Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:27]=1[C:28](Cl)=[O:29].C(NC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1)(=O)C1C=CC=CC=1>>[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:27]=1[C:28]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:29]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3)cc2)c2ccc3ccccc3c2N1
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)c2ccc3ccccc3c2N1
Yield: 64.7 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (20 mg, 0.063 mmol) obtained in Example 1, (3), and 2,6-dichlorobenzoyl chloride (20 mg, 0.095 mmol), the title compound (20 mg, yield 64%) was obtained as pale yellow crystals in the same manner as that of Example 1, (4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[S:11]([CH3:14])(=[O:13])=[O:12].[H-].[Na+].Br[CH2:18][C:19]#[N:20].O.C(OCC)(=O)C>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:18][C:19]#[N:20])[CH:8]=[C:7]2[S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: N#CCBr
Reactant: CS(=O)(=O)c1c[nH]c2c(Cl)cccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1cn(CC#N)c2c(Cl)cccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The 7-chloro-3-methanesulfonyl-1H-indole (2.21 g, 0.00962 mole) of Step 6 was dissolved in 20 ml dry N-methylpyrrolidinone and cooled to 0° C. under a nitrogen atmosphere. Sodium hydride (60% in oil, 0.46 g, 0.0115 mole) was added in portions with stirring and the reaction mixture was allowed to stir until bubbling ceased. Bromoacetonitrile (1.27 g, 0.0106 mole) was added all at once and the resulting solution was stirred and allowed to reach room temperature. After 1 h, the reaction mixture was poured into water-ethyl acetate and the organic layer was washed three times with brine and dried over magnesium sulfate. Evaporation to dryness gave a residue of 3.31 g which was purified by flushing through an alumina (6% water) column using 3:7 and 1:1 ethyl acetate-hexane to elute the product. The purified (7-chloro-3-methanesulfonyl-indol-1-yl)-acetonitrile was crystalline and weighed 2.111 g after thoroughly drying.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH:22]([F:24])[F:23])=[C:17]([CH3:25])[CH:16]=3)[NH:13][C:12](=O)[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.F[B-](F)(F)F.C[O+](C)C.[Cl-].[NH4+:36]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH:22]([F:24])[F:23])=[C:17]([CH3:25])[CH:16]=3)[CH2:9][O:10][CH2:11][C:12]([NH2:36])=[N:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C2(c3cccc(Br)c3)COCC(=O)N2)ccc1OC(F)F
Reactant: [NH4+]
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(C2(c3cccc(Br)c3)COCC(N)=N2)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.7 %

Procedure:
In a vacuum dried flask under an argon atmosphere, a solution of (RS)-5-(3-bromo-phenyl)-5-(4-difluoromethoxy-3-methyl-phenyl)-morpholin-3-one (2.5 g, 1 eq) in dichloromethane (80 ml) was treated with trimethyloxonium tetrafluoroborate (2.7 g, 3 eq). The reaction mixture was stirred at room temperature overnight. The incomplete reaction was then washed with a saturated solution of sodium hydrogen carbonate (50 ml). The organic layer was dried over sodium sulfate and evaporated. The crude was dissolved in methanol (15 ml) and the solution transferred under an nitrogen atmosphere into a dried pressure tube. After the addition of ammonium chloride (0.182 g, 3.4 mmol) the sealed pressure tube was heated at 100° C. for 16 hours. After cooling, the reaction mixture was filtered and evaporated to dryness, taken up with dichloromethane (30 ml) and filtered again. The solvent was removed and the residue was passed through a SCX (50 g) cartridge, washing with a mixture of dichloromethane and methanol. The product was recovered eluting with a solution of ammonia (2M) in methanol. 1.45 g of the (RS)-5-(3-bromo-phenyl)-5-(4-difluoromethoxy-3-methyl-phenyl)-5,6-dihydro-2H-[1,4]oxazin-3-ylamine were obtained as a white solid (58% of theory). MS (ISP): m/z=412.9 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:13])[CH2:3][CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH:9](Br)[CH2:8][CH2:7]1.Cl[SiH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1.Cl[SiH]1CCC(C2C=CC(F)=C(F)C=2)CC1>>[F:1][CH:2]([F:13])[CH2:3][CH2:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([Si@H:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)[CH2:8][CH2:7]1
Reactant: Clc1ccc(C2CC[SiH](Cl)CC2)cc1
Reactant: FC(F)CCCC1CCC(Br)CC1
Agent: Fc1ccc(C2CC[SiH](Cl)CC2)cc1F
Product: FC(F)CCC[C@H]1CC[C@H]([Si@H]2CC[C@H](c3ccc(Cl)cc3)CC2)CC1

