Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][S:15]([NH2:18])(=[O:17])=[O:16].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:14][S:15]([NH:18][C:11](=[O:13])[CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:17])=[O:16]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
3-(tert-butoxycarbonylamino)propanoic acid (4 g, 21.2 mmol, 1.0 equiv) was dissolved in DCM (100 mL). Then methanesulfonamide (1.43 g, 15.1 mmol, 0.7 equiv), EDCI (3.45 g, 18.2 mmol, 0.85 equiv) and DMAP (0.37 g, 3 mmol, 0.15 equiv) were added to the mixture and stirred for 2 h at r.t. The reaction mixture was cooled down to 0° C. ice water (100 mL) was added. The mixture was stirred for 15 min, separated and the water layer was extracted twice with DCM. The combined organic layer was washed by 5% HCl, brine, dried over Na2SO4, concentrated to give tert-butyl 3-(methylsulfonamido)-3-oxopropylcarbamate as a gray oil (3.6 g, 90%). ESI-MS (M+H)+: 267.1. 1H NMR (400 MHz, DMSO-d6) δ: 6.91˜6.83 (brs, 1H), 3.36 (s, 3H), 3.19˜3.12 (m, 2H), 2.41 (t, 2H), 1.37 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].[H-].[Na+].Br[CH2:26][C:27]1[CH:35]=[CH:34][C:30]2=[N:31][S:32][N:33]=[C:29]2[CH:28]=1.O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:26][C:27]2[CH:35]=[CH:34][C:30]3=[N:31][S:32][N:33]=[C:29]3[CH:28]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1[nH]c(=O)c2ccc(Br)cc2c1-c1ccccc1
Reactant: BrCc1ccc2nsnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2nsnc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
To a solution of 6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (600 mg) in DMF (6 ml) was added sodium hydride (60% in oil, 74 mg) under ice-cooling, and the mixture was allowed to warm to room temperature and stirred for 1 hr. To the reaction mixture was added 5-bromomethylbenzo[2,1,3]thiadiazole (460 mg) at room temperature, and the mixture was stirred for 2 hrs. Water was added to the reaction mixture and crystals were collected by filtration, washed with ethyl acetate. The filtrate was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and dried. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from ethyl acetate. The crystals were collected by filtration, combined with the crystals obtained earlier, and subjected to silica gel column chromatography (THF) and further to recrystallization (THF-ethyl acetate) to give the title compound (450 mg).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([O:10][CH:11]2[CH2:16][NH:15][CH2:14][C:13]3[O:17][CH:18]=[CH:19][C:12]2=3)[CH:6]=[CH:7][C:8]=1[Cl:9].I[CH2:21][CH2:22][OH:23].C(OCC)(=O)C.C(OC(=O)C)C.Cl>C(O)C>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([O:10][CH:11]2[CH2:16][N:15]([CH2:21][CH2:22][OH:23])[CH2:14][C:13]3[O:17][CH:18]=[CH:19][C:12]2=3)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Clc1ccc(OC2CNCc3occc32)cc1Cl
Reactant: OCCI
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: OCCN1Cc2occc2C(Oc2ccc(Cl)c(Cl)c2)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
4-(3,4-Dichlorophenyloxy)-4,5,6,7-tetrahydrofuro-[2,3-c]pyridine hydrochloride (Example 119) (50 mg) was dissolved in 5 mL of dehydrated ethanol and then 220 mg of 2-iodoethanol was dropped thereinto. The reaction solution was heated with stirring at 80° C. overnight and concentrated in vacuo to evaporate the solvent and excess 2-iodoethanol. The residue was purified by silica gel column chromatography and the resulting free substance of the objective compound was dissolved in 5 mL of ethyl acetate. Into this ethyl acetate solution was dropped a solution of one equivalent of hydrochloric acid ethyl acetate and the resulting mixed solution was concentrated to give 18 mg of the objective compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:24][CH:25]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=2)=[CH:19][CH:18]=1>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[O:24][CH:25]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=3)=[CH:21][CH:22]=2)=[O:11])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: COC(=O)c1coc(-c2ccc(N)cc2)n1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)OC)co3)cc2)nc1Cl
Yield: 46.4 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.13 g, 0.75 mmol), thionyl chloride (5 mL), methyl 2-(4-aminophenyl)-1,3-oxazole-4-carboxylate obtained in Example (96b) (0.15 g, 0.69 mmol) and pyridine (5 mL), to obtain 0.12 g of the title compound as a light purple solid (47%).
