Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][N:5]([C:7]([C:9]1[C:18]2[C:13](=[C:14](Br)[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[O:22][CH3:23])=[O:8])[CH3:6].CN1CCCC1=O.[F:32][C:33]([F:38])([F:37])C([O-])=O.[Na+].[C-]#N.[K+]>O.C(OCC)(=O)C.[Cu]I.C(OCC)C>[CH3:1][O:2][C:3](=[O:24])[CH2:4][N:5]([C:7]([C:9]1[C:18]2[C:13](=[C:14]([C:33]([F:38])([F:37])[F:32])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[O:22][CH3:23])=[O:8])[CH3:6]
Reactant: O=C([O-])C(F)(F)F
Reactant: COC(=O)CN(C)C(=O)c1c(OC)ccc2c(Br)c(OC)ccc12
Agent: [Cu]I
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)CN(C)C(=O)c1c(OC)ccc2c(C(F)(F)F)c(OC)ccc12
Temperature: 180 °C
Yield: 89 %

Procedure:
A mixture of N-[5-bromo-2,6-dimethoxy-1-naphthalenyl)carbonyl]-N-methylglycine methyl ester (6.24 g, 15.7 mmol, described in Example 3), copper (I) iodide (11.99 g, 62.9 mmol), 1-methyl-2-pyrrolidinone (300 mL), and sodium trifluoroacetate (17.08 g, 12.6 mmol) was heated at 180° C. for 2 hours under an argon atmosphere. Upon cooling the residue was suspended in water (1 L) and ethyl ether (2 L) and potassium cyanide (30 g) were added with stirring. The organic layer was separated and washed sequentially with saturated NaHCO3, water (3X), saturated NaCl and then dried over Na2SO4. After concentration, silica gel chromatography using 10:1 CH2Cl2 :ethyl acetate as eluent gave 4.32 g (71% yield) of the title compound as a pale brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:17][CH2:16][CH2:15][CH:14]([OH:18])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH3:2].C1OCCOCCOCCOCCOCCOC1.[K].Br[CH2:40][C:41]1[C:42]([C:49]2[C:54]([Cl:55])=[CH:53][CH:52]=[CH:51][C:50]=2[Cl:56])=[N:43][O:44][C:45]=1[CH:46]1[CH2:48][CH2:47]1>C(O)(C)(C)C.O1CCCC1>[CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:17][CH2:16][CH2:15][CH:14]([O:18][CH2:40][C:41]3[C:42]([C:49]4[C:50]([Cl:56])=[CH:51][CH:52]=[CH:53][C:54]=4[Cl:55])=[N:43][O:44][C:45]=3[CH:46]3[CH2:48][CH2:47]3)[CH2:13][CH2:12]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: Clc1cccc(Cl)c1-c1noc(C2CC2)c1CBr
Reactant: CCOC(=O)c1ccc(N2CCCC(O)CC2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CCOC(=O)c1ccc(N2CCCC(OCc3c(-c4c(Cl)cccc4Cl)noc3C3CC3)CC2)cc1
Reaction time: 0.08 h

Procedure:
Anhydrous tetrahydrofuran (5 mL) is added at room temperature to a mixture of 4-(4-hydroxy-azepan-1-yl)-benzoic acid ethyl ester (364 mg, 1.38 mmol), 18-crown-6 (407 mg, 1.52 mmol) and tert-butyl alcohol, potassium derivative (178 mg, 1.52 mmol). The mixture is stirred for 5 minutes and then 4-bromomethyl-5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazole (480 mg, 1.38 mmol) is added. After 1.5 h, the solvent is removed and water is added. The aqueous phase is extracted with ethyl acetate. The organic layers are combined, dried over anhydrous sodium sulfate, filtered, and the solvent is removed under reduced pressure. The residue is purified via flash chromatography (40 g silica) eluting with a gradient of ethyl acetate/hexane (0% to 30%) to provide the title compound as a colorless waxy solid (203 mg, 28%). ES/MS m/z 529.0 (M+1).
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[NH2:15])[C:9]([OH:11])=[O:10].[C:16](=O)(O)[O-].[Na+]>CO>[CH3:16][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:14]([NH2:15])=[C:6]([NH2:5])[CH:7]=1
Reactant: O=C([O-])O
Reactant: Nc1ccc(C(=O)O)cc1N
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(N)c(N)c1
Yield: 81 %

