Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[NH:13][CH:14]=O)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CCN(CC)CC.P(Cl)(Cl)(Cl)=O>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[C:4]([CH:12]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[N+:13]#[C-:14])[CH:3]=1
Reactant: O=CNC(c1ccc(F)cc1)c1cc(F)cc(C(F)(F)F)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: [C-]#[N+]C(c1ccc(F)cc1)c1cc(F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.7 %

Procedure:
To a solution of (3-fluoro-5-(trifluoromethyl)phenyl)(4-fluorophenyl)methanamine (315 mg, 1.1 mmol) in CH2Cl2 (2 mL) at 0° C. was added acetic formic anhydride (314 uL, formed by heating a 2:1 v/v ratio of acetic anhydride and formic acid at 60° C. for 2 h). The reaction mixture was allowed to warm to room temperature and stirred for 0.5 h. The reaction mixture was concentrated under reduced pressure and the residue was purified on a 40 g column of silica gel, eluting with 0 to 100% EtOAc/hexane, to give N-((3-fluoro-5-(trifluoromethyl)phenyl)(4-fluorophenyl)methyl)formamide (327 mg, 94% yield) as a clear, viscous oil. LCMS: RT=1.37 min [M+H] 316.1 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% acetonitrile/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDCl3) δ ppm 6.13 (bs, 1H), 6.34 (d, J=7.47 Hz, 1H), 7.05-7.20 (m, 5H), 7.27-7.34 (m, 2H), 8.35 (s, 1H). To a solution of N-((3-fluoro-5-(trifluoromethyl)phenyl)(4-fluorophenyl)methyl)formamide (327 mg, 1.04 mmol) in THF (5 mL) at 0° C. was added Et3N (0.79 mL, 5.7 mmol) followed by phosphorous oxychloride (0.125, 1.35 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was diluted with ice-water (25 mL) and extracted with Et2O (3×20 mL). The combined organic layers were washed with sat. NaCl (20 mL), dried over anhydrous Na2SO4, the filtered through basic alumina. The filtrate was concentrated to give 1-fluoro-3-((4-fluorophenyl)(isocyano)methyl)-5-(trifluoromethyl)benzene (268 mg, 93% yield) as a pale brown oil. LCMS: RT=1.71 min [M−NC] 271.0 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% acetonitrile/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); IR νmax cm−1 neat: 2139 (N═C); NMR: 500 MHz 1H (CDCl3) δ ppm 5.94 (s, 1H), 7.12 (t, J=8.52 Hz, 2H), 7.25-7.29 (m, 1H), 7.30-7.35 (m, 3H), 7.41 (s, 1H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.[C:27]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:32]=[CH:31][C:30](C(Cl)=O)=[CH:29][CH:28]=1.[CH2:42]([N:44]([CH2:48][CH3:49])[CH2:45][CH2:46][NH2:47])[CH3:43]>>[C:36]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:37]=[CH:38][C:39]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[CH2:10][C@H:9]2[C:24]([NH:47][CH2:46][CH2:45][N:44]([CH2:48][CH3:49])[CH2:42][CH3:43])=[O:26])=[O:7])=[CH:40][CH:41]=1
Reactant: CCN(CC)CCN
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccc(Cl)c(Cl)c2)C[C@H]1C(=O)O
Product: CCN(CC)CCNC(=O)[C@@H]1CC(=NOCc2ccc(Cl)c(Cl)c2)CN1C(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and N1,N1-diethyl-1,2-ethanediamine the title compound was obtained in 74% purity by LC/MS. MS(ESI+): m/z=581.6.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:33](=[O:35])=[O:34]>C1COCC1>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:11]=[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:9]=[C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([C:33]([OH:35])=[O:34])[N:7]=3)[CH:13]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(-c2cc(-c3ccccn3)nc(-c3cccc(Br)n3)c2)cc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(-c3ccccn3)nc(-c3cccc(C(=O)O)n3)c2)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A flame dried 3 necked 1 L flask equipped with a mechanical stirrer, pressure equalizing addition funnel, and, attached via silicone rubber tubing, a Gooch tube containing solid 6-bromo-4′-(4-methoxyphenyl)-2,2′:6′2″-terpyridine (42.2 mmole) under nitrogen is charged with 400 mL THF and cooled in a Dry Ice/ether bath to −78° C. A solution of n-butyllithium (20 mL of 2.5 M) is transferred via nitrogen pump to the pressure equalizing addition funnel, and is then added to the THF solution. After stirring 15 minutes at −78° C., the solid 6-bromo-4′-(4-methoxyphenyl)-2,2′:6′2″-terpyridine is added portionwise over an 11 minute period from the Gooch tube. The temperature is not allowed to exceed −75° C. during the addition. After the addition, the bath is lowered, and the reaction mixture is allowed to warm slightly to −70° C. over a 10 minute period. The solution is re-cooled to −78° C., and the reaction mixture is transferred via cannula under nitrogen to a jacketed addition funnel cooled to −78° C. This anionic solution is maintained at −78° C. under nitrogen while it is added with stirring to 400 mL of THF saturated with anhydrous carbon dioxide in a 3 liter 3 necked flask attached to a silicone oil bubbler. Additional anhydrous carbon dioxide is slowly bubbled into the reaction mixture during the addition while the temperature is carefully controlled to remain below −70° C. After stirring for 60 minutes, the cooling bath is removed and the reaction mixture is carefully quenched with 100 ml of a 1 N aqueous HCl solution over a ten minute period. The reaction mixture is allowed to stir and warm to room temperature. The solvent is evaporated under vacuum below 20° C., the crude product is triturated with isopropanol, isolated by filtration, washed with ether and dried under vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[N:17]=[CH:16]2)[C@@H:9]([NH2:11])[CH3:10].[C:29](Cl)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)[N:17]=[CH:16]2)[C@@H:9]([NH:11][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:10]
Reactant: CC(C)(C)C(=O)Cl
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1Cl
Product: C[C@H](NC(=O)C(C)(C)C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1Cl

