Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[CH2:7]([O:14][C:15]1[CH:30]=[C:19]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[C:18]([NH2:31])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C(C)=CC=CC=1C.Br[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]>CN(C=O)C.C(OCC)(=O)C>[C:42]([CH2:41][NH:31][C:18]1[C:19](=[CH:30][C:15]([O:14][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:16][CH:17]=1)[C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Nc1ccc(OCc2ccccc2)cc1C(=O)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)OC(=O)CNc1ccc(OCc2ccccc2)cc1C(=O)OCc1ccccc1
Yield: 76.8 %

Procedure:
A solution of saturated sodium bicarbonate (1.0 liter) was placed in a 4 liter Ehrlenmeyer flask along with 1.0 liter of ethyl acetate. The biphasic mixture was stirred at a rate that insured mixing and 5-benzyloxyanthranilic acid, benzyl ester, hydrochloride (50.0 g, 135 mmol) was added portionwise to the stirred mixture. After addition was complete, the mixture was stirred an additional 15 minutes. The layers were partitioned in a separatory funnel and the aqueous layer was extracted with ethyl acetate (500 mL). The combined organics were dried over MgSO4, filtered, and concentrated in vacuo to yield the free base, which was dissolved in anhydrous DMF (700 mL) under an atmosphere of argon. 2,6-lutidine (20.0 mL, 172 mmol) was added to the solution followed by the addition of t-butyl bromoacetate (29.0 mL, 196 mmol). The reaction mixture was stirred at 70° C. under an atmosphere of argon for 48 hours. The DMF was removed on a rotary evaporator under high vacuum and the crude product residue was partitioned between ethyl acetate (1.0 liter) and water (500 mL). The organic layer was washed with saturated NaCl (250 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to yield crude product as a light brown solid. The product was recrystallized from 7% ethyl acetate/hexanes to yield N-(carbo-t-butoxymethyl)-5-benzyloxyanthranilic acid, benzyl ester (46.4 g, 79% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@H:10]([CH2:24][C:25](O)=[O:26])[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:35]1[C:40]([NH2:41])=[CH:39][CH:38]=[C:37]([NH2:42])[CH:36]=1.O>CN(C)C=O>[NH2:41][C:40]1[CH:35]=[CH:36][C:37]([NH:42][C:25](=[O:26])[CH2:24][C@@H:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]23)=[CH:38][CH:39]=1
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)O)c1nnc(C)n1-2
Reactant: Nc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)Nc1ccc(N)cc1)c1nnc(C)n1-2
Temperature: 25 °C
Reaction time: 12 h
Yield: 15.2 %

Procedure:
(S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetic acid (3.0 g), triethylamine (1.56 ml) and p-phenylenediamine (0.97 g) are dissolved in dimethylformamide (30 ml). Benzotriazol-1-yl-oxy-tris(dimethyl)phosphonium hexafluorophosphate (3.6 g) is added, and the mixture is stirred at room temperature for 12 hours. After the completion of the reaction, water (200 ml) is added, and the mixture is extracted with ethyl acetate. The extract is washed with saturated brine and dried over anhydrous magnesium sulfate. After the solvent is distilled away under reduced pressure, the residue is subjected to silica gel column chromatography and obtained crystals are recrystallized from toluene to give 0.56 g of (S)-N-(4-aminophenyl)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4, 3-a][1,4]diazepine-6-acetamide, melting point 169°-173° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[N+:5]([O-])=[CH:6][CH:7]=1.C[CH2:16][N:17](CC)CC.C[Si](C#N)(C)C>CC#N.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:16]#[N:17])[N:5]=[C:4]([C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH:3]=1
Reactant: CCN(CC)CC
Reactant: CC(C)OC(=O)c1cc(Cl)cc[n+]1[O-]
Agent: C[Si](C)(C)C#N
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)OC(=O)c1cc(Cl)cc(C#N)n1
Yield: 67.3 %

