Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=O.[NH2:12][OH:13].O>CC(O)C>[Br:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=[N:12][OH:13]
Reactant: O=Cc1c(F)cc(Cl)cc1Br
Reactant: NO
Solvent: O
Solvent: CC(C)O
Product: ON=Cc1c(F)cc(Cl)cc1Br
Temperature: 40 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
To a solution of 2-bromo-4-chloro-6-fluoro-benzaldehyde (15 g, 63.16 mmol) in 2-propanol (130 ml) was added hydroxylamine (50% solution in water, 4.55 g, 68.90 mmol) at 25° C. and the mixture was warmed to 40° C. for 2 h. Water (55 ml) was then added slowly to this mixture and the slurry was aged for 1 h at 20° C. The reaction mixture was filtered and the remaining solid was washed with a mixture of 2-propanol and water (1.5:1) and dried under vacuum to yield the title compound (12.5 g, 77%) as white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)[CH3:2].CC([O-])(C)C.[K+].C[N:19](C=O)C>>[CH2:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([NH2:19])[CH:4]=1)[CH3:2]
Reactant: CCc1c[nH]c2ncccc12
Reactant: CN(C)C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCc1cn(N)c2ncccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Ethyl-1H-pyrrolo[2,3-b]pyridine (0.91 g, 6.2 mmol) and KOtBu (1.39 g, 12.4 mmol) are dissolved in DMF (28 mL) and stirred for 2 h at rt. While vigorously sparging with nitrogen, NH2Cl (92 ml 0.15 M in ether) is added in portions. The reaction mixture is stirred at rt for 2 h. The mixture is cooled 0° C. and then quenched with Na2S2O3 (2.7 g) in water (50 mL). After standing at rt for 18 h, the mixture is concentrated, triturated in DCM and filtered. The filtrate is concentrated and chromatographed through silica gel eluting with 10% MeOH in DCM to afford 3-ethyl-pyrrolo[2,3-b]pyridin-1-yl-amine (380 mg). MS: 162 (M+H); 1H NMR (300 MHz, CDCl3): δ 8.32 (d, 1H), 7.90 (d, 1H), 7.04-7.13(m, 2H), 4.96 (broad s, 2H), 2.76 (q, 2H), 1.33 (t, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:13]2[N:18]=[C:17]([CH:19]3[CH:23]([C:24](=[O:27])[NH:25][CH3:26])[CH2:22][CH2:21][N:20]3C(OC(C)(C)C)=O)[CH:16]=[C:15]([CH3:35])[N:14]=2)[CH:12]=[CH:11][N:10]=[CH:9]1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[N:8]1([C:13]2[N:18]=[C:17]([CH:19]3[CH:23]([C:24]([NH:25][CH3:26])=[O:27])[CH2:22][CH2:21][NH:20]3)[CH:16]=[C:15]([CH3:35])[N:14]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: CNC(=O)C1CCN(C(=O)OC(C)(C)C)C1c1cc(C)nc(-n2ccnc2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)C1CCNC1c1cc(C)nc(-n2ccnc2)n1
Temperature: 25 °C
Yield: 43.2 %

