Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17]C(=O)OC(C)(C)C)=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([Br:25])=[CH:4][N:3]=1>C(O)(C(F)(F)F)=O.ClCCl>[NH2:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([Br:25])[C:6]=3[S:10][CH:9]=2)=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2csc3c(Br)cnc(N)c23)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(-c2csc3c(Br)cnc(N)c23)cc1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
A solution of Example 76B (0.5 g, 1.1 mmol) in TFA (4 mL) and dichloromethane (5 mL) was stirred at 0° C. for 5 minutes, warmed to room temperature for 2 hours, then concentrated. The residue was dissolved in dichloromethane, washed with brine, dried (Na2SO4), filtered, and concentrated to provide 0.332 g of the desired product. MS (ESI(+)) m/e 321 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:19][CH2:18][C:13]3([O:17][CH2:16][CH2:15][O:14]3)[CH2:12][CH:11]=2)=[C:6]([F:20])[C:5]=1[F:21])[CH3:2].C([OH:24])C.[OH-].[Na+].OO>C1COCC1.O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:19][CH2:18][C:13]3([O:14][CH2:15][CH2:16][O:17]3)[CH2:12][CH:11]2[OH:24])=[C:6]([F:20])[C:5]=1[F:21])[CH3:2]
Reactant: CCOc1ccc(C2=CCC3(CC2)OCCO3)c(F)c1F
Reactant: CCO
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc(C2CCC3(CC2O)OCCO3)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1400 ml (1.40 mol) of borane/THF complex (1 M solution) are added at −7° C. to a solution of 320.0 g (1.08 mol) of 8-(4-ethoxy-2,3-difluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene in 3000 ml of THF, and the reaction mixture is stirred at room temperature for 3 h. 262 ml (4.50 mol) of ethanol, 650 ml (2.6 mol) of aqueous sodium hydroxide solution (4 M) and 360 ml (4.11 mol) of aqueous hydrogen peroxide soln. (35%) are added successively to the batch, during which the internal temperature does not exceed 47° C. (ice bath). When the addition is complete, the mixture is refluxed for 2 h, and the solution is cooled, added to water and stirred vigorously. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with sat. sodium chloride solution and dried using sodium sulfate. The solution is concentrated to dryness, and the crude product (336 g of yellow oil) is purified by column chromatography (SiO2, dichloromethane: MTBE=8:2), giving 8-(4-ethoxy-2,3-difluorophenyl)-1,4-dioxaspiro[4.5]decan-7-ol as pale-yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]2[C:5]([CH:6]([CH2:16][C:17]([OH:19])=[O:18])[CH2:7][C:8]32[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)=[CH:4][CH:3]=1.Cl[C:21]([O:23][CH:24]1[CH:31]2[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:33][CH:25]1[CH2:26]3)[CH2:30]2)=[O:22]>>[CH3:1][C:2]1[CH:15]=[C:14]2[C:5]([CH:6]([CH2:16][C:17]([OH:19])=[O:18])[CH2:7][C:8]32[CH2:9][CH2:10][N:11]([C:21]([O:23][CH:24]2[CH:25]4[CH2:33][CH:29]5[CH2:28][CH:27]([CH2:32][CH:31]2[CH2:30]5)[CH2:26]4)=[O:22])[CH2:12][CH2:13]3)=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(c1)C1(CCNCC1)CC2CC(=O)O
Reactant: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Product: Cc1ccc2c(c1)C1(CCN(C(=O)OC3C4CC5CC(C4)CC3C5)CC1)CC2CC(=O)O

