Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:14][S:15]([CH2:18][CH2:19][CH2:20]Cl)(=[O:17])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(N(CC)CC)C>CN(C)C=O>[C:25]([O:24][C:22]([N:29]1[CH2:34][CH2:33][N:32]([CH2:20][CH2:19][CH2:18][S:15](=[O:17])(=[O:16])[NH:14][CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:31][CH2:30]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: O=S(=O)(CCCCl)NC(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(CCCS(=O)(=O)NC(c2ccccc2)c2ccccc2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
In a three-neck round bottom flask equipped with argon inlet was charged with anhydrous dimethylformamide and 3-chloro-propane-1-sulfonic acid benzhydryl-amide (893 mg, 2.76 mmol). 1-Boc-piperazine (771 mg, 4.14 mmol, Aldrich) was added, followed by triethylamine (0.77 mL, 5.52 mmol). The mixture was stirred at 60° C. overnight. It was then heated at 120° C. for 10 min and at 180° C. for 15 min using the microwave synthesizer. Upon cooling, the reaction mixture was concentrated, and the residue was diluted with ethyl acetate. The organic layer was washed with water, brine, and concentrated. Purification of the crude residue by flash column chromatography gave 4-[3-(benzhydryl-sulfamoyl)-propyl]-piperazine-1-carboxylic acid tert-butyl ester as yellow oil (688 mg).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]1([CH2:16]Br)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.CO.C(=O)([O-])[O-].[K+].[K+]>O>[CH:10]1([CH2:16][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: BrCC1CCCCC1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=Cc1ccc(OCC2CCCCC2)cc1

Procedure:
4-Hydroxybenzaldehyde (244 g) and 354 g of cyclohexylmethylbromide were added to 1 liter of methanol containing 414 g of anhydrous potassium carbonate (3.0M). The mixture was heated to reflux temperature overnight after which it was poured into cold water and extracted with ethyl acetate. The extracts were dried and evaporated in vacuo to yield the desired subtitled intermediate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[O:21])=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][C:8]=1[C:20](=[O:21])[CH2:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: COc1cccc(OC)c1
Product: COc1ccc(CC(=O)c2ccc(OC)cc2OC)cc1
Yield: 51.6 %

Procedure:
Synthesized from 1,3-dimethoxybenzene (8.2 g) and 4-methoxyphenylacetyl chloride (10.0 g) according to an analogous synthetic method to Preparation Example 66, the title compound (8.0 g) was obtained.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[C@H:21]([CH3:22])[CH2:20][O:19][C@H:18]([CH2:23][OH:24])[CH2:17]3)[N:13]=[C:12]([NH:25][CH3:26])[N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O.[NH2:28][NH2:29]>CCO>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][C:8]([C:10]3[N:11]=[C:12]([NH:25][CH3:26])[N:13]=[C:14]([N:16]4[C@H:21]([CH3:22])[CH2:20][O:19][C@H:18]([CH2:23][OH:24])[CH2:17]4)[CH:15]=3)=[CH:7][CH:6]=2)[NH:29][N:28]=1
Reactant: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2C[C@@H](CO)OC[C@H]2C)n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CNc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2C[C@@H](CO)OC[C@H]2C)n1
Temperature: 100 °C
Reaction time: 42 h
Yield: 72.8 %

Procedure:
A mixture of 2-fluoro-4-[6-[(2S,5R)-2-(hydroxymethyl)-5-methyl-4-morpholinyl]-2-(methylamino)-4-pyrimidinyl]benzonitrile (151 mg, 0.42 mmol) and hydrazine monohydrate (0.41 mL, 8.44 mmol) in EtOH (4 mL) was stirred at 100° C. in a sealed tube for 42 hours. It was then cooled, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (24 g SiO2, CH2Cl2 to 90/10/1 CH2Cl2/CH3OH/NH4OH gradient) to give the title compound (113 mg) as a white solid. LC-MS (ES) m/z=370 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.17 (d, J=6.6 Hz, 3H), 2.72-2.93 (m, 4H), 3.37-3.59 (m, 3H), 3.66 (d, J=11.2 Hz, 1H), 3.77 (d, J=11.1 Hz, 1H), 3.94-4.74 (bs, 2H), 4.38 (t, J=5.7 Hz, 1H), 5.38 (s, 2H), 6.54 (m, 2H), 7.59 (d, J=8.3 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.98 (s, 1H), 11.50 (s, 1H).