Procedure:
Prepared as described in Example 1 using (1R,2S)-1-(2-chlorophenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)propan-2-amine (300a, 18 mg, 0.05 mmol) and Pivaloyl chloride (17 μl, 0.14 mmol). Yield 22 mg (100%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[C:18]([OH:19])=[C:17]([Br:20])[CH:16]=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH2:21]([N:24]([CH2:29][CH2:30][CH3:31])[C:25](=[O:28])[CH2:26]Cl)[CH2:22][CH3:23].O>CC(C)=O>[Br:7][C:8]1[C:18]([O:19][CH2:26][C:25]([N:24]([CH2:29][CH2:30][CH3:31])[CH2:21][CH2:22][CH3:23])=[O:28])=[C:17]([Br:20])[CH:16]=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCCN(CCC)C(=O)CCl
Reactant: CCOC(=O)c1ccc(Br)c(O)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCCN(CCC)C(=O)COc1c(Br)ccc(C(=O)OCC)c1Br

Procedure:
0.853 g of K2CO3, 0.154 g of KI and 1.000 g of ethyl 2,4-dibromo-3-hydroxybenzoate were introduced in 10 ml of acetone. At RT 0.783 g of N,N-di-n-propylchloroacetamide was added. The mixture was then heated at reflux for 4 hours. It was subsequently poured into water and extracted with diisopropyl ether. The organic phases were washed with water, dried over Na2SO4 and concentrated. Chromatography on silica gel (eluent: n-heptane/ethyl acetate) gave ethyl 2,4-dibromo-3-(N,N-di-n-propylaminocarbonylmethoxy)benzoate as brown oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.[CH3:6][C:7]1[C:12](=[O:13])[C:11]2[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([O-:20])=[O:19])[C:10]=2[O:9][C:8]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Na+]>CN(C)C=O.O>[Br:1][CH2:2][CH2:3][CH2:4][O:20][C:18]([C:17]1[C:10]2[O:9][C:8]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[C:7]([CH3:6])[C:12](=[O:13])[C:11]=2[CH:14]=[CH:15][CH:16]=1)=[O:19]
Reactant: BrCCCBr
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)[O-])cccc2c1=O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccc2)oc2c(C(=O)OCCCBr)cccc2c1=O
Temperature: 25 °C
Reaction time: 120 h
Yield: 69.6 %

