Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[O:10]=[C:11]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]1.[Cl-].[NH4+].Cl>C(OCC)C.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]2([OH:10])[CH2:12][N:13]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:14]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: Fc1ccc([Mg]Br)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)(c2ccc(F)cc2)C1
Yield: 43 %

Procedure:
6 ml (11.7 mmol) of a 2M solution of 4-fluorophenylmagnesium bromide in diethyl ether are added dropwise to a solution, immersed in a bath at −50° C., containing 500 mg (2.92 mmol) of 3-oxo-1-(tert-butoxycarbonyl)azetidine in 10 ml of THF. The medium is stirred for 1 hour at −50° C. and hydrolysed by addition of a saturated solution of ammonium chloride. After a return to ambient temperature, a 1N solution of hydrochloric acid is added, followed by extraction with ethyl acetate. The organic phase is dried and evaporated to dryness. The crude product obtained is purified by silica gel chromatography (eluent 7/3 heptane/ethyl acetate). 333 mg in the form of a white powder are obtained with a yield of 43%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][CH2:24][C:25]([C:28]([O:30]C)=[O:29])([CH3:27])[CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]([CH3:35])=[CH2:34])[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][CH2:24][C:25]([C:28]([OH:30])=[O:29])([CH3:27])[CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]([CH3:35])=[CH2:34])[C:5]2=[CH:4][CH:3]=1
Reactant: C=C(C)C1NC(=O)CC(c2cc(Cl)ccc2OCC(C)(C)C(=O)OC)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=C(C)C1NC(=O)CC(c2cc(Cl)ccc2OCC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 80 °C
Yield: 77 %

Procedure:
A mixture of racemic (2′R,3R,4′S)-6-chloro-4′-[5-chloro-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (20 mg), NaOH (80 mg), H2O (5 mL) and MeOH (1 mL) was heated at 80° C. for 2 h. Then the mixture was concentrated. The remaining aqueous solution was acidified by concentrated aqueous HCl solution (1.5 mL). The white precipitate was collected by filtration to give title compound (15 mg).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([C:18](O)=[O:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC>O1CCCC1>[CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][OH:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: OCC1CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
1-Benzhydryl-3-azetidinecarboxylic acid (3.12 g) was suspended in tetrahydrofuran (60 ml), and cooled in an ice-methanol bath under a nitrogen atmosphere. Triethylamine (1.96 ml) was added dropwise, and a solution of ethyl chlorocarbonate (1.34 ml) in tetrahydrofuran (5 ml) was added dropwise over 20 minutes. After the addition, the reaction mixture was stirred at the same temperature for 30 minutes. The reaction mixture was filtered, and the residue was washed with tetrahydrofuran (30 ml). The filtrate was added dropwise to a solution of an aqueous (15 ml) solution of sodium borohydride (1.33 g) cooled in an ice water bath over 15 minutes. After the addition, the reaction mixture was stirred at room temperature. 1N hydrochloric acid (35 ml) was gradually added to the reaction mixture to degrade excess sodium borohydride, and a 1N aqueous solution of sodium hydroxide (35 ml) was added. This was extracted with ethyl acetate (100 ml). The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was concentrated, and the residue was dried under reduced pressure to give the title compound (1.59 g, 54%) as a pale brown solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([B:14]2[O:22][C:19]([CH3:21])([CH3:20])[C:16]([CH3:18])([CH3:17])[O:15]2)[CH:11]=[CH:12][CH:13]=1.[CH3:23][O:24][CH2:25][CH2:26]Br>CN(C=O)C>[CH3:23][O:24][CH2:25][CH2:26][O:7][C:8]1[CH:9]=[C:10]([B:14]2[O:22][C:19]([CH3:21])([CH3:20])[C:16]([CH3:17])([CH3:18])[O:15]2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC1(C)OB(c2cccc(O)c2)OC1(C)C
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Temperature: 100 °C
Yield: 86.9 %

