Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([OH:17])[C:11]#[C:12][C:13]([CH3:16])([OH:15])[CH3:14])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:17])[C:11]#[C:12][C:13]([OH:15])([CH3:14])[CH3:16])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(O)C#CC(C)(C)O)cc1Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)C#CC(C)(C)O)cc1Cl
Reaction time: 1 h
Yield: 65.6 %

Procedure:
To a stirred solution of 1-(3-chloro-4-methoxyphenyl)-4-methylpent-2-yne-1,4-diol (0.69 g, 2.716 mmol) in DCM (20 mL) was added DMP (2.36 g, 5.430 mmol) at RT. The reaction mixture was stirred for 1 h and diluted with water (10 mL). The combined organic layers were washed with a saturated NaHCO3 solution and water, dried over Na2SO4, filtered, and then concentrated in vacuo to afford 1-(3-chloro4-methoxyphenyl)-4-hydroxy-4-methylpent-2-yn-1-one (0.45 g, 65%) as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].CS(O[CH:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])(=O)=O.C([O-])(O)=O.[Na+].O>C(#N)C>[CH2:18]([C:2]1([F:1])[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]1[CH3:9])[CH2:17][CH2:16][CH2:15][CH2:19][CH2:20][CH3:21]
Reactant: Cc1cc(N)ccc1F
Reactant: CCCC(CCC)OS(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCCCCCCC1(F)C=CC(N)=CC1C
Yield: 346.4 %

Procedure:
To a solution of 4.10 g (3.28 mmol) of 4-fluoro-3-methylaniline in 30 mL of acetonitrile was added 7.64 g (3.93 mmol) of 4-methanesulfonyloxyheptane, and 3.4 g (4.1 mmol) of NaHCO3 (s). The mixture was stirred at reflux for 24 hours, then poured into 150 mL of H2O and extracted with diethyl ether (2×30 mL). The combined ether layers were back extracted with brine (1×30 mL), dried over MgSO4, filtered, and concentrated to an oil. This was purified via silica gel chromatography, eluting with 97.5:2.5 hexanes: ethyl acetate, to give 2.56 g (35%) of a pale yellow oil.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].N[C:10](N)=[O:11]>>[NH:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH:8][C:10]1=[O:11]
Reactant: NC(N)=O
Reactant: Nc1ccccc1N
Product: O=c1[nH]c2ccccc2[nH]1
Temperature: 170 °C
Yield: 87.6 %

