Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:18]3[C:19]4[C:11]([CH2:12][CH2:13][C:14]=4[CH:15]=[CH:16][CH:17]=3)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.I[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[N+](C1C=CC=CC=1)([O-])=O>[Cu].C1(C)C=CC=CC=1>[C:1]1([CH3:20])[CH:2]=[CH:3][C:4]([N:7]([C:8]2[C:18]3[C:19]4[C:11]([CH2:12][CH2:13][C:14]=4[CH:15]=[CH:16][CH:17]=3)=[CH:10][CH:9]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(Nc2ccc3c4c(cccc24)CC3)cc1
Reactant: Ic1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ccc(N(c2ccccc2)c2ccc3c4c(cccc24)CC3)cc1
Yield: 83.8 %

Procedure:
4.66 g (0.018 mol) of the above prepared 5-[N-(4-tolyl)amino]acenaphthene was mixed with 4.99 g (0.022 mol) of iodo benzene, 0.13 g (0.002 mol) of copper powder, 2.76 g (0.02 mol) of anhydrous potassium carbonate and 5 ml of nitrobenzene, and the resultant mixture was stirred at 200° C. for 25 hours. The reaction was determined to be finished when disappearance of 5-[N-(4-tolyl)amino]acenaphthene was identified. 100 ml of toluene was added thereto to dissolve the reaction product, and the mixture was filtrated and concentrated. The concentrated material thus obtained was purified by column chromatography (carrier: silica gel, eluent: toluene/hexane=1/4) to obtain 5.06 g (yield: 83.8%, melting point: 147.0°-148.0° C.) of 5-[N-(4-tolyl)-N-phenylamino]acenaphthene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:14]C)=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[N:10][CH:9]=2)[CH:7]=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:14])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[N:10][CH:9]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1ccnnc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(Cl)cc1-c1ccnnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.9 %

Procedure:
To a stirred solution of 4-(5-chloro-2-methoxyphenyl)pyridazine (Preparation 6, 22 g, 100 mmol) in dichloromethane (200 mL) at 0° C. was added drop wise a solution of boron tribromide (48 mL, 499 mmol) in dichloromethane (200 mL). The reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched by pouring onto crushed ice and basifying the mixture to pH 8 with sodium hydrogen carbonate. The mixture was extracted with dichloromethane. The aqueous layer was extracted further with ethyl acetate. The organics were combined and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (0%-4% methanol in dichloromethane gradient elution) to afford the title compound (16.5 g, 80%)
Reaction SMILES: [C:1]([CH:5]1[CH2:15][CH2:14][C:8]2([O:12][CH2:11][CH:10]([OH:13])[CH2:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C1COCC1>[C:1]([CH:5]1[CH2:15][CH2:14][C:8]2([O:12][CH2:11][CH:10]([O:13][S:24]([C:21]3[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=3)(=[O:26])=[O:25])[CH2:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)C1CCC2(CC1)CC(O)CO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OC2COC3(CCC(C(C)(C)C)CC3)C2)cc1
Reaction time: 3 h
Yield: 99.6 %