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[O:17]1[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18]1.CCOCC>C1C=CC=CC=1>[O:17]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:18]1
Reactant: O=Cc1ccoc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCOC(=O)/C=C/c1ccoc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 17.7 g (78.8 mmol) of ethyl diethylphosphonoacetate in 150 ml of benzene, 2.89 g (72.2 mmol) of sodium hydride (60% in oil) was added under ice-cooling, followed by stirring for 30 minutes. To this solution, a solution of 6.308 g (65.65 mmol) of 3-furaldehyde in 50 ml of benzene was added dropwise, followed by stirring at room temperature for 30 minutes and refluxing for 30 minutes. After the reaction mixture was cooled to room temperature, ether was added; the mixture was then washed with water. The ether solution was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane to hexane/ethyl acetate=9/1) to yield the desired product.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:9])=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.CS(C)=O.[O:14]1[C:16]2[CH2:17][CH2:18][CH2:19][C:15]1=2>[Pd].O1CCCC1>[NH2:9][C:3]1[C:2]([CH3:1])=[CH:7][N:6]([CH:18]2[CH2:19][CH:15]([OH:14])[CH:16]=[CH:17]2)[C:5](=[O:8])[N:4]=1
Reactant: Cc1c[nH]c(=O)nc1N
Reactant: C1CC2=C(C1)O2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Cc1cn(C2C=CC(O)C2)c(=O)nc1N
Reaction time: 1.5 h
Yield: 24.4 %

Procedure:
50 g (0.4 mol) of 5-methylcytosine are added to a solution of the palladium(0) catalyst (1.6 mol %) prepared in situ as described above in 200 ml of dry tetrahydrofuran/200 ml of dry dimethylsulfoxide at 5° C. 49.2 g (0.6 mol) of epoxycyclopentene, dissolved in 100 ml of tetrahydrofuran, are added dropwise to this suspension, while stirring (1.5 hours). The mixture is stirred at room temperature for 3 days and then concentrated, and the residue is stirred with 2N sodium carbonate solution, filtered off and washed with water and acetone. 20.2 g (24.4% of theory) of 4-amino-5-methyl-1-[(1RS,4SR)-4-hydroxy-cyclopent-2-en-1-yl]pyrimidin-2(1H)-one of melting point 241°-245° C. are obtained. Chromatography (silica gel, methylene chloride/methanol 3/1) of the neutralized mother liquor gives, in addition to 5-methylcytosine (14.95 g, melting point 264°-269° C.) a further 9.87 g (11.9% of theory) of the title compound; total yield: 36.3% of theory. 1H NMR (270 MHz, d6 -DMSO); δ[ppm]: 7.23 (s, 1H), 7.12 (s, broad, 1H), 6.70 (s, broad, 1H), 6.09 (m, 1H), 5.74 (m, 1H), 5.45 (m, 1H), 5.17 (s, 1H), 4.61 (m, 1H), 2.71 (m, 1H), 1.81 (s, 3H), 1.27 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11](O)=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1.CO>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][OH:12])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)CCc1cc(F)cc(F)c1
Solvent: C1CCOC1
Solvent: CO
Product: OCCCc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
Borane-tetrahydrofuran complex (0.095 mol) was added to a cooled (0°) solution of 3-(3,5-difluorophenyl)propanoic acid (0.043 mol) in tetrahydrofuran (75 ml). The reaction was stirred 2 hours at room temperature, then methanol was carefully added and the reaction was concentrated. The crude product was dissolved in ethyl ether, washed with water, dried over sodium sulfate and concentrated to yield 7 g (95%) of an oily product.