Procedure:
A mixture of o-phenylenediamine (15.0 g) and urea (50.0 g) was heated at a temperature of 170° C. for a period of 45 min. The solid product was washed with water and recrystallised from ethanol to give benzimidazolin-2-one (16.3 g) as colourless crystals, mp>260° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([O:13][CH:14]([F:16])[F:15])[CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[CH3:17][C:18]1([CH3:27])[CH2:23][CH:22]([CH3:24])[C:21](=[O:25])[CH2:20][C:19]1=[O:26].C(#N)C.CC(C)(O)C#N>Cl.C(N(CC)CC)C>[N+:1]([C:4]1[CH:12]=[C:11]([O:13][CH:14]([F:16])[F:15])[CH:10]=[CH:9][C:5]=1[C:6]([CH:20]1[C:19](=[O:26])[C:18]([CH3:17])([CH3:27])[CH2:23][CH:22]([CH3:24])[C:21]1=[O:25])=[O:7])([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc(OC(F)F)cc1[N+](=O)[O-]
Reactant: CC1CC(C)(C)C(=O)CC1=O
Agent: CC(C)(O)C#N
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1CC(C)(C)C(=O)C(C(=O)c2ccc(OC(F)F)cc2[N+](=O)[O-])C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5.03 g of 2-nitro-4-difluoromethoxybenzoyl chloride and 2.57 g of 4,4,6-trimethylcyclohexane-1,3-dione are introduced into 20 ml of acetonitrile, and 4.21 g of triethylamine are added dropwise in such a way that the internal temperature does not exceed 40° C. The mixture is subsequently stirred for 15 minutes at room temperature, 1.29 g of acetone cyanohydrin are added, and stirring is continued for 3 hours at room temperature. The reaction mixture is diluted with 100 ml of ethyl acetates and 50 ml of 1N hydrochloric acid are added. After vigorous shaking, the phases are separated, the organic phases are dried over MgSO4, and the solvent is stripped off under reduced pressure. The oil which remains (7.1 g) is chromatographed on silica gel using ethyl acetate/petroleum ether 1:2 as the eluent. This gives 3.28 g (46% of theory) of 2-(2-nitro-4-difluoromethoxy-benzoyl)-4,4,6-trimethylcyclohexane-1,3-dione of melting point 108°-110° C.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1([CH3:50])[CH2:18][C:17]2[CH:19]=[C:20]([N:23]3[C:28](=[O:29])[C:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]5[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=5)=[CH:33][C:32]=4[F:45])=[C:26]([CH2:46][CH2:47][CH3:48])[N:25]=[C:24]3[CH3:49])[CH:21]=[CH:22][C:16]=2[O:15]1>C(OCC)(=O)C>[CH3:13][C:14]1([CH3:50])[CH2:18][C:17]2[CH:19]=[C:20]([N:23]3[C:28](=[O:29])[C:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=5[C:43]5[NH:3][C:4](=[O:7])[O:5][N:44]=5)=[CH:33][C:32]=4[F:45])=[C:26]([CH2:46][CH2:47][CH3:48])[N:25]=[C:24]3[CH3:49])[CH:21]=[CH:22][C:16]=2[O:15]1
Reactant: O=C([O-])O
Reactant: CCCc1nc(C)n(-c2ccc3c(c2)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc3c(c2)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1F
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
A mixture of hydroxylammonium chloride (0.91 g), sodium hydrogen carbonate (1.4 g) and dimethyl sulfoxide (7 mL) was stirred at 50° C. for 30 min, 4′-{[1-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (0.71 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (7 mL), N,N′-carbonyldiimidazole (0.34 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.31 mL) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.55 g, 70%) as a colorless solid.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[C:11]([CH2:13]C(O)=O)#[N:12].[NH:17]1CCC[CH2:19][CH2:18]1>N1C=CC=CC=1>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([CH:1]([CH2:13][C:11]#[N:12])[CH2:19][C:18]#[N:17])[CH:7]=[CH:6][CH:5]=1
Reactant: C1CCNCC1
Reactant: N#CCC(=O)O
Reactant: COc1cccc(C=O)c1
Solvent: c1ccncc1
Product: COc1cccc(C(CC#N)CC#N)c1

Procedure:
A solution consisting of 25 g of m-anisaldehyde, 47 g of cyanoacetic acid and 3 ml of piperidine in 120 ml of pyridine is placed in a suitable reaction vessel and kept in a 110° oil-bath for 22 hours. Most of the solvent is removed under reduced pressure and the remaining oil is dissolved in about 400 ml of toluene. The solution is washed sequentially with equal volumes of water, 10% hydrochloric acid and saturated sodium bicarbonate. The washed solution is then concentrated under vacuum and the residue is distilled to give 20.7 g of 3-(3-methoxyphenyl)glutaronitrile, bp 146°-153° at 0.01 mm.
Reaction SMILES: [N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Cl[C:25]1[CH:30]=[CH:29][C:28]2=[N:31][N:32]=[C:33]([C:34]([F:37])([F:36])[F:35])[N:27]2[N:26]=1>C(O)C>[F:36][C:34]([F:35])([F:37])[C:33]1[N:27]2[C:28]([CH:29]=[CH:30][C:25]([N:4]3[CH2:5][CH2:6][CH2:7][N:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:2][CH2:3]3)=[N:26]2)=[N:31][N:32]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 25 °C
Yield: 84.5 %