Procedure:
To a solution of 8-t-butyl-3-hydroxy-1-oxaspiro(4,5)decane (4.24 g, 20 mmol) in THF (50 ml) was added sodium hydride (0.72 g, 24 mmol, 80% in mineral oil) and the mixture was heated to reflux for 3 hours. p-Toluenesulfonylchloride (4.56 g, 24 mmol) in THF (10 ml) was then added and heating was continued for another 3 hours. The solvent was evaporated, toluene and water were added (50 ml, each) and the phases were separated. A pale yellow oil (7.3 g) was isolated from the organic layer which was treated with light petroleum to yield colourless crystals (5.6 g), melting at 101° C.
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].C([Li])CCC.[F:13][C:14]([F:21])([F:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18].C(I)C>C1COCC1>[CH2:1]([CH:16]([CH2:15][C:14]([F:21])([F:20])[F:13])[C:17]([OH:19])=[O:18])[CH3:2]
Reactant: CC(C)NC(C)C
Reactant: O=C(O)CCC(F)(F)F
Agent: [Li]CCCC
Solvent: CCI
Solvent: C1CCOC1
Product: CCC(CC(F)(F)F)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (17.1 g, 169 mmol) in THF (180 mL) was stirred under nitrogen at 0° C. n-Butyl lithium (n-BuLi-67.6 mL, 2.5 M in hexane) was added dropwise over 15 min and the resulting solution stirred for 0.5 h at 0° C. After this time period, the reaction was cooled to −78° C., and 4,4,4-trifluorobutyric acid (10.0 g, 70.4 mmol) in THF (20 mL) was added dropwise over 0.5 h. The resulting solution was stirred for an additional 0.5 h at −78° C. After this time period, ethyl iodide (6.19 mL, 77.4 mmol) was added dropwise over 15 min. The resulting solution was stirred for 15 min. at −78° C. then warmed to 25° C. for 24 h. After this time period, the reaction mixture was quenched by slow addition of H2O (˜20 mL). After concentration, the residue was acidified to pH 1 with 2 N aq. HCl and then extracted with Et2O (400 mL). The organic layer was then dried using MgSO4. After concentration, the resulting residue was used directly in the next reaction without further purification.
Reaction SMILES: [CH2:1]([S:3][C:4]1[NH:5][C:6]2[C:7](=[C:9]([C:13]([O:15][CH3:16])=[O:14])[S:10][C:11]=2[CH3:12])[N:8]=1)[CH3:2].[H-].[Na+].[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=1)#[N:20].O>CN(C=O)C>[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:28]=[CH:29][C:30]([CH2:33][N:8]2[C:7]3=[C:9]([C:13]([O:15][CH3:16])=[O:14])[S:10][C:11]([CH3:12])=[C:6]3[N:5]=[C:4]2[S:3][CH2:1][CH3:2])=[CH:31][CH:32]=1)#[N:20]
Reactant: CCSc1nc2c(C(=O)OC)sc(C)c2[nH]1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1nc2c(C)sc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 0.33 h

Procedure:
To a solution of methyl 2-ethylthio-4-methylthieno[3,4-d]imidazole-6-carboxylate (5.7 g) in DMF (30 ml) was added sodium hydride (60% oil, 0.98 g) under ice-cooling. After stirring the reaction mixture for 20 minutes, to the mixture was added dropwise a solution of (2'-cyanobiphenyl-4-yl)methyl bromide (7.25 g) in DMF (20 ml), followed by stirring for one hour at room temperature. To the reaction mixture was added water, which was extracted with ethyl acetate. The extract was washed with water and dried, then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography to give crystals. Recrystallization from ethyl acetate - hexane afforded pale yellow prisms (7.6 g, 77%), m.p. 149°-151° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:22][C:9]2[C:10]([C:17]([O:19][CH2:20]C)=[O:18])=[CH:11][NH:12][CH2:13][C:14]([CH3:16])([CH3:15])[C:8]=2[CH:7]=1)=[O:5])C.[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[F:33])[C:27](Cl)=[O:28]>>[CH3:1][O:3][C:4]([C:6]1[NH:22][C:9]2[C:10]([C:17]([O:19][CH3:20])=[O:18])=[CH:11][N:12]([C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:32]([F:33])=[C:24]([F:23])[CH:25]=3)[CH2:13][C:14]([CH3:16])([CH3:15])[C:8]=2[CH:7]=1)=[O:5]
Reactant: CCOC(=O)C1=CNCC(C)(C)c2cc(C(=O)OCC)[nH]c21
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Product: COC(=O)C1=CN(C(=O)c2ccc(F)c(F)c2)CC(C)(C)c2cc(C(=O)OC)[nH]c21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2 by using 4,4-dimethyl-1,4,5,6-tetrahydro-pyrrolo[2,3-d]azepine-2,8-dicarboxylic acid diethyl ester and 3,4-difluoro-benzoyl chloride. 1H-NMR(CDCl3): δ 11.11 (1H, s), 7.83 (1H, s), 7.48 (1H, m), 7.36 (1H, m), 6.87 (1H, d), 4.33 (2H, q), 4.24 (2H, q), 3.89 (2H, s), 1.36 (3H, t), 1.33 (6H, s), 1.22 (3H, t). MS (ES): 447 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([S:11][CH3:12])[S:10][C:3]=12.[F:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[OH:23].C(=O)([O-])[O-].[Na+].[Na+]>C1(OC2C=CC=CC=2)C=CC=CC=1>[F:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[O:23][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([S:11][CH3:12])[S:10][C:3]=12
Reactant: CSc1cc2nccc(Cl)c2s1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CSc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 200 °C
Yield: 0.1 %

