Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:22][CH2:23][OH:24].CN(C=O)C>C(OCC)(=O)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:22][CH2:23][OH:24])[CH:10]=2)[O:3]1
Reactant: OCCBr
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(CCO)c2)OC1(C)C
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
To a flask charged with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.000 g, 5.154 mmol), Cs2CO3 (2.687 g, 8.246 mmol), and 2-bromoethanol (0.5479 mL, 7.730 mmol) was added 10 mL of DMF and the flask was sealed under nitrogen and heated to 100° C. for 48 hours. The reaction was diluted with ethyl acetate (100 mL) and stirred for 30 minutes before it was passed through a glass microfiber filter and the cake was washed with ethyl acetate. The organic was concentrated under reduced pressure. The crude was then purified by silica gel chromatography eluting with a gradient of 75-100% ethyl acetate in Hexanes to afford 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanol (0.4290 g, 1.622 mmol, 31.47% yield). MS (apci) m/z=239.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][NH2:20])[CH2:14][CH2:13]1)[CH:6]=[CH:5]2.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:23].C(N(CC)C(C)C)(C)C.C(OC(C)C)(C)C>CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:13][CH2:14][CH:15]([CH2:18][CH2:19][NH:20][C:22](=[O:23])[O:24][C:25]3[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=3)[CH2:16][CH2:17]1)[CH:6]=[CH:5]2
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCCC1CCN(c2ccc3cc(Cl)ccc3n2)CC1
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)OC(C)C
Product: O=C(NCCC1CCN(c2ccc3cc(Cl)ccc3n2)CC1)Oc1ccc([N+](=O)[O-])cc1

Procedure:
The process is performed according to the method described in Example 1 (step 1.5.). Starting with 5.00 g (17.25 mmol) of 2-[1-(6-chloroquinolin-2-yl)piperidin-4-yl]ethylamine, prepared in step 6.3., 3.825 g (18.98 mmol) of 4-nitrophenyl chloroformate, 4.46 g (34.51 mmol) of N,N-diisopropylethylamine and 0.105 p (0.86 mmol) of N,N-dimethylaminopyridine, and after triturating from a mixture of diisopropyl ether and hexane, 7.8 g of pure product are obtained in the form of a white powder.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[NH:11][C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=3)=[C:13]([C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]=[CH:20][CH:19]=[CH:18]4)[N:14]=2)=[CH:5][C:3]=1[NH2:4].Br[CH2:33][CH2:34][OH:35].C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1.CN(C=O)C.O>[F:1][C:2]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[NH:11][C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=3)=[C:13]([C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]=[CH:20][CH:19]=[CH:18]4)[N:14]=2)=[CH:5][C:3]=1[NH:4][CH2:33][CH2:34][OH:35]
Reactant: OCCBr
Reactant: Cc1cccc(-c2[nH]c(Cc3ccc(F)c(N)c3)nc2-c2ccc3ncccc3c2)n1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(-c2[nH]c(Cc3ccc(F)c(NCCO)c3)nc2-c2ccc3ncccc3c2)n1
Temperature: 70 °C
Reaction time: 5 h
Yield: 34.3 %

Procedure:
To a suspension of 2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)aniline (Example 73) (100 mg, 0.244 mmol) in toluene (450 uL) and DMF (0.2 mL) were added 2-bromoethanol (21 uL, 0.293 mmol), N,N-diisopropylethylamine (300 uL, 1.72 mmol) and the mixture was stirred at 70° C. After 5 hours, additional 2-bromoethanol (5 uL) was added, and stirred at 100° C. for overnight. The reaction mixture was cooled to room temperature, diluted with H2O (4 mL), and extracted with CH2Cl2 (2 mL, 3 times). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by MPLC on NH silica gel (MeOH:CH2Cl2=1:50 (v/v)) to afford the title compound (38 mg, 34%). 1H NMR (300 MHz, CDCl3) δ 2.49 (3H, s), 3.31 (2H, bs), 3.83 (2H, t), 4.10 (2H, s), 6.56-6.60 (1H, m), 6.76 (1H, d), 6.87-6.96 (2H, m), 7.22 (1H, d), 7.34-7.42 (2H, m), 7.93 (1H, d), 8.09 (1H, d), 8.15 (2H, bs), 8.90 (1H, dd), 10.45 (1H, bs). MS (ESI) m/z 454 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:13][CH2:12][C:11](=O)[CH2:10]1.Cl.[NH2:16][OH:17].C(N(CC)CC)C>CCO>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:13][CH2:12][C:11](=[N:16][OH:17])[CH2:10]1
Reactant: O=C1CCC(c2ccc(O)cc2O)C1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: ON=C1CCC(c2ccc(O)cc2O)C1