Reaction SMILES: [C:1]1(/[CH:19]=[CH:20]\[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][O:18][C:12]=3[CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:27][NH:28][CH3:29].[CH2:30]=O>C(O)(=O)C>[CH3:27][N:28]([CH2:30][C:17]1[O:18][C:12]2[CH2:11][N:10]([S:7]([C:4]3[CH:5]=[CH:6][C:1](/[CH:19]=[CH:20]\[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:2][CH:3]=3)(=[O:9])=[O:8])[CH2:15][CH2:14][C:13]=2[CH:16]=1)[CH3:29]
Reactant: C=O
Reactant: O=S(=O)(c1ccc(/C=C\c2ccccc2)cc1)N1CCc2ccoc2C1
Reactant: CNC
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CN(S(=O)(=O)c1ccc(/C=C\c3ccccc3)cc1)CC2
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.155 g (0.424 mmol) of (Z)-6-(4-stilbenesulfonyl)-4,5,6,7-tetrahydrofuro[2,3-c]pyridin in 10 ml of acetic acid, 57 mg (0.64 mmol) of 50% aqueous dimethylamine and 52 mg (0.64 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 0.5 hours. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with ethyl acetate 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:19])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.C(Cl)(Cl)Cl>C(OCC)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:19])[CH:11]([Br:1])[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: BrBr
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: O=C(c1ccc(Cl)cc1)C(Br)c1ccc(Cl)cc1

Procedure:
Bromine (2 ml.) was added dropwise to a solution of p-chloro-2-(p-chlorophenyl)acetophenone (10 g.; 0.038 mole), chloroform (50 ml.) and diethyl ether (25 ml.). The mixture was heated at reflux for 0.5 hours and cooled (ca. 20°). Following a thorough washing with saturated sodium bicarbonate, the organic solution was dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed at low pressure through silica gel 60 mesh (230-400) with 5% ethyl acetate in hexane. Recrystallization from hexane afforded 2.69 g.; m.p. 81.5°-83°.
Reaction SMILES: [Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C1([C:28]2[C:36]3[C:31](=[CH:32][C:33]([C:37]([O:39]C)=[O:38])=[CH:34][CH:35]=3)[NH:30][CH:29]=2)CCCCC1>C(Cl)(Cl)Cl.C1COCC1>[NH:30]1[C:31]2[C:36](=[CH:35][CH:34]=[C:33]([C:37]([OH:39])=[O:38])[CH:32]=2)[CH:28]=[CH:29]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Agent: [Br-]
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: O=C(O)c1ccc2cc[nH]c2c1
Temperature: 2.5 °C
Reaction time: 2.5 h

Procedure:
Freshly recrystallized pyridinium tribromide (recrystallization from hot AcOH (5 mL per 1 g), rinsed with cold AcOH and dried under high vacuum over KOH) was added in portions (over 10 min.) to a stirring solution of methyl 3-cyclohexyl-1H-indole-6-carboxylate (60 g, 233 mmol) (prepared using procedures describe in WO2004/065367) in CHCl3/THF (1:1, 1.25 L) at 2° C. The reaction solution was stirred at 0-5° C. for 2.5 h, and washed with sat. aq. NaHSO3 (1 L), 1N HCl (1 L) and brine (1 L). The organic layer was dried (MgSO4) and concentrated. The resulting red oil was diluted with Et2O and concentrated. The resulting pink solid was dissolved into Et2O (200 mL) treated with hexanes (300 mL) and partially concentrated. The solids were collected by filtration and rinsed with hexanes. The mother liquor was concentrated to dryness and the procedure repeated. The solids were combined to yield 1H-indole-6-carboxylic acid, 2-bromo-3-cyclohexyl-, methyl ester (64 g, 190 mmol, 82%) as a fluffy pink solid, which was used without further purification. 1H NMR (300 MHz, CDCl3) δ 1.50-1.27 (m, 3H), 1.98-1.72 (m, 7H), 2.82 (tt, J=3.7, 11.7 Hz, 1H), 3.92 (s, 3H), 7.69 (d, J=8.8 Hz, 1H), 7.74 (dd, J=1.4, 8.8 Hz, 1H), 8.03 (d, J=1.4 Hz, 1H), 8.47 (br s, 1H). 13C NMR (75 MHz, CDCl3) δ 26.1, 27.0 (2), 32.2 (2), 37.0, 52.1, 110.7, 112.8, 118.7, 120.3, 120.8, 123.1, 130.2, 135.6, 168.2. LCMS: m/e 334 (M−H)−, ret time 3.34 min., 4 minute gradient. Stop time: 5 minutes; Gradient time: 4 minutes; Starting conc: 0% B; Ending conc: 100% B; Eluent A: 5% CH3CN/95% H2O with 10 mM NH4OAc; Eluent B: 95% CH3CN/5% H2O with 10 mM NH4OAc; Column: Phenomenex 10μ 4.6×50 mm C18.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH2:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[N:15]1[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][CH:16]=1>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:21]([C:18]2[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=2)=[O:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccncc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)c2ccncc2)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A cooled (0° C.) stirred solution of (R)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g, 5.36 mmol) and TEA (1.5 ml, 11.0 mmol) in THF (10 ml) is treated dropwise over 1 minute with pyridine-4 carbonyl chloride hydrochloride (0.935 g, 5.25 mmol). After 5 minutes, the reaction mixture is allowed to warm to room temperature and stirred overnight. The resulting mixture is diluted with EtOAc and washed twice with saturated sodium bicarbonate solution followed by brine. The organic portion is dried (MgSO4) and concentrated in vacuo. The crude product is purified by recrystallisation from EtOAc/iso-hexane to afford the title product. [MH+ 292].