Procedure:
The above compound was obtained in the same manner as Example 6, using 4-(4,4-difluorobutyl)cyclohexylbromide and 4-(4-chloro-4-silacyclohexyl)-1-chlorobenzene instead of 4-(4-fluorobutyl)cyclohexybromide and 4-(4-chloro-4-silacyclohexyl)-1,2-difluorobenzene, respectively.
Reaction SMILES: [CH2:1]([C:7]1[CH2:11][C:10](=[O:12])[O:9][N:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:13]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:26]CO>C(OCC)(OCC)OCC>[CH2:13]([C:19]1[CH:20]=[CH:21][C:22]([NH:23]/[CH:26]=[C:11]2/[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[N:8][O:9][C:10]/2=[O:12])=[CH:24][CH:25]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCO
Reactant: CCCCCCC1=NOC(=O)C1
Reactant: CCCCCCc1ccc(N)cc1
Solvent: CCOC(OCC)OCC
Product: CCCCCCC1=NOC(=O)/C1=C\Nc1ccc(CCCCCC)cc1

Procedure:
1.7 g of 3-n-hexylisoxazol-5(4H)-one (prepared in accordance with Example 3) are dissolved in 10 ml of triethyl orthoformate and heated at 80° C. for 2 hours together with 2.65 g of p-hexylaniline. The dark reaction solution is concentrated and recrystallized in 100 ml of hexane. 1.8 g (50% of theory) of the above-named crystalline compound are obtained. M.p. 88°-90° C., UV (EtOH): 356 nm (ε=26469). This compound is especially suitable as a UV A filter.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.Cl[CH2:19][O:20][CH3:21]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:19][O:20][CH3:21])[CH:3]=1
Reactant: COCCl
Reactant: Oc1cccc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1cccc(Cl)c1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To a solution of 3-chlorophenol (50 g, 390.62 mmol, 1.00 equiv) in DCM (500 mL) was added DIEA (554 g, 4.29 mol, 11.00 equiv), followed by chloro(methoxy)methane (380 g, 10.00 equiv) at 20° C. The resulting mixture was allowed to react, with stirring, for 4 h at 20° C. The reaction mixture was then quenched with water. The separated organic phase was washed with water (2×), dried over Na2SO4 and then concentrated under vacuum to give 1-chloro-3-(methoxymethoxy)benzene as a white oil.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:19]3[C:20]([C:24]#[C:25][Si](C)(C)C)=[CH:21][CH:22]=[CH:23][C:18]=3[NH:17][C:16]3[N:30]=[C:31]([C:34]([F:37])([F:36])[F:35])[CH:32]=[CH:33][C:15]=3[CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+]>CO.O>[C:24]([C:20]1[C:19]2[N:13]([S:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:38])([F:39])[F:1])=[CH:5][CH:6]=3)(=[O:12])=[O:11])[CH2:14][C:15]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[N:30][C:16]=3[NH:17][C:18]=2[CH:23]=[CH:22][CH:21]=1)#[CH:25]
Reactant: C[Si](C)(C)C#Cc1cccc2c1N(S(=O)(=O)c1ccc(OC(F)(F)F)cc1)Cc1ccc(C(F)(F)F)nc1N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#Cc1cccc2c1N(S(=O)(=O)c1ccc(OC(F)(F)F)cc1)Cc1ccc(C(F)(F)F)nc1N2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 6-{[4-(trifluoromethoxy)phenyl]sulfonyl}-2-(trifluoromethyl)-7-[(trimethylsilyl)ethynyl]-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (414 mg, 0.75 mmol) in MeOH (40 mL) was added K2CO3 (306 mg, 3.00 mmol). The reaction was stirred at rt for 1.5 h, diluted with H2O, and the product was extracted with EtOAc. The combined organic extracts were washed with H2O, brine, dried over MgSO4, filtered and concentrated. The resulting residue was purified by silica gel chromatography to give the title compound. 1H NMR (500 MHz, (CD3)2CO): δ 8.50 (s, 1H), 7.76 (d, 1H), 7.40 (m, 4H), 7.27 (m, 1H), 7.15 (d, 3H), 5.27 (d, 1H), 4.70 (d, 1H), 3.81 (s, 1H). LCMS: m/z 514.1 (m+H).
Reaction SMILES: ClC([O:4][C:5](Cl)(Cl)Cl)=O.[CH3:9][C:10]1[C:18]2[C:17](=[O:19])[CH2:16][C:15]([CH3:21])([CH3:20])[CH2:14][C:13]=2[NH:12][N:11]=1.C([N:24](CC)CC)C.[OH-].[NH4+]>ClCCl>[NH2:24][C:5]([N:12]1[C:13]2[CH2:14][C:15]([CH3:21])([CH3:20])[CH2:16][C:17](=[O:19])[C:18]=2[C:10]([CH3:9])=[N:11]1)=[O:4]
Reactant: CCN(CC)CC
Reactant: Cc1n[nH]c2c1C(=O)CC(C)(C)C2
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1nn(C(N)=O)c2c1C(=O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 34.1 %