Procedure:
30 g of 1,3-dibromopropane was added dropwise at ambient temperature to a suspension of 30 g of sodium3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylate in 150 ml of dimethylformamide and 35 ml of water. The reaction mixture was stirred at ambient temperature for 5 days. 100 ml of water was added and stirring was continued for a further 15 minutes. The precipitate was filtered off by suction, washed with water and purified by flash chromatography on silica gel, eluting with chloroform:ethyl acetate 95:5. The collected fractions were evaporated to dryness in vacuo and the residue was recrystallized from ethanol to give 27.7 g of the title compound, m.p. 114°-115° C.
Reaction SMILES: [OH-:1].[K+].[CH3:3]O.C([O:8][CH2:9][CH2:10][CH2:11][C:12]([N:15]=[N:16][C:17]([CH3:20])([CH3:19])[CH3:18])(Cl)[CH3:13])(=O)C.O>C(Cl)Cl>[C:17]([N:16]=[N:15][C:12]([O:1][CH3:3])([CH3:13])[CH2:11][CH2:10][CH2:9][OH:8])([CH3:18])([CH3:19])[CH3:20]
Reactant: [OH-]
Reactant: CC(=O)OCCCC(C)(Cl)N=NC(C)(C)C
Reactant: CO
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COC(C)(CCCO)N=NC(C)(C)C
Temperature: 30 °C

Procedure:
To a 250 ml 3-neck round bottom flask equipped with a magnetic stirrer, thermometer, condenser and addition funnel was added 13.2 grams (0.2 mole) of 85% potassium hydroxide pellets and 130 mls of methanol. The mixture was stirred at approximately 30° C. until the pellets dissolved. The resulting solution was cooled at 10° C. and with rapid stirring 24.9 grams (0.1 mole) of 4-t-butylazo-4-chloropentyl acetate were added over 20 minutes while holding the temperature at 10°-15° C. After the addition was complete, the mixture was stirred for 3 hours at room temperature, poured into 300 mls of water and the organic layer taken up in 100 mls of methylene chloride. The aqueous layer was separated and discarded and the methylene chloride was washed with water, 10% HC1, water and saturated sodium bicarbonate solution. The methylene chloride solution was dried over anhydrous sodium sulfate, filtered and the methylene chloride stripped off on a rotary evaporator under reduced pressure. The resulting light orange liquid weighed 12.5 grams (62% crude yield). The infrared spectrum of the product contained a very broad strong OH band centered at 3400 cm-1 and no carbonyl band. There was a strong carbon-oxygen band at 1180-1220 cm-1.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH2:21][CH2:22][O:23][CH2:24][CH:25]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.O.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>[Br:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:20]2[CH2:25][CH2:24][O:23][CH2:22][CH:21]=2)=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Br
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
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: CCO
Solvent: O
Product: O=[N+]([O-])c1cc(Br)cnc1C1=CCOCC1
Temperature: 70 °C
Reaction time: 19 h