Procedure:
To dry methanol (20 ml) was carefully added thionyl chloride (1 ml) dropwise with stirring. The 3,4-diaminobenzoic acid (1 g) was added in portions at R.T. with stirring then the mixture heated at reflux for 3 h. Saturated sodium bicarbonate was added until the mixture was basic, then the mixture extracted into chloroform containing 25% methanol. The extract was dried and evaporated in vacuo to give the product (0.88 g, 81%) as a brown crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.C(N(CC)CC)C.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=O)C.CO>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([C:18]([F:17])([F:28])[F:29])=[CH:20][CH:21]=2)[C:3]([OH:9])=[N:4][CH:5]=1
Reactant: Nc1cc(Br)cnc1O
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(Nc1cc(Br)cnc1O)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
To a solution of 3-amino-5-bromopyridin-2-ol from Step C (1.5 g, 7.9 mol) and triethylamine (1.64 mL, 11.9 mol) in tetrahydrofuran (15.8 mL) at 0 C was added dropwise 4-trifluoromethylbenzoyl chloride (1.2 mL, 7.9 mol). The reaction mixture was stirred at 0° C. for 1 h and warmed to room temperature for 15 h. Potassium carbonate (1.64 g, 11.9 mol) and methanol (15.8 mL) were added and the reaction mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with saturated ammonium chloride solution and brine. The separated organic layer was dried with sodium sulfate, filtered and concentrated in vacuo. Purification by medium pressure liquid chromatography on silica gel (1:5 ethyl acetate/hexanes) gave 1.72 g (60%) of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:8](Cl)[CH:7]=[CH:6][N:5]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>ClCCl>[CH3:1][O:2][CH2:3][C:4]1[N:9]=[C:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:7]=[CH:6][N:5]=1
Reactant: COCc1nccc(Cl)n1
Reactant: C1COCCN1
Solvent: ClCCl
Product: COCc1nccc(N2CCOCC2)n1

Procedure:
A solution of 12 g of 2-methoxymethyl-4-chloropyrimidine and 15 ml of morpholine in 50 ml of dichloromethane was stirred at room temperature for 3 hours. The reaction solution was washed several times with water. The organic phase was dried and, after purification by column chromatography, yielded 13 g of 2-methoxymethyl4-morpholinopyrimidine as an oil.
Reaction SMILES: C([O:8][C:9](=[O:24])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])C1C=CC=CC=1.CO>O.[Pd]>[C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([OH:24])=[O:8])(=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CCCCCCCC(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.1 %

Procedure:
To a solution of N-octanoyl-L-proline benzyl ester (7.04 g) in 1% water-containing methanol (70 ml) was added 10% Pd-C (0.71 g), and the mixutre was stirred under hydrogen atmosphere at room temperature for 1.5 hours. After the catalyst was filtered off, the filtrate was concentrated to give 5.08 g of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH:11]([OH:24])[CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[S:21][C:20]([CH3:22])=[N:19][C:18]=3[CH:23]=2)[CH2:6][CH2:5]1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>COCCOC>[OH:24][C@@H:11]([CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]2[S:21][C:20]([CH3:22])=[N:19][C:18]=2[CH:23]=1)[CH2:10][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][S:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:33])=[O:32])[CH2:5][CH2:6]1
Reactant: Cc1nc2cc(OCC(O)CN3CCN(CCN)CC3)ccc2s1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: COCCOC
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(CCNS(=O)(=O)c4ccccc4)CC3)ccc2s1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of 1-[4-(2-aminoethyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2-ol (60 mg, 0.171 mmol) in DME (6 mL) was cooled to 0° C. and benzene sulfonyl chloride (0.022 mL, 0.172 mmol) was added. The solution was stirred at 0° C. for 5 min and then at RT for 10 min. The reaction mixture was concentrated to an oil and purified via flash column chromatography (9:1 CHCl3/MeOH) to afford (2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)(phenylsulfonyl)amine.
Reaction SMILES: [CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[N+:15]([O-])=O)[CH:2]([CH3:4])[CH3:3]>C1(C)C=CC=CC=1.[Pd]>[CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[NH2:15])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CC(C)Cc1c(N)cnc2ccccc12