Procedure:
2,2,2-Trifluoroacetic acid (20.0 mL, 269 mmol) was added dropwise over 5 minutes to a 0° C. solution of tert-butyl 2-(2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl)-3-(methylcarbamoyl)pyrrolidine-1-carboxylate (720 mg, 1.86 mmol) in CH2Cl2 (20 mL). The reaction mixture was warmed to rt over 30 minutes then brought to pH=8 with Na2CO3 (400 mL, sat. aqueous solution). The mixture was extracted with CH2Cl2 (5×30 mL), the combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum to afford 2-(2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl)-N-methylpyrrolidine-3-carboxamide (230 mg, 43%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=2)[CH:7]=1.C([O-])=O.[NH4+]>C(O)C.O.[Fe]>[NH2:16][C:12]1[CH:11]=[C:10](/[CH:9]=[CH:8]/[C:6]2[CH:5]=[N:4][CH:3]=[C:2]([Br:1])[CH:7]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cccc(/C=C/c2cncc(Br)c2)c1
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cccc(/C=C/c2cncc(Br)c2)c1
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
A mixture of 3-bromo-5-[(E)-2-(3-nitrophenyl)vinyl]pyridine (5.55 g), iron powder (3.05 g) and ammonium formate (5.73 g) in ethanol (90 ml) and water (30 ml) was stirred at 90pbC. for 30 minutes. The mixture was filtered while hot. The filtrate was added to sodium bicarbonate solution and extracted with ethyl acetate twice. The combined organic solution was washed with sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated to give 3-[(E)-2-(3-aminophenyl)vinyl]-5-bromopyridine (3.57 g).
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([CH:9]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:16][C:17]#[N:18]>>[CH3:11][O:12][C:13]1[CH:14]=[C:15](/[C:16](=[CH:9]/[C:7]2[S:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)/[C:17]#[N:18])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Product: COc1ccc(/C(C#N)=C/c2ccc([N+](=O)[O-])s2)cc1OC
Yield: 8.5 %

Procedure:
5-Nitrothiophene-2-carboxaldehyde (3.14 g) was condensed with 3,4-dimethoxybenzyl cyanide (3.54 g) through Method A (production step 2), to thereby yield the target product (yield: 540 mg, 8.5%).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:13]1([C:22]([OH:24])=O)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1.[F:25][C:26]1[CH:40]=[CH:39][C:29]2[C:30]([CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[N:31][O:32][C:28]=2[CH:27]=1>ClCCl>[F:25][C:26]1[CH:40]=[CH:39][C:29]2[C:30]([CH:33]3[CH2:34][CH2:35][N:36]([C:22]([CH:13]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[CH2:15][CH2:14]4)=[O:24])[CH2:37][CH2:38]3)=[N:31][O:32][C:28]=2[CH:27]=1
Reactant: O=C(O)C1CCc2ccccc21
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(C1CCc2ccccc21)N1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4.2 g of carbonyldiimidazole are added to 3.7 g of 1-indanecarboxylic acid (Synthesis (1987) 845) dissolved in 15 ml of dichloromethane. After stirring for 1 hour 30 minutes at room temperature, 5 g of 6-fluoro-3-piperid-4-yl-1,2-benzisoxazole, dissolved in 10 ml of dichloromethane, are added. The mixture is stirred for 48 hours at room temperature and then concentrated to dryness and the residue is extracted with ethyl acetate. The organic phase is washed with hydrochloric acid, then with sodium bicarbonate solution and finally with water. It is dried over magnesium sulfate and concentrated. The oil obtained is used without further treatment.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([CH2:9][CH2:10][CH2:11][CH3:12])=O)=[CH:3][CH:2]=1.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[NH:14][NH2:15].C(O)C>C1(C)C=CC(S(O)(=O)=O)=CC=1.CO.C(Cl)Cl>[N:1]1[CH:6]=[CH:5][C:4]([C:7](=[N:15][NH:14][C:13]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9][CH2:10][CH2:11][CH3:12])=[CH:3][CH:2]=1
Reactant: CCCCC(=O)c1ccncc1
Reactant: CCOC(=O)NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: CCCCC(=NNC(=O)OCC)c1ccncc1
Yield: 54 %

Procedure:
A mixture of 8.3 gm (0.055 mole) of n-butyl 4-pyridinyl ketone, 6.1 gm (0.059 mole) of ethyl carbazate and 150 ml of absolute ethanol is refluxed 17 hr. A Tlc (3% MeOH/CH2Cl2 on Silica gel) shows 50% starting material remaining. p-Toluenesulfonic acid (0.3 gm) is added and the reaction mixture refluxed 17 hr more. Tlc shows no remaining starting materials. The reaction is concentrated in vacuo. The residue is slurried with water and the solid collected, washed with water and dried. Crystallization yields 7.41 gm of the title compound having a melting point of 102.1° C.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:6][OH:7])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:25](Cl)(=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>ClCCl>[C:25]([O:7][CH2:6][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH:33]=[CH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Reactant: CCCCCCCCCCC(CO)NC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCC=CCCCCCCCC(=O)OCC(CCCCCCCCCC)NC(C)=O
Yield: 82.8 %

