %

Procedure:
2.5M n-butyllithium (6.6 mL, 16 mmol) was added to a stirred solution of diisopropylamine (2.4 mL, 17 mmol) in THF (20 mL) at −78° C. The reaction mixture was then allowed to warm to ambient temperature for 5 minutes before being cooled back down to −78° C. 2-(3-Ethynylpyridin-2-yl)-2-methylpropanenitrile (0.93 g, 5.5 mmol) was then added dropwise as a solution in THF (20 mL). After 15 minutes, ethyl chloroformate (1.7 mL, 17 mmol) in 5 mL of THF was added to the reaction. The resulting solution was allowed to warm to ambient temperature, and was then stirred for 15 minutes. TLC (30% EtOAc/hexane) showed complete reaction and a slightly lower spot than the starting material. 3 mL of MeOH was added at 8° C. and then 3 mL of H2O was added. The mixture was extracted with EtOAc, and the combined organic layers were washed with water (3×), saturated NH4Cl (3×) and brine (3×). The organic layer was then dried over MgSO4 and concentrated in vacuo. The crude product was purified by silica flash chromatography (0-75% EtOAc/hexane) to give the title compound as a white crystalline solid (0.98 g, 74%). MS (m/z)=243 (M+H)+. Calculated for C14H14N2O2 242.3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([F:19])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[O:41][N:40]=[C:39]([CH3:42])[CH:38]=2)[CH:32]=1)=[O:30])(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([F:19])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[O:41][N:40]=[C:39]([CH3:42])[CH:38]=2)[CH:32]=1)=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(F)cc1N
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(F)c(N4CCCC4)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from (2-amino-4-fluoro-5-pyrrolidin-1-yl-phenyl)-carbamic acid tert.-butyl ester (Example J15) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example K4) according to the general procedure M. Obtained as a light yellow solid (126 mg).
Reaction SMILES: [I:1][C:2]1[C:3](=[O:21])[C:4]2[C:9]([O:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:8]1[NH:18][N:19]=[CH:20][C:7]1=[CH:6][CH:5]=2.[H-].[Na+].I[CH3:25]>CN(C=O)C>[I:1][C:2]1[C:3](=[O:21])[C:4]2[CH:5]=[CH:6][C:7]3[C:8](=[N:18][N:19]([CH3:25])[CH:20]=3)[C:9]=2[O:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CI
Reactant: O=c1c(I)c(-c2ccccc2)oc2c1ccc1cn[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc2ccc3c(=O)c(I)c(-c4ccccc4)oc3c2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 19.1 %

Procedure:
To a solution of 7-iodo-8-phenyl-1H-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-6-one (100 mg, 0.26 mmol) in DMF (5 mL) was added sodium hydride (60% dispersion in oil, 30 mg, 0.77 mmol) and the reaction stirred at RT. After 5 min, iodomethane (0.06 mL, 0.90 mmol) was added and the reaction stirred at RT for 6 h. The reaction was quenched by addition of water (3 mL) and extracted with EtOAc (×2). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 100% EtOAc in cyclohexane) to afford the title compound (20 mg, 20%). LCMS (Method B) RT=3.70 min, [M+H]+=403. 7-iodo-1-methyl-8-phenyl-1H-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-6-one was also isolated.
Reaction SMILES: [I:1][CH:2]1[CH2:7][CH:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]([CH3:13])[CH2:4][CH2:3]1.CC1C(C(O)=O)CC=CC1>>[I:1][C@H:2]1[CH2:7][C@@H:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C@H:5]([CH3:13])[CH2:4][CH2:3]1
Reactant: CCOC(=O)C1CC(I)CCC1C
Agent: CC1CC=CCC1C(=O)O
Product: CCOC(=O)[C@@H]1C[C@H](I)CC[C@H]1C

Procedure:
Ethyl(1SR,2SR,5SR)-5-iodo-2-methylcyclohexane-1-carboxylate (4) was generated in an analogous manner from racemic (1RS, 6RS)-6-methyl-3-cyclohexene-1-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:7][CH2:6][CH2:5][N:4](CC2C=CC=CC=2)[C:3]1=[O:15].N>C1COCC1>[CH3:1][C:2]1([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:15]
Reactant: CC1(Cc2ccccc2)CCCN(Cc2ccccc2)C1=O
Agent: N
Solvent: C1CCOC1
Product: CC1(Cc2ccccc2)CCCNC1=O
Yield: 156.4 %

