Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]([F:33])([C:23]([F:32])([F:31])[C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[F:11][C:12]([F:33])([C:23]([F:31])([F:32])[C:24]([F:30])([F:29])[C:25]([F:26])([F:27])[F:28])[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH:21]=[O:22])=[CH:19][CH:20]=1
Reactant: OCc1ccc(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=Cc1ccc(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.8 %

Procedure:
To a solution of oxalyl chloride (80.2 μL, 0.93 mmol) in dichloromethane (8 mL) at −78° C., dimethyl sulfoxide (132.2 μL, 1.86 mmol) was added dropwise. After 15 minutes, 4-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)benzenemethanol (300 mg, 0.85 mmol) was added. After 30 minutes, triethylamine (590 μL, 4.23 mmol) was added. The reaction was then allowed to warm to room temperature. Saturated sodium bicarbonate solution was added. The mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Flash chromatography gave 122 mg of 4-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)benzaldehyde; 1H NMR (300 MHz, CDCl3) δ 10.00 (s, 1H), 7.85 (d, 2H), 7.40 (d, 2H), 3.01 (m, 2H), 2.41 (m, 2H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.N1C=CC=CC=1.Cl[C:26](OC1C=CC=CC=1)=[O:27].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:26]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:27])[S:11][C:7]=2[C:6]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2CCOCC2)c2sc(N)nc12
Reactant: C1COCCN1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C2CCOCC2)c2sc(NC(=O)N3CCOCC3)nc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 21 %

Procedure:
To a solution of 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-ylamine (265 mg, 1.0 mmol) in dichloromethane (15 ml) is subsequently added pyridine (0.24 ml, 3.0 mmol) and phenyl chloroformate (0.5 ml, 1.2 mmol) and the resulting solution stirred for 45 min at ambient temperature. Then morpholine (313 mg, 3.6 mmol) is added and the mixture stirred at ambient temperature for 15 min and at 40° C. for 2.5 h. After cooling to ambient temperature, saturated aqueous sodium carbonate (15 ml) is added, the organic phase is separated, dried and the solvent evaporated in vacuo. Flash chromatography (silica, eluent: dichloromethane containing methanol (gradient from 0 to 5%)) afforded the title compound as white crystals (21% yield), mp 217-220° C. MS: m/e=378 (M+H+).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[C:19]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:20].[CH3:25][N:26]([CH3:40])[C:27](=[O:39])[O:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]=[O:36])=[C:31]([CH:37]=[CH2:38])[CH:30]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:25][N:26]([CH3:40])[C:27]([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([OH:36])[CH2:20][C:19]([O:22][CH2:23][CH3:24])=[O:21])=[C:31]([CH:37]=[CH2:38])[CH:30]=1)=[O:39]
Reactant: C=Cc1cc(OC(=O)N(C)C)ccc1C=O
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=Cc1cc(OC(=O)N(C)C)ccc1C(O)CC(=O)OCC
Yield: 99.8 %

Procedure:
To a solution of diisopropylamine (1.26 g, 12.5 mmol) in tetrahydrofuran (30 ml) was added 1.6M solution of n-butyllithium in hexane (7.20 ml, 11.5 mmol) at −20° C. with stirring, and the resulting mixture was stirred for 20 minutes at −20° C. under a nitrogen atmosphere. Subsequently, ethyl acetate (1.07 ml, 11.0 mmol) was added at −78° C., and the resulting mixture was stirred for 20 minutes at −78° C. under a nitrogen atmosphere. Subsequently, to the reaction mixture was added a solution of 4-formyl-3-vinyl-phenyl dimethylcarbamate (2.11 g, 9.62 mmol) obtained in step (c) of Example 192 in tetrahydrofuran at −78° C., and the resulting mixture was stirred for 30 minutes at −78° C. under a nitrogen atmosphere. After stirring, to the reaction mixture was added saturated aqueous ammonium chloride solution (40 ml), and the resulting mixture was extracted with ethyl acetate (40 ml×2). The organic layer was washed successively with water (40 ml×1) and saturated aqueous sodium chloride solution (40 ml×1), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (1:1-1:2) as the eluent to afford the title compound (2.95 g, yield: 99%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Br:19])[CH:18]=1)[O:5][Si:6]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8].[CH2:20]([C:22]1[C:27]([NH2:28])=[CH:26][CH:25]=[CH:24][N:23]=1)[CH3:21]>>[Br:19][C:17]1[CH:18]=[C:2]([NH:28][C:27]2[C:22]([CH2:20][CH3:21])=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:3]=[C:4]([O:5][Si:6]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8])[CH:16]=1
Reactant: CCc1ncccc1N
Reactant: CC(C)[Si](Oc1cc(Br)cc(Br)c1)(C(C)C)C(C)C
Product: CCc1ncccc1Nc1cc(Br)cc(O[Si](C(C)C)(C(C)C)C(C)C)c1