Procedure:
(±)-3-(2,4-Dihydroxyphenyl)cyclopentanone (5 mg), hydroxylamine hydrochloride (2.7 mg) and triethylamine (5.4 uM) were heated in EtOH (4 ml) under reflux for 3 hr. The reaction mixture was partitioned between ethyl acetate (20 ml) and water (20 ml). The aqueous phase was extracted with ethyl acetate (10 ml), and the combined organic phases were washed with brine (10 ml), dried over magnesium sulfate, and concentrated in vacuo. The crude residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 4:1 v/v) to furnish the title compound as a white solid and a mixture of isomers (3.8 mg, 71%). δH (d4-MeOH) 1.80-1.93 (1H, overlapping m), 2.05-2.20 (0.5H, m), 2.39-2.55 (3H, overlapping m), 2.68-2.74 (1H, overlapping m), 2.94 (0.5H, br dd), 6.26-6.33 (2H, overlapping m), 6.94 (0.5H, d), 6.96 (0.5H, d); m/z (ES−) 266 ((M+60)−1)−.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([F:28])([F:27])[F:26])[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:32]O.Cl>CO.O.C(Cl)Cl>[O:3]=[C:4]1[CH:5]=[C:6]([C@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[CH2:9]2)[O:7][NH:32]1
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2ccccc2C(F)(F)F)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccccc1C(F)(F)F
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 68.2 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-(trifluoromethyl)benzyl)piperidine-1-carboxylate (2.062 g, 4.96 mmol) was dissolved in MeOH (16 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.199 g, 4.96 mmol) dissolved in water (1.600 mL) was added during 10 min and the colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.304 mL, 4.96 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3.5 h. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (25 mL, 150.00 mmol) and the mixture continued to stir at 80° C. for 20 min. DCM and water were added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a yellow semi-solid. The compound was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 5-30% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(2-(trifluoromethyl)benzyl)piperidine-1-carboxylate (1.30 g, 68%) was isolated as a white solid. 1H NMR (600 MHz, cdcl3) δ 1.79-1.95 (m, 2H), 1.95-2.14 (m, 2H), 2.79-2.98 (m, 3H), 3.17-3.27 (m, 1H), 3.34 (s, 3H), 4.04 (dd, 1H), 4.30-4.41 (m, 1H), 5.68 (s, 1H), 7.14 (d, 1H), 7.19-7.28 (m, 1H), 7.39 (t, 1H), 7.57 (d, 1H). MS m/z 385 (M+H)+
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:7][C:6]=1[NH2:8])([O-:11])=[O:10]
Reactant: C1CCNCC1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 4 h
Yield: 21.8 %

Procedure:
A mixture of 5-chloro-2-nitrophenylamine (5 g, 29 mmol), piperidine (2.9 mL, 29 mmol), and K2CO3 (4.0 g, 29 mmol) in DMF (20 mL) was stirred at 120° C. for 4 h. The reaction mixture was cooled to room temperature and poured into ice cold water (100 mL). The crude solid product was collected by filtration, air dried, and purified by flash chromatography (silica gel, 4×15 cm, eluted with CHCl3) to yield the product as orange crystals (1.4 g, 22%). See, Aust. J. Chem., 47:247-262 (1994).
Reaction SMILES: [O:1]1CCC[CH2:2]1.Br[C:7]1[CH:20]=[CH:19][C:10]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.C([Li])CCC.CN(C)C=O>C(OCC)(=O)C.O>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][CH2:11][C:10]1[CH:19]=[CH:20][C:7]([CH:2]=[O:1])=[CH:8][CH:9]=1
Reactant: Brc1ccc(COc2ccccn2)cc1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc(COc2ccccn2)cc1
Reaction time: 0.5 h