Procedure:
To a suspension of 229 (100 mg, 0.463 mmol) in diphenyl ether (4 mL), was added 2-fluoro-4-nitrophenol (109 mg, 0.695 mmol) and sodium carbonate (147 mg, 1.39 mmol). The reaction mixture was heated at 200° C. overnight, cooled to room temperature, loaded onto a flash chromatography column and eluted with EtOAc/hexane (1:1) to afford title compound 230 (0.135 mg, 86% yield) as a yellow solid. MS (m/z): 337.0 (M+1).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][C:9]1[NH:14][C:13](=[O:15])[NH:12][C:11](=[O:16])[C:10]=1[Cl:17])SC)#[N:2].[CH3:18][NH2:19]>C(O)C>[C:1]([NH:3][C:4]([NH:19][CH3:18])=[N:7][CH2:8][C:9]1[NH:14][C:13](=[O:15])[NH:12][C:11](=[O:16])[C:10]=1[Cl:17])#[N:2]
Reactant: CN
Reactant: CSC(=NCc1[nH]c(=O)[nH]c(=O)c1Cl)NC#N
Solvent: CCO
Product: CNC(=NCc1[nH]c(=O)[nH]c(=O)c1Cl)NC#N
Temperature: 50 °C
Yield: 96 %

Procedure:
Next, 150 mg of the N-cyano-N′-(5-chlorouracil-6-ylmethyl)-S-methylisothiourea were suspended in ethanol (3 ml), followed by the addition of 2 ml of a 30% solution of methylamine in ethanol. The resulting mixture was heated at 50° C. for 3.5 hours under stirring. After an insoluble matter was filtered off, the filtrate was allowed to cool back to room temperature. A precipitate from the filtrate was collected by filtration, whereby 12 mg of the title compound were obtained (yield: 96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[C:19]([N:21]2[CH2:26][CH2:25][N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])[CH2:23][CH2:22]2)=[O:20])=[CH:5][CH:4]=1.Cl.[CH3:43][N:44]([CH3:48])[CH2:45][CH2:46]Cl>>[CH3:41][O:40][C:37]1[CH:36]=[CH:35][C:34]([CH:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:46][CH2:45][N:44]([CH3:48])[CH3:43])[C:11]=2[C:19]([N:21]2[CH2:22][CH2:23][N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])[CH2:25][CH2:26]2)=[O:20])=[CH:39][CH:38]=1
Reactant: CN(C)CCCl
Reactant: COc1ccc(C(c2ccc(OC)cc2)c2c(C(=O)N3CCN(c4ccccc4Cl)CC3)[nH]c3ccccc23)cc1
Agent: Cl
Product: COc1ccc(C(c2ccc(OC)cc2)c2c(C(=O)N3CCN(c4ccccc4Cl)CC3)n(CCN(C)C)c3ccccc23)cc1
Yield: 66.5 %

Procedure:
Substantially the same procedure as in Example 2 was repeated using Compound 29 (1.0 g, 1.77 mmol) obtained in Example 29 and 2-dimethylaminoethylchloride hydrochloride (266 mg, 1.85 mmol) to give 0.75 g (yield: 67%) of the title compound.
Reaction SMILES: [C:1]1([C:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])([CH2:10][CH:11]=[CH2:12])[C:8]#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.C(OCC)(=[O:40])C.Cl>C(OCC)C>[C:1]1([C:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])([CH2:10][CH:11]=[CH2:12])[CH:8]=[O:40])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(C)=O
Reactant: C=CCC(C#N)(COCC[Si](C)(C)C)c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C=CCC(C=O)(COCC[Si](C)(C)C)c1ccccc1
Reaction time: 2.5 h
Yield: 39.2 %