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH:3]=O.C(Cl)(Cl)=O.[CH3:10][C:11]1[NH:12][CH:13]=[CH:14][N:15]=1.[F:16][P-:17]([F:22])([F:21])([F:20])([F:19])[F:18].[Na+]>C(Cl)(Cl)Cl>[F:16][P-:17]([F:22])([F:21])([F:20])([F:19])[F:18].[CH3:1][N:2]([CH3:5])[CH:3]=[C:10]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)[CH:1]=[N+:2]([CH3:5])[CH3:3]
Reactant: CN(C)C=O
Reactant: Cc1ncc[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CN(C)C=C(C=[N+](C)C)c1ncc[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The Vilsmeier Haack reagent is prepared using 140 ml. (1.8 mole) of dimethylformamide and 500 ml. of 3N phosgene in chloroform. 2-Methylimidazole (30.8 g., 0.375 mole) is added in portions over one hour maintaining the temperature at or below 10° C. and the mixture is then stirred overnight at ambient temperature. The reaction mixture is poured onto ice (490 g.), shaken and separated. The chloroform solution is extracted with water (35 ml.) and the combined aqueous solutions treated with sodium hexafluorophosphate (63.0 g., 0.375 mole). After filtering, the filtrate is cooled in an ice-bath while sodium carbonate anhydrate (139 g., 1.313 mole) is added in small portions. The crystalline precipitate obtained weighs 50.70 g. (39%) and melts at 185°-187° C. Recrystallization of the crude product from water (5 parts volume by weight) gives purified product melting at 191°-192° C. in the form of colorless crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[NH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][C:15]([Cl:21])=[CH:16][CH:17]=2)[N:12]=1>>[Cl:21][C:15]1[N:14]=[C:13]2[C:18]([CH:19]=[CH:20][C:11]([NH:10][C:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)=[O:9])=[N:12]2)=[CH:17][CH:16]=1
Reactant: O=C(O)c1cnccn1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1cnccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 2-pyrazinecarboxylic acid (7.5 g), N,N'-carbonyldiimidazole (9.7 g) and 2-amino-7-chloro-1,8-naphthyridine (10.8 g). The insoluble product is separated by filtration, washed with tetrahydrofuran (3×50 cc) and then with water (300 cc) and dried in the air. The product is suspended in acetonitrile (100 cc), stirred for 1 hour at 25° C. and separated by filtration, and then dried at 50° C. under reduced pressure (0.07 kPa). N-(7-Chloro-1,8-naphthyridin-2-yl)-2-pyrazinecarboxamide (11.75 g), m.p. 308° C., is thereby obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=[CH:17][C:4]=2[O:3]1.ClC1C=CC=C(C(OO)=[O:31])C=1>ClCCl>[CH3:21][O:20][C:18]([C:15]1[CH:16]=[CH:17][C:4]2[O:3][C:2]([CH3:22])([CH3:1])[CH2:7][CH:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=3[O-:31])[C:5]=2[CH:14]=1)=[O:19]
Reactant: COC(=O)c1ccc2c(c1)C(c1ccccn1)CC(C)(C)O2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)C(c1cccc[n+]1[O-])CC(C)(C)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
313 mg of methyl 3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran-6-carboxylate were dissolved in 10 ml of dichloromethane at room temperature and 283 mg of m-chloroperbenzoic acid were added. After stirring at room temperature for 2 hours the mixture was washed with sodium bisulphite solution and sodium bicarbonate solution. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using initially 2% (v/v) methanol/ethyl acetate and finally 5% (v/v) methanol/ethyl acetate for the elution. There were obtained 250 mg of 2-[3,4-dihydro-6-(methoxycarbonyl)-2,2-dimethyl-2H-1-benzopyran-4-yl]pyridine N-oxide as an oil which solidified upon trituration with diethyl ether. After recrystallization from toluene the product melted at 128°-130° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[C:4](=[O:10])[N:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([O:23][C:24]2[CH:25]=[CH:26][C:27]3[N:28]([CH:30]=[C:31]([NH:33][C:34]([CH:36]4[CH2:38][CH2:37]4)=[O:35])[N:32]=3)[CH:29]=2)=[C:21]([F:41])[CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:36]1([C:34]([NH:33][C:31]2[N:32]=[C:27]3[CH:26]=[CH:25][C:24]([O:23][C:22]4[CH:39]=[CH:40][C:19]([NH:18][C:7]([C:5]5[C:4](=[O:10])[N:3]([C:11]6[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=6[CH3:17])[N:2]([CH3:1])[CH:6]=5)=[O:9])=[CH:20][C:21]=4[F:41])=[CH:29][N:28]3[CH:30]=2)=[O:35])[CH2:37][CH2:38]1
Reactant: Cc1ccccc1-n1c(=O)c(C(=O)O)cn1C
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccccc1-n1c(=O)c(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)cn1C
Yield: 69.4 %

Procedure:
In the same manner as in Example 46 and using 1-methyl-2-(2-methylphenyl)-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylic acid (370 mg, 1.6 mmol), N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (260 mg, 0.80 mmol), HATU (610 mg, 1.6 mmol), N,N-diisopropylethylamine (410 mg, 3.2 mmol) and N,N-dimethylformamide (12 mL) as starting materials, the title compound (300 mg, 70%) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:31])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:21][CH:20]=1)[C:10](=[O:17])[NH:11]2.Cl[CH:34]([F:36])[F:35]>>[CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:31])=[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25](=[O:30])[C:26]([CH3:28])([CH3:27])[CH3:29])=[CH:23][CH:24]=1)[C:10]([O:17][CH:34]([F:36])[F:35])=[N:11]2
Reactant: FC(F)Cl