Procedure:
The title compound was prepared from 2-(6-methyl-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid and 2-adamantyl chloroformate following a procedure analogous to that described in Example 57. LC-MS Method 1 tR=2.24 min, m/z=438; 1H NMR (CDCl3) δ=7.06 (q, 2H), 6.97 (s, 1H), 4.88 (s, 1H), 4.20 (t, 2H), 3.60 (m, 1H), 3.13-2.94 (m, 3H), 2.64 (dd, 1H), 2.48 (dd, 1H), 2.35 (s, 3H).
Reaction SMILES: [CH:1]([NH:4][CH:5]=[NH:6])([CH3:3])[CH3:2].Br[C:8](=[CH:12]OC)[C:9](=[O:11])[CH3:10].C(N(CC)CC)C.S(=O)(=O)(O)O>C(O)(C)C>[C:9]([C:8]1[N:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=[N:6][CH:12]=1)(=[O:11])[CH3:10]
Reactant: COC=C(Br)C(C)=O
Reactant: CC(C)NC=N
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(=O)c1cncn1C(C)C
Temperature: 8 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
In a 300 mL-volume glass vessel equipped with a stirrer, a thermometer and a dropping funnel, the isopropyl alcohol solution containing 13.9 g (0.162 mol) of N-isopropylformamidine (which was prepared in Reference Example 4), 19.3 g (0.108 mol) of 3-bromo-4-methoxy-3-buten-2-one and 16.4 g (0.162 mol) of triethylamine were placed. The mixture was heated to 8° C. under stirring for 8 hours for carrying out reaction. After the reaction was complete, 80 mL of sulfuric acid (2 mol/L) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The concentrate was washed with methyl isobutyl ketone, and the aqueous portion was taken out. The aqueous portion was made basic by adding an aqueous 48% sodium hydroxide, while the mixture was kept at a temperature of not higher than 40° C. The aqueous basic portion was subjected to extraction with methyl isobutyl ketone, and the extracted portion was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluant: ethyl acetate) to give 3.28 g (yield: 20%) of 5-acetyl-1-isopropylimidazole as pale yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:19][CH2:18][C:13]3(OCC[O:14]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C([O-])(O)=O.[Na+]>S(=O)(=O)(O)O.C1COCC1.O>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:19][CH2:18][C:13](=[O:14])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(N2CCC(=O)CC2)cc1

Procedure:
A solution of methyl-4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-benzoate (4.87 g, 17.56 mmol) in 10% aqueous sulfuric acid (50 mL) and THF (50 mL) was stirred at ambient temperature for 72 hours. The reaction mixture was neutralized by cautious addition of NaHCO3 and simultaneously diluting with water. The aqueous mixture was extracted with EtOAc (2×75 mL) and the combined organic extracts were dried (MgSO4), filtered, and concentrated to give the title compound as an off-white, amorphous solid (4.06 g, 99%) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:5]=[O:6]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccccc2)c(Br)c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 81.9 %

Procedure:
To a solution of 3-bromo-4-fluorobenzaldehyde (2.03 g, 10.0 mmol) and phenol (0.941 g, 10.0 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (1.66 g, 12.0 mmol), and the mixture was stirred at 90° C. for 16 hr under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-15:85) to give the title compound (2.27 g, yield 82%) as a pale-yellow oil.
Reaction SMILES: [F-].[C:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][N:15]=1)[CH:12]=[N+:11]([CH3:16])[C:10]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:9]2=1)(=[O:4])[CH3:3].[BH4-].[Na+]>C1COCC1.CO>[Cl:21][C:18]1[CH:19]=[CH:20][C:9]2[C:8]3[C:13](=[CH:14][N:15]=[C:6]([NH:5][C:2](=[O:4])[CH3:3])[CH:7]=3)[CH2:12][N:11]([CH3:16])[C:10]=2[CH:17]=1
Reactant: CC(=O)Nc1cc2c(cn1)c[n+](C)c1cc(Cl)ccc21
Agent: [BH4-]
Agent: [F-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)Nc1cc2c(cn1)CN(C)c1cc(Cl)ccc1-2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 92.7 %

