Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1](OCCCC)=[O:2].[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[CH3:18])([O-:10])=[O:9].CC(C)([O-])C.[K+].O>CN(C)C=O.C(O)(=O)C>[CH3:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N+:8]([O-:10])=[O:9])[C:12]=1[CH:18]=[N:1][OH:2]
Reactant: CCCCON=O
Reactant: Cc1cccc([N+](=O)[O-])c1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc([N+](=O)[O-])c1C=NO
Temperature: -10 °C
Reaction time: 2 h

Procedure:
A solution of 274 g (2.6 mol) of n-butyl nitrite (97%) and 300 g (2.0 mol) of 3-nitro-o-xylene (97%) in 750 ml of dimethylformamide is cooled to from −55 to −60° C., and a solution of 522 g (4.56 mol) of potassium tert-butoxide in 750 ml of dimethylformamide is added dropwise at this temperature over a period of 2.5 hours. During the addition, the color of the solution changes from yellow to deep red and the solution becomes viscous. The reaction is monitored by HPLC. For work-up, initially 300 ml of water are added and then about 300 ml of glacial acetic acid, until the pH has reached 5-6. During the addition, the temperature increases to −10° C., and a yellow suspension is formed. The reaction mixture is then poured onto 6 kg of ice-water and the residue that has formed is filtered off with suction, washed with 5 l of water and dried in a drying cabinet at 30° C. overnight. This gives 339 g of a light-beige crude product which is freed from the impurities by suspension in about 3 l of toluene at 80-90° C. for 2 hours. After cooling, the product is filtered off with suction and dried. This gives 276 g of 2-nitro-6-methyl-benzaldoxime.
Reaction SMILES: [CH2:1]([NH:8][C:9](SC)=[C:10]([C:16]#[N:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]1[CH:33]=[CH:32][C:24]([CH2:25][N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:23][CH:22]=1>C(#N)C>[CH2:1]([NH:8][C:9]([N:29]1[CH2:28][CH2:27][N:26]([CH2:25][C:24]2[CH:32]=[CH:33][C:21]([F:20])=[CH:22][CH:23]=2)[CH2:31][CH2:30]1)=[C:10]([C:16]#[N:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(CN2CCNCC2)cc1
Reactant: CCOC(=O)C(C#N)=C(NCc1ccccc1)SC
Solvent: CC#N
Product: CCOC(=O)C(C#N)=C(NCc1ccccc1)N1CCN(Cc2ccc(F)cc2)CC1
Temperature: 80 °C
Yield: 21 %

Procedure:
To ethyl 3-benzylamino-3-methylthio-2-cyanoacrylate (1.50 g, 5.43 mmol) and 1-(p-fluorobenzyl)piperazine (2.11 g, 10.9 mmol) was added acetonitrile (1 ml) and the mixture was heated under reflux at 80° C. for 2 hours. The reaction product was purified by silica gel column chromatography to give the title compound as a brown oily substance (0.48 g) from the fraction from hexane-ethyl acetate (1/1). Yield=21%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C:8]([CH3:13])([CH3:12])[CH2:9][CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.N1C=CC=CC=1>CS(C)=O.[Cl-].[Na+].O>[C:1]([O:5][C:6](=[O:14])[NH:7][C:8]([CH3:13])([CH3:12])[CH2:9][CH:10]=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(CCO)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(CC=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(3-Hydroxy-1,1-dimethyl-propyl)-carbamic acid tert-butyl ester(9.8 g, 0.048 mol)was dissolved in DMSO(160 mL). The solution was treated with Et3N(20.2 mL, 0.145 mol) followed by a solution of pyridine sufurtrioxide complex(23.15 g, 0.145 mol) in DMSO(160 mL). Upon complete addition, the solution was stirred for 1 h at 25° C. The mixture was diluted with brine and extracted with Et2O(3×125 mL). The organic phase was washed with 10% citric acid(aq), saturated NaHCO3 and brine. The organic was dried(MgSO4) and concentrated to the desired material as a yellow oil(8.3 g, 56%); 1H NMR (DMSO-d6) δ 9.67 (t, J=3 Hz, 1H), δ 2.66 (s, 2H), δ 1.37 (s, 9H), δ 1.28 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[C:6]([C:15]2[CH:16]=[C:17]([O:23][CH3:24])[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=2)=[N:7][C:8](S(C)(=O)=O)=[N:9][CH:10]=1.[CH3:30][S:31]([NH2:34])(=[O:33])=[O:32]>>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[C:6]([C:15]2[CH:16]=[C:17]([O:23][CH3:24])[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=2)=[N:7][C:8]([NH:34][S:31]([CH3:30])(=[O:33])=[O:32])=[N:9][CH:10]=1
Reactant: COc1cc(-c2nc(S(C)(=O)=O)ncc2Oc2ccc(F)cc2F)cn(C)c1=O
Reactant: CS(N)(=O)=O
Product: COc1cc(-c2nc(NS(C)(=O)=O)ncc2Oc2ccc(F)cc2F)cn(C)c1=O