Procedure:
(3,5-Dibromo-phenoxy)-triisopropyl-silane and 2-ethyl-pyridin-3-ylamine were coupled to give (3-bromo-5-triisopropylsilanyloxy-phenyl)-(2-ethyl-pyridin-3-yl)-amine as described for Example 80. (3-Bromo-5-triisopropylsilanyloxy-phenyl)-(2-ethyl-pyridin-3-yl)-amine was converted to 3-(2-ethyl-pyridin-3-ylamino)-5-(1H-indol-4-yl)-phenol as described in Example 35. 1H NMR (400 MHz, CD3OD): δ 8.02 (d, J=4.8 Hz 1H), 7.66 (dd, J=8.0, 1.5 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.22 (d, J=3.1 Hz, 1H), 7.14-7.10 (m, 2H), 7.03 (d, J=7.0 Hz, 1H), 6.76 (t, J=1.6 Hz, 1H), 6.69 (s, 1H), 6.61 (d, J=3.3 Hz, 1H), 6.40 (t, J=2.1 Hz, 1H), 2.86 (q, J=7.5 Hz, 2H), 1.25 (t, J=7.5 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[CH:5]=O.[C:14](#[N:18])[CH2:15][C:16]#[N:17].[CH2:19]1[O:23][C:22]2[CH:24]=[C:25]([OH:28])[CH:26]=[CH:27][C:21]=2[O:20]1.N1CCCCC1>C(O)C>[NH2:17][C:16]1[O:28][C:25]2[CH:24]=[C:22]3[O:23][CH2:19][O:20][C:21]3=[CH:27][C:26]=2[CH:5]([C:4]2[CH:7]=[C:8]([O:12][CH3:13])[C:9]([O:10][CH3:11])=[C:2]([Br:1])[CH:3]=2)[C:15]=1[C:14]#[N:18]
Reactant: N#CCC#N
Reactant: COc1cc(C=O)cc(Br)c1OC
Reactant: Oc1ccc2c(c1)OCO2
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cc(C2C(C#N)=C(N)Oc3cc4c(cc32)OCO4)cc(Br)c1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Bromo-4,5-dimethoxy-benzaldehyde (245 mg, 1 mmol), malononitrile (66 mg, 1 mmol) and sesamol (166 mg, 1.2 mmol) were taken in 10 ml ethanol, charged with piperidine (50 μl, 0.5 mmol) and stirred at room temperature for 3 h. The reaction mixture was then stirred at 80° C. for 64 h. Reaction was complete with the desired product. The reaction mixture was first cooled down to room temperature, diluted with water to about 30 ml, precipitates were collected by filtration, washed with 1:1 mixture of water and methanol (30 ml) and dried to pure solids (348 mg, 81%) under high vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=O.[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:31]3[CH2:30][CH2:29][CH2:28][NH:27][C:26]=3[CH:25]=[N:24]2)=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([N:27]1[CH2:28][CH2:29][CH2:30][C:31]2[N:23]([C:20]3[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=3)[N:24]=[CH:25][C:26]1=2)=[O:15]
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(C(F)(F)F)cc1Cl)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.8 %