Procedure:
The reaction of 3-methyl-1,3-diphenylmethyl-2-piperidinone (2.93 g, 10 mmol) with Li metal (0.70 g, 100 mmol) in THF (30 mL) and liquid NH3 (200 mL), as described above in the preparation of Example 11, gave 3.18 g of a colorless viscous residue. Flash chromatography over silica gel (1% MeOH in CHCl3 -EtOAc, 1:1) afforded the lactam (1.75 g, 86% ) as a colorless solid: mp 76°-78° C. (ether-hexane).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10](=[O:20])[C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1>[Pd].CO.O1CCCC1>[NH2:1][C:2]1[S:3][C:4]([C:10](=[O:20])[C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1
Reactant: Nc1nc(C(=O)O)c(C(=O)c2ccc([N+](=O)[O-])cc2)s1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)c2sc(N)nc2C(=O)O)cc1
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 2-amino-5-(4-nitrobenzoyl)-4-thiazolecarboxylic acid (2.6 g) and 10% palladium on carbon (1 g, 50% wet) in a mixture of methanol (50 ml) and tetrahydrofuran (50 ml) was hydrogenated under atmospheric pressure for 2 hours. The reaction mixture was filtered and then the filtrate was concentrated under reduced pressure. The residue was triturated with ether and the precipitates were collected by filtration, washed with ether and dried in vacuo to give 2-amino-5-(4-aminobenzoyl)-4-thiazolecarboxylic acid (2.10 g, yield: 90.0%).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][CH:7]([CH3:10])[CH2:8][OH:9].N1C=CC=CC=1>C(OCC)C>[Cl:1][CH2:2][C:3]([O:9][CH2:8][CH:7]([CH3:10])[CH3:6])=[O:4]
Reactant: CC(C)CO
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)COC(=O)CCl
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
A solution of chloroacetyl chloride (3.2 mL, 40 mmol) in anhydrous diethyl ether (20 mL) was added dropwise within 1 h to a solution of 2-methylpropanol (2.96 g, 40 mmol) and pyridine (3.25 mL, 40 mmol) in anhydrous diethyl ether (80 mL) at 0° C. After warming to RT, the white suspension was stirred for 3 h. The precipitate was removed by filtration and washed by diethyl ether (15 mL). The combined organic solution was washed with HCl (2 N, 30 mL), followed by sat. NaHCO3 (30 mL), sat. NaCl (30 mL) solutions and dried with Na2SO4. Removal of the solvent at about 60 mmHg/30° C. afford 2-Methylpropyl Chloroacetate (5.65 g, 94%) which was used without further purification.
Reaction SMILES: Cl.[C:2]1([CH2:8][N:9]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:10]2[C:19]3[N:20]=[C:21]([CH2:27][CH2:28][CH:29]([CH3:32])[CH2:30][Cl:31])[N:22](COCC)[C:18]=3[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C(Cl)Cl>[C:34]1([CH2:33][N:9]([CH2:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]2[C:19]3[N:20]=[C:21]([CH2:27][CH2:28][CH:29]([CH3:32])[CH2:30][Cl:31])[NH:22][C:18]=3[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CCOCn1c(CCC(C)CCl)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC(CCl)CCc1nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c2[nH]1
Yield: 88.8 %

Procedure:
Hydrochloric acid (80 mL of 6N) was added to a suspension of N,N-bis(phenylmethyl)-2-(4-chloro-3-methylbutyl)-1-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine (0.64 g, 1.2 mmole) in methanol (40 mL). The reaction mixture was heated at reflux for 2 hours (All of the methanol was driven off during this period.), diluted with methylene chloride and then made basic with 10% sodium hydroxide. The methylene chloride layer was separated, dried over magnesium sulfate and then concentrated to provide about 0.5 g of N,N-bis(phenylmethyl)-2-(4-chloro-3-methylbutyl)-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: C(C#N)(=[O:5])C(C)C.[Cl:8][CH2:9][CH2:10][CH2:11][C:12]([C:14]#[N:15])=[O:13]>>[Cl:8][CH2:9][CH2:10][CH2:11][C:12](=[O:13])[C:14]([NH2:15])=[O:5]
Reactant: N#CC(=O)CCCCl
Reactant: CC(C)C(=O)C#N
Product: NC(=O)C(=O)CCCCl
Yield: 87 %

