Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:24][CH2:25][O:26][CH3:27])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[CH2:28][CH2:29][CH3:30])[CH:7]=1.O.[CH3:32][N:33](C)C=O>[C-]#N.[Zn+2].[C-]#N>[F:19][C:16]([F:17])([F:18])[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:5]=[N:4][CH:3]=[C:2]([CH:7]=2)[C:32]#[N:33])=[C:10]([CH2:28][CH2:29][CH3:30])[CH:11]=1)([O:24][CH2:25][O:26][CH3:27])[C:20]([F:21])([F:22])[F:23]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1cncc(Br)c1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1cncc(C#N)c1
Yield: 84 %

Procedure:
To a solution of 3-bromo-5-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy) pyridine (320 mg, 637 μmol) in N,N-dimethylformamide (5 mL), zinc cyanide (112 mg) and tetrakis triphenylphosphine palladium complex (74 mg) were added at room temperature under an argon atmosphere, and the resultant mixture was allowed to react in a microwave (80 watts, 10 minutes). After completion of the reaction, the reaction solution was added with water at room temperature, extracted with ethyl acetate, and then concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate) and the title compound (239 mg, yield 84%) was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[H-].[Na+].I[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([F:38])([F:37])[C:27]([F:36])([F:35])[C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30].O>O1CCCC1>[CH2:1]([C:8]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]([F:37])([F:38])[C:27]([F:35])([F:36])[C:28]([F:33])([F:34])[C:29]([F:30])([F:31])[F:32])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: C=CCCCCCC(C(=O)OCC)C(=O)OCC
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCCCCC(CCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(C(=O)OCC)C(=O)OCC
Reaction time: 1 h
Yield: 89 %

Procedure:
A solution of diethyl 2-(6-heptenyl)malonate (3.83 g, 14.92 mmol) in anhydrous tetrahydrofuran (50 ml) was slowly added dropwise to a suspension of 60% sodium hydride (0.52 g, 12.94 mmol) in anhydrous tetrahydrofuran (150 ml) at 0° C., and the resulting mixture was stirred for 1 hour. The 1-iodo-5,5,6,6,7,7,8,8,8-nonafluorooctane prepared in Example 2 (4.0 g, 9.95 mmol) was dissolved in anhydrous tetrahydrofuran (50 ml) and then slowly added dropwise to the mixture, followed by stirring for 2 days at room temperature. After the reaction was completed, water was added to the reaction mixture, which was then extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/30) to give diethyl 2-(6-heptenyl)-2-(5,5,6,6,7,7,8,8,8-nonafluorooctyl)malonate (4.7 g, Yield 89%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[S:12][C:13]([C:16]([OH:18])=[O:17])=[CH:14][N:15]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CS(C)=O>[C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[S:12][C:13]([C:16]([O:18][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:17])=[CH:14][N:15]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: BrCc1ccccc1
Reactant: CC(NC(=O)OC(C)(C)C)c1ncc(C(=O)O)s1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(NC(=O)OC(C)(C)C)c1ncc(C(=O)OCc2ccccc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
To a solution of 2-(1-(tert-butoxycarbonylamino)ethyl)thiazole-5-carboxylic acid (0.14 g, 0.5 mmol) in DMSO (1 mL) was added KOH (0.031 g, 0.55 mmol). The mixture was stirred at room temperature until the full dissolution of KOH was observed. Benzyl bromide (0.06 mL, 0.53 mmol) was added and the reaction solution was stirred at room temperature overnight. The solution was partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was dried over anhydrous MgSO4, concentrated and purified by column chromatography to afford a colorless oil (0.133 g, 73%). LC-MS: (FA) ES+ 363.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH3:9][CH2:10][O:11][C:12]([CH:14](P(OCC)(OCC)=O)[F:15])=[O:13].[CH3:24][C:25]1([CH3:44])[CH2:34][CH2:33][C:32]([CH3:36])([CH3:35])[C:31]2[CH:30]=[C:29]([C:37](=O)[CH3:38])[C:28]([O:40][CH2:41][CH2:42][CH3:43])=[CH:27][C:26]1=2>C1COCC1>[CH2:10]([O:11][C:12](=[O:13])/[C:14](/[F:15])=[C:37](\[C:29]1[C:28]([O:40][CH2:41][CH2:42][CH3:43])=[CH:27][C:26]2[C:25]([CH3:44])([CH3:24])[CH2:34][CH2:33][C:32]([CH3:35])([CH3:36])[C:31]=2[CH:30]=1)/[CH3:38])[CH3:9]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CCCOc1cc2c(cc1C(C)=O)C(C)(C)CCC2(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCOc1cc2c(cc1/C(C)=C(/F)C(=O)OCC)C(C)(C)CCC2(C)C
Temperature: -78 °C

