Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][NH:7][C:8](=[O:26])[C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[NH2:25])[CH3:2].[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1.C([SiH](CC)CC)C>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][NH:7][C:8](=[O:26])[C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=2)[CH:12]=[CH:11][C:10]=1[NH:25][CH2:33][C:32]1[CH:35]=[CH:36][C:29]([Cl:28])=[CH:30][CH:31]=1)[CH3:2]
Reactant: CCOC(=O)CCNC(=O)c1cc(OCc2ccc(C#N)cc2)ccc1N
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC[SiH](CC)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCNC(=O)c1cc(OCc2ccc(C#N)cc2)ccc1NCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.5 %

Procedure:
A solution of 1.03 g (2.80 mmol) of N-(5-(4-cyanobenzyloxy)-2-aminobenzoyl)-b-alanine ethyl ester, 394 mg (2.80 mmol) of p-chlorobenzaldehyde, and 20 mg of p-toluenesulfonic acid in 30 mL of toluene was heated at reflux through a Dean-Stark trap for 45 min. The solvent was removed in vacuo and the residue was dissolved in 15 mL of trifluoroacetic acid. Triethylsilane (1.34 mL, 8.40 mmol) was added and the mixture was stirred at room temperature for 12 h, concentrated in vacuo, and partitioned between 1N aqueous sodium bicarbonate and ethyl acetate. The organic phase was washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated. Chromatography (silica gel-60, 2:3 ethyl acetate/hexane) gave 820 mg (59%) of N-(5-(4-cyanobenzyloxy)-2-(4-chlorobenzylamino)benzoyl)-b-alanine ethyl ester as a colorless solid. 1H NMR (300 MHz, CDCl3) d 7.66 (2H, d, J=7.8 Hz, NC-Ar-H2), 7.51 (2H, d, J=7.8 Hz, NC-Ar-H2), 7.27 (4H, s, ClArH4), 6.98 (1H, d, J=2.0 Hz, O-Ar-H), 6.89 (1H, dd, J=2.0, 9.3 Hz, O-Ar-H), 6.78 (1H, b, N-H), 6.66 (1H, d, J=9.3 Hz, O-Ar-H), 5.03 (2H, s, ArCH2O), 4.32 (2H, s, ClArCH2), 4.17 (2H, q, J=7.3 Hz, OCH2CH3), 3.65 (2H, bq, J=5.7 Hz, NHCH2CH2), 2.62 (2H, t, J=5.7 Hz, NHCH2CH2), 1.28 (3H, t, J=7.3 Hz, OCH2 CH3); Exact mass (FAB, M+H+) calcd for C27H27 ClN3O4 : 492.1690; Found: 492.1681.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:26]=[C:27]([F:29])[CH:28]=1)[NH2:25]>>[F:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[C:3]3[CH:4]=[CH:5][C:6]([NH:20][CH2:19][C:17]4[O:18][C:14]([CH3:13])=[CH:15][CH:16]=4)=[N:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH:26]=[C:27]([F:29])[CH:28]=1
Reactant: Cc1ccc(CN)o1
Reactant: Nc1cc(F)cc(F)c1
Reactant: Clc1ccc2c(I)cccc2n1
Product: Cc1ccc(CNc2ccc3c(Nc4cc(F)cc(F)c4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=366.1 (M+H+), was prepared in accordance with the general method of example 1 from 5-iodo-2-chloroquinoline (CAS 455955-26-7), 5-methyl-2-furanmethanamine and 3,5-difluoroaniline.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[C:10]=1[CH3:16].[CH:17](N1CCCCC1)=[O:18].Cl>O1CCCC1.BrC(Br)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:17]=[O:18])[C:10]=1[CH3:16]
Reactant: Cc1c(Br)cccc1COC1CCCCO1
Reactant: O=CN1CCCCC1
Agent: CC(Br)Br
Agent: Cl
Solvent: C1CCOC1
Product: Cc1c(C=O)cccc1COC1CCCCO1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
1.2 g of Mg (magnesium turnings) in 15 ml of absolute tetrahydrofuran are initially taken under a nitrogen atmosphere. A few drops of dibromoethane are added at 65° C. A solution of 14.25 g of 3-bromo-2-methylbenzyl tetrahydro-2-pyranyl ether in 50 ml of tetrahydrofuran is added dropwise while the temperature is kept at 65° C. The stirred mixture is then refluxed for 2 hours. A solution of 5.65 g of N-formylpiperidine in 10 ml of absolute tetrahydrofuran is added dropwise to the reaction mixture, which has been cooled to 0° C. Stirring is carried out for 20 hours at room temperature and the mixture is rendered slightly acidic with about 50 ml of 5% strength hydrochloric acid and is extracted several times with ether. The combined ether extracts are washed with water, dried and evaporated down. The crude product (11 g) can be purified by column chromatography over silica gel using 97.5:2.5 toluene/acetone.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.O.O.O.[F-].[Si]([O:29][C@@H:30]([CH2:41][CH2:42][N:43]([CH3:45])[CH3:44])[C:31]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][N:35]=1)=[O:32])(C(C)(C)C)(C)C.O.CCOC(C)=O>C1COCC1>[CH3:45][N:43]([CH3:44])[CH2:42][CH2:41][C@H:30]([OH:29])[C:31]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][N:35]=1)=[O:32]
Reactant: Cc1ccc(NC(=O)[C@H](CCN(C)C)O[Si](C)(C)C(C)(C)C)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(NC(=O)[C@@H](O)CCN(C)C)nc1
Reaction time: 0.5 h
Yield: 52.7 %