Reactant: COC(=O)COc1ccc(Cl)c2[nH]c(=O)c(Cc3ccc(C(=O)C(C)(C)C)cc3)c(C)c12
Product: COC(=O)COc1ccc(Cl)c2nc(OC(F)F)c(Cc3ccc(C(=O)C(C)(C)C)cc3)c(C)c12

Procedure:
The title compound was prepared by the method of Preparation 10c using (8-chloro-3-[4-(2,2-dimethylpropionyl)benzyl]-4-methyl-2-oxo-1,2-dihydroquinolin-5-yloxy)acetic acid methyl ester and chlorodifluoromethane.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH:9]1([CH:12]=O)[CH2:11][CH2:10]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH2:12][CH:9]1[CH2:11][CH2:10]1
Reactant: Nc1ccccc1Br
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Brc1ccccc1NCC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
A solution of 2-bromoaniline (1.720 g, 10.00 mmol), cyclopropanecarbaldehyde (0.374 mL, 5.00 mmol), and acetic acid (2.86 mL, 50.0 mmol) in dichloromethane (50 mL) was heated at 50° C. for 1 hour. The solution was cooled in an ice bath and sodium triacetoxyborohydride (2.119 g, 10.00 mmol) was added. This mixture was stirred for 2 hours while warming to ambient temperature and then partitioned between saturated sodium bicarbonate solution (100 mL) and ethyl acetate (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-10% ethyl acetate in heptane) to provide the title compound (1.05 g, 93% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:41])[O:37][CH:38]([CH3:40])[CH3:39])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:41])[O:37][CH:38]([CH3:39])[CH3:40])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CC(C)OC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(C)OC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Example 143 was prepared from bis(4-chlorophenyl)acetic acid and isopropyl 3-[1-(3-aminopropyl)-4-piperidinyl]phenylcarbamate according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 7.37 (s, 1H), 7.23–7.10 (m, 9H), 7.00 (d, 1H, J=7.9 Hz), 6.80 (d, 1H, J=7.4 Hz), 6.60 (s, 1H), 4.88 (septet, 1H, J=6.2 Hz), 4.68 (s, 1H), 4.05 (q, 1H, J=7.3 Hz), 3.32 (q, 2H, J=5.9 Hz), 2.90–2.83 (m, 2H), 2.44–2.32 (m, 3H), 1.94–1.86 (m, 2H), 1.78–1.70 (m, 2H), 1.60 (quintet, 2H, J=6.4 Hz), 1.56–1.43 (m, 1H), 1.22 (d, 6H, J=6.2 Hz); ESMS m/e: 582.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=1>CN(C)C=O.O>[N+:32]([C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[O:25][CH2:24][CH2:23][NH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1)([O-:34])=[O:33]
Reactant: O=[N+]([O-])c1cccc(OCCBr)c1
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(NCCOc2cccc([N+](=O)[O-])c2)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A solution of tert-butyl (3-aminophenyl)carbamate (1.0 g, 4.8 mmol) and potassium carbonate (1.3 g, 9.6 mmol) in N,N-dimethylformamide (10 mL) was treated with a solution of 1-(2-bromoethoxy)-3-nitrobenzene (1.2 g, 5.0 mmol) in N,N-dimethylformamide (5 mL) was stirred at 20° C. for 2 h and at 80° C. for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×80 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated to give the desired product as a crude residue. This material was purified by flash column chromatography to give the desired product (1.0 g, 56%) as a yellow gum. LCMS for C19H24N3O5 (M+H)+: m/z=374.2.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].C(=O)/C=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+].Cl>O.CO>[C:14]1([CH:13]=[CH:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)=[O:10])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)c1ccccc1O
Reactant: O=C/C=C/c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(C=Cc1ccccc1)c1ccccc1

Procedure:
A solution of 5.00 g (36.7 mmol) of 2'-hydroxyacetophenone, 4.85 g (36.7 mmol) of trans-cinnamaldehyde, 11.10 g NaOH (in 20 mL of water) and 250 mL MeOH was stirred for 23 hours before the solution was poured into 1000 mL water. The resulting mixture was neutralized with dilute HCl and the yellow precipitate was collected by filtration. Recrystallization from MeOH gave a pure intermediate chalcone product. Further oxidation of the above chalcone was carried out with excess H2O2 (30%) in basic (NaOH aq.) MeOH solution for 12 hours. This solution was poured into water, and neutralized with dilute HCl. The resulting light yellow precipitate was collected by filtration and the pure desired product was obtained by recrystallization from MeOH with 7% overall yield. MP: 189°-191° C. Quantum yield (relative to 3-hydroxyflavone in CH2Cl2) 0.04. Extinction coefficient εmax (M-1 cm-1) 26,000. λmax (abs)=374 nm and λmax (em)=600 nm.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([C:5]([C:12]#[N:13])=[C:6]([CH3:11])[CH:7]=[CH:8]2)=[N:3]1>CO.N.[Ni]>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([C:5]([CH2:12][NH2:13])=[C:6]([CH3:11])[CH:7]=[CH:8]2)=[N:3]1
Reactant: Cc1ccc2cn(C)nc2c1C#N
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cc1ccc2cn(C)nc2c1CN
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 2,6-dimethyl-2H-indazole-7-carbonitrile (1 equiv.) in methanol and aq. ammonia solution (9:1), catalytic amount of Raney Nickel was added. Reaction mass was stirred at room temperature under hydrogen pressure (balloon pressure) for 2-5 h. On completion of reaction, it was filtered through celite bed and filtrate was concentrated under reduce pressure to afford the title compound (quant. yield).