Procedure:
To a mixture of 2-[2-chloro-4-(trifluoromethyl)phenyl]acetic acid (59 mg, 0.23 mmol) and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (50 mg, 0.23 mmol) in DMF (1 mL) was added Hunig's base (59 mg, 0.46 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uranium hexafluorophosphate methanaminium (HATU) (96 mg, 0.2 mmol). The mixture was stirred at room temperature for 1 hour, and then was partitioned between water (4 mL) and ethyl acetate (6 mL). The organic layer was washed with brine and dried (Na2SO4), filtered, concentrated in vacuo, and purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the desired product as a white solid (25 mg, 25%). 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 0.8H), 7.70 (s, 1H), 7.56-7.44 (m, 4H), 7.38 (s, 0.2H), 7.18-7-14 (m, 2H), 4.14 (s, 2H), 3.82 (m, 2H), 2.85 (m, 2H), 2.08 (m, 2H); MS: (ES) m/z calculated for C21H16ClF4N3O [M+H]+ 438.1, found 438.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[F:18][CH:19]([F:31])[CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28]([C:25]3[CH:24]=[CH:23][C:22]([O:21][CH2:20][CH:19]([F:31])[F:18])=[CH:27][N:26]=3)=[O:29])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: O=C(O)c1ccc(OCC(F)F)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Product: C[C@]1(c2cc(NC(=O)c3ccc(OCC(F)F)cn3)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 5-(2,2-difluoro-ethoxy)-pyridine-2-carboxylic acid (CAS 1097730-45-4; WO2009091016) following procedure I yielded the title compound as a white foam. MS (ISP): m/z=427.2 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:9]=[CH:8][C:7]([OH:10])=[CH:6][N:5]=1)[CH3:3].C(=O)([O-])[O-].[K+].[K+].[P:17](=[S:25])(Cl)([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20].[H][H]>C(#N)C>[P:17](=[S:25])([O:10][C:7]1[CH:6]=[N:5][C:4]([CH:2]([CH3:3])[CH3:1])=[N:9][CH:8]=1)([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]
Reactant: CCOP(=S)(Cl)OCC
Reactant: [H][H]
Reactant: CC(C)c1ncc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOP(=S)(OCC)Oc1cnc(C(C)C)nc1

Procedure:
To a stirred mixture of 166 grams of 2-(1-methylethyl) 5 pyrimidinol, 230 grams of finely powdered potassium carbonate and 1400 ml of acetonitrile was added in a slow stream 226 grams of O,O-diethyl phosphorochloridothioate. The mixture warmed to 55° . Stirring was continued until no more O,O-diethyl phosphorochloridothioate could be detected by GLC. The solids present were removed by filtration, the filtrate concentrated under vacuum, the residue taken up in diethyl ether, the ether solution washed twice with 2% aqueous sodium hydroxide, and once with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The ether was removed under vacuum leaving a pale yellow oil having a refractive index at 25° of 1.4944. On elemental analysis the product was found to contain 45.68% carbon; 6.54% hydrogen and 9.57% nitrogen. Theoretical is 45.50% carbon; 6.60% hydrogen and 9.65% nitrogen.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8](N(CC)CC)C.[F:15][C:16]1[CH:17]=[C:18]([N:22]2[C:31]3[C:26](=[CH:27][C:28]([F:33])=C(F)[CH:30]=3)[C:25](=[O:34])[N:24]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:23]2=[O:43])[CH:19]=[CH:20][CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([N:22]2[C:31]3[C:26](=[CH:27][C:28]([F:33])=[C:1]([N:2]4[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]4)[CH:30]=3)[C:25](=[O:34])[N:24]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:23]2=[O:43])[CH:19]=[CH:20][CH:21]=1
Reactant: O=c1c2cc(F)c(F)cc2n(-c2cccc(F)c2)c(=O)n1OCc1ccccc1
Reactant: CN1CCNCC1
Reactant: CCN(CC)CC
Product: CN1CCN(c2cc3c(cc2F)c(=O)n(OCc2ccccc2)c(=O)n3-c2cccc(F)c2)CC1
Yield: 91 %

