Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18]C)[CH:14]=3)[CH2:9]2)=[CH:4][CH:3]=1>C(O)(=O)C.Br>[OH:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:17][CH2:16]2
Reactant: COc1ccc2c(c1)CCN(c1ccc(Cl)cc1)C2
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc2c(c1)CCN(c1ccc(Cl)cc1)C2
Yield: 38 %

Procedure:
7.0 g of the compound prepared under (b) are heated under reflux for 8 hours with a mixture of 50 ml of glacial acetic acid/hydrobromic acid (48% strength) in the volume ratio 1:1. After removing the acid in a rotary evaporator, the residue is taken up with methylene chloride/dilute ammonia, and the organic phase is dried and evaporated in a rotary evaporator. The oily residue is chromatographed on silica gel using a mixture of methylene chloride/ethyl acetate in the ratio 19:1. 2.2 g of pale yellow crystals (38% of theory) are obtained, melting point: 122°-123°.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][C:10]2=[O:15])=[CH:6][CH:5]=1)#[N:3].C(N(CC)CC)C.[Cl:25][CH2:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[Cl:25][CH2:26][S:27]([N:12]1[CH2:13][CH2:14][N:9]([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([C:2]#[N:3])=[CH:17][CH:16]=2)[C:10](=[O:15])[CH2:11]1)(=[O:29])=[O:28]
Reactant: O=S(=O)(Cl)CCl
Reactant: N#Cc1ccc(CN2CCNCC2=O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(CN2CCN(S(=O)(=O)CCl)CC2=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To a solution of 1-(4-cyanobenzyl)-2-piperazinone hydrochloride (3.78 g) and triethylamine (6.27 ml) in dichloromethane (50 ml) was added a solution of chloromethanesulfonyl chloride (2.68 g) in dichloromethane (10 ml) at 0° C. and the mixture was stirred at 0° C. for 1 hour. The reaction solution was diluted with dichloromethane, washed with sodium bicarbonate solution and saturated brine, dried (MgSO4) and concentrated, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:2) to give colorless crystals of 4-chloromethylsulfonyl-1-(4-cyanobenzyl)-2-piperazinone (4.01 g).
Reaction SMILES: [P:1]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[CH:11]([F:13])[F:12])=[O:2].[Br:20]N1C(=O)CCC1=O>C1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[P:1]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Br:20])=[CH:6][C:5]=1[CH:11]([F:13])[F:12])=[O:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOP(=O)(OCC)Oc1ccc(C)cc1C(F)F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CCOP(=O)(OCC)Oc1ccc(CBr)cc1C(F)F
Temperature: 80 °C
Yield: 69.8 %

Procedure:
200 mg of 2-(difluoromethyl)-4-methylphenyl diethyl phosphate (4C) was added to a solution of N-bromosuccinimide (254 mg) in benzene (10 mL), followed by the addition of benzoyl peroxide (3.2 mg). The reaction mixture was refluxed at 80° C. for about 48 hours and then cooled to room temperature and the succinimide residue removed by filtration. The filtrate was then washed successively with an aqueous solution of sodium bicarbonate, water, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation. Subsequent flash column chromatography afforded a light yellow oily liquid (177 mg, 70%): 1H-NMR (CDCl3, 500 MHz) δ 7.7 (s, 1H), 7.6 (d, J=8.4 Hz, 1H), 7.3 (d, J=8.4 Hz, 1H), 6.8-6.9 (t, J=5.6 Hz, 1H), 4.5 (s, 2H), 4.2 (q, 4H), 1.3 (t, J=7.1 Hz, 6H) (FIG. 11). 13C-NMR (CDCl3, 50 MHz) δ 138.8, 130.4, 124.9, 120.4, 110.6, 65.1, 38.5, 15.9 (FIG. 12). 31P-NMR (CDCl3, 81 MHz) δ −6.57. 19F-NMR (CDCl3, 188.3 MHz) δ −116.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)=[O:19])=[CH:15][CH:14]=[C:13]([OH:28])[CH:12]=2)=[O:10])=[N:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38]>CN(C=O)C.CCOC(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]([CH:14]=[CH:15][C:16]=2[NH:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)=[O:19])[O:28][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[O:10])=[N:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: N#Cc1ccc(C(=O)Nc2ccc(O)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(NC(=O)c2ccc(C#N)cc2)c(C(=O)Nc2ccc(Cl)cn2)c1
Reaction time: 1 h
Yield: 112.4 %