Procedure:
To a tetrahydrofuran solution (120 mL) of 2-(4-bromo-benzyloxy)-pyridine described in Preparation Example 1-4-1 (34 g, 128 mmol) was added n-butyl lithium (50 mL, 2.6M hexane solution, 134 mmol) dropwise at −78° C. After stirring for 30 minutes, to this reaction solution was added N,N-dimethylformamide (10 mL, 134 mmol) dropwise at −78° C, which was stirred at room temperature. To the reaction solution were added water and ethyl acetate to carry out liquid separation. The ethyl acetate layer was washed with water (twice) and sodium chloride water (once). The aqueous layers were combined and extracted with ethyl acetate. The resulting ethyl acetate layer was washed with water (twice) and sodium chloride water (once). The ethyl acetate layer obtained earlier and the ethyl acetate layer obtained this time were combined, dried over anhydrous magnesium sulfate and then filtered. The filtrate thereof was concentrated under a reduced pressure to obtain the title compound (26.8 g) as a crude product.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[CH:13][N:12]=[N:11]2)=[N:8][CH:9]=1)(=[O:3])[CH3:2].[Br:15][Si](C)(C)C.O>ClCCl.C(N(CC)CC)C>[Br:15][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[CH:13][N:12]=[N:11]2)=[N:8][CH:9]=1)=[O:3]
Reactant: C[Si](C)(C)Br
Reactant: CC(=O)c1ccc(-n2ccnn2)nc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CBr)c1ccc(-n2ccnn2)nc1
Temperature: 0 °C
Reaction time: 17 h

Procedure:
Next, the obtained 5-acetyl-2-(1H-1,2,3-triazole-1-yl)pyridine is dissolved in dichloromethane and triethylamine. The resulting solution is cooled down to about 0° C., and then bromotrimethylsilane is added thereto. This reaction solution is stirred at room temperature for 10-24 hours. Then, the reaction solution is poured into water and extracted with dichloromethane, and the dichloromethane layer is concentrated. The oily substance resulting from concentration is dried sufficiently and dissolved in tetrahydrofuran. This mixture is cooled down to about 0° C., N-bromosuccinimide is added thereto and stirred at room temperature for about 10-60 minutes. After the completion of the reaction, the solvent is distilled off and purified by chromatography, to obtain 5-(2-bromoacetyl)-2-(1H-1,2,3-triazole-1-yl)pyridine (FIG. 1, step 2). The amount of bromotrimethylsilane may be an amount equivalent or more relative to the reaction substrate, and is typically about 2.0 times greater in molar ratio than 5-acetyl-2-(1H-1,2,3-triazole-1-yl)pyridine. In addition, the amount of triethylamine may be an amount that can neutralize hydrobromic acid generated during reaction, and is typically an amount excessive relative to trimethylsilane bromide. The amount of N-bromosuccinimide may be an amount equivalent or more to the reaction substrate, and is preferably about 1.0 time in molar ratio as much as 5-acetyl-2-(1H-1,2,3-triazole-1-yl)pyridine.
Reaction SMILES: [Br:1][CH:2]1[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]([NH:7][C:8](=[O:9])[CH:3]12)=[O:6].N1C=CC=CC=1.[Cl:20][C:21]1[C:26]([C:27](Cl)=[O:28])=[C:25]([Cl:30])[C:24]([Cl:31])=[C:23]([Cl:32])[C:22]=1[Cl:33]>C1C=CC=CC=1>[Cl:20][C:21]1[C:26]([C:27]([N:7]2[C:8](=[O:9])[CH:3]3[CH:2]([Br:1])[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]3[C:5]2=[O:6])=[O:28])=[C:25]([Cl:30])[C:24]([Cl:31])=[C:23]([Cl:32])[C:22]=1[Cl:33]
Reactant: O=C(Cl)c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: O=C1NC(=O)C2C1CCC(Br)C2Br
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl)N1C(=O)C2CCC(Br)C(Br)C2C1=O
Temperature: 25 °C

Procedure:
3,4-Dibromohexahydrophthalimide (0.10 mole), benzene (300 ml) and pyridine (0.11 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Pentachlorobenzoyl chloride (0.10 mole) is then added dropwise to the flask with stirring at room temperature. After the addition is completed the reaction mixture is heated at reflux with continued stirring for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed filtrate is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(pentachlorobenzoyl)-3,4-dibromohexahydrophthalimide.
Reaction SMILES: [C:1]([O:13]C)(=O)[C:2]1[C:3](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:4]([O:6]C)=O.C[O-].[Na+].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=1.CCOCC>O1CCCC1.O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH:26]2[C:1](=[O:13])[C:2]3[C:3](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:4]2=[O:6])=[O:27])=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccccc1C(=O)OC
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1ccc(Cl)cc1)C1C(=O)c2ccccc2C1=O
Temperature: 20 °C