Procedure:
The nitroxide group on the 4-isobutyl-3-nitro quinoline produced in Example 1 is reduced by catalytic reduction using toluene as solvent, Pd/C5% (50% wet) as catalyst, at 40-45° C. and atmospheric pressure to produce 4-isobutyl 3-amino quinoline. The rate of reaction depends on efficiency of stirring. After catalyst filtration the solution is ready for the next step.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[O:47]1[CH2:52][CH2:51][N:50]([C:53]([C:55]2[N:56]=[C:57]([C:64]([F:67])([F:66])[F:65])[N:58]3[CH2:63][CH2:62][NH:61][CH2:60][C:59]=23)=[O:54])[CH2:49][CH2:48]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:61]1[CH2:62][CH2:63][N:58]2[C:57]([C:64]([F:66])([F:67])[F:65])=[N:56][C:55]([C:53]([N:50]3[CH2:51][CH2:52][O:47][CH2:48][CH2:49]3)=[O:54])=[C:59]2[CH2:60]1)=[O:5]
Reactant: O=C(c1nc(C(F)(F)F)n2c1CNCC2)N1CCOCC1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCOCC3)c2C1
Reaction time: 12 h
Yield: 19.7 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (390 mg, 1.30 mmol) was dissolved in 10 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (983 mg, 2.60 mmol), crude morpholino-[3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl]methanone 20d (400 mg, 1.30 mmol) and N, N-diisopropylethylamine (0.7 mL, 3.90 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[4-fluoro-3-[1-(morpholine-4-carbonyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 20 (150 mg, yield 20.0%) as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[C:4]=1[C:10]#[N:11].Br[CH2:13][CH:14]([CH3:16])[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[CH2:13]([N:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:10]#[N:11])[C:5]1=[O:9])[CH:14]([CH3:16])[CH3:15]
Reactant: COc1cc[nH]c(=O)c1C#N
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccn(CC(C)C)c(=O)c1C#N
Temperature: 50 °C
Reaction time: 24 h
Yield: 63.1 %

Procedure:
A mixture of 4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile (15.00 g), 1-bromo-2-methylpropane (21.4 g), cesium carbonate (65.2 g) and dimethyl sulfoxide (150 mL) was stirred at 50° C. for 24 hr. The reaction mixture was cooled to room temperature, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with ether to give the title compound (13.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:6]([C:7]([O:9]C)=[O:8])[C:5]([OH:12])=[CH:4][CH:3]=1.[OH-].[Na+].S(OC)(O[CH3:19])(=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:19])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)ccc1O
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COc1ccc(Cl)cc1C(=O)O
Reaction time: 0.17 h

Procedure:
To a solution of methyl 5-chlorosalicylate (20 g.) in acetone 110 ml.) was added 2 N sodium hydroxide (66 ml.) and dimethyl sulphate (13.86 g.). The mixture was stirred for 10 minutes, sodium hydroxide 33 ml., 2N) and dimethyl sulphate (6.93 g.) added, and the mixture was heated under reflux for 45 minutes. The product was then cooled, the acetone evaporated off, and the residue was taken up in ether. The ether was extracted with dilute sodium hydroxide, evaporated off, and the residue heated under reflux for 1 hour with 10 aqueous sodium hydroxide (100 ml.). The product was cooled and acidified. The precipitate acid was filtered off and recrystallized from ethanol-water to give 8 g., m.p. 80°-81° (45%) with a second crop of 0.8 g., m.p. 77°-79° (4.5%).
Reaction SMILES: C[O:2][C:3]1[C:16]2[C:7](=[C:8]3[C:13](=[C:14]([F:17])[N:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:6]=[CH:5][CH:4]=1.Br.C(=O)([O-])[O-].[Na+].[Na+]>>[OH:2][C:3]1[C:16]2[C:7](=[C:8]3[C:13](=[C:14]([F:17])[N:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1nc(F)c1ccccc12
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Oc1cccc2c1nc(F)c1ccccc12
Yield: 96.8 %