Procedure:
A solution of trichloromethyl chloroformate (0.37 ml, 3.03 mmol) in 3 ml of dichloromethane was added dropwise to a solution of 3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazole (0.4 g, 2.25 mmol), prepared as described in example 15, and triethylamine (0.42 ml, 3.03 mmol) maintained under magnetic stirring and inert atmosphere at about −15° C. The reaction mixture was allowed to warm to room temperature and stirring was continued for about 3.5 hours. A solution of 32% amonium hydroxide (10 ml) was then added while cooling at −15° C. The mixture was kept at room temperature for about 12 hours and the two layers were separated; dichloromethane was washed with water and brine, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel (cyclohexane:ethyl acetate=20:30), to yield the title compound as a colourless solid (0.170 g, 36%): m.p. 173-175° C.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1.CON(C)[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[N:21]=1)=[O:19].BrC1C=C(C(C2C3C(Cl)=NC=NC=3N(C(C)C)C=2)=O)C=NC=1>>[Br:26][C:22]1[N:21]=[C:20]([C:18]([C:2]2[C:10]3[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=2)=[O:19])[CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)n1cc(Br)c2c(Cl)ncnc21
Reactant: CON(C)C(=O)c1cccc(Br)n1
Agent: CC(C)n1cc(C(=O)c2cncc(Br)c2)c2c(Cl)ncnc21
Product: CC(C)n1cc(C(=O)c2cccc(Br)n2)c2c(Cl)ncnc21
Yield: 68.6 %