Procedure:
Potassium carbonate (1.88 g, 13.65 mmol) was added to a solution of −3-hydroxyphenylboronic acid pinacol ester (Apollo, 1.0 g, 4.55 mmol) in DMF (10 mL). 2-Bromoethyl methyl ether (0.41 mL, 5.46 mmol) was added and the reaction mixture was heated to 100° C. for 1 hr. The reaction mixture was allowed to cool and then partitioned between ethyl acetate (50 mL), and water (150 mL). The phases were separated and the organic phase was washed with brine (150 mL), dried over anhydrous sodium sulphate, filtered and the filtrate solvents removed in vacuo, to afford the title product as a light-brown oil (1.1 g) which was used without further purification.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([C@H:28]([CH3:32])[C:29]([OH:31])=[O:30])[CH:22]=[CH:21]2.[N+:33]([C:36]([CH3:41])([CH2:39]O)[CH2:37][OH:38])([O-:35])=[O:34]>C(Cl)Cl.C1COCC1>[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([C@H:28]([CH3:32])[C:29]([O:31][CH2:39][C:36]([CH3:41])([N+:33]([O-:35])=[O:34])[CH2:37][OH:38])=[O:30])[CH:22]=[CH:21]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: CC(CO)(CO)[N+](=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc2cc([C@H](C)C(=O)OCC(C)(CO)[N+](=O)[O-])ccc2c1

Procedure:
A solution of 1,3-dicyclohexylcarbodiimide (4.23 g, 20.5 mmol), (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 4.34 g, 18.9 mmol), and 2-nitro-2-methyl-1,3-propanediol (2.56 g, 19.0 mmol) in CH2Cl2 (50 mL) and THF (50 mL) was stirred at ambient temperature overnight. The solvent was evaporated and EtOAc (100 mL) was added to the resulting crude material, cooled in a dry-ice bath and the byproduct, dicyclohexyl urea was removed by filtration. The product was separated by silica gel column chromatography eluting with ethyl acetate/hexane (1:3, Rf=0.1) to give the title compound (a mixture of diasteromers) as an oil (2.77 g, 42% yield). 1H NMR (300 MHz, CDCl3) δ 7.69-7.60 (m, 3H), 7.34-7.3 (m, 1H), 7.14-7.08 (m, 2H), 4.44 (d, J=4.2 Hz, 2H), 3.86 (s, 3H), 3.85 (q, J=7.2 Hz, 1H), 3.7 (m, 1H), 1.55 (d, J=7.2 Hz, 3H), 1.36 & 1.40 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 174.14, 174.02, 157.57, 134.53, 134.51, 133.64, 129.13, 128.7, 127.17, 125.87, 125.84, 119.0, 105.47, 89.53, 89.42, 64.67, 64.52, 64.19, 55.12, 45.04, 18.25, 18.03, 17.82, 17.79. Mass spectrum (API-TIS) m/z 348 (MH)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:32]([O:34]C)=[O:33])[CH2:20][CH2:19][N:18]([C:21]([C:23]3([CH3:31])[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25][CH2:24]3)=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH-].[Na+]>O1CCCC1.CO>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([C:15]2([C:32]([OH:34])=[O:33])[CH2:20][CH2:19][N:18]([C:21]([C:23]3([CH3:31])[CH2:24][O:25][C:26]([CH3:29])([CH3:30])[O:27][CH2:28]3)=[O:22])[CH2:17][CH2:16]2)(=[O:13])=[O:14])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(C(=O)C3(C)COC(C)(C)OC3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(C(=O)C3(C)COC(C)(C)OC3)CC2)cc1