Procedure:
To a mixture of compound N-(5-chloro(2-pyridyl)){6-[(4-cyanophenyl)-carbonylamino]-3-hydroxyphenyl}carboxamide (50 mg, 0.13 mmol) and Cs2CO3 (83 mg, 0.25 mmol) in DMF (1 mL) at room temperature was added ethyl bromoacetate (15 μL, 0.13 mmol). The mixture was stirred for 1 hour before diluted with EtOAc (20 mL) and water (10 mL). The organic layer was washed with brine dried and evaporated to give 70 mg of the crude compound, which was used without farther purification. MS found for C24H19ClN4O5 (M+H)+: 479.0.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([F:10])[C:5]([Li])=[CH:4][CH:3]=1.[B:12](OC)([O:15][CH3:16])[O:13][CH3:14]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([B:12]([O:15][CH3:16])[O:13][CH3:14])=[C:6]([F:10])[C:7]=1[O:8][CH3:9]
Reactant: COB(OC)OC
Reactant: [Li]c1ccc(Cl)c(OC)c1F
Product: COB(OC)c1ccc(Cl)c(OC)c1F

Procedure:
Another embodiment of the present disclosure includes a method of forming 2-(4-chloro-2-fluro-3-methoxylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane that comprises contacting 2-chloro-6-fluoroanisole with n-butyl lithium to form 6-chloro-2-fluoro-3-lithioanisole. The 6-chloro-2-fluoro-3-lithioanisole may be contacted with trimethyl borate to form dimethyl 4-chloro-2-fluoro-3-methoxyphenylboronate. The dimethyl 4-chloro-2-fluoro-3-methoxyphenylboronate may be reacted with aqueous potassium hydroxide to form potassium (4-chloro-2-fluoro-3-methoxyphenyl)trihydroxyborate. The potassium (4-chloro-2-fluoro-3-methoxyphenyl)trihydroxyborate then may be reacted with aqueous hydrochloric acid to form 4-chloro-2-fluoro-3-methoxyphenylboronic acid. The 4-chloro-2-fluoro-3-methoxyphenylboronic acid may be reacted with 2,3-dimethyl-2,3-butanediol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](N)=[N:8][C:7]=1[C:12]([F:15])([F:14])[F:13])=[O:5])[CH3:2].N([O-])=O.[Na+].[BrH:20]>O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([Br:20])=[N:8][C:7]=1[C:12]([F:15])([F:14])[F:13])=[O:5])[CH3:2]
Reactant: Br
Reactant: CCOC(=O)c1sc(N)nc1C(F)(F)F
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1sc(Br)nc1C(F)(F)F
Reaction time: 0.5 h

Procedure:
To a solution of 2-amino-4-trifluoromethyl-thiazole-5-carboxylic acid ethyl ester (10 g) in 48% HBr (75 mL) at 0° C. is added a solution of sodium nitrite (4.25 g) in water (50 mL) dropwise over 1 h. The mixture is stirred at the same temperature for an additional 30 min, then a solution of CuBr (6 g) in 48% HBr (50 mL) is added dropwise over 30 min. The reaction mixture is stirred for additional 30 min at 0° C. and for 2 h at RT. The mixture is extracted three times with methylene chloride. The combined organic extracts are dried over magnesium sulfate and concentrated in vacuo. The residue is purified by chromatography (silica gel, hexane to 3% EtOAc/Hexane) to yield the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)#[N:2].[N:15]([Sn](CCCC)(CCCC)CCCC)=[N+:16]=[N-:17]>>[NH:15]1[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:2][N:17]=[N:16]1
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Product: c1ccc(N2CCNCC2)c(-c2nnn[nH]2)c1

Procedure:
A solution of 4-(2-cyano-phenyl)-piperazine (1.7 g, 9.0 mmol, 1.0 eq) in azidotributyltin (5.0 g, 15 mmol, 1.5 eq.) was stirred at 80° C. for about 5 days. Purification by SCX (10 g) ion exchange chromatography afforded crude 4-(2-tetrazole-5-yl-phenyl)-piperazine. LRMS (ESI+): 231.0 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:15]=2)[CH2:12][C:11]([C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])=[N:10]1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:20]3[CH2:25][CH2:24][N:23]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:22][CH2:21]3)[CH:15]=2)[CH2:12][C:11]([C:26]([F:32])([F:31])[C:27]([F:29])([F:30])[F:28])=[N:10]1
Reactant: CS(=O)(=O)Cl
Reactant: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2cccc(N3CCNCC3)c2)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccccc3Cl)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.6 %