Procedure:
To a solution of LDA (12.1 mL, 2.0 M in heptane/THF/ethylbenzene) in THF (10 mL) at −78° C. was added triethyl 2-fluoro-2-phosphonoacetate (5.0 g, 20.7 mmol) in THF (10 mL). The reaction flask was removed from dry ice cooling bath for 12 min and then re-cooled to −78° C. 1-(5,5,8,8-tetramethyl-3-propoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethanone (Intermediate 5, 1.98 g, 6.89 mmol) in THF (10 mL) was added and the reaction was allowed to warm up to ambient temperature over night. The reaction was quenched with aqueous NH4Cl and extracted with Et2O (×3). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (3% EtOAc-hexane) to give a ˜10:1 mixture of the title compound and its 2-Z isomer (2.2 g). The mixture was used directly in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[O:21]1[CH:25]=[CH:24][C:23]([C:26](O)=[O:27])=[CH:22]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:26]([C:23]3[CH:24]=[CH:25][O:21][CH:22]=3)=[O:27])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccoc1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1ccoc1

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-phenyl)-6-(2, 2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and 3-furancarboxylic acid (CAN 488-93-7) as starting materials; LC-MS (UV peak area/ESI) 98.2%, 395.0414 (M−H)−.
Reaction SMILES: [Na].[N+](C(C)C)([O-])=[O:3].Br[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[N:20]=[C:19]([C:21]#[N:22])[CH:18]=[N:17]2)=[CH:12][CH:11]=1>C(O)C>[CH:9]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[N:20]=[C:19]([C:21]#[N:22])[CH:18]=[N:17]2)=[CH:12][CH:11]=1)=[O:3]
Reactant: CC(C)[N+](=O)[O-]
Reactant: N#Cc1cnn(-c2ccc(CBr)cc2)n1
Agent: [Na]
Solvent: CCO
Product: N#Cc1cnn(-c2ccc(C=O)cc2)n1

Procedure:
4.6 g of sodium are dissolved in 300 ml of absolute ethanol, with stirring and whilst passing a vigorous stream of nitrogen over the mixture. 23.2 g of 2-nitropropane (purity: about 95%) are then added dropwise at 21° C. in the course of 5 minutes and the reaction mixture is stirred at 20° to 25° C. for a further 2 hours. 52.6 g of 2-(p-bromomethyl-phenyl)-4-cyano-2H-1,2,3-triazole are then introduced and the reaction mixture is slowly heated up to the reflux temperature and refluxed for 2 hours. After cooling, the product which has crystallised out is filtered off with suction, stirred with 500 ml of water, again filtered off with suction and washed well with about 2 liters of water. This gives 21.8 g of 2-(p-formyl-phenyl)-4-cyano-2H-1,2,3-triazole with a melting point of 148° to 150° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]([CH2:12][CH2:13][N:14]1[C:22]2[C:17](=[CH:18][C:19]([CH2:23][CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])=[CH:20][CH:21]=2)[C:16]([CH2:32][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)=[CH:15]1)=[O:11]>ClCCl>[C:25]([CH2:24][CH2:23][C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[N:14]([CH2:13][CH2:12][C:10]([O:9][CH3:8])=[O:11])[CH:15]=[C:16]2[CH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)([OH:27])=[O:26]
Reactant: COC(=O)CCn1cc(Cc2cccnc2)c2cc(CCC(=O)OC(C)(C)C)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CCn1cc(Cc2cccnc2)c2cc(CCC(=O)O)ccc21
Reaction time: 18 h
Yield: 86.5 %