Procedure:
Dimethyl phthalate (15.0 g) in tetrahydrofuran (100 ml) was added to a stirred suspension of sodium methoxide (8.31 g) in tetrahydrofuran (60 ml) followed by 4′-chloroacetophenone (11.8 g) in tetrahydrofuran (100 ml) at 20° C. under nitrogen. The mixture was then boiled under reflux for 18 hours then cooled to 20° C. and poured into ether (250 ml) and water (250 ml). The aqueous layer was separated and the organic layer was washed with water (3×75 ml). The combined aqueous extract and washings were acidified with concentrated hydrochloric acid and the solid which precipitated was collected by filtration. The filtrate was extracted with dichloromethane, dried and evaporated. The residue was recrystallized from ethanol to give 2-(4-chlorobenzoyl)-indan-1,3-dione.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C@@H:10]([OH:20])[C:9](=[O:21])[C:8]=3[CH:7]=[CH:6][N:5]2[C:22]=1[CH3:23].[OH-].[Na+].[CH3:26]I.Cl>ClCCl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C@:10]([CH3:26])([OH:20])[C:9](=[O:21])[C:8]=3[CH:7]=[CH:6][N:5]2[C:22]=1[CH3:23]
Reactant: CI
Reactant: Cc1nc2c3c(ccn2c1C)C(=O)[C@H](O)[C@@H](c1ccccc1)N3
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: Cc1nc2c3c(ccn2c1C)C(=O)[C@@](C)(O)[C@@H](c1ccccc1)N3
Temperature: 25 °C
Reaction time: 16 h

Procedure:
20 g of (8R,9R)-2,3-dimethyl-8-hydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridin-7-one (WO 98/42707) are dissolved in 100 ml of dichloromethane, and the solution is treated with 4 g of tetrabutylammonium hydrogensulfate, 70 ml of 50% strength aqueous sodium hydroxide solution and with 5 ml of methyl iodide, stirred vigorously at room temperature for 16 h, adjusted to pH 7 using ½ conc. hydrochloric acid with cooling and extracted three times with 100 ml of dichloromethane each time. The organic phases are combined, washed twice with a little water and concentrated to dryness on a rotary evaporator, and the residue obtained is purified twice on silica gel (1st eluent: dichloromethane/methanol 100/3; 2nd eluent: dichloromethane/methanol 100/1). 7.9 g of the title compound are obtained as a yellowish crystallizate of melting point 240° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[C:9](=[O:17])[N:8]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=1[CH2:23]Cl)[CH2:2][CH2:3][CH3:4].[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.[K].O>CN(C)C=O>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[C:9](=[O:17])[N:8]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=1[CH2:23][N:29]1[C:25](=[O:35])[C:26]2[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:28]1=[O:30])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCCOc1c(CCl)n(CC(C)(C)C)c(=O)c2ccc(F)cc12
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1c(CN2C(=O)c3ccccc3C2=O)n(CC(C)(C)C)c(=O)c2ccc(F)cc12
Yield: 86.6 %

Procedure:
A solution of 4-butoxy-6-fluoro-3-chloromethyl-2-neopentyl-1(2H)-isoquinolinone (1.59 g, 4.5 mmol) and potassium phthalimide (1.26 g, 6.8 mmol) in N,N-dimethylformamide (20 ml) was stirred at room temperature for 6 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give 2-{(4-butoxy-6-fluoro-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione (1.81 g, 86.6%) as crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:5])=[C:3]=[O:4].[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[N:18]=[N:19][NH:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[C:31]#[N:32])#[N:7]>C(OCC)(=O)C.CCOCC>[C:3]([N:18]([C:9]1[CH:10]=[C:11]([C:14]([F:15])([F:16])[F:17])[CH:12]=[CH:13][C:8]=1[C:6]#[N:7])[N:19]=[N:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[C:31]#[N:32])(=[O:4])[CH:2]([CH3:5])[CH3:1]
Reactant: CC(C)=C=O
Reactant: N#Cc1ccc(C(F)(F)F)cc1N=NNc1cc(C(F)(F)F)ccc1C#N
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)C(=O)N(N=Nc1cc(C(F)(F)F)ccc1C#N)c1cc(C(F)(F)F)ccc1C#N
Reaction time: 12 h