Procedure:
To a stirred solution of 2-acetamido-8-chloro-6-methylbenzo[c][2,7]naphthyridin-6-ium fluoride (2.1 g, 2.47 mmol) in a mixture of THF (20 mL) and MeOH (5 mL) at 0° C. was added NaBH4 (0.199 g, 5.27 mmol) in three portions and the reaction was stirred at rt for 45 min. The volatile organics were removed under reduced pressure; saturated ammonium chloride solution (30 mL) was added and the solution extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (25 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to afford N-(8-chloro-6-methyl-5,6-dihydrobenzo[c][2,7]naphthyridin-2-yl)acetamide (0.71 g, 2.29 mmol, 93% yield) as a yellow solid. LC/MS (ESI) m/e 288.2 [(M+H)+, calcd for C15H15ClN3O 288.1]; LC/MS retention time (method C); tR=1.87 min; HPLC retention time (method A): tR=12.76 min; HPLC retention time (method B): tR=13.07 min; 1H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.36 (s, 1H), 8.16 (d, J=0.40 Hz, 1H), 7.63 (d, J=8.40 Hz, 1H), 6.88 (dd, J=2.00, 8.00 Hz, 1H), 6.82 (d, J=2.00 Hz, 1H), 4.26 (s, 2H), 2.89 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5](=O)[CH2:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C(O)(=O)C.O.[NH2:22][NH2:23].C([O-])(O)=O.[Na+]>O>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:23][N:22]=1)=[O:16])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(=O)c1ccccc1
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cc(-c2ccccc2)[nH]n1
Yield: 87.7 %

Procedure:
A solution of 2,4-dioxo-4-phenyl-butyric acid ethyl ester (1.68 g, 0.0076 mole), acetic acid (10 mL) and hydrazine hydrate (0.42 g, 0.0083 mole) was heated to reflux for 5 hours. The reaction mixture was then poured into iced water, basified with saturated aqueous NaHCO3 solution and the product was extracted with ethyl acetate. The ethyl acetate layer was collected and washed with brine solution, dried over sodium and concentrated under reduced pressure. The resulting residue was purified by column chromatography using basic aluminium oxide (50% ethyl acetate in hexane) to afford 1.442 g (88%) of 5-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester. LCMS: 217.09 (M+1)+, 97.92%. To a stirred solution of 5-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester (1.4 g, 0.00667 mol) in a mixture of THF (30 mL), methanol (15 mL) and H2O (10 mL) was added LiOH.H2O (0.839 g, 0.0199 mol) at ambient temperature. The resulting mixture was stirred at 45° C. overnight. Volatiles were evaporated and the residue was diluted with water, acidified with concentrated HCl solution and the product was extracted with ethyl acetate. The ethyl acetate layer was collected, dried over sodium sulfate and concentrated under reduced pressure to afford 1.26 g (86%) of 5-phenyl-1H-pyrazole-3-carboxylic acid. LCMS: 189.06 (M+1)+, 97.7%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:14]1[CH2:16][CH2:15]1)[CH:6]=[C:5]2[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)(=[O:19])=[O:18].[CH:33]1([NH:36][C:37](=[O:55])[C:38]2[CH:43]=[C:42](B3OC(C)(C)C(C)(C)O3)[C:41]([CH3:53])=[C:40]([F:54])[CH:39]=2)[CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH:33]1([NH:36][C:37]([C:38]2[CH:39]=[C:40]([F:54])[C:41]([CH3:53])=[C:42]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8](=[O:12])[N:7]([CH2:13][CH:14]3[CH2:15][CH2:16]3)[CH:6]=[C:5]4[S:17]([N:20]3[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:24][CH2:25]3)(=[O:19])=[O:18])[CH:43]=2)=[O:55])[CH2:35][CH2:34]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cn(CC3CC3)c(=O)c3ccc(Br)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(S(=O)(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
A solution of tert-butyl 4-{[6-bromo-2-(cyclopropylmethyl)-1-oxo-1,2-dihydroisoquinolin-4-yl]sulfonyl}piperazine-1-carboxylate (Example 47b, 0.890 g) in DMF (10 mL) was treated with N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide (0.491 g), Pd-118 (0.030 g) and potassium carbonate (0.425 g). The mixture was stirred at 70° C. for 1 h. The cooled reaction mixture was diluted with water (100 mL), and extracted into ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (3×100 mL), dried (MgSO4), filtered and evaporated. The crude product was purified (SiO2 chromatography, elution with 10% ethyl acetate/DCM) to afford the subtitle compound (0.713 g) as beige foam, which was used without further analysis.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[N:12][C:11]([CH:14]([OH:16])[CH3:15])=[N:10]1.[H-].[Na+].[CH:19]1([N:22]2[C:26](S(C)(=O)=O)=[N:25][N:24]=[C:23]2[C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[CH2:21][CH2:20]1>>[CH:19]1([N:22]2[C:26]([O:16][CH:14]([C:11]3[N:12]=[N:13][N:9]([C:3]4[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=4[F:1])[N:10]=3)[CH3:15])=[N:25][N:24]=[C:23]2[C:31]2[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=2)[CH2:21][CH2:20]1
Reactant: Cc1ccc(F)c(-n2nnc(C(C)O)n2)c1
Reactant: CS(=O)(=O)c1nnc(-c2ccncc2)n1C1CC1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(F)c(-n2nnc(C(C)Oc3nnc(-c4ccncc4)n3C3CC3)n2)c1

