Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[Br:12][C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[C:14]=1[NH2:15]>>[Br:12][C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1c(Br)cccc1Br
Product: O=C(O)Cc1ccccc1Nc1c(Br)cccc1Br

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2,6-dibromoaniline to yield 2-[(2,6-dibromophenyl)amino]phenylacetic acid.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:33])[N:22]([CH:24]([C:29]([NH:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26])[CH3:23])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[CH:1]1([NH:4][CH2:5][C:7]2[CH:8]=[CH:9][C:10]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([C:21](=[O:33])[N:22]([CH:24]([C:29]([NH:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26])[CH3:23])=[CH:17][CH:16]=3)=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(C#Cc2ccc(C=O)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(C#Cc2ccc(CNC3CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 76 %

Procedure:
Cyclopropylamine (0.15 g) and acetic acid (0.16 g) were added to a chloroform (20 mL) solution of 1-formyl-4-[(4-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}phenyl)ethynyl]benzene (1.0 g) as obtained in Example 10-(5), and the mixture was stirred for 2.5 hours at room temperature. Then, sodium triacetoxyborohydride (0.89 g) was added, and the mixture was stirred for 15 hours at room temperature. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and then the mixture was extracted with chloroform. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. Then, the desiccant was filtered out, and the solvent was distilled off under reduced pressure. The resulting residue was purified by OH type silica gel chromatography (gradient elution with hexane/ethyl acetate=34/66→1/100) to obtain 1-[(cyclopropylamino)methyl]-4-[(4-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}phenyl)ethynyl]benzene (colorless foam) (0.84 g, 74%).
Reaction SMILES: [Cl:1][C:2]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:5]2[N:6]([CH:10]([CH3:12])[CH3:11])[C:7](=O)[NH:8][C:4]=2[CH:3]=1.C1(=O)OCCO1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:7]1[N:6]([CH:10]([CH3:12])[CH3:11])[C:5]2[CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)n1c(=O)[nH]c2cc(Cl)c([N+](=O)[O-])cc21
Solvent: O=C1OCCO1
Product: CC(C)n1c(Cl)nc2cc(Cl)c([N+](=O)[O-])cc21

Procedure:
To 5-chloro-1-isopropyl-6-nitrobenzimidazol-2-one (1.0 g) were added ethylene carbonate (0.7 g) and phosphorus oxychloride (1.1 ml) and the mixture was refluxed for 5 hours. Phosphorus oxychloride was distilled off under reduced pressure and the residue was dissolved in ethyl acetate and the solution was added to ice-water and the mixture was neutralized with an aqueous sodium hydroxide solution. The organic layer was washed with water and dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure to give 2,5-dichloro-1-isopropyl-6-nitrobenzimidazole (0.9 g). A part of the obtained product was recrystallized from ethanol, which showed the following physical properties:
Reaction SMILES: [N:1]([CH:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][C:5]1([F:17])[F:16])=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][CH:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:6][C:5]1([F:17])[F:16]
Reactant: CC(C)(C)OC(=O)N1CC(N=[N+]=[N-])C(F)(F)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(N)C(F)(F)C1
Reaction time: 16 h
Yield: 97.8 %

Procedure:
A solution of tert-butyl 4-azido-3,3-difluoropyrrolidine-1-carboxylate (3.01 g, 12.1 mmol) in ethanol (300 mL) was degassed with nitrogen and 20% Pd/C (300 mg) was added. The resulting mixture was stirred under hydrogen atmosphere (balloon) for 16 hr. The catalyst was removed by filtration. The filtrate was evaporated to give the title product as an oil (2.63 g, 98% yield, >85% purity). 1H NMR (400 MHz, chloroform-d) δ ppm 3.73-3.87 (m, 2 H) 3.69 (d, J=10.64 Hz, 1 H) 3.50-3.62 (m, 1 H) 3.13 (d, J=6.85 Hz, 1 H) 1.45-1.48 (m, 9 H). 19F NMR (376 MHz, chloroform-d) δ ppm −115.05-−110.78 (m, 1F) −120.95-−117.90 (m, 1 F). m/z (APCI+) for C9H16F2N2O2 123 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][C:6](=[O:7])[C:5]2=[CH:11][C:12]=1S(=O)(=O)N.C(O)CCCC>>[O:7]=[C:6]1[C:5]2[C:4](=[CH:3][CH:2]=[CH:12][CH:11]=2)[C:9](=[O:10])[NH:8]1
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)NC2=O
Solvent: CCCCCO
Product: O=C1NC(=O)c2ccccc21
Yield: 57 %