Procedure:
1-(2-Chloro-phenyl)-5-[3-(piperazin-1-yl)-phenyl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Step 1, triethylamine (41.0 uL, 0.30 mmol) and methanesulfonyl chloride (8.3 mg, 0.07 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 3 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to give 15.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:12][N:11]([C:13](Cl)=[O:14])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:16][NH2:17]>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:12][N:11]([C:13]([NH:17][CH3:16])=[O:14])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CC(Sc2ccc(Cl)cc2)C1
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)N1CC(Sc2ccc(Cl)cc2)C1
Reaction time: 3 h
Yield: 93.5 %

Procedure:
A stirred solution of 2.6 g (0.01 mole) of 3-[(4-chlorophenyl)thio]-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was cooled in a water bath and treated with 2 ml (0.02 mole) of 40% methylamine in water. After 3 hr, the reaction mixture was diluted with 200 ml of water and the precipitated product collected by filtration (2.6 g). Recrystallization from benzene/methanol yielded 2.4 g (93.8%) of fine white crystals, m.p. 161°-162° C.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[Br:7][C:8]1[CH:9]=[C:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1.Cl>O1CCOCC1.CCOC(C)=O>[Br:7][C:8]1[CH:9]=[C:10]([S:14]([NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: CC(C)(N)CO
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(CO)NS(=O)(=O)c1cccc(Br)c1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
To a solution of commercially available 2-amino-2-methyl-1-propanol (8.91 g, 100 mmol) in dioxane (20 mL) at 5° C. was added commercially available 3-bromobenzenesulfonyl chloride (2.88 mL, 20 mmol) and the mixture was vigorously stirred at 23° C. for 1 h. Poured into 1 N HCl, diluted with EtOAc, separated phases, washed organic layer with brine, dried over Na2SO4. Removal of the solvent in vacuum left the title compound as a white solid (5.47 g, 89%). MS (ISN) 306.1 [(M−H)−] and 308.2 [(M+2−H)−]; mp 138° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([C:13]1[C:14](=[O:25])[O:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([OH:23])=[C:18]([OH:24])[CH:17]=2)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(OCC)(=O)C>[C:5]([C:13]1[C:14](=[O:25])[O:15][C:16]2[C:21]([CH:22]=1)=[C:20]([N+:1]([O-:4])=[O:2])[C:19]([OH:23])=[C:18]([OH:24])[CH:17]=2)(=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(c1ccccc1)c1cc2cc(O)c(O)cc2oc1=O
Reactant: O=[N+]([O-])O
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)c1cc2c([N+](=O)[O-])c(O)c(O)cc2oc1=O

Procedure:
Nitric acid solution (1.6 ml, 2 M in CH2Cl2) was added to a solution of 3-benzoyl-6,7-dihydroxy-chromen-2-one (0.89 g) in ethyl acetate (50 ml) at −16-10° C. The solvent was evaporated and the product run through a silica column with toluene-ethyl acetate acetic acid (8:1:1) as the solvent. The product was crystallized from ether. Yield: 40 mg, melting point 94-96° C.
Reaction SMILES: [CH2:1]([NH:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH3:5].Br[CH2:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:27]([CH3:38])[CH:26]=1.C(N(CC)C(C)C)(C)C>CC#N>[CH3:38][C:27]1[CH:26]=[C:25]([CH2:24][N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]2[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][CH:14]=3)[CH:10]=[CH:11][CH:12]=2)[CH:37]=[CH:36][C:28]=1[O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCCCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CCOC(=O)COc1ccc(CBr)cc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.9 %