Procedure:
tert-Butyl 1,4-diazepane-1-carboxylate (4.00 g, 20.0 mmol) was added to a mixture of diisopropylethylamine (4.11 mL, 23.7 mmol) and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[3,4-f]pyridazine (4.0 g, 18.2 mmol) in ethanol (80 mL). The mixture was heated under reflux for 6 hours and then allowed to cool to ambient temperature to give a precipitate. The precipitate was collected by filtration, washed with ethanol, and dried under vacuum to afford tert-butyl 4-[3-(trifluoromethyl)-[1,2,4]triazolo[3,4-f]pyridazin-6-yl]-1,4-diazepane-1-carboxylate (5.94 g, 85.4%) as a white solid. 1H NMR (300.132 MHz, DMSO) δ 1.15 (9H, d), 1.72-1.93 (2H, m), 3.27-3.39 (2H, m), 3.50-3.63 (2H, m), 3.66-3.75 (2H, m), 3.83 (2H, t), 7.46-7.56 (1H, m), 8.19-8.31 (1H, m); apparently as a mixture of rotamers; m/z 387 (M+H)+.
Reaction SMILES: [Li+].[OH-].C([O:5][C:6]([C:8]12[CH2:25][CH:24]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH3:26])[C:16](=[O:27])[CH:15]1[CH:11]([CH2:12][CH:13]([O:28][C:29]3[C:38]4[C:33](=[C:34]([CH3:41])[C:35]([O:39][CH3:40])=[CH:36][CH:37]=4)[N:32]=[C:31]([C:42]4[N:43]=[C:44]([CH:47]5[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]5)[S:45][CH:46]=4)[CH:30]=3)[CH2:14]1)[C:10](=[O:53])[NH:9]2)=[O:7])C>CO.C1COCC1.O>[CH:47]1([C:44]2[S:45][CH:46]=[C:42]([C:31]3[CH:30]=[C:29]([O:28][CH:13]4[CH2:12][CH:11]5[CH:15]([C:16](=[O:27])[N:17]([CH3:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[CH:23][CH:24]6[C:8]([C:6]([OH:7])=[O:5])([NH:9][C:10]5=[O:53])[CH2:25]6)[CH2:14]4)[C:38]4[C:33](=[C:34]([CH3:41])[C:35]([O:39][CH3:40])=[CH:36][CH:37]=4)[N:32]=3)[N:43]=2)[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]1
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3cc(-c4csc(C5CCCCC5)n4)nc4c(C)c(OC)ccc34)CC1C(=O)N2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3csc(C4CCCCC4)n3)nc2c1C
Temperature: 50 °C
Reaction time: 19 h
Yield: 95 %

Procedure:
An aqueous solution of LiOH (1M, 5 mL) was added to a solution of 17-[2-(2-cyclo-hexylthiazol-4-yl)-7-methoxy-8-methyl-quinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid ethyl ester (121) in MeOH (10 mL), THF (20 mL) and water (5 mL). The resulting solution was stirred at 50° C. for 19 h. Then, the pH of the reaction mixture was adjusted to 6 with myriatic acid (3M, 1.7 mL). The resulting solution was evaporated on silica and purified by column chromatography (AcOEt/MeOH/AcOH, 74:25:1) to give 273 mg (95%) of the title compound 122 as a white powder: m/z=687 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[C:6]([NH2:10])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.CO.[CH:13](I)([CH3:15])[CH3:14]>C(N(CC)CC)C>[CH:13]([NH:10][C:6]1[C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=[CH:8][CH:7]=1)([CH3:15])[CH3:14]
Reactant: CC(C)I
Reactant: Nc1cccc2c1OCC2
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)Nc1cccc2c1OCC2

Procedure:
To a solution of 15 g. of 2,3-dihydro-7-benzofuranamine in 150 ml. of methanol is added 8.5 ml. of isopropyl iodide and 13.4 ml. of triethylamine. The solution is refluxed for 45 hours and then concentrated in vacuo. The resulting oil is extracted several times with diethyl ether, the ether extracted combined filtered through Celite, and the ether removed in vacuo to obtain an oil of N-isopropyl-2,3-dihydro-7-benzofuranamine.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:15][C:14]=3[CH:23]=2)=[CH:6][CH:5]=1)(=O)[CH3:2].C(O)C.Cl.[NH2:28][OH:29].C(=O)([O-])[O-].[Na+].[Na+]>O.O1CCCC1>[OH:29][N:28]=[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:15][C:14]=3[CH:23]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)=O)cc3)ccc2o1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc2cc(-c3ccc(C(C)=NO)cc3)ccc2o1