Procedure:
6-Chloro-2,3-dihydro-1,3-dioxo-2-[2-[N-methyl-N-(phenylmethyl)]ethyl]-1H-isoindole-5-sulfonamide. Reaction of 4-chloro-5-sulfamoylphthalimide (9.5 g., 0.0365 mole) and 2-[N-methyl-N-(phenylmethyl)]ethylamine (6.0 g., 0.0365 mole) in 200 ml. of amyl alcohol at reflux temperature for a 24 hr. period under nitrogen according to the procedure of Example 1(a) afforded a 57% yield of the 1,3-dioxoisoindole intermediate, m.p. 182°-187° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=O)[CH:8]=2)[CH:3]=[CH:2]1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2[CH:23]=[N:24][C:25]([S:28][CH2:29][C:30]([NH:32][CH2:33][CH:34]3[CH2:39][CH2:38][CH2:37][NH:36][CH2:35]3)=[O:31])=[N:26][CH:27]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].C(N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.CO>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2[CH:23]=[N:24][C:25]([S:28][CH2:29][C:30]([NH:32][CH2:33][CH:34]3[CH2:39][CH2:38][CH2:37][N:36]([CH2:10][C:7]4[CH:8]=[C:9]5[C:4]([CH:3]=[CH:2][NH:1]5)=[CH:5][CH:6]=4)[CH2:35]3)=[O:31])=[N:26][CH:27]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: O=Cc1ccc2cc[nH]c2c1
Reactant: COc1ccc(-c2cnc(SCC(=O)NCC3CCCNC3)nc2)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cnc(SCC(=O)NCC3CCCN(Cc4ccc5cc[nH]c5c4)C3)nc2)cc1OC
Reaction time: 8 h
Yield: 64.3 %

Procedure:
1H-indole-6-carbaldehyde (238 mg, 1.64 mmol, 1.36 equiv) [Moyer, Mikel P.; Shiurba, John F.; Rapoport, Henry; J. Org. Chem.; 1986, 51, 5106-5110] was added to the solution of the 2-[5-(3,4-dimethoxy-phenyl)-pyrimidin-2-ylsulfanyl]-N-piperidin-3-ylmethyl-acetamide 1h (TFA)n (1.20 mmol, obtained from step 6) and diisopropylethylamine (0.85 mL, 4.8 mmol, 4 equiv) in 50 mL dichloroethane. Sodium triacetoxyborohydride (0.47 g, 2.24 mmol, 1.8 equiv) was added to the solution and the resulting suspension was stirred vigorously overnight. Methanol (5 mL) was added to quench the reaction. The mixture was concentrated and the residue was diluted with ethyl acetate. The solution was poured into saturated NaHCO3 solution (40 mL) and extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), and concentrated. Chromatography on silica gel (10% methanol in chloroform) afforded 2-[5-(3,4-dimethoxy-phenyl)-pyrimidin-2-ylsulfanyl]-N-[1-(1H-indol-6-ylmethyl)-piperidin-3-ylmethyl]-acetamide (free base, 410 mg, 64%) as a light tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([S:13]([C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Na+]>O>[Cl:1][C:2]1[CH:12]=[C:11]([S:13]([C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH:10]=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1ccc(S(=O)(=O)C(C)(C)C)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)S(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Yield: 81.5 %

Procedure:
A mixture of ethyl 2-chloro-4-(1,1-dimethylethylsulphonyl)-benzoate (7.66 g) and sodium hydroxide (6.09 g) in water was stirred and heated at reflux for 2 hours. It was cooled, diluted with water and acidified to pH1. It was extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 2-chloro-4-(1,1-dimethylethylsulphonyl)benzoic acid (5.67 g) as an off white solid mp 155.2°-156.8° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:37][C:38]1[CH:43]=[CH:42][C:41](Br)=[CH:40][CH:39]=1)[CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7].[C:46]([C:48]1[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=1)#[CH:47].CCN(CC)CC.CN(C=O)C>C(O)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CC#N>[CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:47]#[C:46][C:48]2[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=2)=[CH:40][CH:39]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: C#Cc1cccnc1
Reactant: COC(=O)N[C@H](C(=O)NN(Cc1ccc(Br)cc1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)NN(Cc1ccc(C#Cc2cccnc2)cc1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C
Yield: 45.4 %