Procedure:
Tetrabutylammoniumfluoride trihydrate (417 mg, 1.32 mmol) was added to a stirred solution of (2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-(dimethylamino)-N-(5-methylpyridin-2-yl)butanamide (Step 3) (310 mg, 0.88 mmol) in THF (5 mL). The reaction mixture was kept at ambient temperature for 30 minutes. Water and EtOAc were added and the two phases were separated. The organic phase was dried over MgSO4 and concentrated in vacuo. The residue was purified with column chromatography (silica gel, eluting with EtOAc/MeOH:10/1) to give the title compound as a solid (110 mg), 1H NMR (300 MHz, CDCl3) δ 9.44 (br s, 1H), 8.15 (d, 1H), 8.12 (d, 1H), 7.51 (dd, 1H), 4.39 (dd, 1H), 2.63 (m, 2H), 2.28 (m, 9H), 2.09 (m, 1H), 1.92 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][N:9]=2)[C:5]([Cl:16])=[CH:4][N:3]=1.[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.[F-].[Cs+]>CS(C)=O.CCOC(C)=O>[Cl:16][C:5]1[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][N:9]=2)=[CH:7][C:2]([N:20]2[CH2:19][CH2:18][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21]2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cnc(-c2cc(Cl)ncc2Cl)c(C)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1cnc(-c2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ncc2Cl)c(C)c1
Temperature: 120 °C
Yield: 78.1 %

Procedure:
To a solution of 2′,5′-dichloro-3,5-dimethyl-2,4′-bipyridine (4.5 g, 17.8 mmol) and tert-butyl piperazine-1-carboxylate (4.0 g, 21.4 mmol) in DMSO (80 mL) was added CsF (5.4 g, 35.6 mmol). Then the mixture was heated at 120° C. for 18 hours. TLC (petroleum ether/EtOAc=2:1) showed that the reaction was complete. It was diluted with EtOAc (200 mL), washed with H2O (70 mL) and brine (70 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (petroleum ether/EtOAc=3:1) to afford title compound (5.6 g, 78%) as white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])=[C:6]([OH:8])[CH:7]=1.[Br:13]C1C=CC(O)=CC=1.C(O)(C)(C)C.S(=O)(=O)(O)O>C(Cl)(Cl)(Cl)Cl>[Br:13][C:3]1[CH:2]=[CH:7][C:6]([OH:8])=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:4]=1
Reactant: CC(C)(C)c1ccc(Br)cc1O
Reactant: Oc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(C)(C)O
Product: CC(C)(C)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Using the same procedure as for the preparation of 5-bromo-2-t-butylphenol (Compound D), but instead using 50 g (289.0 mmol) of 4-bromophenol, 21.40 g (27.25 ml, 289.0 mmol) of t-butanol and 14 ml of conc. sulfuric acid (added slowly) and 140 ml of distilled carbon tetrachloride, stirred at room temperature for 24 hours produced a dull green-colored solution and a white precipitate. At this time an additional 3.5 ml of conc. sulfuric acid was added and the solution was allowed to stir for 4 days more at room temperature. After aqueous workup, a dark yellow oil was isolated. Purification by flash chromatography (silica, 2% ethyl acetate in hexane) yielded the title compound as a clear, light yellow oil. PMR (CDCl3): d 1.38 (9H, s), 4.79 (1H, s), 6.54 (1H, d, J=8.5 Hz), 7.16 (1H, dd, J=8.5, 2.5 Hz), 7.35 (1H, d, J=2.5 Hz).
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([Li])CCC.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27]>C1COCC1>[CH2:27]([C:1]1([S:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])(=[O:6])=[O:5])[CH2:2][CH2:3]1)[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]=[CH2:21]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)C1CC1
Reactant: C=CCCCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCCCCCC1(S(=O)(=O)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 44.3 %