Procedure:
The title compound (34.0 g, 69%) was prepared from 5-Bromo-4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (35.8 g, 130.5 mmol) and 6-Bromo-pyridine-2-carboxylic acid methoxy-methyl-amide (32.0 g, 130.5 mmol) by procedures analogous to those described for the preparation (5-Bromo-pyridin-3-yl)-(4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone. MS: 380.6 (MH+); HPLC Rf: 6.05 min. (HPLC method 4); HPLC purity: 100%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:14])=[C:6]([CH:8]=[C:9]([Cl:13])[C:10]([O-:12])=[O:11])[CH:7]=1.[C:15]1(=[O:25])[O:20][C:18](=O)[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[C:26](O)(=O)[CH3:27]>O>[Cl:13][C:9](=[CH:8][C:6]1[CH:7]=[C:2]([N:1]2[C:15](=[O:25])[C:16]3=[CH:24][CH:23]=[CH:22][CH:21]=[C:17]3[C:18]2=[O:20])[CH:3]=[CH:4][C:5]=1[Cl:14])[C:10]([O:12][CH2:26][CH3:27])=[O:11]
Reactant: CC(=O)O
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1ccc(Cl)c(C=C(Cl)C(=O)[O-])c1
Solvent: O
Product: CCOC(=O)C(Cl)=Cc1cc(N2C(=O)c3ccccc3C2=O)ccc1Cl

Procedure:
A mixture of 0.52 g of 3-(5-amino-2-chlorophenyl)-2-chloroacrylate, 0.36 g of phthalic anhydride, and 4 ml of acetic acid was heated under reflux for 2 hours under stirring. After cooling, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The solid thus obtained was washed with water, dried, and purified by silica gel column chromatography (chloroform-hexane=3:1) to yield 0.71 g of the title compound (No. 18 of Table 2).
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([O:19][CH2:20][CH2:21][O:22][CH2:23][CH3:24])[C:7]2=[O:25])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:40]=[N:41][C:42]([NH2:45])=[CH:43][CH:44]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>C1(C)C=CC=CC=1.C(Cl)Cl>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:40]=[N:41][C:42]([NH:45][C:13]3[N:14]=[CH:15][C:10]4[CH:9]=[C:8]([O:19][CH2:20][CH2:21][O:22][CH2:23][CH3:24])[C:7](=[O:25])[N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:11]=4[N:12]=3)=[CH:43][CH:44]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: CCOCCOc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOCCOc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 110 °C
Yield: 22 %

Procedure:
8-Cyclopentyl-6-(2-ethoxy-ethoxy)-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.2 mL of a 0.46 M solution in toluene, 0.552 mmol) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.307 g, 1.1 mmol) were combined in toluene under nitrogen and heated to 110° C. After 4 h the toluene was replaced by xylenes (1 mL) and heating was continued under reflux overnight. After cooling to room temperature the crude reaction mixture was dissolved in CH2Cl2 and washed with saturated aqueous ammonium chloride solution then with brine. The organic layer was dired (MgSO4), filtered and evaporated to dryness. Chromotagraphy on silica gel eluting with 5% CH3OH in CH2Cl2 followed by a second chromatography step eluting with ethyl acetate provided 4-{6-[8-cyclopentyl-6-(2-ethoxy-ethoxy)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester (70 mg, 22%) as a yellow solid. MS (APCI); M++1: Calc'd, 580.32. Found 580.2. 1H NMR: δ(400 MHz, DMSO) 8.50 (s, 1H), 8.26 (d, J=9 Hz, 1H) 7.94 (d, J=3 Hz, 1H), 7.39 (dd, J=3, 9 Hz, 1H), 6.78 (s, 1H), 5.89-5.98 (m, 1H), 4.15 (t, J=5 Hz, 2H), 3.86 (t, J=5 Hz, 2H), 3.56-3.62 (m, 6H), 3.09 (br t, J=5 Hz, 4H), 2.29-2.33 (m, 2H), 2.07-2.10 (m, 2H), 1.84-1.92 (m, 2H), 1.63-1.69 (m, 2H), 1.47 (s, 9H), 1.22 (t, J=7 Hz, 3H).
Reaction SMILES: [C:1]1([C:11]2[CH:26]=[CH:25][C:14]3[C@:15]4([CH3:24])[C@@H:20]([CH2:21][CH2:22][C:13]=3[CH:12]=2)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]4)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C[Si](C([Si](C)(C)C)(C(F)(F)F)C(N)=O)(C)C>O1CCOCC1.C(OCC)(=O)C>[C:1]1([C:11]2[CH:26]=[CH:25][C:14]3[C@:15]4([CH3:24])[C@@H:20]([CH2:21][CH2:22][C:13]=3[CH:12]=2)[NH:19][C:18](=[O:23])[CH:17]=[CH:16]4)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3cccc4ccccc34)ccc12
Agent: C[Si](C)(C)C(C(N)=O)(C(F)(F)F)[Si](C)(C)C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@]12C=CC(=O)N[C@@H]1CCc1cc(-c3cccc4ccccc34)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.4 %