Procedure:
Compound 38 was prepared according to Method D, using compound 19 (85.8 mg, 0.126 mmol), 3-(ethynyl)pyridine (0.0260 mL, 0.252 mmol), Et3N (0.176 mL, 1.26 mmol), Pd(PPh3)2Cl2 (4.42 mg, 0.0063 mmol), CuI (2.40 mg, 0.0126 mmol) and DMF (2.1 mL). RP-LC-MS (35 min gradient of 25-100% CH3CN in 0.05% aqueous formic acid) afforded the title compound (40.3 mg, 45%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][N:5]=[C:4]([NH2:9])[N:3]=1.[N:10]1[CH:15]=[CH:14][CH:13]=[C:12](B(O)O)[CH:11]=1.B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[Cl:1][C:2]1[C:7]([C:12]2[CH:11]=[N:10][CH:15]=[CH:14][CH:13]=2)=[CH:6][N:5]=[C:4]([NH2:9])[N:3]=1
Reactant: Nc1ncc(I)c(Cl)n1
Reactant: OB(O)c1cccnc1
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: OBO
Solvent: C1COCCO1
Product: Nc1ncc(-c2cccnc2)c(Cl)n1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
4-Chloro-5-(pyridin-3-yl)pyrimidin-2-amine 131 was prepared from the coupling of 4-chloro-5-iodopyrimidin-2-amine with pyridin-3-ylboronic acid as follows: the amine (150 mg, 0.587 mmol), and the boronic acid (144 mg, 1.174 mmol) were suspended in dioxane (2.5 mL) and Na2CO3 (783 μA, 1.174 mmol) The mixture was bubbled with Ar for 5 min then charged with Pd(Ph3P)4 (136 mg, 0.117 mmol). The mixture was stirred at 90° C. for 2 h, then cooled to room temperature. The mixture was partitioned between EtOAc and water. The organic layer was dried, filtered, and concentrated to give a residue which was purified by silica gel column chromatography to give 4-chloro-5-(pyridin-3-yl)pyrimidin-2-amine 131.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[NH:15][C:14](=[O:16])[C:13]([CH:17]([NH:20][C:21]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=O)[CH2:18][CH3:19])=[N:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>ClC(Cl)C>[CH:23]1([C:21]2[N:12]3[C:13]([C:14](=[O:16])[NH:15][C:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)=[N:11]3)=[C:17]([CH2:18][CH3:19])[N:20]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCC(NC(=O)C1CCCC1)c1nnc(-c2cccc([N+](=O)[O-])c2)[nH]c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: CCc1nc(C2CCCC2)n2nc(-c3cccc([N+](=O)[O-])c3)[nH]c(=O)c12
Temperature: 0 °C