Procedure:
The procedure was the same as that described in Example 1 except that instead of isobutyryl cyanide there were employed 131.5 grams (1.0 mole) of 4-chlorobutyryl cyanide. After recrystallization from water there were isolated 130 grams (87% of theory) of 5-chloro-2-oxovaleramide having a melting point of 87° C.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:8]=[C:9]([C:13]3[CH2:17][CH2:16][C:15](=O)[CH:14]=3)[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.Cl.[NH2:22][OH:23]>>[F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:8]=[C:9]([C:13]3[CH2:17][CH2:16][C:15](=[N:22][OH:23])[CH:14]=3)[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1C=C(c2cccc(Oc3ccc(F)cc3)c2)CC1
Agent: Cl
Product: ON=C1C=C(c2cccc(Oc3ccc(F)cc3)c2)CC1
Reaction time: 4 h
Yield: 113.6 %

Procedure:
To a stirred solution of 3-[3-(4-fluorophenoxy)phenyl]-2-cyclopentenone (10 g; 0.0373M) in ethanol-pyridine (75 ml-21 ml) was added hydroxylamine hydrochloride (3.37 g; 0.0485M) at room temperature. After stirring for 4 hrs, solvent was removed. To the residue was added dilute aqueous HCl (100 ml), and the whole was extracted with ethyl acetate (200 ml×1, 100 ml×1). The combined organic layers were washed with water (100 ml), brine (100 ml), dried over MgSO4, and concentrated in vacuo to give 12 g of crude subtitle compound [E] as a brown oil, which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[NH:13][CH2:12][C:11]2[O:14][C:15]([C:17]([O:19]C)=[O:18])=[N:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+:23]>O1CCCC1>[C:1]([O:5][C:6]([CH:8]1[NH:13][CH2:12][C:11]2[O:14][C:15]([C:17]([O-:19])=[O:18])=[N:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3].[Li+:23]
Reactant: COC(=O)c1nc2c(o1)CNC(C(=O)OC(C)(C)C)C2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1Cc2nc(C(=O)[O-])oc2CN1
Reaction time: 0.17 h

Procedure:
To a solution of 6-(tert-butoxycarbonyl)-2-methoxycarbonyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine (311 mg) in tetrahydrofuran (8.0 ml) were added water (2.0 ml) and lithium hydroxide (25.0 mg) at room temperature. After stirring for 10 minutes, the reaction mixture was distilled under reduced pressure to remove the solvent, whereby the title compound (280 mg) was obtained as a colorless solid. The residue was provided for the subsequent reaction without purification.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]([O:10][C@H:11]2[CH2:16][C@@H:15]([CH3:17])[CH2:14][CH2:13][C@@H:12]2[CH:18]([CH3:20])[CH3:19])=[O:9])[CH2:6][CH2:5][CH2:4][NH:3]1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:31])(=O)=O)=CC=1>C(O)C>[F:31][C@@:7]1([C:8]([O:10][C@H:11]2[CH2:16][C@@H:15]([CH3:17])[CH2:14][CH2:13][C@@H:12]2[CH:18]([CH3:20])[CH3:19])=[O:9])[CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[O:1]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CC(C)[C@H]1CC[C@H](C)C[C@@H]1OC(=O)C1CCCNC1=O
Solvent: CCO
Product: CC(C)[C@H]1CC[C@H](C)C[C@@H]1OC(=O)[C@]1(F)CCCNC1=O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
(1S,2R,5S)-5-Methyl-2-(1-methylethyl)cyclohexyl 2-oxo-3-piperidinecarboxylate (1 wt) is dissolved in ethanol (1.5 vol) and N-fluorobenzenesulfonimide (NFSI) (1.07 wt) added, followed by [(S)-BINAP]Pd(CH3CN)2(OTf)2 (0.038 wt) at 20° C. Residual NFSI and catalyst were washed in with ethanol (3 vol). The jacket is cooled to 0° C. and 2,6-lutidine (0.21 vol) charged slowly, maintaining the temperature below 20° C. The jacket temperature is then raised to 20° C. The reaction mixture is stirred for 24 h, cooled to 0° C. and stirred for an additional 2 h. The solids are isolated by filtration, washing with ethanol (3 vol) and dried under vacuum at 40° C. The dried crude solid is charged to a reactor, and dichloromethane (5 vol) added. The dichloromethane phase is washed sequentially with 2M aqueous NaOH (3 vol), water (3 vol), 5% w/w aqueous HCl (3 vol) and water (3 vol). The dichloromethane extract is transferred to a rotary evaporator and solvent swapped with n-heptane under reduced pressure to give a mobile slurry and a final volume of ca 11 vol. The product is isolated by filtration, washed with heptane (3 vol) and dried under vacuum at 40° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10](=[O:18])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[N+:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20].[NH4+].[OH-]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:26](=[O:27])[C:25]4[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:30][CH:29]=4)[CH:16]=3)[NH:11][C:10](=[O:18])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C1CC(c2cccc(Cl)c2)c2ccccc2N1
Agent: [NH4+]
Agent: [OH-]
Product: O=C1CC(c2cccc(Cl)c2)c2cc(C(=O)c3ccc([N+](=O)[O-])cc3)ccc2N1
Temperature: 140 °C
Reaction time: 72 h
Yield: 26.9 %