Procedure:
A solution of 2-phenyl-2-(2-(trimethylsilyl)ethoxymethyl)pent-4-enenitrile (354 mg, 1.23 mmol) in ethyl ether (1.0 mL) was cooled in an ice bath and a 1.5 M solution of diisobutylaluminum hydride in toluene (1.25 mL, 1.88 mmol) was added. After 2.5 h, ethyl acetate (0.30 mL, 270 mg, 3.1 mmol) was added and the mixture was transferred to a stirred mixture of 30 mL of ethyl ether and 10 mL of 2 N aqueous HCl at 0° C. After 10 min, the layers were separated and the aqueous layer was stirred for 0.5 h with another 30 mL of ethyl ether. The two organic layers were washed in succession with 10 mL each of 2 N aqueous HCl, saturated aqueous sodium bicarbonate, and brine. The combined organic layers were dried over sodium sulfate and evaporated, The residue was dissolved in 5.0 mL of THF and 0.7 mL of water was added followed by 1.0 g of silica gel. After stirring for 40 min at RT, the mixture was filtered and the silica gel was washed with additional THF. The filtrate was evaporated and the residue was purified by flash column chromatography on silica gel, eluting with 2% ethyl ether in hexane, to give 140 mg of the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3): δ9.56 (s, 1H), 7.35 (t, 2H, J=7 Hz), 7.26 (t, 1H, J=7 Hz), 7.16 (d, 2H, J=7 Hz), 5.47 (ddt, 1H, J=17, 10, 7 Hz), 5.06-4.96 (m, 2H), 3.98 (d, 1H, J=9 Hz), 3.80 (d, 1H, J=9 Hz), 3.58-3.47 (m, 2H), 2.73 (d, 2H, J=7 Hz), 0.88 (t, 2H, J=8 Hz) −0.03 (s, 9 H). Mass spectrum (CI): m/z=263 (M−27, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])/[C:5](=[CH:14]/[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]2)=[C:17]([O:27][CH3:28])[CH:16]=1)/[CH2:6][CH2:7][CH2:8][CH:9]1OCC[O:10]1)[CH3:2].C(O)(=O)C.FC(F)(F)C(O)=O.O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:29])/[C:5](=[CH:14]/[C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]2)=[C:17]([O:27][CH3:28])[CH:16]=1)/[CH2:6][CH2:7][CH2:8][CH:9]=[O:10])[CH3:2]
Reactant: CCOC(=O)/C(=C/c1ccc(-n2cnc(C)c2)c(OC)c1)CCCC1OCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)/C(=C/c1ccc(-n2cnc(C)c2)c(OC)c1)CCCC=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 93.6 %

Procedure:
To an aqueous solution (2.0 mL) of (E)-5-dioxolan-2-yl-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]valeric acid ethyl ester (480 mg), acetic acid (1.0 mL) and trifluoroacetic acid (1.0 mL) were added one by one, and the reaction solution was agitated at room temperature for 2.5 hours. A saturated sodium bicarbonate water and ethyl acetate were added to the reaction solution after confirming disappearance of the starting materials, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: ethyl acetate->ethyl acetate:ethanol 10:1), and 400 mg of the title compound was obtained.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:27][CH2:28][C:29]([NH:31][CH3:32])=[O:30])[C:20]([O:22]C(C)(C)C)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1>ClCCl.FC(F)(F)C(O)=O>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:27][CH2:28][C:29]([NH:31][CH3:32])=[O:30])[C:20]([OH:22])=[O:21])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CNC(=O)CC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)CC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.4 %