Procedure:
A mixture of 6.2 g of 10A, 100 ml of ethanol and 200 ml of tetrahydrofuran was heated to 60°-70° C. A solution of 1.53 g of hydroxylamine hydrochloride and 1.16 g of sodium carbonate in 20 ml of water was added. The mixture was heated for 3 hours at 60°-70° C. The resulting solid was collected, washed with water, then ethanol, and extracted with methylene chloride. The solvent was evaporated from the extract under reduced pressure to give ethyl 5-(4-(1-(hydroxyimino)ethyl)phenyl)-2-benzofurancarboxylate (12A), mp: 220°-222° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([S:9][CH3:10])=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.CC(=O)OCC>CC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:5]([S:9][CH3:10])=[CH:4][N:3]=1
Reactant: CSc1cnc(Cl)nc1Cl
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CSc1cnc(Cl)nc1N1CCOCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
A solution of the 2,4-dichloro-5-(methylthio)pyrimidine (1.16 g, 6 mmole) in acetone (10 ml) at 0° C. containing Na2CO3 (1.1 eq, 6.6 mmole, 0.7 g) was treated dropwise with a solution of morpholine (1.0 eq, 6.6 mmole, 0.6 ml) in acetone (2 ml) and stirred for 1 hr at 0° C. TLC (EA:Hex=1:2, Rf=0.6) showed completion of the reaction to give two products. The acetone was removed in vacuo, the residue was partitioned between water and EA, and the organic layer was dried (MgSO4) and evaporated in vacuo. Column chromatography (EA/Hex=1/6) gave the product (700 mg, 47%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[O:14][CH2:13][CH2:12][O:11]1.[OH:15][C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][CH:29]=1)[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[O:11]1[CH2:12][CH2:13][O:14][CH:10]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:15][C:16]1[CH:17]=[C:18]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])[CH:27]=[CH:28][CH:29]=1
Reactant: O=C(c1ccccc1)c1cccc(O)c1
Reactant: BrCCCCCCCCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccccc1)c1cccc(OCCCCCCCCC2OCCO2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 84.2 %

Procedure:
2-(8-Bromooctyl)-1,3-dioxolane (3.89 g, 14.69 mmol) was added to a mixture of 3-hydroxybenzophenone (3 g, 15.13 mmol) and potassium carbonate (4.17 g, 30.21 mmol) in dimethyl formamide (50 mL). The reaction mixture was stirred at 80° C. for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution, saturated aqueous ammonium chloride solution and dried (sodium sulfate), filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 0-100% ethyl acetate in iso-hexane to afford the title compound (4.73 g, 84%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[C@@H:5]1[O:7][CH2:6]1)[CH3:2].[Cl-].[NH4+].[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:8])[C@H:5]([OH:7])[CH2:6][N:11]=[N+:12]=[N-:13])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)[C@H]1CO1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](O)CN=[N+]=[N-]
Temperature: 75 °C
Yield: 69.1 %

Procedure:
Ethyl-(2R)-2,3-epoxyproprionate (0.5 g, 4.3 mmol), ammonium chloride (0.253 g, 4.73 mmol), and sodium azide (0.336 g, 5.17 mmol) were combined in DMF (8 mL), and the mixture was heated at 75° C. for 14 hours. The reaction was cooled to room temperature, and was partitioned between water and ether/hexanes (1:1 v/v). The phases were separated, and the organic phase was washed once each with water, brine, dried over MgSO4, filtered, and concentrated to an oil, which was purified by flash chromatography (silica gel/hexanes:10% ethyl acetate) to give (R)-ethyl-3-azido-2-hydroxypropionate as a clear oil (0.47 g, 2.97 mmol, 69% yield). Rf 0.27 (hexanes: 10% EtOAc, v/v, p-anisaldehyde); MS m/e [M+Na]+ calcd 182.1. found 182.0.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[C:8]([CH3:10])[CH:9]=1)=[O:4].O.N>[Zn].C(O)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH3:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(C)c(Br)s1
Agent: N
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc(C)cs1
Yield: 90.6 %