Procedure:
The title compound of Example 150 was treated with MeSO2NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 11.37 (s, 1H), 8.34 (s, 1H), 8.26 (s, 1H), 7.58 (s, 1H), 7.54-7.50 (m, 1H), 7.28-7.23 (m, 1H), 7.10-7.06 (m, 1H), 3.74 (s, 3H), 3.52 (s, 3H), 3.39 (s, 3H). LCMS: 439.0 (M+1)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][S:10][C:11]2[NH:26][C:14]3=[N:15][C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:17]([CH3:19])[CH:18]=[C:13]3[N:12]=2)[C:4]=1[CH3:27].ClC1C=CC=C(C(OO)=[O:36])C=1.C(=O)(O)[O-].[Na+]>CO.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][S:10]([C:11]2[NH:26][C:14]3=[N:15][C:16]([O:20][CH2:21][C:22]([F:23])([F:24])[F:25])=[C:17]([CH3:19])[CH:18]=[C:13]3[N:12]=2)=[O:36])[C:4]=1[CH3:27]
Reactant: COc1ccnc(CSc2nc3cc(C)c(OCC(F)(F)F)nc3[nH]2)c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccnc(CS(=O)c2nc3cc(C)c(OCC(F)(F)F)nc3[nH]2)c1C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
2-(((4-Methoxy-3-methyl-2-pyridinyl)methyl)thio)-6-methyl-5-(2,2,2-trifluoroethoxy)-3H-imidazo[4,5-b]pyridine (270 mg, 0.68 mmol) was dissolved in a mixture of methanol (2 ml) and toluene (18 ml), and a solution of metachloroperbenzoic acid (162 mg) in a mixture of methanol (0.5 ml) of toluene (0.5 ml) were added dropwise at −40° C. under nitrogen flow. After stirred at −20° C. to −40° C. for 2 hours, a sodium bicarbonate solution was added, the mixture was extracted with chloroform (30 ml), and dried over sodium sulfate. The solvent was evaporated, and the solid was precipitated from a mixture of chloroform and n-hexane to yield the title compound (263 mg, 0.63 mmol, 93%) as a purple gray solid.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:26]=[C:27]([OH:29])[CH:28]=1)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:9]1.Cl[CH2:31][C:32]1[N:33]=[C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[S:35][CH:36]=1.O>CN(C)C=O>[C:37]1([C:34]2[S:35][CH:36]=[C:32]([CH2:31][O:3][C:4]3[CH:5]=[C:6]([CH:26]=[C:27]([O:29][CH2:31][C:32]4[N:33]=[C:34]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)[S:35][CH:36]=4)[CH:28]=3)[CH2:7][N:8]3[CH:12]=[C:11]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:10]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:9]3)[N:33]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: ClCc1csc(-c2ccccc2)n1
Reactant: CCOC(=O)CCc1cn(Cc2cc(O)cc(O)c2)cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2cc(OCc3csc(-c4ccccc4)n3)cc(OCc3csc(-c4ccccc4)n3)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28.8 %

Procedure:
Sodium hydride (601, oily, 0.30 g) was added to a solution of ethyl 3-[1-(3,5-dihydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (1.83 g) in N,N-dimethylformamide (20 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-2-phenylthiazole (1.05 g) was added to the mixture and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[1-[3,5-bis(2-phenyl-4-thiazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (513 mg, yield: 14%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [CH2:1]([P:5]([CH2:8][CH:9]([CH3:11])[CH3:10])(=[O:7])[OH:6])[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].[Al:14](Cl)(Cl)Cl.O.O.O.O.O.O>O>[Al:14].[CH2:1]([P:5]([CH2:8][CH:9]([CH3:11])[CH3:10])(=[O:6])[OH:7])[CH:2]([CH3:4])[CH3:3]
Reactant: Cl[Al](Cl)Cl
Agent: CC(C)CP(=O)(O)CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: [Al]