Procedure:
To a solution of tert-butyl cyclopropylsulfonylcarbamate (885 mg, 4 mmol) in THF (20 mL) at −78° C. was added n-Butyllithium (3.36 mL, 8.40 mmol) (2.5 M in hexanes) dropwise. The formed solution was warmed up to r.t. and stirred for 1.5 h. Cooled this light yellow solution back to −78° C. 7-Bromo-1-heptene (1.219 mL, 8.00 mmol) was added dropwise. The final solution was allowed to warm up to r.t. over the period of 16 h. Quenched with sat. NH4Cl, extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by Biotage column, eluted with gradient 5%˜40% EtOAc-Hexane to afford the desired product tert-butyl 1-(hept-6-enyl)cyclopropylsulfonylcarbamate (625 mg, 1.772 mmol, 44.3% yield) as a viscous oil, which solidified upon standing on bench. 1H NMR (400 MHz, CHLOROFORM-D) ppm 0.88-1.02 (m, 2 H) 1.26-1.49 (m, 6 H) 1.53 (s, 9 H) 1.60-1.71 (m, 2 H) 1.82-1.94 (m, 2 H) 2.06 (q, J=6.94 Hz, 2 H) 4.81-5.08 (m, 2 H) 5.68-5.88 (m, 1 H) 6.88 (b, NH). LC-MS (retention time: 2.76 min, Method A), MS m/z 218 (M+H-Boc).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[CH3:13][O-:14].[Na+]>CO>[CH3:13][O:14][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=c1ccc2ccc(Cl)nc2[nH]1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2ccc(=O)[nH]c2n1

Procedure:
To a solution of 7-chloro-1H-[1,8]naphthyridin-2-one (prepared as described in J. Org. Chem. (1990), 55, 4744; 5.36 g, 29.68 mmol) in MeOH (98 mL) was added sodium methoxide (25 wt % in MeOH, 161 mL). The resulting solution was stirred at reflux for 15 h. The solvent was removed in vacuo. Water (100 mL) and EA (80 mL) were added. The phases were separated and the aq layer was extracted with EA (8×80 mL). The combined org. layers were washed with brine (50 mL), dried over MgSO4, filtered and evaporated under reduced pressure. The title compound was obtained as a beige solid (5.22 g, 100% yield).
Reaction SMILES: [N:1]1([C:6]2([CH2:16][CH:17]=O)[CH2:15][C:10]3([CH2:14][CH2:13][CH2:12][CH2:11]3)[O:9][CH2:8][CH2:7]2)[CH:5]=[CH:4][CH:3]=[N:2]1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][NH2:25].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(C(F)(F)F)=O>>[N:1]1([C:6]2([CH2:16][CH2:17][NH:25][CH2:24][C:20]3[S:19][CH:23]=[CH:22][CH:21]=3)[CH2:15][C:10]3([CH2:14][CH2:13][CH2:12][CH2:11]3)[O:9][CH2:8][CH2:7]2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=CCC1(n2cccn2)CCOC2(CCCC2)C1
Reactant: NCc1cccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: c1csc(CNCCC2(n3cccn3)CCOC3(CCCC3)C2)c1
Reaction time: 8 h
Yield: 82 %