Procedure:
4-(4-But-2-ynyloxybenzenesulfonyl)-1-[(2,2,5-trimethyl-1,3-dioxan-5-yl)carbonyl]-4-piperidinecarboxylic acid was prepared following the procedure of Example 40 (step 5). Starting from Methyl 4-(4-but-2-ynyloxybenzenesulfonyl)-1-[(2,2,5-trimethyl-1,3-dioxan-5-yl)carbonyl]-4-piperidinecarboxylate (335 mg, 0.66 mmol) in 4 ml of tetrahydrofuran:methanol (1:1), and 1N sodium hydroxide (1.3 ml, 1.3 mmol) to obtain 315 mg (97%) of the acid. HR-MS: m/z Calculated for C24H31NO8S 494.1843; Found 494.1835.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:11])[O:8][CH:7]([CH2:9][OH:10])[CH2:6][O:5]1.CN(C=O)C.CS([C:21]1[N:22]=[C:23]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=2)[C:24]2[CH2:30][CH2:29][N:28]([C:31]3[C:36]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:34]=[CH:33][N:32]=3)[CH2:27][CH2:26][C:25]=2[N:41]=1)(=O)=O>CO>[CH3:3][C:4]1([CH3:11])[O:8][C@@H:7]([CH2:9][O:10][C:21]2[N:22]=[C:23]([NH:42][C:43]3[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:50])[F:51])=[CH:45][CH:44]=3)[C:24]3[CH2:30][CH2:29][N:28]([C:31]4[C:36]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:34]=[CH:33][N:32]=4)[CH2:27][CH2:26][C:25]=3[N:41]=2)[CH2:6][O:5]1
Reactant: CS(=O)(=O)c1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1C(F)(F)F)CC2
Reactant: CC1(C)OCC(CO)O1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](COc2nc3c(c(Nc4ccc(C(F)(F)F)cc4)n2)CCN(c2ncccc2C(F)(F)F)CC3)O1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
A dispersion of NaH in mineral oil (12.0 mg, 0.28 mmol) was added to a flask containing (2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (116 μL, 0.94 mmol) and DMF (1.0 mL). After 30 min, the mixture was transferred to a flask containing [2-methanesulfonyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine (Example 53; 50 mg, 0.094 mmol). The resulting mixture was then heated at 70° C. for 24 h. The mixture was cooled, diluted with MeOH (1.0 mL) and purified by reverse phase HPLC, yielding 39 mg (70%) of the title compound. MS (ESI): mass calcd. for C27H27F6N5O3, 583.20; m/z found, 584.2 [M+H]+. 1H NMR (CDCl3): 8.39-8.37 (m, 1H), 7.89-7.86 (m, 1H), 7.69 (d, J=11.0 Hz, 2H), 7.59 (d, J=11.0 Hz, 2H), 6.98-6.94 (m, 1H), 6.68 (s, 1H), 4.52-4.56 (m, 1H), 4.42-4.38 (m, 1H), 4.28-4.24 (m, 1H), 4.16-4.12 (m, 1H), 3.94-3.90 (m, 1H), 3.63-3.56 (m, 4H), 3.18-3.15 (m, 2H), 2.96-2.93 (m, 2H), 1.46 (s, 3H), 1.38 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][C@H:5]([C:8](Cl)=[O:9])[CH2:4][CH:3]=1.[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([C:31]#[C:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:18][C:19]=1[NH:20][CH:21]1[CH2:30][CH2:29][C:24]2([O:28][CH2:27][CH2:26][O:25]2)[CH2:23][CH2:22]1)=[O:14].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CCOC(C)=O>ClC(Cl)C>[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([C:31]#[C:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:18][C:19]=1[N:20]([CH:21]1[CH2:30][CH2:29][C:24]2([O:28][CH2:27][CH2:26][O:25]2)[CH2:23][CH2:22]1)[C:8]([C@H:5]1[CH2:6][CH2:7][C:2]([CH3:1])=[CH:3][CH2:4]1)=[O:9])=[O:14]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1NC1CCC2(CC1)OCCO2
Reactant: CC1=CC[C@@H](C(=O)Cl)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@@H]1CC=C(C)CC1)C1CCC2(CC1)OCCO2
Temperature: 90 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
(1S)-4-Methyl-cyclohex-3-enecarboxylic acid chloride (1.5 mmol), 5-(3,3-dimethyl-but-1-ynyl)-3-(1,4-dioxa-spiro[4.5]dec-8-ylamino)-thiophene-2-carboxylic acid methyl ester (159 mg, 0.42 mmol) and potassium phosphate tribasic (266 mg, 1.25 mmol) was suspended in dichloroethane (1 mL), sealed with a cap and heated to 90° C. After 16 h, the reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was separated and the aqueous extracted again with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Flash chromatography (15-60% EtOAc:Hexanes) afforded 128 mg (61% yield) of the desired 5-(3,3-dimethyl-but-1-ynyl)-3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-((1S)-4-methyl-cyclohex-3-enecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester as a white foam.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].[H-].[Na+].[F:10][C:11]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[CH:16][C:12]=1[C:13](Cl)=[O:14].C(Cl)Cl>O1CCCC1>[C:1]([C:3](=[C:13]([OH:14])[C:12]1[CH:16]=[C:17]([F:22])[C:18]([F:21])=[C:19]([F:20])[C:11]=1[F:10])[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1F
Reactant: COC(=O)CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)C(C#N)=C(O)c1cc(F)c(F)c(F)c1F
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
Methyl cyanoacetate (51.1 g) is added dropwise to a suspension of sodium hydride (43.3 g, in oil, 55-65 w/w %) in dry tetrahydrofuran (600 ml) while maintaining the internal temperature between 15° C. and 20° C. on an ice bath. To the reaction mixture is added dropwise the crude 2,3,4,5-tetrafluorobenzoyl chloride (110.5 g) as obtained above, and the mixture is stirred while maintaining the internal temprature as above. After 30 minutes, methylene chloride is added to the reaction mixture and the reaction product is extracted with 3% aqueous sodium bicarbonate. The extract is then washed with methylene chloride to remove the remaining methyl cyanoacetate. The extract is acidified with conc. HCl and the resulting precipitate is filtered and washed with dil. HCl to afford methyl 2-cyano-3-hydroxy-3-(2,3,4,5-tetrafluorophenyl)acrylate (122.2 g) as pale yellow crystals, m.p. 71°-73° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:6]=1[CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl>ClCCl>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[C:7]2[C:6]=1[CH2:13][CH2:14][CH2:15][C:16]2=[O:18])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(F)c(F)cc1CCCC(=O)O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)Nc1cc(F)c(F)c2c1CCCC2=O
Temperature: 25 °C