Procedure:
A solution of 200 mg (0.86 mmol) of isopropyl 4-chloropyridine-2-carboxylate 1-oxide (Intermediate 223), 0.14 ml (1 mmol) Et3N and 0.36 ml (2.7 mmol) of trimethylsilylcyanide in 3 ml CH3CN was heated at 90° C. overnight. The solution was diluted with EtOAc and washed with water and brine. Drying (MgSO4) and removal of solvent gave an oil that was purified by chromatography on silica gel (100% CH2Cl2 followed by gradient elution to 10% EtOAc in CH2Cl2) to afford 130 mg of product as a white solid. MS (ES) (MH+): 224 for C19H9ClN2O2; NMR (d6-DMSO): 1.35 (d, 6H), 5.2 (septet, 1H), 8.4 (s, 1H), 8.6 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.Cl[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[N:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1
Reactant: Clc1ccccn1
Reactant: OC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: OC1CCN(c2ccccn2)CC1
Yield: 27.3 %

Procedure:
A solution of piperidin-4-ol (100 mg, 0.99 mmol), desired 2-chloropyridine (0.99 mmol, 1.0 equiv.), and DIPEA (345 μL, 1.98 mmol) in isopropanol (1.5 mL) was heated by microwave irradiation at 160° C. for 2.5 h. The reaction was purified directly by silica gel chromatography to give the desired 3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ol (using 5-bromo-2-chloropyridine, 5′-bromo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ol was isolated in 27% yield, 69.1 mg, 0.27 mmol; using 5-trifluoromethyl-2-chloropyridine, 5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ol was isolated in 62% yield, 150.1 mg, 0.61 mmol).
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:3]=1[C:4](N(OC)C)=[O:5].[CH3:24][Mg]Br>O1CCCC1>[F:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C:3]=1[C:4](=[O:5])[CH3:24]
Reactant: C[Mg]Br
Reactant: COc1ccc(COc2cccc(F)c2C(=O)N(C)OC)cc1
Solvent: C1CCOC1
Product: COc1ccc(COc2cccc(F)c2C(C)=O)cc1
Temperature: 25 °C
Yield: 20 %

Procedure:
To a cold (0° C.) solution of 2-fluoro-N-methoxy-6-[(4-methoxybenzyl)oxy]-N-methylbenzamide (6.926 g, 21.70 mmol) in tetrahydrofuran (10 mL) was added 1N methyl magnesium bromide in tetrahydrofuran (43.40 mL, 43.40 mmol). The reaction mixture was stirred at reflux for 4 hrs. After cooled to room temperature, the reaction mixture was quenched with saturated aqueous NaHCO3 solution, and extracted with ethyl acetate. The separated organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (hexane:ethyl acetate, 3/1) to give 1-{2-fluoro-6-[(4-methoxybenzyl)oxy]phenyl}ethanone as a pale yellow solid (1.21 g, yield; 20%).
Reaction SMILES: C([C:4]1([O:26][C@H:25]([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:6]1[F:36])[OH:5])(=O)C.C(O)(=O)C.NN>CN(C=O)C.ClCCl>[F:36][C@@H:6]1[C@@H:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@H:16]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C@@H:25]([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:26][CH:4]1[OH:5]
Reactant: CC(=O)C1(O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1F
Agent: NN
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
Acetyl-2-deoxy-2-fluoro-3,4,6-tri-O-benzyl-glucopyranose (750 mg) was dissolved in anhydrous DMF (7.5 mL). Hydrazine acetate (300 mg) was added and the reaction mixture was stirred for 3 hours at room temperature until most of the starting material was converted into product. The solution was diluted with dichloromethane (150 mL) and the organic layer was washed with water (3×150 mL), dried over sodium sulfate, filtered and evaporated. Chromatography of the material on silica gel using hexane-ethyl acetate (5:1) as eluent provided 2-deoxy-2-fluoro-3,4,6-tri-O-benzyl glucopyranose (500 mg).
Reaction SMILES: [Br-].[O:2]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Zn+])=[CH:6][CH:5]=1)[CH3:3].I[C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([C:20]2[N:21]=[C:22]([NH:25][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[S:23][CH:24]=2)=[C:15]([CH3:34])[CH:14]=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:3][O:2][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][C:13]2[CH:14]=[C:15]([CH3:34])[C:16]([C:20]3[N:21]=[C:22]([NH:25][C:26](=[O:33])[C:27]4[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=4)[S:23][CH:24]=3)=[C:17]([CH3:19])[CH:18]=2)=[CH:6][CH:5]=1
Reactant: Cc1cc(I)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Reactant: COc1ccc(C[Zn+])cc1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(Cc2cc(C)c(-c3csc(NC(=O)c4ccncc4)n3)c(C)c2)cc1