Procedure:
The title compound is prepared from 1-[2-(2-fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-ethanol (1 mmol), sodium hydride (1.5 mmol) and 4-(4-cyclopropyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-yl)-pyridine (1.25 mmol).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[CH2:15][O:14][N:13]([C:16]3([C:22]([O:24][CH3:25])=[O:23])[CH:20]=[CH:19][C:18](=[O:21])[O:17]3)[C:12]2=[O:26])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O1CCCC1.[H][H].[C].[Pd]>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[CH2:15][O:14][N:13]([C:16]3([C:22]([O:24][CH3:25])=[O:23])[CH2:20][CH2:19][C:18](=[O:21])[O:17]3)[C:12]2=[O:26])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: COC(=O)C1(N2OC[C@@H](NC(=O)Cc3ccccc3)C2=O)C=CC(=O)O1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)C1(N2OC[C@@H](NC(=O)Cc3ccccc3)C2=O)CCC(=O)O1
Yield: 79.6 %

Procedure:
In 3 ml of tetrahydrofuran was dissolved 30 mg of the Compound (30) obtained in Example 30. To the solution was added 30 mg of 10% palladium-carbon, and the mixture was stirred at room temperature for 30 minutes in hydrogen streams. The catalyst was filtered off and washed with tetrahydrofuran. The filtrate and the washing were combined, then the solvent was evaporated off. The residue was subjected to a silica gel column chromatography, followed by elution with hexane-ethyl acetate (2:3) to give 24 mg of the subject Compound (31) as colorless oil.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:14][CH2:15][C:16](=[O:18])[CH3:17].N1C=CC=CC=1.[Mn]([O-])(=O)(=O)=[O:26].[K+]>O>[O:26]=[C:12]1[C:13]2[CH:1]=[C:2]([CH2:14][CH2:15][C:16](=[O:18])[CH3:17])[CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CC(=O)CCc1ccc2c(c1)Cc1ccccc1-2
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)CCc1ccc2c(c1)C(=O)c1ccccc1-2
Temperature: 60 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
4-(2-Fluorenyl)-butan-2-one (4.72grams) was dissolvedin a mixture of 60 ml of pyridine and 5 ml of water, the mixture was heated at 60° C., and stirred. Potassium permanganate (6.8 grams) was added thereto little by little during 2 hours. When the addition was finished, the mixture was stirred for 2 hours more. The reaction solution was filtered, the filtrate was concentrated, and the resulting residue was dissolved in chlroform, the solution was washed with in the order of 10% hydrochloric acid, water, saturated sodium bicarbonate, and water, then dried with magensium sulfate, the solvent was evaporated therefrom, and the residue was recrystallized from ethanol to give 1.3 grams of 4-(9-oxo-2fluorenyl)-butan-2-one, yellow crystals, m.p. 75°-77° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:6](=O)[NH:7][CH:8]=[CH:9][C:10]=2[CH:11]=1.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:24]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[N:7][C:6]=2[Cl:24]
Reactant: O=c1[nH]ccc2cc(Br)cnc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nccc2cc(Br)cnc12
Temperature: 130 °C
Yield: 67.8 %