Procedure:
3.5 g (9.4 mmol) N-{1-[3-(3-nitrophenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}-cyclopentanecarboxamide (Example 19A) are suspended in 60 ml dichloroethane, and 1.45 g (9.4 mmol) phosphoroxychloride are added. The mixture is stirred at reflux for 3 hour. After cooling down to 0° C., 10 ml saturated NaHCO3 (aq) is added dropwise. The mixture is stirred for about 20 min at room temperature and then evaporated to dryness in vacuo. The product is purified by chromatography (flash or column chromatography).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][C:8]2[S:12][C:11]([NH2:13])=[N:10][N:9]=2)=[CH:5][CH:4]=1.CCN(CC)CC.[CH3:23][C:24]1[O:28][C:27]([CH2:29][CH2:30][C:31](Cl)=[O:32])=[CH:26][CH:25]=1>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[S:12][C:11]([NH:13][C:31](=[O:32])[CH2:30][CH2:29][C:27]3[O:28][C:24]([CH3:23])=[CH:25][CH:26]=3)=[N:10][N:9]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(Cc2nnc(N)s2)cc1
Reactant: Cc1ccc(CCC(=O)Cl)o1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc(Cc2nnc(NC(=O)CCc3ccc(C)o3)s2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(4-methoxybenzyl)-1,3,4-thiadiazol-2-amine (88b, 221 mg, 1.0 mmol), Et3N (0.38 ml) in 1,4-dioxane (8.0 ml) was slowly added 3-(5-methylfuran-2-yl) propanoyl chloride and stirred for further 16.0 hours at room temperature. The reaction mixture was then quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4(s), and concentrated under reduced pressure to give N-[5-(4-methoxy-benzyl)-[1,3,4]thiadiazol-2-yl]-3-(5-methyl-furan-2-yl)-propionamide (88): 1H NMR (500 MHz, DMSO) δ7.24(d, 2H), δ6.89(d, 2H), δ5.90(d, 2H), δ4.24(s, 2H), δ3.72(s, 3H), δ2.83 (d, 3H), δ2.71(d, 2H), δ2.17(s, 3H). ESI-MS: 358.0 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]([CH2:16][SH:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12].[C:18](Cl)(=[O:22])[CH2:19][CH2:20][CH3:21]>C(Cl)Cl>[C:18]([NH:9][CH:10]([CH2:16][SH:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:22])[CH2:19][CH2:20][CH3:21]
Reactant: CCCC(=O)Cl
Reactant: CCOC(=O)C(N)CS
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)NC(CS)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (4.5 mL) was added to a suspension of ethyl 2-amino-3-mercaptopropanoate hydrochloride (5 g) in DCM (50 mL). The resulting mixture was cooled in an ice/salt bath and butyryl chloride (3.3 mL) was added dropwise. The resulting mixture was allowed to warm to RT and stirred overnight. The reaction was quenched with saturated sodium bicarbonate solution (50 mL) and the layers separated. The aqueous phase was extracted with DCM (2×100 mL). The combined organic solutions were washed with brine (100 mL), dried over sodium sulphate, filtered and evaporated. The resulting white solid was purified by silica gel chromatography eluting with 4:1 to 1:1 isohexane:ethyl acetate gradient. The fractions containing product were combined and evaporated to give the subtitled compound as a white solid. Yield 3 g.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[Cl:5][C:6]1[C:7]([F:37])=[C:8]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:35][CH3:36])=[C:20]([CH2:23][N:24]([CH3:34])[C:25]4([C:31]([NH2:33])=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH:21]=3)[N:16]=[CH:15][N:14]=2)[CH:9]=[CH:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>S1(=O)(=O)CCCC1>[Cl:5][C:6]1[C:7]([F:37])=[C:8]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:35][CH3:36])=[C:20]([CH2:23][N:24]([CH3:34])[C:25]4([C:31]([NH2:33])=[O:32])[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][OH:4])[CH2:27][CH2:26]4)[CH:21]=3)[N:16]=[CH:15][N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: OCCBr
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CCN(CCO)CC1
Temperature: 90 °C
Yield: 15.7 %

Procedure:
2-Bromoethanol (47 μl, 0.66 mmol) was added to a stirred suspension of 4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]piperidine-4-carboxamide (250 mg, 0.53 mmol) (Example 16) and anhydrous potassium carbonate (150 mg, 1.08 mmol) in tetrahydrothiophene 1,1-dioxide (Sulfolane) (5 ml). The mixture was heated at 90° C. for 3 hours and partitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate. The organic phase was washed with brine and evaporated. The residues were purified by column chromatography on silica, eluting with 7M ammonia in methanol/methylene chloride (16/84). Fractions containing the desired product were combined and evaporated to a foam. This was triturated with diethyl ether to give the title product as a white solid (43 mg, 16%); 1H NMR Spectrum: (DMSO-d6+CD3COOD) 2.13-2.21 (m, 2H), 2.25 (s, 3H), 2.26-2.33 (m, 2H), 3.13-3.17 (t, 2H), 3.17-3.25 (m, 2H), 3.42-3.49 (m, 2H), 3.71-3.77 (m, 4H), 3.94 (s, 3H), 7.18-7.22 (m, 1H), 7.23 (s, 1H), 7.33-7.38 (m, 1H), 7.58-7.63 (m, 1H), 8.28 (s, 1H), 8.39 (s, 1H); Mass Spectrum: (M+H)+ 517.
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>[Cu](I)I.CN(C)C>[CH3:15][Si:16]([CH3:18])([CH3:17])[C:19]#[C:20][C:3]1[C:4]2[CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][CH:2]=1
Reactant: C#C[Si](C)(C)C
Reactant: Ic1ccc2c(c1)Cc1ccccc1-2
Agent: I[Cu]I
Agent: CN(C)C
Product: C[Si](C)(C)C#Cc1cccc2c1Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
Thereafter, to 150 ml of trimethylamine were added 7.89 g of 2-iodofluorene, 379 mg (0.54 mmol) of bis[triphenylphosphine]palladium dichloride and 51 mg (0.27 mmol) of copper iodide. 4.2 ml (29.7 mmol) of trimethylsilylacetylene was added slowly to the reaction mixture. After the reaction was stirred for 8 h at room temperature, solvent was removed under reduced pressure. The residue was extracted with benzene and the benzene layer was washed with distilled water. The washed benzene layer was concentrated to give 6.02 g (85%) of 2-trimethylsilylethynyl fluorene.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH:9]=[O:10].C1(=[O:18])CCCCC1>N(C(C)(C)C#N)=NC(C)(C)C#N>[C:3]1([CH3:8])[CH:4]=[C:5]([CH3:7])[CH:6]=[C:1]([CH3:11])[C:2]=1[C:9]([OH:18])=[O:10]
Reactant: O=C1CCCCC1
Reactant: Cc1cc(C)c(C=O)c(C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: Cc1cc(C)c(C(=O)O)c(C)c1
Yield: 87.9 %