Procedure:
A portion of the above pure diisobutylphosphinic acid (135.01 g, 0.758 mol) was mixed with water and neutralized with dilute aqueous sodium hydroxide solution. The neutralized product was then mixed with a solution of 61.83 g (0.256 mol) AlCl3 6H2O in 2 L water. A large amount of white precipitate was observed. The precipitate was filtered and dried to a constant weight in an oven at 105° C. A white powder, aluminum salt of diisobutylphosphinic acid, of 139.43 g was obtained. The yield was 98.9%.
Reaction SMILES: C1(C2CC(O)C3C(=CC=C(O)C=3)O2)C=CC=CC=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]2[CH2:35][C:34](=[O:36])[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([OH:37])[CH:32]=3)[O:27]2)[CH:23]=[CH:24][CH:25]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]2[CH2:35][CH:34]([OH:36])[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([OH:37])[CH:32]=3)[O:27]2)[CH:23]=[CH:24][CH:25]=1
Reactant: O=C1CC(c2cccc(Cl)c2)Oc2ccc(O)cc21
Agent: Oc1ccc2c(c1)C(O)CC(c1ccccc1)O2
Product: Oc1ccc2c(c1)C(O)CC(c1cccc(Cl)c1)O2

Procedure:
2-(3-Chlorophenyl)chroman-4,6-diol was prepared as described for 2-phenylchroman-4,6-diol in Example 8(a) starting from 730 mg of 2-(3-chloro-phenyl)-6-hydroxychroman-4-one. 1H NMR (400 MHz, d6-DMSO) δ: 8.85 (s, 1H), 7.50 (d, 1H, J 1.7 Hz), 7.46-7.38 (m, 3H), 6.88 (d, 1H, J 2.5 Hz), 6.62 (d, 1H, J 8.6 Hz), 6.55 (dd, 1H, J 8.6, 2.5 Hz), 5.44 (d, 1H, J 6.6 Hz), 5.15 (dd, 1H, J 11.8, 1.4 Hz), 4.87 (m, 1H), 2.29 (m, 1H), 1.85 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21](O)=[O:22])[N:4]=1)#[N:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:38]([O:42][C:43](=[O:49])[C@@H:44]([CH3:48])[C@H:45]([NH2:47])[CH3:46])([CH3:41])([CH3:40])[CH3:39].CCN(C(C)C)C(C)C.Cl>C(Cl)Cl>[C:38]([O:42][C:43](=[O:49])[C@@H:44]([CH3:48])[C@H:45]([NH:47][C:21]([C:5]1[N:4]=[C:3]([C:1]#[N:2])[C:12]2[C:7]([C:6]=1[OH:20])=[CH:8][CH:9]=[C:10]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:11]=2)=[O:22])[CH3:46])([CH3:39])([CH3:41])[CH3:40]
Reactant: N#Cc1nc(C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Reactant: C[C@H](C(=O)OC(C)(C)C)[C@@H](C)N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](C(=O)OC(C)(C)C)[C@@H](C)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.3 %