Procedure:
To a suspension of (+)-(4aR)-(10bR)-8-(1-naphthyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one (295 mg, 0.865 mmol), in 3.5 mL of 1,4-dioxane was added DDQ (216 mg, 1.1 equiv.) followed by bistrimethylsilyltrifluoromethyl acetamide (998 mg, 4.5 equiv.), and the solution was stirred at room temperature for 2 h, then heated at 100° for 20h. The mixture was cooled to room temperature, diluted with ethyl acetate, and washed with 2M sodium hydroxide. The organic phase was washed with brine, dried over sodium sulfate, concentrated and chromatographed on silica gel (ethyl acetate eluent) to give, after trituration from ether/hexanes, 60 mg (20%) of the title compound as a white solid. mp 199°-201° (decomp.) FDMS m/e=339. α[D]589 =+35.98 (c=0.67, chloroform).
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].B(OCCCC)(OCCCC)OCCCC.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][C:35](=[O:57])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=[CH:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH:29]=O.O=[CH:59][C:60]1[CH:68]=[CH:67][C:65]([OH:66])=[C:62]([O:63][CH3:64])[CH:61]=1.C(N)CCC>CN(C=O)C.C(O)(=O)C>[C:35]([O:34][C:33]1[CH:32]=[CH:31][C:28]([CH:29]=[CH:6][C:5](=[O:7])[CH2:4][C:1](=[O:3])[CH:2]=[CH:59][C:60]2[CH:68]=[CH:67][C:65]([OH:66])=[C:62]([O:63][CH3:64])[CH:61]=2)=[CH:27][C:26]=1[O:25][CH3:24])(=[O:57])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=[CH:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56]
Reactant: CCCCCCCCCC=CC=CC=CC=CC=CC=CC(=O)Oc1ccc(C=O)cc1OC
Reactant: CC(=O)CC(C)=O
Reactant: COc1cc(C=O)ccc1O
Agent: CCCCOB(OCCCC)OCCCC
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCCCN
Product: CCCCCCCCCC=CC=CC=CC=CC=CC=CC(=O)Oc1ccc(C=CC(=O)CC(=O)C=Cc2ccc(O)c(OC)c2)cc1OC
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 25.6 %

Procedure:
To a solution of boric oxide (183 mg, 2.65 mmol) in DMF (1 mL), was added acetyl acetone (0.236 mL, 2.30 mmol) followed by tributyl borate (1.25 mL, 4.62 mmol) at rt and stirred at 65° C. for 15 min. To the above borate complex, a mixture of 3-methoxy-4-docosahexaenoyloxybenzaldehyde (1 g, 2.30 mmol) and vanillin (350 mg, 2.30 mmol) was added and stirred for 5 min at the same temperature. A mixture of n-butyl amine (0.045 mL) and acetic acid (0.13 mL) in DMF (1 mL) was added to the reaction mixture and stirred at 90-95° C. for 4 h. After cooling to 15° C., acetic acid (20%, 20 mL) was added with stirring and again the reaction mixture was stirred at 70° C. for another 1 h. Then it was cooled to rt, extracted with chloroform (3×100 mL) and the combined chloroform layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and the residue was chromatographed over silica gel column using hexane-ethyl acetate (85:15) as eluents to give 1-(4-docosahexaenoyloxy-3-methoxyphenyl)-7-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (400 mg, 25%). LCMS (ESI, negative ion mode): m/z (M-H)−.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][O:10][CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:4]=1)#[N:2].[C:20](OC)(=[O:28])[C:21]1[C:22](=[CH:24][CH:25]=[CH:26][CH:27]=1)[SH:23].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:28]=[C:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[S:23][C:1]([C:3]2[N:4]=[C:5]([CH2:9][O:10][CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=[CH:7][CH:8]=2)=[N:2]1
Reactant: COC(=O)c1ccccc1S
Reactant: CC(C)(C)OC(=O)CCOCc1cccc(C#N)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CCOCc1cccc(-c2nc(=O)c3ccccc3s2)n1