Procedure:
5-Bromo-4-methyl-2-thiophenecarboxylic acid (3.33 g) was dissolved in dimethylformamide (50 ml), and potassium carbonate (4.0 g) and iodomethane (4.0 ml) were added. The mixture was stirred at room temperature for 2 hours, diluted with ethyl acetate, washed with 1N hydrochloric acid, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-bromo-4-methyl-2-thiophenecarboxylic acid methyl ester (3.47 g). A mixture of 5-bromo-4-methyl-2-thiophenecarboxylic acid methyl ester (2.36 g), zinc powder (1.65 g), acetic acid (10 ml) and water (10 ml) was stirred under reflux for 3 hours. Zinc powder (1 g) and acetic acid (10 ml) were further added. The mixture was stirred under reflux for 1 day, cooled, poured into concentrated aqueous ammonia and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-methyl-2-thiophenecarboxylic acid methyl ester (1.42 g). 4-Methyl-2-thiophenecarboxylic acid methyl ester (1.42 g) was dissolved in a mixture of methanol (10 ml) and tetrahydrofuran (30 ml), and 1N aqueous sodium hydroxide (15 ml) was added. The mixture was stirred at room temperature for 1 hour and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-methyl-2-thiophenecarboxylic acid (1.16 g).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5](O)=O)O.C1(C[O:17][CH2:18][CH2:19][C@@H:20]([OH:23])[CH2:21]O)C=CC=CC=1.[C:24]1(COCC[C@@H]2CO2)C=CC=CC=1.OC(CCOCC1C=CC=CC=1)CCCC=C>>[OH:23][C@H:20]([CH2:19][CH2:18][OH:17])[CH2:21][CH2:5][CH2:4][CH2:2][C:1]([O:9][CH3:24])=[O:8]
Reactant: O=C(O)CC(O)C(=O)O
Reactant: c1ccc(COCC[C@@H]2CO2)cc1
Reactant: OC[C@H](O)CCOCc1ccccc1
Agent: C=CCCCC(O)CCOCc1ccccc1
Product: COC(=O)CCCC[C@H](O)CCO

Procedure:
Chem. Soc. Perkin Trans. I (1988) 9 describes the preparation thereof from the malic acid derivative (S)-4-phenylmethoxy-1,2-butanediol by a multistage reaction sequence with the intermediates (R)-4-phenylmethoxy-1,2-butanediol, (R)-(2-phenylmethoxyethyl)oxirane, 6-hydroxy-8-(phenylmethoxy)-l-octene to give methyl (6S)-6,8-dihydroxyoctanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH:12]=[C:11](Br)[CH:10]=[C:9]([C:14]([O:16][CH3:17])=[O:15])[C:8]2=[O:18])=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:26]3[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)[CH:10]=[C:9]([C:14]([O:16][CH3:17])=[O:15])[C:8]2=[O:18])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(Br)cn(Cc2ccc(Cl)cc2)c1=O
Reactant: COc1ccc(B(O)O)cc1
Product: COC(=O)c1cc(-c2ccc(OC)cc2)cn(Cc2ccc(Cl)cc2)c1=O
Yield: 82 %

Procedure:
According to Scheme 3 Method A: The title compound was prepared from methyl 1-(4-chlorobenzyl)-5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylate (1 eq, 7.00 mmol, 2.50 g) and 4-methoxyphenyl boronic acid (1.5 eq, 11.0 mmol, 1.60 g) according to the procedure described for Example 1 Step 3. Reaction conditions: 4 hours at 80° C. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 80 g SiO2) using CH2Cl2/AcOEt 80/20 and by recrystallization with Et2O/pentane to afford methyl 1-(4-chlorobenzyl)-5-(4-methoxyphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (5.74 mmol, 2.22 g, 82%) as a beige solid.
Reaction SMILES: FC1C=CC=CC=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]3)=[CH:13][CH:12]=1.NC1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(OC)=O)C3)=CC=1.[F:61][C:62]1[CH:67]=[CH:66][C:65](N=C=S)=[CH:64][CH:63]=1>>[F:61][C:62]1[CH:63]=[C:64]([NH:8][C:9](=[S:35])[NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:33])[CH3:34])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]4)=[CH:15][CH:16]=2)[CH:65]=[CH:66][CH:67]=1
Reactant: Fc1ccc(N=C=S)cc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)ccc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4cccc(F)c4)cc3)ccc2C1=O