Procedure:
The compound obtained in (4) above (9.07 gm) was dissolved into 450 ml of dichloromethane. To the mixture was added 7.71 gm of phosphorous pentachloride while stirring at room temperature. After stirring for a further 1 hour, the reaction mixture was concentrated and dichloromethane was added to the residue. Dichloromethane was evaporated again and 500 ml of 1,2-dichloroethane and 9.88 gm of anhydrous aluminum chloride were added to the residue. The mixture was stirred for 1 hour at 70° C. and gently heated under reflux for 15 hours. The reaction product was poured into ice-cold water, extracted with chloroform, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was subjected to silica gel column chromatography using chloroform-methanol (50:1) as an eluant to obtain fractions containing the target compound. The fractions were concentrated to obtain 2.31 gm of the title compound.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].[CH2:16]([N:19]1[C:28]2[C:23](=[CH:24][C:25]([CH:32]([CH3:34])[CH3:33])=[CH:26][C:27]=2[C:29](=O)[CH3:30])[C:22]([CH3:36])([CH3:35])[CH2:21][CH2:20]1)[CH2:17][CH3:18]>>[CH2:2]([O:3][C:4](=[O:5])/[C:6](/[F:7])=[C:29](\[C:27]1[CH:26]=[C:25]([CH:32]([CH3:34])[CH3:33])[CH:24]=[C:23]2[C:28]=1[N:19]([CH2:16][CH2:17][CH3:18])[CH2:20][CH2:21][C:22]2([CH3:35])[CH3:36])/[CH3:30])[CH3:1]
Reactant: CCCN1CCC(C)(C)c2cc(C(C)C)cc(C(C)=O)c21
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Product: CCCN1CCC(C)(C)c2cc(C(C)C)cc(/C(C)=C(/F)C(=O)OCC)c21

Procedure:
Following General Procedure E, triethyl-2-fluoro-2-phosphonoacetate (8.36 g, 34.5 mmol) and 1-(1-n-propyl-6-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-8-yl)-ethanone (Intermediate 14, 2.78 g, 9.86 mmol) were reacted to give the title compound as a yellow oil after purification by flash chromatography (SiO2, 2:98 ethyl acetate:hexane).
Reaction SMILES: [C:1]1([CH2:11][OH:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:12][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCCCBr
Reactant: OCc1cccc2ccccc12
Product: BrCCCCCOCc1cccc2ccccc12

Procedure:
1-Naphthalenemethanol (6.00 g) and 1,5-dibromopentane (11.5 ml) were treated according to the method of Intermediate 1. FCC eluting with ether-cyclohexane (1:49→2:48) gave the title compound as a colourless oil (8.41 g), t.l.c. (Cyclohexane-ether 19:1) Rf 0.22.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH:13]=O)=[O:9])[CH2:4][CH2:3]1.[CH2:18]([CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([CH:25]1[CH2:30][CH2:29][N:28]([CH2:13][C:12]2[CH:11]=[C:10]([C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:9])[CH:17]=[CH:16][CH:15]=2)[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: CN1CCN(C(=O)c2cccc(C=O)c2)CC1
Product: CN1CCN(C(=O)c2cccc(CN3CCC(Cc4ccccc4)CC3)c2)CC1