Procedure:
A stirred mixture of 2,5-dibromo-3-nitropyridine (0.31 g, 1.11 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (0.26 g, 1.23 mmol), tetrakis(triphenylphosphine)palladium (64.7 mg, 0.056 mmol), and 2.0M sodium carbonate (3.0 mL, 6.00 mmol) in toluene (3.0 mL) and EtOH (1.0 mL) was heated to 70° C. After 19 h, the reaction was cooled to rt then diluted with water. After extraction with EtOAc, the organic layer was dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified on silica gel (0-20% EtOAc in hexanes) to afford a light yellow solid as 5-bromo-2-(3,6-dihydro-2H-pyran-4-yl)-3-nitropyridine. 1H NMR (400 MHz, CDCl3) δ ppm 8.81 (1H, d, J=2.0 Hz), 8.20 (1H, d, J=2.0 Hz), 6.09 (1H, m), 4.30 (2H, q, J=2.8 Hz), 3.94 (2H, t, J=5.4 Hz), 2.61 (2H, m).
Reaction SMILES: [CH2:1]([C:3]1[CH2:4][CH:5]([OH:8])[CH2:6][CH:7]=1)[CH3:2].[CH3:9][C:10]1([CH3:20])[C@@H:12]([CH:13]=[C:14]([Cl:16])[Cl:15])[C@H:11]1[C:17](Cl)=[O:18].C(C1CC(O)CC=1C)C.Cl/C(/C(F)(F)F)=C\[C@@H]1[C@H](C(Cl)=O)C1(C)C>>[CH3:9][C:10]1([CH3:20])[C@@H:12]([CH:13]=[C:14]([Cl:15])[Cl:16])[C@H:11]1[C:17]([O:8][CH:5]1[CH2:6][CH:7]=[C:3]([CH2:1][CH3:2])[CH2:4]1)=[O:18]
Reactant: CC1(C)[C@H](C(=O)Cl)[C@@H]1C=C(Cl)Cl
Reactant: CCC1=CCC(O)C1
Agent: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Agent: CCC1=C(C)CC(O)C1
Product: CCC1=CCC(OC(=O)[C@@H]2[C@H](C=C(Cl)Cl)C2(C)C)C1
Yield: 85.1 %

Procedure:
(RS)-3-ethyl-3-cyclopenten-1-ol (500 mg) and (1R)-cis-2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropanecarbonyl chloride (1014 mg) were respectively used instead of (RS)-3-ethyl-4-methyl-3-cyclopenten-1-ol and (1RS)-cis-3-(Z-2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride used in Example 1 above and the reaction procedures were carried out in the same manner as in Example 1 to afford 1150 mg of (RS)-3-ethyl-3-cyclopentenyl (1R)-cis-2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropanecarboxylate (Compound No. 132). Yield 80% nD25 1.5063
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[C:15]([F:16])=[CH:14][C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[N:27]([CH2:28][CH3:29])[N:26]=[CH:25][CH:24]=2)=[CH:12][C:11]=1[F:30])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH2:28]([N:27]1[C:23]([C@H:19]2[CH2:20][CH2:21][CH2:22][C@@H:18]2[O:17][C:13]2[CH:14]=[C:15]([F:16])[C:10]([S:7]([NH:6][C:31]3[CH:36]=[CH:35][N:34]=[CH:33][N:32]=3)(=[O:9])=[O:8])=[C:11]([F:30])[CH:12]=2)=[CH:24][CH:25]=[N:26]1)[CH3:29]
Reactant: CCn1nccc1[C@H]1CCC[C@@H]1Oc1cc(F)c(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ccncn2)c(F)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1nccc1[C@H]1CCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)c(F)c1
Yield: 87.3 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,6-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (231 mg, 0.385 mmol) prepared in Example 50a, triethylsilane (0.20 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield the title compound (151 mg, 87%) as a colorless amorphous solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[F:13][C:14]1[CH:19]=[C:18]([C:20]([O:22]C)=[O:21])[CH:17]=[CH:16][C:15]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[F:13][C:14]1[CH:19]=[C:18]([CH:17]=[CH:16][C:15]=1[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[CH:3]=1)[C:20]([OH:22])=[O:21]
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: COC(=O)c1ccc(B(O)O)c(F)c1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(-c2ccc3cc(O)ccc3c2)c(F)c1
Reaction time: 1 h
Yield: 75.1 %