Procedure:
tert-Butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-(methylamino)-5-oxopentanoate (Compound SP445) (13.3 g, crude product) was dissolved in a mixture of dichloromethane (140 ml) and trifluoroacetic acid (140 ml), followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the resulting solid was washed with hexane and then dried in vacuo to afford (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-(methylamino)-5-oxopentanoic acid (Compound SP446) (5.84 g, 93%, two steps).
Reaction SMILES: CI.[Br:3][C:4]1[CH:14]=[N:13][C:7]2[O:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=1.[C:15](=O)([O-])[O-].[K+].[K+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C>[Br:3][C:4]1[CH:14]=[N:13][C:7]2[O:8][CH2:9][C:10](=[O:12])[N:11]([CH3:15])[C:6]=2[CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1COc2ncc(Br)cc2N1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CN1C(=O)COc2ncc(Br)cc21
Temperature: 60 °C
Reaction time: 6 h

Procedure:
0.16 mL (2.62 mmol) of methyl iodide is added to a suspension of 0.5 g (2.18 mol) of 7-bromo-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine, 0.24 g (1.09 mmol) of benzyltriethylammonium chloride and 0.75 g (5.46 mmol) of potassium carbonate in 25 mL of acetonitrile. The mixture is stirred for 6 hours at 60° C. After this time, a precipitate is removed by filtration. The filtrate is concentrated under reduced pressure and the resulting solid is taken up in 15 mL of dichloromethane and then washed successively with 20 ml of water, 10 mL of 0.1N hydrochloric acid solution, 10 mL of saturated sodium hydrogen carbonate solution and then 10 mL of water. After drying over sodium sulfate, the solution is finally concentrated under reduced pressure to give the expected product, which is used without further purification in the following step.
Reaction SMILES: [Cl:1][C:2]1[C:13]([O:14][CH2:15][CH2:16][Br:17])=[C:12]([O:18][CH3:19])[CH:11]=[CH:10][C:3]=1[C:4]([O:6]CCBr)=[O:5].[OH-].[Na+].Cl>C(O)C>[Br:17][CH2:16][CH2:15][O:14][C:13]1[C:2]([Cl:1])=[C:3]([CH:10]=[CH:11][C:12]=1[O:18][CH3:19])[C:4]([OH:6])=[O:5]
Reactant: COc1ccc(C(=O)OCCBr)c(Cl)c1OCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(=O)O)c(Cl)c1OCCBr
Temperature: 50 °C
Yield: 94.2 %

Procedure:
To a suspension of bromoethyl 2-chloro-3-bromoethoxy-4-methoxybenzoate (2.0 g, 4.8 mmol) in ethanol (6 ml) is added 2.5 N aqueous sodium hydroxide (4.8 ml, 12 mmol). The resulting mixture is heated at 50° C. until dissolved plus an additional 10 minutes. The solution is cooled, acidified with 3 N HCl, transferred to a separatory funnel and extracted with ethyl acetate (4×25 ml). The combined organic layers are washed with brine (25 ml), dried over magnesium sulfate and evaporated to obtain 1.4 g (93%) of 3-bromoethoxy-2-chloro-4-methoxybenzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:24](=[O:34])[NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)=[CH:20][C:21]=1[CH2:22][CH3:23])=[O:16])[CH2:5][NH:6]C(OC(C)(C)C)=O.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>C(Cl)Cl>[F:39][C:38]([F:41])([F:40])[C:36]([OH:42])=[O:37].[CH3:1][O:2][C:3](=[O:35])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:24](=[O:34])[NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)=[CH:20][C:21]=1[CH2:22][CH3:23])=[O:16])[CH2:5][NH2:6]
Reactant: CCc1cc(C(=O)NCc2cccc(O)c2)sc1C(=O)N[C@@H](CNC(=O)OC(C)(C)C)C(=O)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cc(C(=O)NCc2cccc(O)c2)sc1C(=O)N[C@@H](CN)C(=O)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-3-tert-Butoxycarbonylamino-2-{[3-ethyl-5-(3-hydroxy-benzylcarbamoyl)-thiophene-2-carbonyl]-amino}-propionic acid methyl ester (0.24 g, 0.46 mmol) in DCM (5 mL) was added TFA (1.0 mL). The mixture was stirred at room temperature 1 h and evaporated to give crude product which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][CH2:26][NH2:27]>>[Cl:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:27][CH2:26][CH2:25][C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2Cl)cn1
Reactant: NCCc1cccs1
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3cccs3)cc2Cl)cn1
Yield: 72.9 %