Procedure:
To a solution of 2.43 g of 2-ethanoylaminododecanol, 3 g of triethylamine in 50 ml of dichloromethane is added 3.2 g of oleoyl chloride. The reaction mixture is worked up as under Example 9 to give 4.2 g of product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH2:19][C@H:20]([OH:27])[C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[CH2:28]([O:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:38]=1[C:39]([O:41][CH3:42])=[O:40])[CH:29]([CH3:31])[CH3:30].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:14]([O:13][C:12]([N:11]([CH2:19][C@H:20]([OH:27])[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:35]2[CH:36]=[CH:37][C:38]([C:39]([O:41][CH3:42])=[O:40])=[C:33]([O:32][CH2:28][CH:29]([CH3:31])[CH3:30])[CH:34]=2)=[CH:3][CH:4]=1)=[O:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)c1ccc(B(O)O)cc1OCC(C)C
Reactant: CC(C)(C)OC(=O)N(CCCc1ccc(Br)cc1)C[C@H](O)c1cccnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc(CCCN(C[C@H](O)c3cccnc3)C(=O)OC(C)(C)C)cc2)cc1OCC(C)C
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 92.7 %

Procedure:
To a mixture of tert-butyl [3-(4-bromophenyl)propyl]-[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]carbamate (312 mg), [3-isobutoxy-4-(methoxycarbonyl)phenyl]boronic acid (207 mg), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (58.4 mg) and 1,1′-bis(diphenylphosphino)ferrocene (7.93 mg) in N,N-dimethylformamide (3.12 ml) was added 2.0M aqueous sodium carbonate solution (1.25 ml) and the mixture was stirred at 90° C. for 2.5 hours. After cooling to room temperature, palladium was removed by filtration through a Celite cake. The mixture was extracted with ethyl acetate and the extract was washed with water and brine and dried over magnesium sulfate. Filtration followed by evaporation under reduced pressure gave a crude product which was purified by column chromatography on silica gel (hexane/ethyl acetate=1/1) to give methyl 4′-[3-[(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]-propyl]-3-isobutoxy-4-biphenylcarboxylate (374 mg) as a yellow solid (foam).
Reaction SMILES: [C:1]1([CH:7]=[C:8]2[C:13](=O)[C:12](=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][S:10](=[O:23])(=[O:22])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:24][NH2:25]>CO>[C:1]1([CH:7]2[NH:25][N:24]=[C:13]3[C:12](=[CH:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:11][S:10](=[O:23])(=[O:22])[CH2:9][CH:8]23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: O=C1C(=Cc2ccccc2)CS(=O)(=O)CC1=Cc1ccccc1
Solvent: CO
Product: O=S1(=O)CC(=Cc2ccccc2)C2=NNC(c3ccccc3)C2C1
Yield: 90.1 %

Procedure:
A mixture of 5.0g of tetrahydro-3,5-bis-(phenylmethylene)-4H-thiopyran-4-one-1,1-dioxide and 600mg of anhydrous hydrazine in 300ml of methanol is heated at reflux temperature for 2 hours. The mixture is cooled in an ice bath, filtered, and the product is washed with fresh methanol. The filtrate and washings are concentrated to about 100ml and cooled in an ice bath, yielding an additional small amount of product. The combined yield is 4.7g of the title compound, melting point 202°-208°C, dec.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.NO[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.ClC1C=CC=CC=1CC(Cl)=O>>[C:13]1([CH:2]2[CH2:3][NH:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[O:1]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1ccc2c(c1)NCCO2
Reactant: NOc1ccccc1
Agent: O=C(Cl)Cc1ccccc1Cl
Product: c1ccc(C2CNc3ccccc3O2)cc1