Procedure:
A mixed solution comprising 115 mg of 4-methoxy-6-fluorophenanthridine and 5 ml of 48% hydrobromic acid was allowed to react at 116° C. for a period of 14 hr. After the completion of the reaction, the reacted solution was introduced into an aqueous solution of sodium carbonate and the product was extracted by ethyl acetate. After ethyl acetate was distilled away, the residue was purified by column chromatography to obtain 104.5 mg of 4-hydroxy-6-fluorophenanthridine on recrystallization from hexane (yield 96.9%).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:13])[CH3:2].N1C=CC=CC=1.[Cl:20][CH2:21][C:22](Cl)=[O:23]>ClCCl>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:22](=[O:23])[CH2:21][Cl:20])=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:13])[CH3:2]
Reactant: CCN1C(=O)Cc2cc(O)ccc21
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN1C(=O)Cc2cc(OC(=O)CCl)ccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a slurry of 100 g. (0.565 mole) of 1-ethyl-5-hydroxyoxindole in 91.3 ml. (1.13 moles) of pyridine and 565 ml. of dichloromethane at 0° C. was added dropwise a solution of 89.3 ml. (1.13 moles) of chloroacetyl chloride in 100 ml. of dichloromethane. The reaction mixture was allowed to stir for 15 minutes, and was then added to 1 l. of ice cold 2N hydrochloric acid and 500 ml. of dichloromethane. The aqueous layer was extracted once again with 300 ml. of dichloromethane and the combined organic extracts washed once with 500 ml. of a saturated brine solution, dried over magnesium sulfate and concentrated to give the desired product in quantitative yield. A small sample was crystallized from hexane, m.p. 53°-57° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]12[CH2:12][CH2:11][C:8]([C:13]([O:15][CH3:16])=[O:14])([CH2:9][CH2:10]1)[CH2:7][CH2:6]2.N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl.C(OCC)(=O)C>[CH3:23][S:24]([O:1][CH2:2][CH2:3][CH2:4][C:5]12[CH2:10][CH2:9][C:8]([C:13]([O:15][CH3:16])=[O:14])([CH2:11][CH2:12]1)[CH2:7][CH2:6]2)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C12CCC(CCCO)(CC1)CC2
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C12CCC(CCCOS(C)(=O)=O)(CC1)CC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Hydroxyester 11-4 (430 mg, 1.9 mmol) was dissolved in 2.5 mL of anhydrous methylene chloride under nitrogen atmosphere, treated with pyridine (0.5 mL) and methanesulfonyl chloride (0.368 mL, 4.8 mmol) and stirred for 4 h at room temperature. The mixture was diluted with 100 mL of ethyl acetate and washed with 1N aqueous HCl, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated. The crude methyl 4-{3-[(methylsulfonyl)oxy]propyl}bicyclo-[2.2.2]octane-1-carboxylate (11-5) thus afforded was used without purification in the next reaction. 1H NMR (500 MHz, CDCl3): δ 4.22 (2H, t, J=7.5 Hz), 3.68 (3H, s), 3.04 (3H, s), 1.82 (6H, m), 1.70 (2H, m), 1.44 (6H, m), 1.24 (2H, m) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[CH3:10].C(Br)(Br)(Br)[Br:12].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:12])=[CH:4][C:3]=1[CH3:10]
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cc(CO)ccc1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(CBr)ccc1Br
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(4-Bromo-3-methylphenyl)methanol (14.4 g, 71.6 mmol) is dissolved in anhydrous CH2Cl2 (150 mL) and CBr4 (26.1 g, 79.0 mmol) is added. The reaction mixture is cooled to 0° C. and PPh3 (20.7 g, 79.0 mmol) is added in small portions. The reaction mixture is stirred 2 h and the triphenylphosphine oxide that forms is filtered off and the solvent removed in vacuo. The resulting semi solid is filtered on a silica gel pad and rinsed with hexane/EtOAc (9:1) to provide the expected product 1-Bromo-4-(bromomethyl)-2-methylbenzene as a clear oil contaminated with bromoform which is used directly in the next step. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 4.39-4.44 (m, 3H) 7.07 (dd, J=8.20, 2.34 Hz, 1H) 7.26 (t, J=1.17 Hz, 1H) 7.49 (d, J=8.20 Hz, 1H)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH2:27][Cl:28]>CC(=O)CC.C(OCC)(=O)C>[Cl:28][CH2:27][CH2:26][CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(-c2ccc(OCCCCl)cc2)cc1
Temperature: 25 °C
Yield: 91.6 %