Procedure:
(±)-4-(3-chlorophenyl)-3,4-dihydro-2(1H)-quinolinone (described in WO 97/21701) (0.0776 mol), then 4-nitro-benzoic acid (0.233 mol) were added at 100° C. to polyphosphoric acid (200 g). The mixture was stirred at 140° C. for 72 hours, cooled at 80° C., poured out into ice water, basified with NH4OH (concentrated) and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (19.4 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 98/2; 15–35 μm). One fraction was collected and the solvent was evaporated. The residue (9.1 g) was crystallized from 2-propanone. The precipitate was filtered off and dried, yielding 8.5 g (27%) of (±)-4-(3-chlorophenyl)-3,4-dihydro-6-(4-nitrobenzoyl)-2(1H)-quinolinone, mp. 147° C. (intermediate 15).
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[CH:32][CH:33]=O)[CH2:7][C:8]([CH3:31])([CH3:30])[CH2:9][C:10]=1[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])=[CH:15][C:14]=1[O:28][CH3:29])[CH2:2][CH2:3][CH3:4].[C:35]([C:37]1[C:38](=[C:53]([C:56]#[N:57])[C:54]#[N:55])[O:39][C:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:43]([F:46])([F:45])[F:44])[C:41]=1[CH3:42])#[N:36]>>[CH2:1]([C:5]1[C:6](=[CH:32][CH:33]=[CH:42][C:41]2[C:40]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:43]([F:46])([F:44])[F:45])[O:39][C:38](=[C:53]([C:56]#[N:57])[C:54]#[N:55])[C:37]=2[C:35]#[N:36])[CH2:7][C:8]([CH3:30])([CH3:31])[CH2:9][C:10]=1[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])=[CH:15][C:14]=1[O:28][CH3:29])[CH2:2][CH2:3][CH3:4]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(c1ccccc1)C(F)(F)F
Reactant: CCCCC1=C(C=Cc2ccc(N(CCCC)CCCC)cc2OC)CC(C)(C)CC1=CC=O
Product: CCCCC1=C(C=Cc2ccc(N(CCCC)CCCC)cc2OC)CC(C)(C)CC1=CC=CC1=C(C#N)C(=C(C#N)C#N)OC1(c1ccccc1)C(F)(F)F
Temperature: 50 °C
Yield: 69.7 %

Procedure:
118 mg (0.25 mmol) of [2-butyl-3-[2-(4-dibutylamino-2-methoxyphenyl)vinyl]-5,5-dimethyl-2-cyclohexenylidene]acetaldehyde and 90 mg (0.29 mmol) of 2-(3-cyano-4-methyl-5-phenyl-5-trifluoromethyl-2(5H)-furanylidene]propanedinitrile were dissolved, and the mixture was stirred with heating at 50° C. for 40 minutes. The solvent was evaporated off. The residue was purified by silica gel column chromatography and washed with methanol to give 133 mg of a black crystal having a mp of 109-113° C. (yield: 68.9%).