Procedure:
A flask was charged with 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid (40 mg, 0.13 mmol), HOBt (18 mg, 0.13 mmol) and CH2Cl2 (2 mL). EDC (35 mg, 0.18 mmol) was added, and the mixture was stirred for 10 min. (2S,3R)-3-Amino-2-methyl-butyric acid tert-butyl ester (22 mg, 0.13 mmol) and Hunig's base (0.050 mL, 0.26 mmol) were then added, and the resulting mixture was stirred for 16 h at r.t. Hydrochloric acid (0.1 M) was added to acidify the mixture, and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-10% EtOAc/hexanes+2% AcOH) to give 32 mg of the title compound as a white solid. MS: (−) m/z 460.31 (M−1).
Reaction SMILES: B.[Na].C([O:5][CH2:6][C:7]1[O:8][C:9]([CH:12]=[O:13])=[CH:10][CH:11]=1)=O.Cl.C(=O)([O-])O.[Na+]>C(O)C>[OH:5][CH2:6][C:7]1[O:8][C:9]([CH2:12][OH:13])=[CH:10][CH:11]=1
Reactant: O=COCc1ccc(C=O)o1
Agent: B
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Product: OCc1ccc(CO)o1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Sodium borane (1.2 g, 32 mmol) was added to a solution of 5-formylfuran-2-yl-methyl formate (5.05 g, 30 mmol) in absolute ethanol (150 mL) at 0° C. Then it was warmed to room temperature and stirred for 48 hours. Then it was cooled to 0° C. and acidified with concentrated hydrochloric acid to pH 4 and then neutralized immediately with 5% sodium hydrogen carbonate solution. The mixture was filtered and the filtrate was evaporated to dryness under vacuum. The residue was taken up in ethanol (30 mL), filtered, and the filtrate was concentrated to dryness.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH2:13][CH3:14])[CH:12]=1)[C:6]([O:8]C)=[O:7])#[N:2].[Li+].[OH-]>C1COCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH2:13][CH3:14])[CH:12]=1)[C:6]([OH:8])=[O:7])#[N:2]
Reactant: CCc1cc(C#N)cc(C(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(C#N)cc(C(=O)O)c1
Temperature: 0 °C
Yield: 80.4 %

Procedure:
The compound methyl 3-cyano-5-ethylbenzoate (270 mg, 1.42 mmol) was dissolved in THF—H2O (7:3 v/v, 10 mL), solution was cooled to 0° C. and LiOH (59 mg, 1.42 mmol) was added. The reaction mixture was allowed to come to room temperature and stirred for 3 h (monitored by TLC; petroleum ether/EtOAc 1:1). Solvent THF was removed under reduced pressure and the aqueous layer was washed with EtOAc to remove the non-polar impurities. The pH of the aqueous layer was adjusted to 2-3 using 1.5N HCl. The product was extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to yield 3-cyano-5-ethylbenzoic acid (200 mg, yield 80%), which was carried through without further purification. 1H NMR (400 MHz, CDCl3) δ 8.23 (m, 1H), 8.17 (m, 1H), 7.74 (m, 1H), 2.81 (q, J=7.6 Hz, 2H), 1.32 (t, J=7.6 Hz, 3H).
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[N:7][C:8]([OH:12])=[CH:9][N:10]=2)[N:5]=[C:4]([CH2:13][O:14][CH2:15][O:16][CH3:17])[N:3]=1.[OH-:18].[K+].Cl>O>[OH:12][C:8]1[N:7]=[C:6]2[C:11]([C:2](=[O:18])[NH:3][C:4]([CH2:13][O:14][CH2:15][O:16][CH3:17])=[N:5]2)=[N:10][CH:9]=1
Reactant: COCOCc1nc(N)c2ncc(O)nc2n1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: COCOCc1nc2nc(O)cnc2c(=O)[nH]1

Procedure:
1.1 g (0.00464 mole) of 4-amino-7-hydroxy-2-(methoxymethoxymethyl)pteridine is added to a solution of 1.5 g (0.0267 mole) of potassium hydroxide in 20 ml of water. The mixture is refluxed for 8 hours. After cooling, the reaction mixture is acidified with 10% hydrochloric acid to pH 5.5. The precipitate formed is isolated by filtration and washed with water. It is extracted with a mixture of 50 ml of ethanol and 60 ml of N,N-dimethylformamide under reflux. This extract, concentrated under reduced pressure, is recrystallized from a mixture of ethanol and N,N-dimethylformamide. Yld: 0.2 g (18%), m.p. 224°-226° C. (ethanol).
Reaction SMILES: [OH:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:9]=2)=[O:7])=[CH:4][C:3]=1[O:28][CH2:29][CH2:30][CH2:31][Cl:32].Br[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][O:1][C:2]2[CH:27]=[CH:26][C:5]([C:6]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([S:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:9]=3)=[O:7])=[CH:4][C:3]=2[O:28][CH2:29][CH2:30][CH2:31][Cl:32])=[CH:37][CH:36]=1
Reactant: O=C(c1ccc(O)c(OCCCCl)c1)c1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Reactant: Cc1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(COc2ccc(C(=O)c3cn(S(=O)(=O)c4ccccc4)c4ccccc34)cc2OCCCCl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.7 %