Procedure:
A THF solution of 4-methoxylbenzylzinc(II) bromide (4.0 mL, 2.0 mmol) was added to a degassed solution of N-(4-(4-iodo-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide (435 mg, 1.0 mmol) and tetrakistriphenylphosphine palladium (57.8 mg, 0.10 mmol) in THF (5.0 mL). The reaction mixture was heated at reflux for 16 h under N2 then poured into saturated aqueous NaHCO3. The mixture was extracted with ethyl acetate, washed with brine, dried MgSO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give N-(4-(4-(4-methoxybenzyl)-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide: 1H NMR (500 MHz, CDCl3) δ 8.69 (d, J=5.2 Hz, 2 H), 7.66 (d, J=4.9 Hz, 2 H), 7.11 (d, J=−8.4 Hz, 2 H), 6.86 (d, 2 H), 6.80 (s, 1 H), 6.75 (s, 2 H), 3.80 (s, 2 H), 3.78 (s, 2 H), 1.98 (s, 6 H); ESI-MS: m/z 399.9 (M+H)+.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=2[O:2]1.[CH2:13]([NH2:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19].[OH-:21].[K+]>C(Cl)CCl>[CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([C:6]([NH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][NH:20][C:6](=[O:7])[C:5]3[CH:9]=[CH:10][C:11]4[O:21][CH2:1][O:2][C:3]=4[CH:4]=3)=[O:7])=[CH:4][C:3]=2[O:2]1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: NCCCCCCN
Reactant: [OH-]
Agent: [K+]
Solvent: ClCCCl
Product: O=C(NCCCCCCNC(=O)c1ccc2c(c1)OCO2)c1ccc2c(c1)OCO2

Procedure:
m.p. 183°-185° C., 19.4 g., was prepared as in Example 1 using 3,4-methylenedioxybenzoyl chloride (from 30 g. of 3,4-methylenedioxybenzoic acid as in Example 6) in 100 ml. of ethylene dichloride, 9.3 g. of 1,6-hexanediamine, 200 ml. of 10% aqueous potassium hydroxide solution, 500 ml. of ethylene dichloride and recrystallization from ethanol using decolorizing charcoal.
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[NH2:17][C:18]1[C:19]([Cl:33])=[C:20]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:21][NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25]>O1CCOCC1>[Cl:33][C:19]1[C:18]([N:17]=[C:1]=[S:2])=[C:31]([Cl:32])[CH:30]=[CH:29][C:20]=1[CH2:21][NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N)c1Cl
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,1′-Thiocarbonyldi-2-pyridone (4.87 g, 21 mmol) is added to a mixture of N-(3-amino-2,4-dichloro-benzyl)-2,2-dimethyl-propionamide (5.50 g, 20 mmol) and dioxane (200 mL) and stirred at rt for 2 h and at reflux for 8 h. The mixture is concentrated, diluted with DCM and filtered over silica gel. The filtrate is concentrated to give the sub-title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[C:18](OCC)(OCC)(OCC)[CH3:19]>>[CH3:18][C:19]1[NH:17][C:15](=[O:16])[C:3]2[N:4]=[C:5]([C:8]3[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=3)[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: NC(=O)c1nc(-c2ccc(F)cc2)ccc1N
Product: Cc1nc2ccc(-c3ccc(F)cc3)nc2c(=O)[nH]1
Temperature: 25 °C
Yield: 70 %