Procedure:
To a mixture of 2-[9-(1H-pyrazol-1-yl)-6-oxaspiro[4.5]decan-9-yl]acetaldehyde (15 mg, 0.06 mmol) and thiophen-2-ylmethanamine (19 uL, 0.18 mmol) was stirred ar rt for 1 h before NaBH(OAc)3 (25.4 mg, 0.12 mmol) was added. The solution stirred overnight. After removal of solvent, the residue was purified by HPLC to provide {2-[9-(1H-pyrazol-1-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl}(thiophen-2-ylmethyl)amine (17 mg, 61% yield) as a TFA salt. LCMS m/z 346 (M+1) observed.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[C:13]([OH:15])=[O:14].C([O-])([O-])=O.[K+].[K+].I[CH2:23][CH3:24]>CN(C=O)C>[CH2:23]([O:14][C:13]([C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1)=[O:15])[CH3:24]
Reactant: COc1ccc2nccc(C(=O)O)c2c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccnc2ccc(OC)cc12
Temperature: 55 °C

Procedure:
To a suspension of 6-methoxy-quinoline-4-carboxylic acid (prepared according to U.S. Pat. No. 5,338,851; 43.8 g, 215.6 mmol) in DMF (215 mL) were added K2CO3 (99%; 60.2 g, 431.2 mmol) and iodoethane (19.4 mL, 237.2 mmol). The mixture was heated at 55° C. overnight. The solvent was evaporated to dryness, and the residue was partitioned between EA (1.5 L) and water (600 mL). The org. layer was washed twice with brine (2×300 mL), dried over Na2SO4, filtered and concentrated to dryness to yield a purple solid (37.5 g).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[B:21](OC)([O:24]C)[O:22]C.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[O:14]([CH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[B:21]([OH:24])[OH:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COB(OC)OC
Reactant: Brc1ccccc1COc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccccc1COc1ccccc1
Reaction time: 2 h

Procedure:
90 ml of n-butyllithium (1.6 M) in solution in hexane are added dropwise at −70° C. to 36 g of 1-bromo-2-(phenoxymethyl)benzene, obtained in step 1.1, in solution in 150 ml of tetrahydrofuran. After 2 hours at −70° C., 16 ml of trimethyl borate are introduced dropwise. The temperature of the reaction medium is allowed to rise to −30° C. The medium is hydrolysed with a saturated ammonium chloride solution, and then extracted with ethyl acetate and the organic phase is dried with anhydrous sodium sulphate. After evaporation, 33 g of a white solid are obtained.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[CH:11]([O-:13])=O.[NH4+:14].O>C(O)=O>[C:5]1([C:3]2[N:14]=[CH:11][O:13][CH:2]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: [NH4+]
Reactant: O=C[O-]
Reactant: O=C(CBr)c1ccccc1
Solvent: O
Solvent: O=CO
Product: c1ccc(-c2cocn2)cc1
Yield: 31 %

Procedure:
A mixture of 2-bromoacetophenone and ammonium formate in formic acid was stirred at reflux under nitrogen for 2 hours. The cooled reaction mixture was treated with 400 mL of H2O and extracted with ether (3×200 mL). The combined organics were washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluting with EtOAc/hexanes, 1:9) to afford 8.9 g (31%) of 4-phenyloxazole as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[OH:5][C:6]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]2[C:7]=1[CH2:8][CH2:9][C:10](=[O:17])[NH:11]2.C(=O)([O-])[O-].[K+].[K+].C(Br)C#C>O>[CH2:4]([O:16][C:13]1[CH:14]=[CH:15][C:6]([OH:5])=[C:7]2[C:12]=1[NH:11][C:10](=[O:17])[CH2:9][CH2:8]2)[C:2]#[CH:1]
Reactant: O=C1CCc2c(O)ccc(O)c2N1
Reactant: CC(C)=O
Agent: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C#CCOc1ccc(O)c2c1NC(=O)CC2