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([C:10]2[S:11][C:12]3[CH2:18][CH2:17][CH2:16][CH2:15][C:13]=3[N:14]=2)[CH:7]=[CH:6][C:5]=1[OH:19])[CH2:2][CH3:3].Br[CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH:29]=[CH:28]2.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([C:4]1[CH:9]=[C:8]([C:10]2[S:11][C:12]3[CH2:18][CH2:17][CH2:16][CH2:15][C:13]=3[N:14]=2)[CH:7]=[CH:6][C:5]=1[O:19][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH:29]=[CH:28]2)[CH2:2][CH3:3]
Reactant: CCCc1cc(-c2nc3c(s2)CCCC3)ccc1O
Reactant: COC(=O)Cn1ccc2cc(OCCCBr)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1cc(-c2nc3c(s2)CCCC3)ccc1OCCCOc1ccc2c(ccn2CC(=O)OC)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 67.1 %

Procedure:
2-Propyl-4-(4,5,6,7-tetrahydro-benzothiazol-2-yl)-phenol (Example 36, 0.75 g, 2.76 mmol) was combined with [5-(3-bromo-propoxy)-indol-1-yl]-acetic acid methyl ester (Example 47, 0.75 g, 2.30 mmol) in 12 mL DMF (containing 1 v/v % of water). To this mixture was added Cs2CO3 (1.50 g, 4.60 mmol), and the resulting mixture was allowed to stir at rt for 14 h. At this time, the reaction mixture was diluted with EtOAc (50 mL) and then washed three times with water (75 mL total). The water layers were extracted with EtOAc (25 mL) and the combined organic extracts were dried over MgSO4, filtered, and then concentrated under reduced pressure. Purification via flash silica gel chromatography (1:1 hexane/EtOAc) gave the title compound (800 mg, 64%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.75-7.70 (m, 2H), 7.18-7.10 (m, 2H), 7.05 (d, 1H), 6.92-6.85 (m, 2H), 6.48 (d, 1H), 4.84 (s, 2H), 4.30-4.20 (m, 4H), 3.75 (s, 3H), 2.90-2.75 (m, 4H) 2.70-2.60 (m, 2H), 2.40-2.30 (m, 2H), 1.95-1.85 (m, 4H), 1.70-1.58 (m, 2H), 0.95 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([OH:10])[CH2:7][NH:6]1)=[O:4].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18]Cl)=[CH:14][C:13]=1[Cl:20]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[CH2:18][C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[C:13]([Cl:20])[CH:14]=1)=[O:4]
Reactant: COC(=O)C1CC(O)CN1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Product: COC(=O)[C@@H]1C[C@@H](O)CN1Cc1ccc(Cl)c(Cl)c1
Yield: 70 %

Procedure:
As described for Example 64a, 4-hydroxy-pyrrolidine-2-carboxylic acid methyl ester (10 mmol) was converted, using 1,2-dichloro-4-chloromethyl-benzene instead of 1-chloro-3-chloromethyl-benzene, to the title compound (2.14 g) in 70% yield as yellow oil.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[NH3:8].C[Si](C)(C)[C:11]#[N:12]>C(O)C>[NH2:8][C:4]1([C:11]#[N:12])[CH2:5][CH2:6][S:1][CH2:2][CH2:3]1
Reactant: C[Si](C)(C)C#N
Reactant: N
Reactant: O=C1CCSCC1
Solvent: CCO
Product: N#CC1(N)CCSCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tetrahydro-4H-thiopyran-4-one (215 g, 1.85 mol) in ethanol (1500 mL) was bubbled ammonia gas at 0° C. After 4 hours, trimethylsilanecarbonitrile (184 g, 1.86 mol) was added dropwise and then the reaction mixture was allowed to warm to ambient temperature. After 5 hours, the reaction mixture was concentrated under reduced pressure and then diluted with hexane (800 mL). The mixture was filtered, and the solids were washed with hexanes (2×400 mL) and dried under reduced pressure to afford 4-aminotetrahydro-2H-thiopyran-4-carbonitrile. The material was used without further purification.