Procedure:
A suspension of 3-amino-6-(4-fluorophenyl)-pyridine-2-carboxylic acid amide (0.46 g, 2.0 mmol) in triethyl orthoacetate (10 ml) was heated under reflux for 3 hours. After cooling to room temperature, the precipitate was collected by filtration and washed with diethyl ether, yielded the title compound as a white solid (360 mg, yield 70%) which was characterised as follows: MS (m/z): 256 ([M+H]+, 100).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[N:16]=[C:15]([N:17]3[CH2:20][CH2:19][CH2:18]3)[CH:14]=[C:13]([NH:21][C:22]3[NH:23][N:24]=[C:25]([CH3:27])[CH:26]=3)[N:12]=2)=[CH:6][CH:5]=1.[OH-].[Na+].O1CCCC1>CO>[N:17]1([C:15]2[CH:14]=[C:13]([NH:21][C:22]3[NH:23][N:24]=[C:25]([CH3:27])[CH:26]=3)[N:12]=[C:11]([S:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:28])=[O:2])=[CH:5][CH:6]=3)[N:16]=2)[CH2:18][CH2:19][CH2:20]1
Reactant: COC(=O)c1ccc(Sc2nc(Nc3cc(C)n[nH]3)cc(N3CCC3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Nc2cc(N3CCC3)nc(Sc3ccc(C(=O)O)cc3)n2)[nH]n1
Temperature: 25 °C
Yield: 109.8 %

Procedure:
A 50 ml round bottom flask equipped with a condenser was charged with 4-[4-azetidin-1-yl-6-(5-methyl-2H-pyrazol-3-ylamino)-pyrimidin-2-ylsulfanyl]-benzoic acid methyl ester (800 mg, 2.0 mmol), 2M sodium hydroxide aqueous solution (5 ml), tetrahydrofuran (30 ml) and methanol (5 ml). The reaction mixture was heated to reflux for one hour. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The solid residue was taken up in methanol (30 ml) and concentrated hydrochloric acid (1 ml). The solvent was then removed under reduced pressure to give the title compound (0.84 g, 100%) as a mono HCl salt. 1H NMR (DMSO) 2.05-2.10 (3H, s), 2.20-2.30 (2H, m), 3.80-3.85 (2H, t), 4.05-4.10 (2H, s), 7.40-7.45 (2H, d), 7.85-7.90 (2H, d). MS (ES+): 383
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[ClH:11].Cl.[Cl:13][C:14]1[CH:30]=[CH:29][C:17]([CH2:18][N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][SH:28])[CH2:21][CH2:20]2)=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:13].[ClH:11].[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[SH:28][CH2:27][CH2:26][CH2:25][N:22]2[CH2:23][CH2:24][N:19]([CH2:18][C:17]3[CH:16]=[CH:15][C:14]([Cl:13])=[CH:30][CH:29]=3)[CH2:20][CH2:21]2)[OH:10])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: SCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OC(Nc1ccc(F)cc1)=[SH]CCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 92.3 %

Procedure:
The procedure described in Example 2 was followed, using 0.8 g of 4-fluorophenyl isocyanate, 2.2 g of 3-[4-(4-chlorobenzyl)piperazin-1-yl]propanethiol dihydrochloride, 0.6 g of triethylamine and 25 ml of methylene chloride, to give 1.41 g (47% of theory) of N-(4-fluorophenyl)-S-{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 250°-252° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1ccc(F)c([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 70.5 %