Procedure:
6-Bromonaphthalen-2-ol (1 g, 4.48 mmol) was mixed with 880 mg of 2-fluoro-4-(methoxycarbonyl)phenylboronic acid (4.48 mmol), 1.2 g of K2CO3 (9.23 mmol), 120 mg of Pd(PPh3)4 (2.5 mol %), and then suspended in 17 mL of 1,4-Dioxane and 4 mL of H2O. The mixture was degassed 3× with argon and then heated to reflux while stirring for 1 hour. 4N NaOH (5 mL) was then added and stirred at room temperature for 2 hours, back extracted with EtOAc, and filtered through Celite. The basic aqueous solution was then acidified to pH=4.3 and the solids were filtered to give about 950 mg of off-white solid. This was triturated in 8 mL DCM and 2 mL EtOAc and filtered to yield about 830 mg of off-white Example 2 (65.8% overall yield). 1H-NMR (DMSO-d6 500 MHz): δ 13.31 (bs, 1H), 9.97 (bs, 1H), 8.05 (s, 1H), 7.90 (m, 2H), 7.80 (m, 3H), 7.64 (dt, 1H), 7.19 (m, 2H); MS (ESI): m/z 281.53 [MA]−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:16]3[N:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:21])[NH:13][C:12]3[CH:22]=[CH:23][CH:24]=[N:25][C:11]2=3)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:28]I.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:16]3[N:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:21])[N:13]([CH3:28])[C:12]3[CH:22]=[CH:23][CH:24]=[N:25][C:11]2=3)=[CH:5][CH:4]=1
Reactant: COc1ccc(CN2c3ncccc3NC(=O)c3cccnc32)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2c3ncccc3C(=O)N(C)c3cccnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
10.0 g (0.030 mol) of 5,11-dihydro-11-[(4-methoxyphenyl)methyl]-6H-dipyrido-[3,2-b:2',3'-e][1,4]diazepin-6-one was added to a flask containing 2.16 g of a 50% dispersion of sodium hydride in mineral oil and 100 ml of dimethylformamide. The resulting mixture was stirred at room temperature for 30 min. and then heated to 50° C. for 30 min. After cooling, 8.51 g (0.060 mol) of methyl iodide in 10 ml of dimethylformamide was added dropwise and the mixture was allowed to stir at room temperature overnight. Excess sodium hydride was decomposed by the careful addition of ice. Water was then added, and the product was extracted with ether, dried (anhydrous sodium sulfate), and concentrated to give 10.3 g (99% of theory) of 5,11-dihydro- 11-[(4-methoxy-phenyl)-methyl]-5-methyl-6H-dipyrido-[3,2-b:2',3'-e][1,4]diazepin-6-one as a light yellow oil suitable for use in the next reaction.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].C1COCC1.[NH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[C:16](=[O:36])[N:17]([CH:24]1[CH2:29][CH2:28][C:27](=[O:30])[N:26]([CH2:31][CH2:32][O:33][CH3:34])[C:25]1=[O:35])[C:18]2=[O:23]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:34][O:33][CH2:32][CH2:31][N:26]1[C:27](=[O:30])[CH2:28][CH2:29][CH:24]([N:17]2[C:18](=[O:23])[C:19]3[C:15](=[C:14]([NH:13][C:1](=[O:3])[CH3:2])[CH:22]=[CH:21][CH:20]=3)[C:16]2=[O:36])[C:25]1=[O:35]
Reactant: COCCN1C(=O)CCC(N2C(=O)c3cccc(N)c3C2=O)C1=O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COCCN1C(=O)CCC(N2C(=O)c3cccc(NC(C)=O)c3C2=O)C1=O