Procedure:
2 liters of acetone and 500 ml of water were added to 150 g of 5,8-dihydroxy-3,4-dihydrocarbostyril, and 138 g of potassium carbonate and 150 g of 2-propynyl bromide were further added thereto. The resulting mixture was heated while refluxing for 3 hours on a water bath. After completion of the reaction, the acetone and the 2-propynyl bromide were evaporated under reduced pressure, and the residue was made acidic with concentrated hydrochloric acid. The mixture was extracted with chloroform, and the chloroform layer was washed with water and dried over anhydrous sodium sulfate. The chloroform was evaporated under reduced pressure, and the residual crystals were recrystallized from isopropanol-diethyl ether to obtain 110 g of 8-(2-propynyloxy)-5-hydroxy-3,4-dihydrocarbostyril having a melting point of 141°-142° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([C:12]([O:14]C)=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:16]1([Li])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>C1COCC1>[C:16]1([C:12]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([OH:1])[CH:11]=2)[OH:14])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [Li]c1ccccc1
Reactant: COC(=O)c1cc(O)nc2ccccc12
Solvent: O
Solvent: C1CCOC1
Product: Oc1cc(C(O)(c2ccccc2)c2ccccc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 194.3 %

Procedure:
A solution of methyl 2-hydroxy-4-quinolinecarboxylate (406 mg, 2 mmol) in THF (20 mL) at 0° C. was treated with a solution of phenyl lithium (1.8-M in THF, 2.3 mL, 4.2 mmol), stirred at room temperature for 2 h, poured into water (100 mL), the resulting precipitate filtered and dried to give the title compound (636 mg, 97%) as a cream solid: mp>350° C.; IR νmax (Nujol)/cm−1 3550-3300,3085, 3059, 2924, 2854, 1652, 1461, 1377, 759, 750 and 698; NMR δH (400 MHz, ?) 5.66 (1H, s), 6.88 (1H, t, J 7.6 Hz), 7.28-7.39 (11H, m), 7.47 (1H, t, J 7.5 Hz), 7.66 (1H, d, J 8.6 Hz), 7.81 (1H, d, J 7.6 Hz) and 11.63-11.88 (1H, s); M/Z 328 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:27])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[N:9]=2)[CH:7]=1.[Cl:28][C:29]1[C:30](F)=[CH:31][C:32]([F:55])=[C:33]([S:35]([N:38](CC2C=CC(OC)=CC=2OC)[C:39]2[S:40][CH:41]=[N:42][N:43]=2)(=[O:37])=[O:36])[CH:34]=1.C(=O)([O-])[O-].[K+].[K+].[F:63][C:64]([F:69])([F:68])[C:65]([OH:67])=[O:66]>CS(C)=O.O>[F:63][C:64]([F:69])([F:68])[C:65]([OH:67])=[O:66].[Cl:28][C:29]1[C:30]([O:27][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=2[C:8]2[CH:13]=[CH:12][N:11]=[C:10]([N:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[N:9]=2)=[CH:31][C:32]([F:55])=[C:33]([S:35]([NH:38][C:39]2[S:40][CH:41]=[N:42][N:43]=2)(=[O:36])=[O:37])[CH:34]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc(-c3cc(Cl)ccc3O)n2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=S(=O)(Nc1nncs1)c1cc(Cl)c(Oc2ccc(Cl)cc2-c2ccnc(N3CCNCC3)n2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.3 %

Procedure:
tert-Butyl 4-[4-(5-chloro-2-hydroxyphenyl)pyrimidin-2-yl]piperazine-1-carboxylate (Preparation 2, 48.6 mg, 0.11 mmol), 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 6, 49.1 mg, 0.11 mmol) and potassium carbonate (21.9 mg, 0.16 mmol) were mixed in dimethylsulfoxide (1 mL) and shaken at ambient temperature for 18 hours. The reaction mixture was diluted with water and the precipitate collected by filtration. The solid was dissolved in dichloromethane (2.0 mL) and dried over anhydrous magnesium sulfate. The mixture was filtered and trifluoroacetic acid (0.060 mL, 0.78 mmol) was added to the filtrate. After 2 hours the reaction mixture was concentrated in vacuo to a residue and purified by reverse phase HPLC to afford the title compound as a tan glass (35.5 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][NH:10][CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:12][C:13]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])[CH3:14].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:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:9][NH:10][CH3:11])=[CH:3][C:2]=1[C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([CH2:25][N:22]2[CH2:23][CH2:24][N:19]([C:17]([O:16][C:13]([CH3:15])([CH3:14])[CH3:12])=[O:18])[CH2:20][CH2:21]2)[CH:27]=1
Reactant: CNCc1ccc(F)c(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(B(O)O)c2)CC1
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: CNCc1ccc(F)c(-c2cccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c2)c1
Temperature: 150 °C
Yield: 65.8 %