Procedure:
A suspension of 4-fluorophenylacetic acid (10.0 g, 64.9 mmol) in concentrated sulfuric acid (100 ml) was cooled to 0° C. Concentrated nitric acid (4.5 ml, 65 mmol) was added drop-wise, keeping the temperature at 0-5° C. At the end of the addition the mixture was poured into ice-water (400 ml). The precipitate was filtered off, washed thoroughly with water and dried with suction to yield 1i (9.11 g,70%).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:17]#[CH:18])[CH:7]=[C:8]3[C:13]=2[C:12](=[O:14])[CH2:11][CH2:10][C:9]3([CH3:16])[CH3:15])[CH2:3][CH2:2]1.[CH2:19]([O:21][C:22](=[O:32])/[CH:23]=[CH:24]/[C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=1)[CH3:20]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[CH2:19]([O:21][C:22](=[O:32])[CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][C:28]([C:18]#[C:17][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[C:13]3[C:12](=[O:14])[CH2:11][CH2:10][C:9]([CH3:15])([CH3:16])[C:8]=3[CH:7]=2)=[CH:27][CH:26]=1)[CH3:20]
Reactant: CCOC(=O)/C=C/c1ccc(I)cc1
Reactant: C#Cc1cc(C2CC2)c2c(c1)C(C)(C)CCC2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CCC3=O)cc1

Procedure:
Following General Procedure B and using 8-cyclopropyl-4,4-dimethyl-6-ethynyl-1-tetralone (Intermediate 160, 0.1 g, 0.42 mmol), (E)-3 (4-iodo-phenyl) acrylic acid ethyl ester (0.13 g 0.42 mmol), triethyl amine (1 mL), copper(I)iodide (0.02 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.070 g, 0.1 mmol) followed by flash column chromatography over silica gel (230–400 mesh), the title compound was obtained (0.12 g, 69%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:8]1[C:24]2[C:16]3[C:17]4[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=4[O:19][C:15]=3[C:14](B(O)O)=[CH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[C:2]1([C:14]2[C:15]3[O:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[C:16]=3[C:24]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cc2ccccc2c2c1oc1ccccc12
Reactant: Brc1ccccc1
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: CCO
Solvent: Cc1ccccc1
Product: c1ccc(-c2cc3ccccc3c3c2oc2ccccc23)cc1
Yield: 56 %

Procedure:
Into a 200 mL three-neck flask were placed 0.90 g (5.7 mmol) of bromobenzene and 1.5 g (5.7 mol) of benzo[b]naphtho[1,2-d]furan-6-boronic acid, and the air in the flask was replaced with nitrogen. To this mixture were added 20 mL of toluene, 10 mL of ethanol, and 6.0 mL of an aqueous solution of sodium carbonate (2.0 mol/L). While the pressure was reduced, this mixture was stirred to be degassed. To this mixture was added 0.33 g (0.28 mmol) of tetrakis(triphenylphosphine)palladium(0), and the mixture was stirred at 80° C. for 2 hours under a nitrogen stream. After that, the aqueous layer of this mixture was subjected to extraction with toluene, and the obtained solution of the extract and the organic layer were combined and washed with saturated brine. The organic layer was dried with magnesium sulfate, and this mixture was gravity-filtered. An oily substance obtained by concentration of the obtained filtrate was purified by silica gel column chromatography (a developing solvent in which the ratio of hexane to toluene was 19:1) to give a white solid. The obtained solid was recrystallized with a mixed solvent of toluene and hexane, so that 0.95 g of white needle-like crystals of the object of the synthesis were obtained in 56% yield. The reaction scheme is illustrated in (R-1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:17](Cl)(=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>ClCCl.[Cl-].[Na+].O>[C:17]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:23]
Reactant: c1ccc2c(c1)CCN2
Reactant: CCOC(=O)C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C(=O)N1CCc2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 108.6 %