Procedure:
Acetic anhydride (0.5 mL) and DMAP (3 mg) were added to a THF solution of 4-amino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (50 mg). The reaction mixture was allowed to react for 8 hrs at room temperature. Then, DCM (15 mL) were added and solvents were removed by rotary evaporation in vacuo. The residue was washed with 0.5 N aqueous hydrochloric acid, saturated sodium bicarbonate, and brine, dried over anhydrous magnesium sulfate, and filtered. Pale white solid (38 mg) was obtained after removal of solvent by rotary evaporation in vacuo. MS (m/e): 374 (M+H).
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:12]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][C:14]=2C)=[C:11]([CH3:23])[O:10][N:9]=1.O[N:25]=[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][C:35]([F:38])([F:37])[F:36])[NH2:27].CCN(C(C)C)C(C)C>>[CH3:7][C:8]1[C:12]([C:13]2([CH3:1])[CH:14]=[CH:15][C:16]([C:17]3[O:19][N:27]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][C:35]([F:38])([F:37])[F:36])[N:25]=3)=[CH:20][CH2:21]2)=[C:11]([CH3:23])[O:10][N:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(C(=O)O)ccc1-c1c(C)noc1C
Reactant: NC(=NO)c1ccccc1OC(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(C)c1C1(C)C=CC(c2nc(-c3ccccc3OC(F)(F)F)no2)=CC1

Procedure:
Oxalyl chloride (132 μL; 1.56 mmol; 3 eq.), Intermediate 30 (120 mg; 0.52 mmol; 1 eq.), Intermediate 2 (114 mg; 0.52 mmol, 1 eq.) and DIEA (268 μl; 1.56 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography (c-hexane/ethyl acetate, 80/20) afforded the title compound as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[F:11][C:12]([F:24])([F:23])[O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[F:11][C:12]([F:23])([F:24])[O:13][C:14]1[CH:15]=[C:16]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[CH:5][NH:6]3)[CH:17]=[CH:18][CH:19]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Brc1cccc2[nH]ccc12
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: FC(F)(F)Oc1cccc(-c2cccc3[nH]ccc23)c1
Temperature: 75 °C
Reaction time: 16 h
Yield: 87.4 %

Procedure:
To a mixture of 4-bromoindole (4.50 g, 22.95 mmol), and 4-trifluoromethoxyphenylboronic acid (4.73 g, 22.95 mmol) in THF (78 mL)) were added Palladium catalyst Pd(PPh3)4 (795.6 mg, 0.69 mmol) and the freshly prepared sodium hydroxide solution (2.75 g, 68.9 mmol in 32 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 75° C. oil bath for 16 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes-EtOAc (9:1) to provide 5.56 g (78%) of the product 4-(4-trifluoromethoxy-phenyl)-1H-indole.
Reaction SMILES: [Li]CCCC.[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH3:12][C:13]1[N:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]([CH3:20])=[C:16]([PH2:19])[C:17]=1[PH2:18].[CH3:27][C@H:28](O)[CH2:29][CH2:30][C@@H:31](O)[CH3:32]>C1COCC1>[CH3:12][C:13]1[N:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]([CH3:20])=[C:16]([P:19]2[C@H:31]([CH3:32])[CH2:30][CH2:29][C@H:28]2[CH3:27])[C:17]=1[P:18]1[CH:10]([CH3:11])[CH2:9][CH2:8][CH:7]1[CH3:6]
Reactant: Cc1c(P)c(P)c(C)n1-c1ccccc1
Reactant: C[C@H](O)CC[C@H](C)O
Reactant: CCCCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1c(P2C(C)CCC2C)c(P2[C@H](C)CC[C@H]2C)c(C)n1-c1ccccc1
Reaction time: 1.5 h
Yield: 44 %

Procedure:
A solution of BuLi 1.6M in hexane (0.96 mL, 1.53 mmol) was dropped in a solution of 2,5-dimethyl-3,4bis-(phosphino)1-phenyl-pyrrole prepared as described in the previous stage (180 mg, 0.77 mmol) in THF (14.4 mL) and the reaction mixture was left under stirring for 1.5 h. 233 mg (1.53 mmol) of the cyclic sulfate of (2S,5S) hexanediol dissolved in 1.2 mL of THF were dropped in the reaction mixture, which was subsequently left under stirring for 1 h. The reaction mixture was quenched with methanol (0.3 mL) and the solvent evaporated under reduced pressure. The solid was then washed with n-heptane (3×20 mL) and the solvent was removed from the filtrate by evaporation under reduced pressure (20 torr), thereby obtaining the desired product (133 mg, yield 44%).