Reaction SMILES: O[CH2:2][C:3]([NH:6][C:7](=[O:24])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[O:18][CH2:17][C:16]3[CH:19]=[CH:20][S:21][C:15]=3[C:14](=[O:22])[C:13]=2[CH:23]=1)([CH3:5])[CH3:4].O=S(Cl)Cl.[CH2:29](Cl)Cl>>[CH:17]([O:18][CH:12]([CH3:11])[CH3:13])([CH3:16])[CH3:29].[O:22]=[C:14]1[C:13]2[CH:23]=[C:9]([CH2:8][C:7]3[O:24][CH2:5][C:3]([CH3:4])([CH3:2])[N:6]=3)[CH:10]=[CH:11][C:12]=2[O:18][CH2:17][C:16]2[CH:19]=[CH:20][S:21][C:15]1=2
Reactant: ClCCl
Reactant: CC(C)(CO)NC(=O)Cc1ccc2c(c1)C(=O)c1sccc1CO2
Solvent: O=S(Cl)Cl
Product: CC(C)OC(C)C
Product: CC1(C)COC(Cc2ccc3c(c2)C(=O)c2sccc2CO3)=N1
Reaction time: 16 h
Yield: 52 %

Procedure:
To a suspension of 8.3 g (0.02 m) of 4,10-dihydro-N-(1-hydroxy-2-methyl-2-propyl)-10-oxothieno[3,2-c][1]benzoxepin-8-yl acetamide of Example 1 and 200 ml of methylene chloride, SOCl2 (3.09 g) was added dropwise keeping the temperature at approximately 5° C. The suspended material gradually dissolved. The mixture was stirred overnight (about 16 hours). The organic layer was washed with 10% NaOH, dried (Na2SO4) and evaporated to give an oil. Trituration with isopropyl ether gave 4.1 g (52%) of 2-(4,10-dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-yl)methyl-4,4-dimethyl-oxazoline, m.p. 85°-87° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O-:14])(=[O:13])[CH2:10][CH2:11][CH3:12].[K+].C(OC(=O)CCC)(=O)CCC>>[CH2:11]([C:10](=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([OH:14])=[O:13])[CH3:12]
Reactant: O=Cc1ccccc1
Reactant: CCCC(=O)[O-]
Agent: CCCC(=O)OC(=O)CCC
Agent: [K+]
Product: CCC(=Cc1ccccc1)C(=O)O

Procedure:
Benzaldehyde was condensed with potassium butyrate and butyric anhydride according to the procedure as outlined in the patent to Archer, U.S. Pat. No. 2,931,830 to give α-ethyl cinnamic acid, with a m.p. at 104°-104.8° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5](=[CH:11][N:12]([CH3:25])[C:13]1[S:14][CH:15]=[CH:16][C:17]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[Cl-].[CH2:28]=[N+:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH2:9]([O:8][C:6](=[O:7])[C:5](=[CH:11][N:12]([CH3:25])[C:13]1[S:14][C:15]([CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:16][C:17]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:4]([O:3][CH2:1][CH3:2])=[O:26])[CH3:10]
Reactant: CCOC(=O)C(=CN(C)c1sccc1C(=O)OC(C)(C)C)C(=O)OCC
Reactant: C=[N+]1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)C(=CN(C)c1sc(CN2CCOCC2)cc1C(=O)OC(C)(C)C)C(=O)OCC
Yield: 96.2 %

Procedure:
A mixture of N-(3-tert-butoxycarbonyl-thien-2-yl)-methylaminomethylenemalonic acid diethyl ester (19.0 g) from Preparation No. 2 and 4-methylene morpholinium chloride (Dimmock, JR, et al Eur. J. Med. Chem. 1989, 24, 379-383) (13.4 g) in dry acetonitrile (50 ml) is heated at reflux for about 4 hr. The solution is then cooled in an ice bath and saturated aqueous sodium carbonate (98 ml) is slowly added. The solution is extracted three times with ethyl acetate (300 ml total) and the combined organic layers are then washed three times with water (600 ml total). The solvents are removed in vacuo to afford 23.0 g (96%) of the title compound as a brown oil.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH2:17][C:18]([OH:20])=[O:19])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(O)=O.[Pd]>[CH2:1]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH2:17][C:18]([OH:20])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CC(=O)O)c(C(=O)c2ccccc2)c1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc(CC(=O)O)c(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 104.9 %

Procedure:
2-Benzoyl-4-methoxyphenylacetic acid (215.5 g, 0.80 mole) was divided into two equal portions, and each was dissolved in glacial AcOH (1.5 L) in a 2.5 L pressure bottle. 5% Pd/C (10 g, 0.0048 mole) was added to each, and each mixture was shaken at ambient temperature under hydrogen on a Parr apparatus. After 2.5 hr, the mixtures were filtered to remove the catalyst, and the filter pads were washed with EtOAc. The combined filtrates were concentrated to give the title compound (215 g, quantitative) as a heavy yellow oil which crystallized on standing: 1H NMR (250 MHz, CDCl3) δ7.05-7.35 (m, 6 H), 6.77 (dd, J=8.3, 2.7 Hz, 1 H), 6.71 (d, J=2.7 Hz, 1 H), 4.00 (s, 2 H), 3.76 (s, 3 H), 3.54 (s, 2 H).
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[N:26]([CH2:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:32][CH2:31]1)[CH2:27][CH3:28])[C:8]1[N:13]=[CH:12][C:11]([OH:14])=[CH:10][N:9]=1.Br[CH2:52][CH2:53][OH:54].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[F:50][C:2]([F:1])([F:49])[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:46])([F:47])[F:48])[CH:44]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[N:26]([CH2:29][C@H:30]1[CH2:31][CH2:32][C@H:33]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:34][CH2:35]1)[CH2:27][CH3:28])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:52][CH2:53][OH:54])=[CH:12][N:13]=1
Reactant: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2ccc(C(F)(F)F)cc2CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(O)cn2)CC1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2ccc(C(F)(F)F)cc2CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(OCCO)cn2)CC1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Ethyl trans-(4-{[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-hydroxy-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-methyl}-cyclohexyl)-acetate (300 mg) is dissolved in N,N-dimethylformamide (4 ml), and thereto are added 2-bromoethanol (87 μl) and potassium carbonate (172 mg), and the mixture is stirred at 60° C. for 1 day. The reaction solution is cooled to room temperature, and thereto are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=7:3% 1:1) to give ethyl trans-[4-({[2-({(3,5-bis-trifluoromethyl-benzyl)-[5-(2-hydroxy-ethoxy)-pyrimidin-2-yl]-amino}-methyl)-4-trifluoromethyl-phenyl]-ethyl-amino}-methyl)-cyclohexyl]-acetate (138 mg). MS (m/z): 765 [M+H]+
Reaction SMILES: [Li].[F:2][C:3]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7](Br)=[CH:8]2.I[C:16]1[CH:21]=[CH:20][C:19]([C@H:22]2[CH2:27][CH2:26][C@H:25]([CH2:28][CH2:29][CH3:30])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1.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.C1COCC1>[F:2][C:3]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:16]1[CH:17]=[CH:18][C:19]([C@H:22]3[CH2:27][CH2:26][C@H:25]([CH2:28][CH2:29][CH3:30])[CH2:24][CH2:23]3)=[CH:20][CH:21]=1)=[CH:8]2
Reactant: Fc1ccc2cc(Br)ccc2c1F
Reactant: CCC[C@H]1CC[C@H](c2ccc(I)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Li]
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H](c2ccc(-c3ccc4c(F)c(F)ccc4c3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a THF solution of an organic lithium reagent prepared from 5,6-difluoro-2-bromonaphthalene were added dropwise 4-iodo-1-(trans-4-propylcyclohexyl)benzene and a THF solution of tetrakis(triphenylphosphine)palladium (0) in the catalytic amount. The reaction mixture were then stirred at room temperature for 3 hours. To the reaction mixture were then added water and toluene to terminate the reaction. To the reaction solution was then added diluted hydrochloric acid until the aqueous phase became weakly acidic. The reaction solution was then extracted with toluene. The material thus extracted and the organic phase were together washed with water and then with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain an oily matter. The oily matter was purified through silica gel column chromatography (hexane), and then recrystallized from ethanol to obtain 5,6-difluoro-2-[4-(trans-4-propylcyclohexyl)phenyl]naphthalene in the form of white crystal,