Procedure:
A solution of 3.5 g. (0.05 mol.) of dimethylketene in ethyl acetate is added dropwise under a nitrogen atmosphere to a cooled (0°) solution of 18.6 g. (0.05 mol.) of 1,3-bis(2-cyano-5-trifluoromethylphenyl)triazene in ether. The reaction mixture is stirred for 12 hours then concentrated at reduced pressure. Crystallization of the residue from ether gives 3-isobutyryl-1,3-bis(2-cyano-5-trifluoromethylphenyl)triazene.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:16]([F:18])[CH3:17])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])[CH2:20][CH3:21].C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C.C(OCC)(=O)C>[CH2:19]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:13](=[O:15])[CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH:16]([F:18])[CH3:17])[CH2:27][CH2:26]1)=[O:24])[CH2:20][CH3:21]
Reactant: CCCOC(=O)N1CCNCC1
Reactant: CC(F)C(NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOC(=O)N1CCN(C(=O)C(NC(=O)OCc2ccccc2)C(C)F)CC1
Reaction time: 12 h

Procedure:
To a solution of 500 mg 2-Benzyloxycarbonylamino-3-fluoro-butyric acid in 3 ml DMF were added 310 mg 1-propoxycarbonylpiperazine, 0.50 ml N-ethylmorpholine and 643 mg TOTU. After stirring for 12 h it was diluted with ethyl acetate and extracted with aqueous LiCl (4% w/w), aqueous NaHCO3, 0.1 M HCl and brine. The organic layer was dried over MgSO4 and concentrated to furnish the crude coupling product which was used without further purification in the next step. Yield: 591 mg
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[O:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH:8]1[C:17]([OH:19])=O.C[N:21](C)C=O>O1CCCC1.O>[O:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH:8]1[C:17]([NH2:21])=[O:19]
Reactant: O=C(O)C1CCc2ccccc2O1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)C1CCc2ccccc2O1
Temperature: 25 °C
Yield: 97 %

Procedure:
Oxalyl chloride (11.0 mL, 126 mmol) was added dropwise to a cooled (0° C.) solution of the compound from Example 20 (15 g, 84.3 mmol) and N,N-dimethylformamide (1 mL) in tetrahydrofuran (250 mL). Upon completion of gas evolution the mixture was warmed to room temperature and concentrated in vacuo. The residue was dissolved in tetrahydrofuran (450 mL). The solution was cooled to -78° C. and ammonia condensed onto the mixture. After 30 minutes the mixture was warmed to room temperature, diluted with water, and extracted with ethyl acetate (2×). The combined organic phase was washed with saturated aqueous sodium chloride solution (2×), dried (MgSO4), and concentrated to give a solid. The solid was triturated with 1:1 diethyl ether/hexanes and dried at 50° C. in vacuo to give a colorless solid (14.5 g, 97%). Mp 125-127° C.; 1H NMR (acetone-d6, 300 MHz) δ 7.08 (m, 3 H), 6.86 (m, 2 H), 6.75 (br s, 1 H), 4.47 (dd, 9.2 Hz, 2.9 Hz, 1 H), 2.76 (m, 2 H), 2.28 (m, 1 H), 0.96 (m, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[C:21](Cl)(=[O:23])[CH3:22].[Cl-].[Cl-].[Cl-].[Al+3]>[N+](C1C=CC=CC=1)([O-])=O>[C:21]([C:9]1([C:14]2[CH:15]=[CH:16][C:17]([Br:20])=[CH:18][CH:19]=2)[CH2:10][CH:11]=[CH:12][CH:13]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: Brc1ccc(-c2ccccc2-c2ccc(Br)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)C1(c2ccc(Br)cc2)CC=CC=C1c1ccc(Br)cc1
Temperature: 80 °C

Procedure:
To 3.8 (0.01 mole) 4,4"-dibromoterphenyl in 200 ml nitrobenzene is added 0.86 g (0.011 mole) acetyl chloride and 1.46 g (0.011 mole) aluminum trichloride. The mixture is heated to 80° C. under inert atmosphere for three hours. The mixture is cooled to room temperature and washed with 1 m HCl. The organic layer of 2'-acetyl-4,4"-dibromoterphenyl is separated and the solids filtered and washed with several portions of ethanol, and dried.