Procedure:
Prepared from the product of Example 17 and 4-benzylpiperidine.
Reaction SMILES: C[O:2][C:3](=[O:44])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([C@H:14]2[C@H:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=3[F:26])[C@:17]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[F:36])([C:27]#[N:28])[C@H:16]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[NH:15]2)=[O:13])=[CH:6][C:5]=1[O:42][CH3:43].C1COCC1.O.[OH-].[Li+]>O>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([C@@:17]2([C:27]#[N:28])[C@H:16]([CH2:37][C:38]([CH3:40])([CH3:41])[CH3:39])[NH:15][C@@H:14]([C:12]([NH:11][CH2:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:44])=[O:2])=[C:5]([O:42][CH3:43])[CH:6]=3)=[O:13])[C@@H:18]2[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=2[F:26])=[C:30]([F:36])[CH:31]=1
Reactant: COC(=O)c1ccc(CNC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CNC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)ccc1C(=O)O
Temperature: 25 °C
Yield: 90.3 %

Procedure:
In a manner similar to the method described in Example 380, rac-4-({[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-2-methoxy-benzoic acid methyl ester (75.2 mg, 0.117 mmol), was combined with THF (7 ml) and lithium hydroxide hydrate (33.5 mg, 0.798 mmol) in water (3.5 mL). It was stirred at room temperature to give rac-4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-2-methoxy-benzoic acid as a white lyophilized solid (66.6 mg, 89%).
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:28])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([CH3:27])[C:19](=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=O)[CH2:12][CH2:11]1.[NH2:35][C:36]1[CH:37]=[C:38]([CH:46]=[CH:47][CH:48]=1)[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)C.C(OCC)(=O)C>[C:1]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([CH3:27])[C:19](=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:35][C:36]2[CH:37]=[C:38]([CH:46]=[CH:47][CH:48]=2)[C:39]([O:41][C:42]([CH3:44])([CH3:45])[CH3:43])=[O:40])[CH2:12][CH2:11]1)=[O:28]
Reactant: CC(C)(C)OC(=O)c1cccc(N)c1
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1cccc(C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.9 %

Procedure:
The compound (100 mg, 0.215 mmol) obtained in Example 4g was dissolved in ethanol (6 mL), tert-butyl 3-aminobenzoate (54 mg, 0.279 mmol) and sodium triacetoxyborohydride (59 mg, 0.279 mmol) were added under ice cooling, and the mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added, and ethyl acetate was further added to separate the layers. The organic layer was separated, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate:methanol, 10:1, v/v) to give the title compound (80.0 mg; yield, 58%) as a colorless oily substance.
Reaction SMILES: Br[C:2]1[C:3](=[O:18])[C:4](=[O:17])[C:5]2[CH:6]=[CH:7][C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=3.[CH2:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH:19]([C:12]1[CH:11]=[CH:10][C:9]2[C:4](=[O:17])[C:3](=[O:18])[C:2]3[C:7]([C:8]=2[CH:13]=1)=[CH:6][C:5]([CH:7]=[CH:6][C:5]1[CH:14]=[CH:15][CH:2]=[CH:3][CH:4]=1)=[CH:14][CH:15]=3)=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1C(=O)c2ccc3ccc(Br)cc3c2C=C1Br
Reactant: C=Cc1ccccc1
Product: O=C1C(=O)c2ccc(C=Cc3ccccc3)cc2-c2cc(C=Cc3ccccc3)ccc21
Yield: 62 %

Procedure:
The Heck reaction between 3,6-dibromophenanthrenequinone (JYC-I-117-A) and styrene gave 3,6-distyrylphenanthrene-9,10-dione (JYC-I-139-A) as an orange solid in 62% yield. The scheme of the reaction is shown in FIG. 19.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH2:19]1[O:27][C:26]2[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=2[O:20]1.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl.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>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:24]4[CH:23]=[CH:22][C:21]5[O:20][CH2:19][O:27][C:26]=5[CH:25]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc5c(c4)OCO5)cc3CC[C@@H]12
Yield: 57.2 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 3,4-methylenedioxyphenyl boronic acid (131 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (50 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 130 mg (57%) of the title compound as an amorphous solid. mp 146°-152°. FDMS: m/e=349. α[D]589 =+67.92 (c=1.06, chloroform).