Procedure:
tert-Butyl 3-[(2-cyano-6-pyridyl)]methoxypropanoate (2.62 g, 10 mmol) and methyl thiosalicylate (1.85 g, 11 mmol) were dissolved in toluene (30 ml), and triethylamine (1.70 ml, 12 mmol) were added thereto. The reaction mixture was refluxed under nitrogen atmosphere for 15 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The titled compound (2.92 g, 71%) was given from the fraction eluted with ethyl acetate-hexane (1:2, v/v) and recrystallized from ethyl acetate-isopropyl ether.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[C:7]([C:24](O)=[O:25])=[CH:6]2)#[N:2].Cl.[NH2:28][CH2:29][C:30]1([OH:35])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[OH:35][C:30]1([CH2:29][NH:28][C:24]([C:7]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=3)[C:9]3[C:5]([CH:6]=2)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)=[O:25])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: N#Cc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc(OC(F)(F)F)c1
Reactant: NCC1(O)CCCC1
Agent: Cl
Product: N#Cc1ccc2c(c1)cc(C(=O)NCC1(O)CCCC1)n2Cc1cccc(OC(F)(F)F)c1

Procedure:
The title compound was prepared using 5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid [prepared from 3-(trifluoromethoxy)benzyl bromide and ethyl 5-cyanoindole-2-carboxylate] and 1-aminomethyl-cyclopentanol hydrochloride in a manner similar to that described in Example 11.
Reaction SMILES: [Br:1][CH2:2][CH2:3][NH2:4].[C:5](Cl)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>ClCCl>[Br:1][CH2:2][CH2:3][NH:4][C:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: NCCBr
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: BrCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 62.7 %

Procedure:
To a solution of 2-bromoethanamine (5.00 g) and trityl chloride (6.80 g) in dichloromethane (24 mL) was slowly added triethylamine (7.48 mL) under ice-cooling, and the reaction mixture was stirred under ice-cooling for 2 hr. The resulting solid was removed by filtration, the filtrate was poured into water, and the mixture was extracted with dichloromethane. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from dichloromethane/cyclohexane to give the title compound (5.60 g).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[CH3:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[O:15]>C(OC)(C)(C)C.Cl>[F:9][C:2]([F:1])([F:8])[C:3](=[O:5])[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[O:15]
Reactant: CC(=O)c1ccc(F)cc1
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Product: O=C(CC(=O)C(F)(F)F)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.5 %

Procedure:
To a solution of ethyl trifluoroacetate (23.9 mL, 199 mmol) in tertbutylmethylether (230 mL) containing sodium methoxide (5.4 M, 39.6 mL, 214 mmol) was added 4-fluoroacetophenone (25 g, 181 mmol) and the resulting mixture stirred at room temperature for 3 h and then poured into ice-water. The mixture was then diluted with HCl (2 N, 200 mL) and then extracted with ethyl acetate. The combined organic extracts were then dried over sodium sulfate and evaporated to afford the title compound (40.9 g, 97%) which was obtained as an orange oil. MS: m/e=232.9 [M−H]−.