Procedure:
To a solution of N-pentyl-N-[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amine (70 mg, 0.23 mmol) in anhydrous MeCN (6 mL) under nitrogen at room temperature, was added ethyl [4-(bromomethyl)-2-methylphenoxy]acetate (65.4 mg, 0.23 mmol) and N,N-diisopropyethylamine (39.6 μL, 0.23 mmol). The resultant solution was heated to reflux and stirred for 4 h. The reaction mixture was allowed to cool to room temperature and the solvent was removed in vacuo. The residue was partitioned between CHCl3 (20 mL) and water (10 mL). The organic solution was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification by SPE (5 g Silica cartridge) eluted with 1:200–1:100 EtOAc:cyclohexane afforded the title compound as a colourless oil (66 mg).
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH3:13].[C:14]12([CH2:24][C:25](Cl)=[O:26])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2>>[C:14]12([CH2:24][C:25]([NH:1][N:2]3[C:11](=[O:12])[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:4]=[C:3]3[CH3:13])=[O:26])[CH2:21][CH:20]3[CH2:19][CH:18]([CH2:17][CH:16]([CH2:22]3)[CH2:15]1)[CH2:23]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: Cc1nc2ccccc2c(=O)n1N
Product: Cc1nc2ccccc2c(=O)n1NC(=O)CC12CC3CC(CC(C3)C1)C2

Procedure:
3-Amino-2-methyl-4(3H)-quinazolinone and 1-adamantaneacetyl chloride were reacted as described in Example 5 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.60-1.74 (m, 9H), 1.94-1.98 (m, 3H), 2.13 (d, J=1.7 Hz, 1H), 2.39 (s, 3H), 7.50-7.56 (m, 1H), 7.63-7.65 (m, 1H), 7.82-7.88 (m, 1H), 8.11 (dd, J=8.1, 1.0 Hz, 1H), 10.87 (s, 1H) ppm; MS (DCI/NH3) m/z 352 (M+H)+; Elemental Analysis: Calculated for C20H25N3O2.H2O: C, 68.27; H, 7.37; N, 11.37. Found: C, 68.16; H, 7.40; N, 11.40.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[F:10])[CH:5]=O.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15]>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:13][C:14]([OH:16])=[O:15])[CH:7]=[C:8]([F:11])[C:9]=1[F:10]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: O=C(O)CC(=O)O
Product: O=C(O)C=Cc1cc(F)c(F)c(F)c1

Procedure:
According to the previously described general procedure (GP1), Knoevenagel condensation (75° C.; 3 h) between 3,4,5-trifluorobenzaldehyde (7.000 g; 43.724 mmol) and malonic acid (8.644 g; 83.076 mmol) gave the product 3-(3,4,5-trifluoro-phenyl)-acrylic acid as a yellow solid (8.600 g; 97%). LC-MS: tR=0.91 min.; [M+H]+: no ionisation.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([O:14][C:15]1[CH:24]=[C:23]([CH:25]2[CH2:28][CH2:27][CH2:26]2)[CH:22]=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:29]Br.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:7]([O:14][C:15]1[CH:24]=[C:23]([CH:25]2[CH2:28][CH2:27][CH2:26]2)[C:22]([Br:29])=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(C2CCC2)cc1OCc1ccccc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cc(Br)c(C2CCC2)cc1OCc1ccccc1
Reaction time: 1 h

Procedure:
Sodium carbonate (7.51 g) was added to a dichloromethane (150 mL) solution of methyl 2-(benzyloxy)-4-cyclobutylbenzoate (14 g), then a dichloromethane (25 mL) solution of bromine (3.17 mL) was slowly added thereto at 10 C, and the mixture was stirred at the same temperature as above for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, followed by extraction with ethyl acetate twice. The obtained organic layer was washed with a saturated aqueous solution of sodium bisulfite and saturated saline in this order and dried over anhydrous sodium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (12.2 g).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1F.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:16][C:17]1[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:21][C:22]=1[O:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc(CCCn3ccnc3)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.4 %

Procedure:
To a solution of 4-[3-(1H-imidazol-1-yl)propyl]phenol (405 mg) and 3-chloro-4-fluoronitrobenzene (370 mg) in N,N-dimethylformamide (4 mL) was added potassium carbonate (415 mg), and the mixture was stirred at room temperature for 16 hrs. Under ice-cooling, water was added and the mixture was extracted with ethyl acetate. The extract washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by basic silica gel column chromatography (eluent, ethyl acetate:hexane=80:20→100:0) to give the title compound (669 mg) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].[CH3:31][O:32][C:33]1[CH:34]=[N:35][CH:36]=[C:37]([Sn](CCCC)(CCCC)CCCC)[CH:38]=1.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.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>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([C:37]3[CH:36]=[N:35][CH:34]=[C:33]([O:32][CH3:31])[CH:38]=3)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc(-c2cncc(OC)c2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 60.8 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (70 mg, 0.15 mmol), 3-methoxy-5-tributylstannanyl-pyridine (90 mg, 0.23 mmol) and PdCl2(PPh3)2 (21 mg, 0.030 mmol) in 3 mL of DMF was heated at 120° C. for 3 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and brine were added. 1 M HCl was added with stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (10-85% EtOAc/hexanes+1% AcOH) to give 45 mg of the title compound as a light yellow solid. MS: (+) m/z 494.51 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:12]([CH3:23])([CH3:22])[C:4]=2[N:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.C(N(CC)C(C)C)(C)C.[F:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>C1COCC1>[F:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([NH:1][C:2]2[C:3]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:12]([CH3:22])([CH3:23])[C:4]=3[N:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=2)=[O:39])=[CH:36][CH:35]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)n1nc(N)c2c1C(C)(C)N(C(=O)OC(C)(C)C)C2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)n1nc(NC(=O)c2ccc(F)cc2)c2c1C(C)(C)N(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.9 %