Procedure:
3-[4-Hydroxy-3-(3-chloropropoxy)benzoyl]-1-(phenylsulfonyl)indole (0.72 g) obtained in Step 1 was dissolved in N,N-dimethylformamide (7 ml). α-bromo-p-xylene (0.37 g) and potassium carbonate (0.28 g) were added to the resultant solution and stirred for 2 hours at room temperature. 2N HCl was added to the reaction mixture, followed by extraction with ethyl acetate. The resultant extract was sequentially washed with saturated sodium bicarbonate solution and brine and then dried. The solvent was distilled off. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), obtaining 0.49 g of 3-[4-(4-methylphenylmethoxy)-3-(3-chloropropoxy)benzoyl]-1-(phenylsulfonyl)indole as a yellow oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N+:7]2[O-].FC(F)(F)C(OC(=O)C(F)(F)F)=[O:16].C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:16])[NH:7]2
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: [O-][n+]1cccc2c(Br)cccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1ccc2c(Br)cccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.2 %

Procedure:
To a solution of 5-bromoquinoline 1-oxide (2.7 g, 12.05 mmol) in DMF (8 mL) was added trifluoroacetic anhydride (8.51 mL, 60.3 mmol) in three portions at 0° C. The reaction was allowed to warm to room temperature where it stirred overnight. At the conclusion of this period, the reaction mixture was poured into a saturated aq. NaHCO3 (100 mL) solution, and extracted with DCM (2×50 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to afford the title compound (2.76 g, 98% yield) as a light yellow solid. LCMS, [M+H]+=223.9. 1H NMR (400 MHz, DMSO-d6) δ 11.98 (s, 1H), 8.05 (d, J=9.8 Hz, 1H), 7.50 (dd, J=8.0 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 6.63 (d, J=9.8 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:16]=[CH:17][C:18]([F:24])=[C:19]([C:21](=[O:23])[CH3:22])[CH:20]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[C:21]([C:19]1[CH:20]=[C:15]([N:10]2[CH2:11][CH2:12][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:13])[CH:16]=[CH:17][C:18]=1[F:24])(=[O:23])[CH3:22]
Reactant: CC(=O)c1cc(Br)ccc1F
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CC(=O)c1cc(N2CCN(c3cnccc3C)C2=O)ccc1F
Yield: 24.9 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 0.500 g, 2.82 mmol) was reacted with 1-(5-bromo-2-fluoro-phenyl)-ethanone (0.612 g, 2.82 mmol), 1,4-dioxane (30 mL), copper iodide (53.81 mg, 0.282 mmol), trans-1,2-diamino cyclohexane (97.03 mg, 0.846 mmol) and potassium phosphate (1.79 g, 8.46 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3) afforded 220 mg of 1-(3-Acetyl-4-fluoro-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (24.9% yield).
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH2:6][C:7]1[CH:8]=[C:9]([O:22]C)[C:10]2[C:19]3[NH:18][CH2:17][CH2:16][CH2:15][C:14]=3[C:13](=[O:20])[NH:12][C:11]=2[CH:21]=1)[CH3:5].B(Br)(Br)Br.O>ClCCl>[CH3:5][N:4]([CH2:6][C:7]1[CH:8]=[C:9]([OH:22])[C:10]2[C:19]3[NH:18][CH2:17][CH2:16][CH2:15][C:14]=3[C:13](=[O:20])[NH:12][C:11]=2[CH:21]=1)[CH3:3]
Reactant: COc1cc(CN(C)C)cc2[nH]c(=O)c3c(c12)NCCC3
Agent: BrB(Br)Br
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CN(C)Cc1cc(O)c2c3c(c(=O)[nH]c2c1)CCCN3
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
8-[(Dimethylamino)methyl]-10-methoxy-6-(methoxymethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine-5-(6H)-one (28 mg, 0.084 mmol) prepared in Example 72 was dissolved in dichloromethane (10 ml), added dropwise with boron tribromide (0.6 mmol, 152 mg) at 0° C. The mixture was stirred at room temperature for 2 hours and then water was added carefully. The solution was washed with chloroform, the water layer was concentrated under reduced pressure, and the residue was purified by flash column chromatography (chloroform:ethanol=1:5) to obtain the title compound (14 mg, yield: 58%, white solid).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:12]=[CH:13][C:14]2[CH2:18][O:17][B:16]([OH:19])[C:15]=2[CH:20]=1)[C:5]#[N:6].C([O-])([O-])=O.[K+].[K+].[Cl:27]C1C=C(C=CC=1F)C#N.CCOC(C)=O>CS(C)=O>[Cl:27][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:12]=[CH:13][C:14]2[CH2:18][O:17][B:16]([OH:19])[C:15]=2[CH:20]=1)[C:5]#[N:6]
Reactant: N#Cc1ccc(Oc2ccc3c(c2)B(O)OC3)c(F)c1
Reactant: N#Cc1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2ccc3c(c2)B(O)OC3)c(Cl)c1
Temperature: 90 °C
Yield: 33.3 %