Procedure:
Using a method similar to Example 405, using 5-(2-chloro-4-formylphenoxy)pyridine-2-carboxamide (0.0388 g, 0.140 mmol) and 2-(2-thienyl)ethylamine (0.018 g, 0.140 mmol) gives the title compound (0.0396 g, 72.8%): TOF MS ES+ 388.1 (M+H)+. HRMS calcd for C19H19N3O2ClS 388.0887 (M+H)+, found 388.0866, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=7.6 min, 100% purity.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2([C:17]([O:19][CH3:20])=[O:18])[CH:10]([C:11](I)=[CH:12][CH2:13][CH:14]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CO.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>[CH2:1]([N:8]1[CH2:16][C:15]2([C:17]([O:19][CH3:20])=[O:18])[CH:10]([C:11]([C:32]3[CH:33]=[CH:34][C:29]([Br:28])=[CH:30][CH:31]=3)=[CH:12][CH2:13][CH:14]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(I)=CCC2c1ccccc1
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: Cc1ccccc1
Solvent: CO
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(c1ccc(Br)cc1)=CCC2c1ccccc1
Yield: 72.5 %

Procedure:
By carrying out the reaction as in Stage C of Example 45, but from 1 g of methyl (3aRS,4SR,7aRS)-2-benzyl-7-iodo-4-phenyl-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate in 20 cm3 of toluene, from 120 mg of tetrakis(triphenylphosphine)palladium, from 0.46 g of 4-bromophenylboronic acid in 10 cm3 of methanol and from 15 cm3 of a 2N aqueous sodium carbonate solution at reflux for eighteen hours, 0.77 g (73%) of methyl (3aRS,4SR,7aRS)-2-benzyl-7-(4-bromophenyl)-4-phenyl-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate was obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution was carried out with a mixture of cyclohexane and of ethyl acetate (90/10 by volume), in the form of a white foam, the characteristic of which was as follows:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].Cl[CH2:13][CH:14]1[CH2:16][O:15]1.C[O-].[Na+]>CO>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:13][CH:14]2[CH2:16][O:15]2)=[C:3]([C:9](=[O:11])[CH3:10])[CH:4]=1
Reactant: ClCC1CO1
Reactant: CC(=O)c1cc(C)ccc1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)c1cc(C)ccc1OCC1CO1
Reaction time: 1 h
Yield: 55 %

Procedure:
To a stirred mixture of 20 parts of 1-(2-hydroxy-5-methylphenyl)ethanone, 50.5 parts of (chloromethyl)oxirane and 40 parts of methanol are added dropwise 25 parts of sodium methoxide solution 30%. Upon completion, stirring is continued for 1 hour at room temperature. The reaction mixture is filtered and the filtrate is evaporated. The residue is dissolved in methylbenzene. The latter is washed with water, dried, filtered and evaporated. The residue is distilled, yielding 15 parts (55%) of 1-[5-methyl-2-(oxiranylmethoxy)phenyl]ethanone; bp. 140°-150° C. at 0.3 mm. pressure.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH:7]([N:9]1[C:17]2[C:12](=[C:13]([O:18][CH2:19][C:20]3[S:24][C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)=[N:22][C:21]=3[CH3:35])[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)[CH3:8])(C)(C)C.[OH-].[Na+]>>[CH3:35][C:21]1[N:22]=[C:23]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=2)[S:24][C:20]=1[CH2:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[CH:11]=[CH:10][N:9]2[CH:7]([CH3:8])[C:6]([OH:36])=[O:5]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1cccc2c1ccn2C(C)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1cccc2c1ccn2C(C)C(=O)O

Procedure:
In analogy to the procedure described in example 2 c], [rac]-2-{4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-indol-1-yl}-propionic acid tert-butyl ester was treated with NaOH to obtain [rac]-2-{4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-indol-1-yl}-propionic acid as light yellow gum.