Procedure:
By a procedure similar to that described for the synthesis of 3,4-dihydro-2H-1,4-benzoxazine (Example 142), O-aminophenol and 2-chlorophenylacetyl chloride produces 3,4-dihydro-2-phenyl-2H-1,4-benzoxazine, m.p. 113°-116° which, according to the reaction scheme of Example 110 is converted to the title compound, m.p. 311°-313° .
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([C:18]2[C:19]([CH3:34])=[N:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)[CH2:15][CH2:16][CH3:17])=[CH:9][C:8]=1[CH3:35])C.C(OC(=O)COC1C=CC(O)=CC=1C)C>>[CH3:35][C:8]1[CH:9]=[C:10]([O:13][CH:14]([C:18]2[C:19]([CH3:34])=[N:20][C:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:28][CH:29]=3)=[CH:22][CH:23]=2)[CH2:15][CH2:16][CH3:17])[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:36])=[O:3]
Reactant: CCCC(Oc1ccc(OCC(=O)OCC)c(C)c1)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: CCOC(=O)COc1ccc(O)cc1C
Product: CCCC(Oc1ccc(OCC(=O)O)c(C)c1)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1C

Procedure:
A] The title compound was prepared in analogy to example 35, via [rac]-(2-methyl-4-{1 -[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-butoxy}-phenoxy)-acetic acid ethyl ester, but using in step A] (4-hydroxy-2-methyl-phenoxy)-acetic acid ethyl ester (WO02092590) instead of 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester, as colorless, viscous oil.
Reaction SMILES: [CH:1]([CH:3]1[CH2:10][CH2:9][CH2:8][CH2:7][NH:6][C:4]1=[O:5])=C.[CH3:11][N:12](CCCC=C(C)C(N)=O)[CH3:13].[C:23]([O:28][CH2:29][CH2:30][OH:31])(=[O:27])[C:24]([CH3:26])=[CH2:25]>O>[CH3:1][C:3]([C:4]([NH:6][CH2:7][CH2:8][CH2:9][N:12]([CH3:13])[CH3:11])=[O:5])=[CH2:10].[CH3:26][C:24]([C:23]([O:28][CH2:29][CH2:30][OH:31])=[O:27])=[CH2:25]
Reactant: CC(=CCCCN(C)C)C(N)=O
Reactant: C=CC1CCCCNC1=O
Agent: C=C(C)C(=O)OCCO
Solvent: O
Product: C=C(C)C(=O)NCCCN(C)C
Temperature: 60 °C

Procedure:
Five hundred grams (500 g) of de-ionized water was added to 1000 g of a 30% aqueous solution of a terpolymer of vinyl caprolactam (VCap), dimethylamino propyl methacrylamide (DMAPMA), and 2-hydroxyethyl methacrylate (HEMA). GMA (12 g) was added drop-wise with continuous stirring. The obtained solution was heated at 60° C. for one hour. The resulting product was freeze dried to render a solid, white powder. A representative structure for the polymeric reaction is presented below, wherein x+y+z+a=100:
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:5]2=[C:4]([C:18](=[O:29])[NH:19][C@@H:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:21]([NH:23][CH3:24])=[O:22])[N:3]=1.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:26][C:25]([CH3:28])([CH3:27])[C@H:20]([NH:19][C:18]([C:4]1[N:3]=[C:2]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:5]=12)=[O:29])[C:21]([NH:23][CH3:24])=[O:22]
Reactant: OB(O)c1ccccc1
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(Br)n2c1CN(C(=O)OC(C)(C)C)CC2)C(C)(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CC2)C(C)(C)C
Temperature: 150 °C
Yield: 76.1 %