Procedure:
Using General Method 4, the reaction of N-methylpiperazine (0.16 mL, 1.43 mmol), triethylamine (0.2 mL, 1.43 mmol), and 1-(3-fluorophenyl)-3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example G-1, 0.19 g, 0.48 mmol) provided 0.209 g of the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[OH:10])=[CH:5][CH:4]=1.CN1C(C(C2C=CC=CN=2)O)=CN=C1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(O)c2cccnc2)cc1
Agent: Cn1cncc1C(O)c1ccccn1
Product: COc1ccc(C(=O)c2cccnc2)cc1

Procedure:
The title compound was prepared analogously to the method in Intermediate 33: step b using (4-methoxyphenyl)(pyridin-3-yl)methanol (Intermediate 35: step a) in place of (1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([S:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][OH:16])=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([S:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][O:16][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[O:25][CH3:24])=[CH:6][CH:7]=1
Reactant: COc1ccccc1O
Reactant: OCCCc1oc(Sc2ccccn2)nc1-c1ccc(Cl)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1ccccc1OCCCc1oc(Sc2ccccn2)nc1-c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
To a mixture of 4-(4-chlorophenyl)-2-(2-pyridinylsulfanyl)-5-oxazolepropanol (340 mg), 2-methoxyphenol (250 mg), tributylphosphine (400 mg) and tetrahydrofuran (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (500 mg) at room temperature, and the resulting mixture was stirred for 1 hour. After the reaction mixture was concentrated, the residue was subjected to silica gel column chromatography, and 4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]-2-(2-pyridylsulfanyl)oxazole was obtained as an oil (251 mg, 57%) from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([SH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:36][CH3:37])=[C:29]([O:32][CH2:33][CH2:34][Cl:35])[CH:30]=2)[N:25]=[CH:24][N:23]=1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:36][CH3:37])=[C:29]([O:32][CH2:33][CH2:34][Cl:35])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(S)c2)no1
Reactant: COc1cc2ncnc(Cl)c2cc1OCCCl
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCl
Yield: 79 %

Procedure:
To 1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described in Example 44A (1.07 g, 3.70 mmol) was added 4-chloro-6-(2-chloroethoxy)-7-methoxyquinazoline (1.0 g, 3.70 mmol) from Example 16B according to the procedure described in Example 46 to give 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-chloroethoxy)-7-methoxyquinazolin-4-ylthio)phenyl)urea (1.54 g, 2.92 mmol, 79%). 1H NMR (300 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.02 (s, 1H), 8.71 (s, 1H), 7.85 (s, 1H), 7.51 (d, 1H), 7.44 (t, 1H), 7.38 (s, 2H), 7.28 (d, 1H), 6.49 (s, 1H), 4.50 (t, 2H), 4.07 (t, 2H), 4.01 (s, 3H), 1.29 (s, 9H); LC-MS (ESI) m/z 528 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:22][CH2:23][N:24]([CH2:27][CH3:28])[CH2:25]C.C(Cl)(=O)[O:30]C1C=CC=CC=1.N1CCCC1>C1COCC1>[N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:25]([N:24]3[CH2:27][CH2:28][CH2:22][CH2:23]3)=[O:30])[CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCN(CC)CC
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Solvent: C1CCNC1
Solvent: C1CCOC1
Product: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ccn1)N1CCCC1
Temperature: 25 °C