Procedure:
The product from Example 10A (4.50 g, 19.7 mmol), K2CO3 (4.0 g, 29.6 mmol) and 3-bromochloropropane (3.88 g, 24.6 mmol) in 2-butanone (100 mL) were heated at reflux for 24 hours. The mixture was allowed to cool to ambient temperature and then diluted with ethyl acetate (200 mL). The mixture was washed with water (2×100 mL) and brine (100 mL) and the remaining organic layer was dried over MgSO4 and filtered. The filtrate was evaporated under reduced pressure to provide the title compound as an off-white solid (5.5 g, 92% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:26])=[C:8]([C:16]([C:18]2[CH:19]=[N:20][N:21]([CH2:24][CH3:25])[C:22]=2[OH:23])=[O:17])[CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:14])=[O:13].C(N(CC)CC)C.[CH3:34][CH2:35][S:36][C:37](Cl)=[O:38].C(OCC)(=O)C>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:26])=[C:8]([C:16]([C:18]2[CH:19]=[N:20][N:21]([CH2:24][CH3:25])[C:22]=2[O:23][C:37]([S:36][CH2:35][CH3:34])=[O:38])=[O:17])[CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(OCCOC)c2C)c1O
Reactant: CCSC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCSC(=O)Oc1c(C(=O)c2ccc(S(C)(=O)=O)c(OCCOC)c2C)cnn1CC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The crude 5-hydroxy-1-ethylpyrazol-4-yl 3-(2-methoxyethoxy)-2-methyl-4-(methylsulfonyl)phenyl ketone obtained in the above step (1) was dissolved in anhydrous THF (10 mL), and triethylamine (139 mg) and 96% S-ethyl chlorothiolformate (111 mg) were added, followed by stirring for 1 hour at room temperature. Ethyl acetate (200 mL) was added to the obtained reaction mixture, and the mixture was washed twice with a saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain the desired product (170 mg).
Reaction SMILES: OC1C=C(CNC=C2C3C(=CC=C(I)C=3)C(=O)NC2=O)C=CC=1C1C=CC=CC=1.[C:30]([C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[C:40](=[O:44])[NH:39][C:38](=[O:45])[C:37]2=[CH:46]OC)([CH3:33])([CH3:32])[CH3:31].[NH2:49][CH2:50][C:51]1[CH:52]=[CH:53][C:54]([C:58]2[CH:62]=[CH:61][O:60][CH:59]=2)=[C:55]([OH:57])[CH:56]=1>>[C:30]([C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[C:40](=[O:44])[NH:39][C:38](=[O:45])[C:37]2=[CH:46][NH:49][CH2:50][C:51]1[CH:52]=[CH:53][C:54]([C:58]2[CH:62]=[CH:61][O:60][CH:59]=2)=[C:55]([OH:57])[CH:56]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: NCc1ccc(-c2ccoc2)c(O)c1
Reactant: COC=C1C(=O)NC(=O)c2ccc(C(C)(C)C)cc21
Agent: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccccc2)c(O)c1
Product: CC(C)(C)c1ccc2c(c1)C(=CNCc1ccc(-c3ccoc3)c(O)c1)C(=O)NC2=O
Yield: 50 %

Procedure:
Following the same procedure for the preparation of 4-{[(2-Hydroxy-biphenyl-4-ylmethyl)-amino]-methylene}-6-iodo-4H-isoquinoline-1,3-dione, the title compound (purified through chromatography) is prepared from 6-tert-Butyl-4-methoxymethylene-4H-isoquinoline-1,3-dione (˜15 mg, 0.058 mmol) and 5-Aminomethyl-2-furan-3-yl-phenol (40 mg, 0.21 mmol) in 50% yield: MS (ESI): 415.1 (M−1)−1.
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.[C:9]1([CH:15]2[CH2:21][CH2:20][CH2:19][CH2:18][NH:17][CH2:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH:22]([C:24]1[CH:39]=[CH:38][C:27]([O:28][C:29]2[CH:37]=[CH:36][C:32]([C:33]([NH2:35])=[O:34])=[CH:31][N:30]=2)=[CH:26][CH:25]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[C:9]1([CH:15]2[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:22][C:24]3[CH:39]=[CH:38][C:27]([O:28][C:29]4[CH:37]=[CH:36][C:32]([C:33]([NH2:35])=[O:34])=[CH:31][N:30]=4)=[CH:26][CH:25]=3)[CH2:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Reactant: c1ccc(C2CCCCNC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: NC(=O)c1ccc(Oc2ccc(CN3CCCCC(c4ccccc4)C3)cc2)nc1
Yield: 92.4 %

Procedure:
Using a method similar to Example 345, using 3-phenyl-azepane fumaric acid salt (0.122 g, 0.419 mmol), 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.100 g, 0.415 mmol), sodium triacetoxyborohydride (0.129 g, 0.609 mmol), and acetic acid (0.034 mL, 0.594 mmol) in 1,2-dichloroethane (8.0 mL) provides 0.154 g (93%) of the title compound as a white solid: high resolution mass spectrum (electrospray): m/z calc for C25H28N3O2 402.2182, found 402.2199; 1H NMR (DMSO-d6): 8.61 (d, 1H, J=1.8 Hz), 8.25 (dd, 1H, J=2.6, 8.8 Hz), 8.02 (s, 1H), 7.47 (s, 1H), 7.38 (d, 2H, J=8.4 Hz), 7.27-7.02 (m, 5H), 3.70 (d, 1H, J=13.5 Hz), 3.64 (d, 1H, J=13.5 Hz), 2.89-2.63 (m, 5H), 1.81-1.59 (m, 6H).