Procedure:
Intermediate 1J (0.20 g, 0.42 mmol) was dissolved in dioxane (4 mL) and phenylboronic acid (0.10 g, 0.85 mmol) was added, followed by 2N Na2CO3 solution (0.70 mL, 1.39 mmol). The resulting mixture was degassed with nitrogen and tetrakis(triphenylphosphine) palladium(0) (0.073 g, 0.06 mmol) was added. The mixture was heated in a microwave reactor at 150° C. for 20 min. The reaction mixture was filtered through a celite pad, rinsed with methanol and the combined filtrate and washings were concentrated. The residue was purified by normal phase chromatography, eluting with 0-100% hexanes/ethyl acetate to provide Compound 1 as a yellow solid (0.15 g, 75%).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:12]Br.Br>C(Cl)(Cl)(Cl)Cl>[Br:12][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: BrBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(Br)C(=O)OCC
Temperature: 25 °C
Yield: 80 %

Procedure:
16.0 g of diethyl malonate was added to 27.3 g of carbon tetrachloride. Into the resultant mixture was dropped 16.4 g of bromine under stirring at room temperature. After the completion of the dropping, the mixture was heated to 80° C. and refluxed for 1 hour to thereby remove hydrogen bromide formed by the reaction. The liquid reaction mixture thus obtained was washed with a 5% aqueous solution of sodium carbonate and carbon tetrachloride was distilled off. Then distillation was carried out to give 19.1 g (yield: 80.0%) of diethyl bromomalonate.
Reaction SMILES: [O:1]=[C:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.C(N(C(C)C)CC)(C)C.Cl[C:41](=[O:46])[C:42]([O:44][CH3:45])=[O:43]>ClCCl.C(OCC)(=O)C>[CH3:45][O:44][C:42](=[O:43])[C:41]([N:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:2](=[O:1])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[CH2:7][CH2:6]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:46]
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)c2ccccc2Nc2ccccc2)CC1
Reactant: COC(=O)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C(=O)N(c1ccccc1)c1ccccc1C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
To a solution of the compound prepared in Example 303 (350 mg) in dichloromethane (3.0 mL) at 0° C. was added diisopropylethylamine (0.746 mL) followed by methyl 2-chloro-2-oxoacetate (262 mg). The reaction was allowed to warm to room temperature and then stirred for 2 hours. The solution was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate and brine. The organics were dried over magnesium sulfate, and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 10% ethyl acetate/hexane) to furnish the title compound (374 mg) with the following physical properties.
Reaction SMILES: [F:1][CH:2]([F:12])[CH2:3][NH:4][C:5]1[C:6]([NH2:11])=[CH:7][CH:8]=[CH:9][CH:10]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=O)[C:21](O)=[O:22])=[CH:16][CH:15]=1>CO>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:22])[N:4]([CH2:3][CH:2]([F:12])[F:1])[C:5]3[C:6]([N:11]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:16][CH:15]=1
Reactant: O=C(O)C(=O)c1ccc(Cl)cc1
Reactant: Nc1ccccc1NCC(F)F
Solvent: CO
Product: O=c1c(-c2ccc(Cl)cc2)nc2ccccc2n1CC(F)F
Yield: 31.7 %