Procedure:
To a solution of 4-(4-nitronaphthalen-1-yloxy)pyridin-2-amine (100 mg, 0.356 mmol) and Et3N (100 μL, 0.71 mmol) in dry THF was added phenyl carbonochloridate (49 μL, 0.39 mmol) and the mixture maintained at RT for 2 hr. Pyrrolidine (88 μL, 1.068 mmol) was added and after 16 h at RT the resulting mixture was partitioned between aq NH4Cl (10 mL) and DCM (10 mL). The aq layer was separated and extracted with DCM (3×10 mL) and the combined organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 40 g, EtOAc in isohexane, 0-100%, gradient elution) to afford N-(4-(4-nitronaphthalen-1-yloxy)pyridin-2-yl)pyrrolidine-1-carboxamide, Intermediate K2, as a yellow solid (110 mg, 79%); Rt 1.84 min (Method 2); m/z 379 (M+H)+ (ES+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:32])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:31])[CH2:20][O:21][CH:22]2CC3C(=CC=CC=3)C2)[CH2:14][CH2:13]1.[F:33][C:34]1[CH:41]=[CH:40][C:37](CO)=[CH:36][CH:35]=1>CC(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:32])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:31])[CH2:20][O:21][CH2:22][C:37]2[CH:40]=[CH:41][C:34]([F:33])=[CH:35][CH:36]=2)[CH2:14][CH2:13]1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)COC2Cc3ccccc3C2)CC1
Reactant: OCc1ccc(F)cc1
Solvent: CC(C)O
Product: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)COCc2ccc(F)cc2)CC1

Procedure:
Compound 21 was prepared in a similar manner to compound 7, substituting the commercially available 4-fluoro-benzylalcohol for 2-propanol in part C. MS (M+1)=430.40
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[O:21][CH:20]([CH3:22])[CH2:19][C:18]2=[C:23]([NH2:25])[CH:24]=1.[OH-].[Na+]>C(Cl)(Cl)Cl>[C:1]1([CH2:7][O:8][C:9](=[O:10])[NH:25][C:23]2[C:18]3[CH2:19][CH:20]([CH3:22])[O:21][C:17]=3[CH:16]=[C:15]([O:14][CH3:13])[CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1cc(N)c2c(c1)OC(C)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: COc1cc(NC(=O)OCc2ccccc2)c2c(c1)OC(C)C2
Reaction time: 2 h
Yield: 88.5 %

Procedure:
0.65 grams of phenylmethylchlorocarbonate are dripped at 5° C. into a stirred mixture containing 0.7 grams of 2,3-dihydro-6-methoxy-2-methyl-4-benzofuranamine hydrochloride, 5 cc of 2N NaOH and 10 cc of chloroform. When the addition is terminated vigorous stirring is continued for one hour at the same temperature and for two hours at room temperature. Then the organic phase is separated, washed with water, dried over Na2SO4 and concentrated to dryness. The obtained residue crystallized twice from ethyl ether-petroleum ether yields 0.9 grams (88 percent of theoretical) of (2,3-dihydro-6-methoxy-2-methyl-4-benzofuranyl)carbamic acid phenylmethyl ester which melts at 82°-83° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.[I:19][CH2:20][CH2:21][CH3:22]>CC(=O)C(C)(C)C.CC(C)=O>[I-:19].[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][N+:16]([CH2:20][CH2:21][CH3:22])=[CH:15][CH:14]=1
Reactant: CCCI
Reactant: COc1cc(-c2ccncc2)c(C)cc1[N+](=O)[O-]
Solvent: CC(=O)C(C)(C)C
Solvent: CC(C)=O
Product: CCC[n+]1ccc(-c2cc(OC)c([N+](=O)[O-])cc2C)cc1
Product: [I-]
Temperature: 102 °C
Yield: 535.3 %