Procedure:
Trifluoroacetic acid (15 ml) was added to a stirred solution of t-butyl 1-(2-methoxycarbonylethyl)-3-(3-pyridylmethyl)-1H-indole-5-propanoate (7.60 g) in dry dichloromethane (100 ml) at room temperature, and stirringwas continued for 18 hours. The solution was evaporated and the residue wasazeotroped with toluene and then dissolved in ethyl acetate. Saturated sodium bicarbonate solution was added slowly with shaking until the pH of the aqueous layer was 4-5. The organic layer was then separated, washed with water and dried (MgSO4). The solvent was evaporated and the residue was triturated with ether to give the title compound (5.70 g), m.p. 108°-110° C. Found: C,68.80; H,6.16; N,7.57%. C21 H22N2O4 requires: C,68.83; H,6.05; N,7.65%.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:41]([N:45]1[CH2:51][CH2:50][CH2:49][CH2:48][C@H:47]([NH:52]C(=O)OC(C)(C)C)[C:46]1=[O:60])[CH:42]([CH3:44])[CH3:43]>>[CH2:34]([C@H:14]([CH2:13][CH2:12][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:52][C@H:47]1[CH2:48][CH2:49][CH2:50][CH2:51][N:45]([CH2:41][CH:42]([CH3:43])[CH3:44])[C:46]1=[O:60])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][CH:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)CN1CCCC[C@H](NC(=O)OC(C)(C)C)C1=O
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Product: COC(=O)[C@@H]1CCCC2SCC[C@H](NC(=O)[C@@H](CC[C@@H](Cc3ccccc3)C(=O)N[C@H]3CCCCN(CC(C)C)C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S)-Methyl 4-((2S,5S)-2,5-dibenzyl-6-((S)-1-isobutyl-2-oxoazepan-3-ylamino)-6-oxohexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (40 mg, 0.070 mmol) and Intermediate 80 (26 mg, 0.088 mmol) to give a white solid (40 mg, 77% yield). Anal. Calcd. for C41H56N4O6S m/z 732.4. found: 733.4 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.90 (d, J=7.3 Hz, 2H), 7.67 (d, J=6.8 Hz, 1H), 7.18 (m, 10H), 6.96 (m, 1H), 6.48 (m, 1H), 5.62 (m, 1H), 5.15 (m, 1H), 5.02 (m, 1H), 4.45 (m, 1H), 3.75 (m, 1H), 3.57 (s, 3H), 3.49 (m, 2H), 3.20-3.00 (m, 2H), 2.79 (m, 3H), 2.63 (m, 4H), 2.80-2.57 (m, 4H), 1.82-1.59 (m, 13H), 1.26 (m, 1H), 0.81 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:12]OS(C)(=O)=O)=[CH:5][CH:4]=1.[C-:18]#[N:19].[Na+]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:12][C:18]#[N:19])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(COS(C)(=O)=O)CC2
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc2c(c1)C(CC#N)CC2
Temperature: 0 °C

Procedure:
12.8 g (50 mmol) of methanesulphonic acid (6-methoxyindan-1-ylmethyl) ester and 3.7 g (75 mmol) of sodium cyanide are dissolved in 70 ml of dimethyl sulphoxide and heated at 80° for 6 hours. The reaction mixture is poured onto 200 ml of ice-water and extracted three times by shaking with 100 ml of toluene each time. The organic phases are combined, subsequently washed with saturated sodium chloride solution and dried over magnesium sulphate. After removing the solvent in vacuo, crude 2-(6-methoxyindan-1-yl)acetonitrile is obtained.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.CCN(C(C)C)C(C)C.[C:42](O)(C(F)(F)F)=[O:43]>CN(C=O)C>[F:1][C:2]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:23][CH2:24][N:25]([CH:42]=[O:43])[CH2:26][CH2:27]3)=[CH:18][CH:17]=2)[CH:7]=1
Reactant: O=C(O)C(F)(F)F
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1cc(F)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1cnc(Nc2ccc(C3CCN(C=O)CC3)cc2)cc1NCc1cc(F)ccc1F