Procedure:
3-Bromo-7H-[1,7]naphthyridin-8-one (1.5 g, 6.67 mmol) was suspended in toluene (20 ml). DIPEA (3.5 ml, 20 mmol) and POCl3 (1.8 ml, 20 mmol) were added and the reaction mixture was heated to 130° C. for 36 h. The reaction mixture was cooled to rt and partitioned between water (75 ml) and EtOAc (150 ml). The phases were separated and the aq phase was extracted twice with EtOAc (25 ml). The combined organic layer was washed with NaHCO3 solution and brine, treated with MgSO4 and filtered. The filtrated was concentrated to give the desired product as a beige solid (1.1 g, 4.52 mmol).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][CH3:19])[CH:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]2[C:32]1=[O:41])(OCC)=O>O.C(#N)C>[C:32]1(=[O:41])[N:2]([CH:3]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][CH3:19])[CH:10]=2)[CH2:4][C:5]([O:7][CH3:8])=[O:6])[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]12
Reactant: CCOc1cc(C(N)CC(=O)OC)ccc1OC
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOc1cc(C(CC(=O)OC)N2C(=O)c3ccccc3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.9 %

Procedure:
To a stirred solution of methyl 3-amino-3-(3-ethoxy-4-methoxyphenyl)propionate hydrochloride (0.87 g, 3.0 mmol) and sodium carbonate (0.32 g, 3.0 mmol) in a mixture of water (10 mL) and acetonitrile (10 mL) was added N-carbethoxyphthalimide (0.68 g, 3.0 mmol). The resulting solution was stirred for 3 hours at room temperature. The acetonitrile was removed in vacuo. To the resulting mixture was added ether (5 mL) and the mixture was stirred at room temperature overnight allowing the ether to evaporate. The resulting white solid was filtered. The solid was washed with water, air dried, and dried in vacuo (60° C.,<1 mm) to afford 1.0 g (87%) of methyl 3-phthalimido-3-(3-ethoxy-4-methoxyphenyl)propionate as a white solid: mp 86-87° C.; 1H NMR (CDCl3)δ 7.86-7.63 (m, 4H), 7.16-7.05 (m, 2H), 6.88-6.76 (m, 1H), 5.77 (dd, J=5.9, 10 Hz, 1H), 4.11 (q, J=7 Hz, 2H), 3.84 (s, 3H), 3.77 (dd, J=10, 6.7 Hz, 1H), 3.63 (s, 3H), 3.25 (dd, J=5.9, 16.5 Hz, 1H), 1.45 (t, J=7 Hz, 3H); 13C NMR (CDCl3)δ 171.0, 168.0, 149.0, 148.2, 133.9, 131.7, 130.9, 123.2, 120.2, 112.5, 111.1, 64.3, 55.8, 51.8, 50.7, 35.8, 14.6; HPLC (Waters Nova-Pak C18 column, 3.9×150 mm, 4 micron, 1 mL/min, 240 nm, 45/55, acetonitrile/0.1% aqueous phosphoric acid 6 min, 100%, Anal. Calcd. for C21H21NO6. Theoretical: C, 65.79; H, 5.52; N, 3.65. Found: C, 65.71; H, 5.70; N, 3.63.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.Br[C:18]1[C:29]([Cl:30])=[CH:28][C:21]2[O:22][C:23]([F:27])([F:26])[CH2:24][O:25][C:20]=2[CH:19]=1>O1CCOCC1.CC#N.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[Cl:30][C:29]1[C:18]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=2)=[CH:19][C:20]2[O:25][CH2:24][C:23]([F:27])([F:26])[O:22][C:21]=2[CH:28]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC1(F)COc2cc(Br)c(Cl)cc2O1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Solvent: C1COCCO1
Solvent: CC#N
Product: Nc1ccc(-c2cc3c(cc2Cl)OC(F)(F)CO3)cn1
Temperature: 85 °C
Yield: 8.7 %