Reaction SMILES: BrC1C=CC(O)=C([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.C([C:40]1[CH:41]=[CH:42][C:43]2[O:48][CH2:47][C:46](=[O:49])[NH:45][C:44]=2[CH:50]=1)(=O)C.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:40]2[CH:41]=[CH:42][C:43]4[O:48][CH2:47][C:46](=[O:49])[NH:45][C:44]=4[CH:50]=2)[CH:17]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)c1ccc2c(c1)NC(=O)CO2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1COc2ccc(-c3ccc4cc(-c5nc6cc(C(=O)O)ccc6n5C5CCCCC5)ccc4n3)cc2N1
Yield: 8 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 6-acetyl-4H-benzo[1,4]oxazin-3-one (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (11 mg, 8% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[C:5]([NH2:19])=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1.O.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O.Cl>[Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][CH:10]=2)=[CH:6][C:5]2[NH:19][C:12]([C:15]([F:18])([F:17])[F:16])=[N:20][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Oc2ccc(C(F)(F)F)cc2)cc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc(Oc2cc3[nH]c(C(F)(F)F)nc3cc2Cl)cc1
Yield: 124.5 %

Procedure:
To a solution of 4,5-dichloro-2-nitroaniline (5 g, 24.15 mmol) in DMSO (15 ml) was added potassium carbonate (6.62 g, 47.90 mmol) and 4-(trifluoromethyl)phenol (6.6 g, 40.71 mmol) in several batches. The resulting solution was stirred for 8 h at 90° C. in an oil bath maintained with an inert atmosphere of nitrogen. The reaction mixture was then quenched by the addition of water (200 ml), extracted with ethyl acetate (5×100 ml) and the organic layers combined. The resulting mixture was washed with sodium chloride (3×100 m), dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 2% to 10% ethyl acetate in petroleum ether to produce 4-chloro-2-nitro-5-[4-(trifluoromethyl)phenoxy]aniline as a yellow solid (1.43 g, 18%). Next, to a solution of 4-chloro-2-nitro-5-[4-(trifluoromethyl)phenoxy]aniline (499 mg, 1.50 mmol) in ethanol (30 ml) was added hydrogen chloride (conc) (0.4 mL) and Zn powder (586 mg) in several bacthes. The resulting solution was stirred for 1.5 h at 85° C. in an oil bath and then concentrated under vacuum. The residue was dissolved in ethyl acetate (150 ml), washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column with 2% to 10% ethyl acetate in petroleum ether to afford 4-chloro-5-[4-(trifluoromethyl)phenoxy]benzene-1,2-diamine as a red solid (359 mg, 79%). Finally, a solution of 4-chloro-5-[4-(trifluoromethyl)phenoxy]benzene-1,2-diamine (100 mg, 0.33 mmol) in trifluoroacetic acid (5 ml) and HCl ((conc), 1 ml) was stirred for 4.5 h at 80° C. in an oil bath. The solution was poured into water (100 ml), adjusted pH value of the solution to 8 with sodium bicarbonate (sat) and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by Pre-TLC with 11% ethyl acetate in petroleum ether to produce 5-chloro-2-(trifluoromethyl)-6-[4-(trifluoromethyl)phenoxy]-1H-1,3-benzodiazole as a white solid (78.2 mg, 62%).