Procedure:
Compound 4-(2,5-difluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 214) (70 mg, 0.15 mmol) was stirred in 4 mL DMF with DIEA (300 μL) at 120° C. in a sealed tube for two days. The mixture was acidified with 0.5 mL TFA and subjected to reverse phase preparative HPLC to isolate the title compound (46 mg). MS found for C25H25F2N5O2 as (M+H)+ 466.4. UV: λ=259 nm. 1H NMR: (CD3OD) δ 8.05 (1H, s), 7.97 (1H, s), 7.25 (2H, dt, J=8.8; 2.0 Hz), 7.08-6.98 (4H, m), 6.94 (1H, m), 5.74 (1H, s), 4.41 (2H, s), 4.38 (1H, m), 3.77 (1H, m), 3.17 (1H, m), 2.83 (1H, m), 2.72 (1H, m), 1.85 (2H, m), 1.53 (2H, m) ppm.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH2:13][C:12](=O)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.Cl.Cl.[NH2:17][NH2:18].NN.C(O)CO>O>[NH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[C:12]1[NH:18][N:17]=[C:4]([CH2:3][O:2][CH3:1])[CH:13]=1
Reactant: NN
Reactant: COCC1=Nc2ccccc2C(=O)C1
Agent: Cl
Solvent: O
Solvent: OCCO
Product: COCc1cc(-c2ccccc2N)[nH]n1
Yield: 85.5 %

Procedure:
A mixture of 7.5 g (0.04 mol) of 2-methoxymethyl-4-quinolone, 4.2 g (0.04 mol) of hydrazine dihydrochloride, 12.8 ml (0.4 mol) of 95% hydrazine and 30 ml of ethylene glycol is slowly heated to reflux. The resulting solution is refluxed for 5 hours, cooled, diluted with 200 ml of distilled water, and extracted twice with methylene chloride (1×400 ml, 1×200 ml). The combined methylene chloride extracts are washed with 100 ml of distilled water, dried over sodium sulfate, and evaporated to 8.0 g of clear oil. Trituration with 25 ml of hexane gives 6.95 g (86%) of the 5-(2-aminophenyl)-3-methoxymethylpyrazole as a white powder, m.p. 74.0-78.0° C.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:24]1[CH2:26][O:25]1)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:24]([OH:25])[CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: C1COCCN1
Reactant: CCCC(=O)c1cnc2c(C3CO3)cccc2c1Nc1ccccc1C
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(C(O)CN3CCOCC3)cccc2c1Nc1ccccc1C
Yield: 47.1 %

Procedure:
3-Butyryl-4-(2-methylphenylamino)-8-oxiranylquinoline (1.0 g, 2.89 mmol) and morpholine (1.0 g, 11.55 mmol) in dioxan (20 ml) were heated under reflux for 9 hours. The dioxan was evaporated and the residue dissolved in ethyl acetate, washed with brine, dried and evaporated to an oil which crystallised from ether. Recrystallisation from dichloromethane/ether gave 3-butyryl-4-(2-methylphenylamino)-8-(1-hydroxy-2-morpholinoethyl)quinoline (0.59 g, 47%), m.p. 135°-137°.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][N:10]([CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[C:9]2[CH:18]=[CH:19][CH:20]=[C:21](/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:26][CH:25]=3)[C:8]=2[O:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:47](I)[CH3:48].O>CN(C)C=O>[CH2:47]([O:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12][N:10]1[C:9]2[CH:18]=[CH:19][CH:20]=[C:21](/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)=[CH:26][CH:25]=3)[C:8]=2[O:7][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11]1)[CH3:48]
Reactant: CCI
Reactant: CCOC(=O)C1CN(CCCC(=O)O)c2cccc(/C=C/c3ccc(OCCCCc4ccccc4)cc3)c2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN1CC(C(=O)OCC)Oc2c(/C=C/c3ccc(OCCCCc4ccccc4)cc3)cccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
To a solution of the compound prepared in Example 46 (330 mg) in dimethylformamide (5 mL) were added potassium carbonate (252 mg) and ethyl iodide (142 mg), and the mixture was stirred for 2 hours at room temperature. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine sequentially, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=8:2) to give the title compound (210 mg) having the following physical data.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[F:16])[C:5]([OH:7])=O)[CH3:2].[NH2:17][CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:23]([C:22]1[CH:25]=[CH:26][C:19]([CH2:18][NH:17][C:5](=[O:7])[CH:4]([O:3][CH2:1][CH3:2])[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[F:16])=[C:20]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:21]=1)#[N:24]
Reactant: CCOC(C(=O)O)c1ccc(OC)cc1F
Reactant: N#Cc1ccc(CN)c(Oc2ccccc2)c1
Product: CCOC(C(=O)NCc1ccc(C#N)cc1Oc1ccccc1)c1ccc(OC)cc1F