Procedure:
To a solution of 400 mg (2.32 mM) of N-(2,2-difiuoroethyl)benzene-1,2-diamine in 7 ml of methanol were added 428 mg (2.32 mM) of 4-chloro-α-oxo-benzeneacetic acid. The mixture was refluxed for 3 h. A solid was filtered, washed and dried under vacuum to give 236 mg of 3-(4-chlorophenyl)-1-(2,2-difluoroethyl) quinoxalin-2(1H)-one Yield: 32%.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[C:32]([CH3:40])[CH:31]=4)[N:21]=3)[CH:19]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:40][C:32]1[CH:31]=[C:30]([C:22]2[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[N:25]=[C:20]([N:18]3[CH:19]=[C:15]([C:12]4[CH:13]=[CH:14][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:10][CH:11]=4)[N:16]=[CH:17]3)[N:21]=2)[CH:35]=[CH:34][C:33]=1[C:36]([F:39])([F:38])[F:37]
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(-c4ccc(S(=O)(=O)NC(C)(C)C)cc4)c3)n2)ccc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(-c4ccc(S(N)(=O)=O)cc4)c3)n2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.8 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-4-{1-[6-(3-methyl-4-trifluoromethylphenyl)-4-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.057 g) in dichloromethane (2 mL) was added TFA (2 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (2.5 mL) and MeOH (2.5 mL) were added. The mixture was stirred at room temperature for 30 min, the precipitate was collected by filtration and washed with water. The crude product was further purified by crystallization (dichloromethane/heptane/MeOH) to yield the title compound as a white solid (0.038 g, 7%). MS (ISN) 526.5 [(M−H)−]; mp 287° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[C:22]([C:23](=[O:26])[C:24]=2[OH:25])=[CH:21][CH:20]=[C:19]([O:27][CH2:28][O:29][CH3:30])[CH:18]=3)=[CH:11][C:10]=1[O:31][CH2:32][O:33][CH3:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[CH2:45][O:46][CH3:47]>C(Cl)Cl.CCOCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[C:22]([C:23](=[O:26])[C:24]=2[O:25][CH2:45][O:46][CH3:47])=[CH:21][CH:20]=[C:19]([O:27][CH2:28][O:29][CH3:30])[CH:18]=3)=[CH:11][C:10]=1[O:31][CH2:32][O:33][CH3:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCl
Reactant: COCOc1ccc2c(=O)c(O)c(-c3ccc(OCc4ccccc4)c(OCOC)c3)oc2c1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc2c(=O)c(OCOC)c(-c3ccc(OCc4ccccc4)c(OCOC)c3)oc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
To 2-(4-(benzyloxy)-3-(methoxymethoxy)phenyl)-3-hydroxy-7-(methoxymethoxy)-4H-chromen-4-one (55 mg, 0.12 mmol) in 2 mL of DCM was added DIPEA (31 mg, 0.24 mmol), followed by slow addition of chloro(methoxy)methane (15 mg, 0.18 mmol). The reaction mixture was stirred at rt under Ar atmosphere for 3 h and diluted with ether (30 mL). It was washed with water (3×30 mL) and dried over MgSO4 and concentrated. The crude product was purified with silica chromatography (hexane/EtOAc) to afford 2-(4-(benzyloxy)-3-(methoxymethoxy)phenyl)-3,7-bis(methoxymethoxy)-4H-chromen-4-one as a white solid (55 mg, 90%). 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J=8.8 hz, 1H), 7.91 (d, J=2.0 Hz, 1H), 7.71 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.46-7.44 (m, 2H), 7.39 (m, 2H), 7.34-7.31 (m, 1H), 7.12 (d, J=2.4 Hz, 1H), 7.05 (dd, J=8.8, 2.4 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 5.30 (s, 2H), 5.28 (s, 2H), 5.24 (s, 2H), 5.21 (s, 2H), 3.55 (s, 3H), 3.51 (s, 3H), 3.18 (s, 3H); MS (ESI) m/z 509 (M+H+).
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[CH3:23])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C1C=C(Cl)C=C(C(OO)=[O:33])C=1>>[O-:33][N+:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[C:6]2[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[CH3:23])[C:4]([CH2:1][CH2:2][CH3:3])=[N:16][C:7]=2[CH:8]=1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCCC(C)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCCc1nc2c[n+]([O-])c3ccccc3c2n1CCCCCC(C)=O

Procedure:
The general method described in Steps 9 and 10 of Example 1 was used to aminate 7-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)heptan-2-one (5.0 g, 15.5 mmol) by reaction with m-CPBA (8.0 g) to provide 7-(5-oxido-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)heptan-2-one followed by reaction with p-toluenesulfonyl chloride (4.42 g, 23.2 mmol) and ammonium hydroxide solution (50 mL) to provide 7-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)heptan-2-one) as an off-white solid after recrystallization from a mixture of acetonitrile, ethyl acetate, and hexane, mp 161-163° C.