Procedure:
The compound of example 276 was prepared analogous to compound of example 256 by reaction of compound of example 223 with 4-fluorophenyl isothiocyanate. The compound of example 276 was used directly without isolation, for the preparation of compound of example 277.
Reaction SMILES: Br[C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[N:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1>COCCOC>[F:31][C:28]1[CH:27]=[CH:26][C:25]([N:8]2[CH2:9][CH2:10][C:11]3[C:16](=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:12]=3)[CH:7]2[CH2:6][C:5]2[CH:4]=[CH:3][C:2]([C:45]3[CH:46]=[CH:47][N:42]=[CH:43][CH:44]=3)=[CH:33][CH:32]=2)=[CH:30][CH:29]=1
Reactant: OB(O)c1ccncc1
Reactant: Fc1ccc(N2CCc3cc(OCc4ccccc4)ccc3C2Cc2ccc(Br)cc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Fc1ccc(N2CCc3cc(OCc4ccccc4)ccc3C2Cc2ccc(-c3ccncc3)cc2)cc1
Temperature: 90 °C
Yield: 51.9 %

Procedure:
To a solution of 1-(4-bromobenzyl)-6-phenylmethoxy-2-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (500 mg, 1 mmol) in ethylene glycol dimethyl ether (15 mL) was added potassium phosphate (2.12 g, 10 mmol) and pyridine-4-boronic acid (185 mg, 1.5 mmol). The reaction mixture was heated to 90° C. for 18 hours under nitrogen. The resulting mixture was concentrated and water added and extracted with ethyl acetate. The organic layer was dried using sodium sulfate, filtered and concentrated to give a crude black oil. The oil was purified by column chromatography (SiO2, 40% ethyl acetate/hexanes) to provide the title compound (260 mg, 50% yield): ES-MS (m/z) 501 [M+H]+, 1H NMR (CDCl3) δ 8.64 (d, 2H), 7.49 (m, 4H), 7.38 (m, 5H), 7.13 (d, 2H), 6.92 (t, 2H), 6.78 (m, 3H), 6.72 (s, 2H), 5.04 (s, 2H), 4.79 (t, 1H), 3.59 (m, 1H), 3.49 (m, 2H), 3.22 (m, 1H), 3.01 (m, 1H), 2.71 (t, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][C:17]=3[Br:26])[CH2:10]2)=[C:6]([CH2:29][CH2:30][CH3:31])[C:5]=1[OH:32])(=[O:3])[CH3:2].[C:33](C1C=CC(O[C@@H]2CCC[C@H](OS(C)(=O)=O)C2)=C(CCC)C=1O)(=O)C>>[C:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:33])=[O:24])=[CH:18][C:17]=3[Br:26])[CH2:10]2)=[C:6]([CH2:29][CH2:30][CH3:31])[C:5]=1[OH:32])(=[O:3])[CH3:2]
Reactant: CCCc1c(O[C@@H]2CCC[C@H](OS(C)(=O)=O)C2)ccc(C(C)=O)c1O
Reactant: CCCc1c(O[C@H]2CCC[C@H](Oc3ccc(CC(=O)O)cc3Br)C2)ccc(C(C)=O)c1O
Product: CCCc1c(O[C@@H]2CCC[C@H](Oc3ccc(CC(=O)OC)cc3Br)C2)ccc(C(C)=O)c1O

Procedure:
By following Step E of Example 8, but substituting the title compound of Step D of Example 8 for the title compound of Step C of Example 8, the title compound of this step was obtained as an oil.