Procedure:
To a solution of 3H-benzo[c][1,2]oxaborole-1,6-diol (5) (300 mg, 2 mmol) in DMSO (30 mL) were added K2CO3 (828 mg, 6 mmol) and 3-chloro-4-fluoro-benzonitrile (933 mg, 6 mmol). The reaction was heated at 90° C. for 7 hours. After the cooling of reaction solution, EtOAc (50 mL) was added. The organic layer was washed with water (5×50 mL). The organic layer was evaporated under vacuum. The residue was purified by reverse phase chromatography to afford 3-chloro-4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yloxy)-benzonitrile (6) 190 mg in 33.3% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.24 (s, 1 H), 8.22 (s, 1 H), 7.77 (d, J=7.81 Hz, 1 H), 7.50 (d, J=8.20 Hz, 1 H), 7.34 (s, 1 H), 7.28 (d, J=8.20 Hz, 1 H), 7.01 (d, J=8.59 Hz, 1 H), 4.99 (s, 2 H). ESMS (m/z): 284 (M−H)−. HPLC: 96.41% (220 nm), 96.0% (maxplot).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:20])=[CH:4][C:5]([F:19])=[C:6]([S:8]([NH:11][C:12]2[N:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C(N(CC)C(C)C)(C)C.[CH2:30]([O:32][CH2:33]Cl)[CH3:31]>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([F:20])=[CH:4][C:5]([F:19])=[C:6]([S:8]([N:11]([CH2:33][O:32][CH2:30][CH3:31])[C:12]2[N:13]=[CH:14][C:15]([F:18])=[CH:16][N:17]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: O=S(=O)(Nc1ncc(F)cn1)c1cc(Cl)c(F)cc1F
Reactant: CCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOCN(c1ncc(F)cn1)S(=O)(=O)c1cc(Cl)c(F)cc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 52.7 %

Procedure:
To a solution of 5-chloro-2,4-difluoro-N-(5-fluoropyrimidin-2-yl)benzenesulfonamide (Preparation 12, 0.28 g, 0.86 mmol) in dichloromethane (7 mL) at 0° C. was added N,N-diisopropylethylamine (0.23 mL, 1.32 mmol) and chloromethyl ethyl ether (0.088 mL, 0.95 mmol). The reaction mixture was stirred for 20 hours allowing the solution to gradually warm to ambient temperature. The reaction mixture was diluted with ethyl acetate, washed with 1N aqueous sodium hydroxide solution, water, and brine and then dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexanes to ethyl acetate gradient elution) to afford the title compound as a white solid (173 mg).
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]=[O:12].[NH2:14][C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1>C(COC)OC>[F:1][CH:2]([F:13])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:14][C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1)=[O:12]
Reactant: Nc1cnccn1
Reactant: O=C=Nc1ccccc1OC(F)F
Solvent: COCCOC
Product: O=C(Nc1cnccn1)Nc1ccccc1OC(F)F
Temperature: 25 °C

Procedure:
2-(Difluoromethoxy)phenylisocyanate (1.0 g, 5.4 mmol) and aminopyrazine (0.51 g, 5.4 mmol) were reacted for 6 hours in refluxing dimethoxyethane (20 mL). The reaction mixture was cooled to room temperature to precipitate the product, which was collected by filtration, washed with ethyl acetate, and dried in vacuo (765 mg, 50%). 1H NMR (300 Mhz, d6-DMSO) δ: 10.49 (br s, 1H), 10.26 (s, 1H), 8.83 (s, 1H), 8.35-8.24 (m, 3H), 7.53-7.00 (m,4H).