Procedure:
To a solution of indoline (2.0 g, 16.8 mmol) and triethylamine (5 mL) in dichloromethane (30 mL) was added slowly ethyl chlorooxalate (2.3 mL, 20.1 mmol) at 0° C. The mixture was stirred for 10 min at 0° C. and then for 1 h at room temperature. Brine was added and organic layer was separated. The organic layer was washed with diluted aqueous hydrochloric acid and successively brine, dried over magnesium sulfate, and concentrated to give 4.0 g of N-ethoxalylindoline (100%): 1H NMR (270 MHz, CDCl3) δ8.18 (dd, 1H, J=8, 1 Hz), 7.22 (m, 2H), 7.10 (dd, 1H, J=8, 1 Hz), 4.38 (q, 2H, J=7 Hz), 4.22 (t, 2H, J=8 Hz), 3.20 (t, 2H, J=8 Hz), 1.40 (t, 3H, J=7 Hz).
Reaction SMILES: C(C1C=C([C:10]2=[C:11]([CH:37]=[CH:38][C:39]3[C:47]([CH3:49])([CH3:48])[C:46]4[C:41](=[CH:42][CH:43]=[C:44]([S:50]([O-:53])(=[O:52])=[O:51])[CH:45]=4)[N+:40]=3[CH2:54][CH2:55][CH2:56][CH2:57][S:58]([O-:61])(=[O:60])=[O:59])[CH2:12][CH2:13]/[C:14]/2=[CH:15]\[CH:16]=[C:17]2/[C:18]([CH3:36])([CH3:35])[C:19]3[C:20](=[N:34]/2)[N:21]([CH2:26][CH2:27][CH2:28][CH2:29][S:30]([O-:33])(=[O:32])=[O:31])[CH:22]=[C:23]([Cl:25])[CH:24]=3)C=CC=1)(O)=O.[Na+:62].[Na+].B([C:67]1[CH:68]=[C:69]([CH2:73][CH2:74][CH2:75][C:76]([OH:78])=[O:77])[CH:70]=[CH:71][CH:72]=1)(O)O>>[C:76]([CH2:75][CH2:74][CH2:73][C:69]1[CH:68]=[C:67]([C:10]2=[C:11]([CH:37]=[CH:38][C:39]3[C:47]([CH3:49])([CH3:48])[C:46]4[C:41](=[CH:42][CH:43]=[C:44]([S:50]([O-:53])(=[O:52])=[O:51])[CH:45]=4)[N+:40]=3[CH2:54][CH2:55][CH2:56][CH2:57][S:58]([O-:61])(=[O:60])=[O:59])[CH2:12][CH2:13]/[C:14]/2=[CH:15]\[CH:16]=[C:17]2/[C:18]([CH3:35])([CH3:36])[C:19]3[C:20](=[N:34]/2)[N:21]([CH2:26][CH2:27][CH2:28][CH2:29][S:30]([O-:33])(=[O:32])=[O:31])[CH:22]=[C:23]([Cl:25])[CH:24]=3)[CH:72]=[CH:71][CH:70]=1)([OH:78])=[O:77].[Na+:62].[Na+:62]
Reactant: O=C(O)CCCc1cccc(B(O)O)c1
Reactant: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C1\CCC(C=CC2=[N+](CCCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)=C1c1cccc(C(=O)O)c1
Agent: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C1\CCC(/C=C/C2=[N+](CCCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)=C1c1cccc(C(=O)O)c1
Agent: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C1\CCC(/C=C/C2=[N+](CCCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)=C1c1cccc(CCCC(=O)O)c1
Agent: [Na+]
Product: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C1\CCC(C=CC2=[N+](CCCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)=C1c1cccc(CCCC(=O)O)c1

Procedure:
Compound 41 is prepared analogously to compound 40 (Example 51), except with 4-(3-boronophenyl)butanoic acid as a starting material.