Procedure:
2-Aminopyridine-5-boronic acid pinacol ester (62 mg, 0.28 mmol) and 254 (67 mg, 0.23 mmol) were dissolved in 2 mL 1,4-dioxane and 2 mL MeCN. Next 1 ml of 2 M K3PO3 was added and the mixture was bubbled with Ar for 2 min before bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (A-Phos, 14 mg, 0.02 mmol) was added. The reaction was then heated at 85° C. for 2 h. The reaction was cooled and the mixture worked-up with a EtOAc extraction. The resulting crude product was purified by flash column and afforded 255 (6 mg, 9%) as yellow solid.
Reaction SMILES: [F:1][C:2]1(B(O)O)[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[OH:19]O.O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:3]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:4]([OH:19])[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: CCCCCCOC1C=C(F)C=CC1(F)B(O)O
Reactant: OO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCOc1c(F)ccc(F)c1O
Reaction time: 0.75 h
Yield: 87 %

Procedure:
White crystals of 1,4-difluoro-2-hexyloxybenzene-1-boronic acid (48 g) were dissolved in warm toluene (150 ml) and hydrogen peroxide (43 ml, 30%) was added drop-wise. Heating was continued for 45 min at 100° C. Once the solution had cooled to room temperature water was added (50 ml) and the layers were separated. The toluene layer was washed with ferrous ammonium sulphate (10%, 2×50 ml) and water (2×50 ml). The combined organic extracts were dried with magnesium sulphate, filtered and the solvent was removed to yield crude 3,6-difluoro,2-hexyloxyphenol as a pale yellow oil (31.67 g, 100%). The crude product was dissolved in toluene (150 ml), extracted with sodium hydroxide solution (10%w/v in methanol, 3×50 ml). The purple, aqueous extract, containing the phenoxide anion of the product, was then re-acidified with concentrated HCl until all of the colour had been displaced (pH˜4). The phenol was then extracted with dichloromethane (3×100 ml), washed with water (3×50 ml), dried with magnesium sulphate and filtered. Removal of the solvent in vacuo yielded the required product as an orange/brown oil (27.2 g, 87%). Kugelrohr distillation was performed under reduced pressure (2 mbar), the colourless distillate collected when the oven temp was 100° C. was found to contain only 4 (26.5 g, 82%), (Found: C, 62.65; H, 6.9. C12H16O2F2 requires C, 62.6; H, 6.9; O, 13.91; F, 16.52%); vmax(film)/cm−1 3524 and 2932 (C—H aliph), 2300 (C═C); δH(300 MHz; CDCl3) 0.90 (3H, t, 3J(H,H)=7 Hz, —CH3), 1.32 (4H, m, 2×—CH2—), 1.34 (2H, septet, 3J(H,H)=7 Hz, —CH2CH2CH2O—Ar), 1.76 (2H, quintet, 3J(H,H)=7 Hz, —CH2CH2CH2O—Ar), 4.17 (2H, t, 3J(H,H)=7 Hz, —CH2CH2O—Ar), 5.70 (1H, s, —OH, removed with D2O), 6.58 (1H, ddd, 3J(H,F)=13.3, 3J(H,H)=7.4, 4J(H,F)=4.5 Hz, C3H), 6.74 (1H, ddd, 3J(H,F)=18.3, 3J(H,H) 7.4, 4J(H,F)=4.6 Hz, C4H); δC(75 MHz 1H{BB}, INEPT; CDCl3) 14.31 (CH3), 22.91 (CH2), 25.78 (CH2), 30.34 (CH2), 31.87 (CH2), 74.90 (CH2), 106.65 (CH, dd, 2J(C,F)=15.1, 3J(C,F)=8.4 Hz, C4), 110.75 (CH, dd, 2J(C,F)=15.1, 3J(C,F)=8.4 Hz, C5), 135.67 (C, dd, 2J(C,F)=15.1, 3J(C,F)=8.4 Hz, C1), 138.42 (C, dd, 2J(C,F)=15.1, 3J(C,F)=8.4 Hz, C2), 147.65 (C, dd, 1J(C,F)=239, 4J(C,F)=2.6 Hz, C6), 151.7 (C, dd, 1J(C,F)=248, 4J(C,F)=2.6 Hz, C3); m/z 230 (M+, 10%), 146 (M+-alkoxy chain, 100%), 43 (50%).