Procedure:
5-tert-Butyl 1-ethyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate (2.0 g, 6.16 mmol) was dissolved in THF (40 ml), treated first with N,N-diisopropylethylamine (5.4 ml, 30.80 mmol) and then, at 0° C., with 4-fluorobenzoyl chloride (800 μl, 6.77 mmol) dissolved in THF (8 ml) dropwise. The reaction mixture was stirred at room temperature for 5 hours, concentrated and dissolved in DCM, washed with saturated sodium hydrogencarbonate aqueous solution and with brine. The organic phase was dried over sodium sulfate, evaporated and purified by flash chromatography (eluent hexane/EtOAc 80/20) to afford 2.5 g of the title compound in 90% yield.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]1[C:18]1[CH:37]=[CH:36][C:21]2[N:22]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][C:23]3=[N:24][C:20]=2[CH:19]=1.Cl>>[CH2:25]1[C:23]2=[N:24][C:20]3[CH:19]=[C:18]([N:3]4[CH:4]=[CH:5][C:6]([C:8]5[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][CH:9]=5)=[CH:7][C:2]4=[O:1])[CH:37]=[CH:36][C:21]=3[N:22]2[CH2:28][CH2:27][NH:26]1
Reactant: CC(C)(C)OC(=O)N1CCn2c(nc3cc(-n4ccc(-c5ccc(C(F)(F)F)cc5)cc4=O)ccc32)C1
Agent: Cl
Product: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(c1)nc1n2CCNC1
Yield: 53 %

Procedure:
tert-Butyl 8-(2-oxo-4-(4-(trifluoromethyl)phenyl)pyridin-1(2H)-yl)-3,4-dihydropyrazino[1,2-a]benzimidazole-2(1H)-carboxylate (15 mg, 0.023 mmol) was deprotected and converted to the hydrochloride according to Example 18 (step h) to provide the title compound (5 mg, 38%) as an orange solid: 1H NMR (500 MHz, DMSO-d6) δ 9.71 (s, 2H), 8.01 (d, J=8.3 Hz, 2H), 7.88 (d, J=8.3 Hz, 2H), 7.82 (d, J=7.8 Hz, 1H), 7.75 (m, 2H), 7.37 (d, J=8.4 Hz, 1H), 6.88 (s, 1H), 7.73 (d, J=7.5 Hz, 1H), 4.67 (s, 2H), 4.47-4.41 (m, 2H), 3.83-3.77 (m, 2H); ESI MS m/z 411 [M+H]+; HPLC (Method B) 91.3% (AUC), tR=12.8 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:28][CH3:29])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][C:21]=1[CH:26]=O)=[O:19])[CH3:13].N1CCCCC1>C(O)C>[CH2:28]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][C:21]=1[CH:26]=[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)[NH:7][C:6]1=[O:11])=[O:19])[CH3:29]
Reactant: CCN(CC)CCNC(=O)c1cc(C)[nH]c1C=O
Reactant: O=C1Cc2cc(Br)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1cc(C)[nH]c1C=C1C(=O)Nc2ccc(Br)cc21
Temperature: 80 °C

Procedure:
A mixture of 5-bromo-2-oxindole (106 mg, 0.5 mmol), 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (126 mg, 1 equiv.) and piperidine (0.2 mL) in ethanol (2 mL) was heated in a sealed tube at 80° C. for 1 hr and then cooled. The precipitate was collected by vacuum filtration, washed with ethanol and ethyl acetate and dried to give the title compound as an orange solid.