Procedure:
(RS)-Ethoxy-(2-fluoro-4-methoxy-phenyl)-acetic acid, described in example 63.1 was coupled with 4-aminomethyl-3-phenoxy-benzonitrile according to general procedure B to give (RS)-N-(4-cyano-2-phenoxy-benzyl)-2-ethoxy-2-(2-fluoro-4-methoxy-phenyl)-acetamide. Colorless oil. MS 435.2 ([M+H]+)
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[CH2:21]([NH:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(-c2ccc(CCN)cc2)cc1
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc(CCNCc3ccccc3)cc2)cc1
Reaction time: 1 h
Yield: 92.5 %

Procedure:
To a solution of methyl 4′-(2-aminoethyl)-1,1′-biphenyl-4-carboxylate hydrochloride (420 mg) and benzaldehyde (153 mg) in dichloromethane (5 ml) was stirred for 3 hours, and the mixture was evaporated in vacuo. To the residue in methanol (10 ml) was added sodium borohydride (65 mg) on ice cooling, and stirred at the same temperature for 1 hour. The resulting mixture was poured into saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate) over silica gel to afford methyl 4′-[2-(benzylamino)ethyl]-1,1′-biphenyl-4-carboxylate (460 mg) as a colorless powder.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.[CH2:27]([C:31]1[CH:32]=[CH:33][C:34](CCl)=[N:35][CH:36]=1)[CH2:28][CH2:29][CH3:30]>>[ClH:19].[CH2:27]([C:31]1[CH:32]=[CH:33][C:34]([CH2:21][S:20][C:15]2[C:12]3[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=3[CH:18]=[CH:17][C:16]=2[Cl:19])=[N:35][CH:36]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCc1ccc(CCl)nc1
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Product: CCCCc1ccc(CSc2c(Cl)ccc3c2CCNCC3)nc1

Procedure:
Use a method similar to the Example 315, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 5-butyl-2-chloromethylpyridine hydrochloride to give the title compound as a white solid. MS (APCI+) m/z: 330 (M+H)+.
Reaction SMILES: [CH2:1]([CH:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C.[Br:46][CH2:47][CH2:48][C:49](Cl)=[O:50]>C(Cl)Cl>[Br:46][CH2:47][CH2:48][C:49]([O:20][CH:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:50]
Reactant: O=C(Cl)CCBr
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(O)CCCCCCCC/C=C\C/C=C\CCCCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\CCCCCCCCC(CCCCCCCC/C=C\C/C=C\CCCCC)OC(=O)CCBr
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of dilinoleylmethanol (II, 560 mg, 1 mmol) and dry triethylamine (0.44 g, 4.2 mmol) in 50 mL of anhydrous CH2Cl2 was added dropwise 3-bromopropionyl chloride (technical grade, 0.34 mL) under nitrogen. The resulting mixture was stirred at room temperature for 3 days. The organic phase was diluted with 50 mL of dichloromethane and washed with water (3×50 mL), brine (50 mL), and dried over anhydrous Na2SO4. The solvent was evaporated to afford 610 mg of brownish oil as a crude product. The crude product was purified by column chromatography on silica gel (230-400 mesh, 100 mL) with 0-3% ethyl acetate gradient in hexanes as eluent. This resulted in 540 g of a mixture of III as a major product and a by-product. The mixture was used in the following step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1.[CH3:17][O:18][C:19](=[O:26])[C@H:20]([CH2:22][CH2:23][S:24][CH3:25])[NH2:21]>>[CH3:17][O:18][C:19](=[O:26])[C@H:20]([CH2:22][CH2:23][S:24][CH3:25])[NH:21][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: O=C(O)c1ccc(F)cc1-c1ccccc1
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(F)cc1-c1ccccc1

Procedure:
The resultant product from Example 13B is coupled to methionine methyl ester according to the procedure of Example 1C to give the title compound.