Procedure:
To a solution of [(3-bromo-4-fluorophenyl)methyl]methylamine (0.52 g, 2.39 mmol) in p-dioxane/H2O (15/5 mL) was added {3-[(4-{[(1,1-dimethylethyl)oxy]carbonyl}-1-piperazinyl)methyl]phenyl}boronic acid (1.15 g, 3.60 mmol), Pd(PPh3)4 (139 mg, 0.12 mmol), and K2CO3 (1.33 g, 9.6 mmol). The mixture was heated with a microwave at 150° C. for 15 min. The organic layer was separated, concentrated. The residue was redissolved in EtOAc (˜70 mL), which was washed with H2O (20 mL), brine (20 mL), dried over Na2SO4, filtered, concentrated and purified by CombiFlash chromatograph to afford the title compound 0.65 g (66%). LC-MS m/z 414 (M+H)+.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([NH2:7])[C:4]2[C:8]([NH:10][NH:11][C:12](=[O:13])[C:3]=2[CH:2]=1)=[O:9].[Cl:14][CH2:15][C:16](Cl)=[O:17].N1C=CC=CC=1>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[Cl:14][CH2:15][C:16]([NH:7][C:5]1[CH:6]=[CH:1][CH:2]=[C:3]2[C:4]=1[C:8](=[O:9])[NH:10][NH:11][C:12]2=[O:13])=[O:17]
Reactant: Nc1cccc2c(=O)[nH][nH]c(=O)c12
Reactant: O=C(Cl)CCl
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: c1ccncc1
Product: O=C(CCl)Nc1cccc2c(=O)[nH][nH]c(=O)c12
Temperature: 25 °C

Procedure:
Luminol (1.55 g; 8.75 mmol) was reacted with 2-chloro-acetylchloride (1.24 g; 10.99 mmol), in the presence of pyridine (1.07 g, 13.6 mmol) in acetic:acid (45 ml). Contents were stirred and refluxed for 1 h, allowed to cool to RT, and transferred to a refrigerator for precipitation of the product to obtain 2-Chloro-N-(1,4-dioxo-1,2,3,4-tetrahydrophthalazine-5-yl)acetamide. Thereafter, acetic acid (20 ml) was added to the cold precipitates prior to filtration (for uniform transfer into the filtration unit). Finally, precipitates were filtered, washed with methylene chloride (three times) and dried under vacuum to yield 2-Chloro-N-(1,4-dioxo-1,2,3,4-tetrahydrophthalazine-5-yl)acetamide (1.6 g; 6324 mmol; 72.2%). 1H NMR (300 MHz, DMSO-d6) δ: 8.82-8.87 (t, 1H), 7.71-7.89 (dd, 1H), 7.61-7.69 (dd, 1H), 4.34 (s, 2H), 2.16 (s, 3H, Methyl for Acetic Acid); ESMS: Calcd for C10H8ClN3O3: 253.0, Found, 253.8.
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.[N+:6]([C:9]1[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1)([O-:8])=[O:7].C(N(CC)CC)C.O>O1CCOCC1>[N+:6]([C:9]1[CH:10]=[C:11]([S:15]([NH:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1)([O-:8])=[O:7]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: NCC1CC1
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc(S(=O)(=O)NCC2CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.8 %

Procedure:
To a stirred solution of cyclopropylmethylamine (1.28 ml, 15 mmol) in dioxane (37 ml) was added at room temperature 3-nitrobenzenesulfonyl chloride (3.0 g, 14 mmol) and triethylamine (2.06 ml, 15 mmol). The light yellow suspension was stirred at room temperature for 4 h, poured into water (100 ml) and extracted with dichloromethane (3×75 ml). The combined organic layers were washed with water (100 ml) and brine (70 ml), dried (MgSO4) and evaporated. The crude product was further purified by column chromatography on silica gel (heptane/ethyl acetate 1:1) to yield 3-nitro-N-cyclopropylmethyl-benzenesulfonamide (3.08 g, 89%) as an off-white solid. MS (ISP) 254.9 [(M−H)−]; m.p. 91° C.