Procedure:
To a flask equipped with a stirrer, oxygen inlet and condenser were added mesitaldehyde (10.0 g, 67.6 mmol), 25 mL (0.242 mol) of cyclohexanone and 100 mg of azobisisobutyronitrile. Oxygen was bubbled in while the solution was stirred and maintained at 60°. After 45 hr the solution was mixed with 250 mL of water and 250 mL of methylene chloride; 20% aqueous potassium hydroxide was added dropwise until a pH of 8-9 was reached. The aqueous layer was separated and acidified with concentrated hydrochloric acid, after which the white solid product was collected by filtration, washed with water and air dried: 9.76 g (88% yield) of mesitoic acid.
Reaction SMILES: Cl.[F:2][C:3]([F:7])([F:6])[CH2:4]N.N([O-])=O.[Na+].[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][CH:20]=[O:21]>C(Cl)Cl.O.[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20](=[O:21])[CH2:4][C:3]([F:7])([F:6])[F:2]
Reactant: O=CCc1ccccc1Br
Reactant: NCC(F)(F)F
Agent: [Zr+4]
Agent: Cl
Agent: O=N[O-]
Solvent: ClCCl
Solvent: O
Product: O=C(Cc1ccccc1Br)CC(F)(F)F
Temperature: 78 °C
Reaction time: 1 h

Procedure:
To a solution of 2,2,2-trifluoroethanamine hydrochloride (27.1 g, 200 mmol) in DCM (400 ml) and water (50 ml) was added NaNO2 (15.43 g, 241 mmol) at 0° C. and stirred for 1 h. Then cooled to 78° C. then added 2-(2-bromophenyl)acetaldehyde (20 g, 100 mmol) and ZrCl4 (30.4 g, 130 mmol) and stirred for 2 h. The reaction mixture was quenched with MeOH (30 ml). The title compound was purified by separation methods A and E. (Yield 13.0 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([O:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][N:17]=3)[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]>C1COCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][N:17]=3)[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2c(Oc3ccc([N+](=O)[O-])cn3)cccc21
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ccc2c(Oc3ccc(N)cn3)cccc21
Reaction time: 18 h
Yield: 105.6 %

Procedure:
[4-(5-Nitropyridin-2-yloxy)indol-1-yl]acetic acid ethyl ester (1.49 g, 4.35 mmol) was dissolved in THF (15 mL). To the solution was added 5% Pd/C (0.15 g) and the resulting solution was subjected to catalytic reduction for 18 hours at room temperature under atmospheric pressure. The catalyst was removed by filtration, and the filtrate was concentrated to yield 1.43 g of the title compound as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10](=[O:20])[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:30]([CH3:39])([CH3:38])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].O>C(#N)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][C:30]([CH3:39])([CH3:38])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:20])=[CH:4][CH:3]=1
Reactant: O=C(CCc1ccccc1O)NCCOc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccccc1CCC(=O)NCCOc1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 96 h

Procedure:
N-(4-Chlorophenoxyethyl)-3-(2-hydroxyphenyl)propanamide (11.6 g, 36.3 mmol) was dissolved in acetonitrile (15 mL), and potassium carbonate (15.0 g, 109 mmol) was added thereto. Subsequently, tert-butyl 2-bromoisobutyrate (20.2 g, 90.7 mmol) was added thereto, followed by stirring for 4 days at 70° C. Subsequently, water was added thereto, and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with brine, and the resultant mixture was subjected to drying over anhydrous sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (chloroform/methanol=50/1), whereby the target compound was obtained (7.4 g, 44%).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11])=[C:2]=[O:3].[NH2:13][C@H:14]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[CH3:32][CH:31]([CH3:33])[C:30]([NH:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([CH:20]2[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][C@H:14]([NH:13][C:2]([NH:1][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N+:10]([O-:12])=[O:11])=[O:3])[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:22][CH2:21]2)[CH:24]=1)=[O:34]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)Nc3ccccc3[N+](=O)[O-])c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure P and Scheme AB using 1-isocyanato-2-nitrobenzene and N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 543.6 (M+H)+.