Procedure:
To 4-[2-methyl-5-(methyloxy)-4-nitrophenyl]pyridine (750 mg, 3.07 mmol) in 15 mL of pinacolone was added, 1-iodopropane (2.1 g, 2.66 mmol). The mixture was heated to 102° C. for 24 h. The mixture was cooled and diluted with acetone. The resulting slurry was filtered and washed with acetone. The product was dried under vacuum to give the title compound of step B (1.1 g, 14.24 mmol, 86%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.19 (d, J=6.78 Hz, 2H), 8.30 (d, J=6.59 Hz, 2H), 7.94 (s, 1H), 7.37 (s, 1H), 4.61 (t, J=7.23 Hz, 2H), 3.93 (s, 3H), 2.26 (s, 3H), 1.92-2.02 (m, 2H), 0.92 (t, J=7.42 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.[C:24]1([CH3:33])[C:25]([N:30]=[C:31]=[O:32])=[CH:26][CH:27]=[CH:28][CH:29]=1.CO>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:31]([NH:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH3:33])=[O:32])=[C:18]([F:23])[CH:17]=1
Reactant: Cc1ccccc1N=C=O
Reactant: COc1cc2ncnc(Oc3ccc(N)c(F)c3)c2cc1OC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4ccccc4C)c(F)c3)c2cc1OC
Temperature: 60 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluoroaniline (50 mg) was dissolved in chloroform (3 ml), and o-toluyl isocyanate (30 μl) was then added to the solution. The mixture was stirred at 60° C. overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 17 mg (yield 24%) of the title compound.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9]C2N=C(N3C4C=CC(C(O)=O)=CC=4N=C3)C=CN=2)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28]1([C@@H:34]([NH:36][C:37]2[N:42]=[C:41]([N:43]3[C:47]4[CH:48]=[C:49]([C:52]([OH:54])=O)[CH:50]=[CH:51][C:46]=4[N:45]=[CH:44]3)[CH:40]=[CH:39][N:38]=2)[CH3:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N)C1C=CC=CC=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:28]1([C@@H:34]([NH:36][C:37]2[N:42]=[C:41]([N:43]3[C:47]4[CH:48]=[C:49]([C:52]([NH:9][CH2:7][C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)=[O:54])[CH:50]=[CH:51][C:46]=4[N:45]=[CH:44]3)[CH:40]=[CH:39][N:38]=2)[CH3:35])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(C(=O)O)ccc32)n1)c1ccccc1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccc(C(=O)O)cc32)n1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: NCc1ccccc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](Nc1nccc(-n2cnc3ccc(C(=O)NCc4ccccc4)cc32)n1)c1ccccc1
Reaction time: 4 h

Procedure:
To a solution of a mixture 10 mg (0.028 mmol) of 2-[(S)-1-phenylethylamino]-4-[5-carboxy-benzimidazol-1-yl]pyrimidine and 2-[(S)-1-phenylethylamino]-4-[6-carboxy-benzimidazol-1-yl]pyrimidine (EXAMPLE 106 Step C) and benzylamine (0.003 mL, 0.028 mmol) in 0.6 mL CH2Cl2 was added N-methylmopholine (0.004 mL) followed by 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (10 mg). The solution was stirred for 4 hours then quenched with water. The organic fraction was concentrated and the product purified by chromatography to afford the title compounds. Partial 1H NMR (500 MHz CD3OD): δ 8.73 (brs, 1H); 8.57 (brs, 1H); 8.33 (brs, 1H); 7.82 (d J=10 Hz, 1H); 7.70 (d J=10 Hz, 1H); 6.82 (brs, 1H); 6.63 (brs, 1H); 5.23 (br, 1H); 4.70 (d J=5.5 Hz, 2H); 1.63 (d J=6.5 Hz, 3H). Partial 1H NMR (500 MHz CD3OD): δ 8.47 (br, 1H); 8.36 (br, 1H); 8.20 (s, 1H); 6.79 (d J=5.5 Hz, 1H); 6.60 (br, 1H); 5.18 (br, 1H); 4.72 (d J=5.5 Hz, 2H); 1.62 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:3]=1.[CH2:26]([Br:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[Br-:33].[CH2:26]([N:3]1[C:2]([CH3:1])=[CH:6][C:5]([CH3:7])=[N+:4]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCn1nc(C)cc1C
Product: CCCCCCCCCCCCCCCCCC[n+]1c(C)cc(C)n1Cc1ccccc1
Product: [Br-]

Procedure:
Reaction of 3,5-dimethyl-1-octadecyl-pyrazole with benzyl bromide yields 2-benzyl-3,5-dimethyl-1-octadecyl-pyrazolium bromide; m.p. 165.5°-167.5° C.