Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[C:19]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH:18]=[C:17]([F:28])[CH:16]=2)=[O:13])[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C1([O:35][C:36](=O)[NH2:37])C=CC=CC=1.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>CS(C)=O.C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:13])[NH:14][C:15]2[CH:20]=[C:19]([CH:18]=[C:17]([F:28])[CH:16]=2)[O:21][CH:22]2[CH2:23][CH2:24][N:25]([C:36]([NH2:37])=[O:35])[CH2:26][CH2:27]2)[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NC(=O)Oc1ccccc1
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1cc(F)cc(OC2CCNCC2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1cc(F)cc(OC2CCN(C(N)=O)CC2)c1
Temperature: 85 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
Nitrogen gas is bubbled trough a solution of 1-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-3-{3-fluoro-5-(piperidin-4-yloxy)-phenyl}-urea (390.6 mg, 1.0 mmol) and carbamic acid phenyl ester (140.6 mg, 1.0 mmol) in DMSO (2 mL) for 5 minutes. Next, N,N-diisopropylethylamine (350 μL, 2.0 mmol) is added. After stirred at 85° C. overnight, the reaction mixture is distributed between ethyl acetate (15 mL) and saturated sodium bicarbonate (50 mL). The aqueous phase is isolated and extracted with ethyl acetate (2×15 mL). The combined organic phases are dried over sodium sulfate and concentrated. The residue is purified on a silica gel chromatography with hexanes and ethyl acetate to give a white solid (250 mg, 58% yield, ES+(m/z) 433.3 [M+H]).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2[C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][N:14]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(c1)NCCC2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Product: COc1cc2ncnc(N3CCCc4ccc(Br)cc43)c2cc1OC
Yield: 11 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 11% yield from 7-bromo-1,2,3,4-tetrahydroquinoline and 4-chloro-6,7-dimethoxy-quinazoline. (film; LC-MS: 399 (MH+)).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[C:30]([C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)[CH:29]=[C:28]([C:37](=[O:41])N(C)C)[CH:27]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2].C(OC(CCC1C(OCCCC(OCC)=O)=CC=CC=1CCCCCCOC1C=C(C=C(C2C=CSC=2)C=1)C(O)=O)=O)C.[CH:85]1([NH2:88])[CH2:87][CH2:86]1>>[C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[C:30]([C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)[CH:29]=[C:28]([C:37](=[O:41])[NH:88][CH:85]3[CH2:87][CH2:86]3)[CH:27]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2]
Reactant: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccsc2)c1
Reactant: NC1CC1
Agent: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(C(=O)NC3CC3)cc(-c3ccsc3)c2)c1CCC(=O)O

Procedure:
The title compound was prepared by the same method as 4-{2-(2-carboxy-ethyl)-3-[6-(3-dimethylcarbamoyl-5-thiophen-3-yl-phenoxy)-hexyl]-phenoxy}-butyric acid starting from 3-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-5-thiophen-3-yl-benzoic acid and cyclopropylamine.
Reaction SMILES: [C:1]([S:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][C:17]1[CH:22]=[C:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:20]=[CH:19][C:18]=1[O:29][CH3:30])[C:10](O)=[O:11])([CH3:4])([CH3:3])[CH3:2].[C:31]([NH2:35])([CH3:34])([CH3:33])[CH3:32].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][C:21]1[CH:20]=[CH:19][C:18]([O:29][CH3:30])=[C:17]([O:16][C:15]2[CH:14]=[CH:13][C:9]([C:10](=[O:11])[NH:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:8][C:7]=2[CH2:6][S:5][C:1]([CH3:3])([CH3:4])[CH3:2])[CH:22]=1)[CH3:28]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(=O)O)cc2CSC(C)(C)C)c1
Reactant: CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(=O)NC(C)(C)C)cc2CSC(C)(C)C)c1
Reaction time: 8 h

Procedure:
3-tert-Butylsulfanylmethyl-4-(5-ethoxycarbonylmethyl-2-methoxy-phenoxy)-benzoic acid (0.2 g, 0.46 mmol), tert-butylamine (0.15 mL, 13.9 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (0.1 g, 0.55 mmol), and N-hydroxybenzotriazole (0.074 g, 0.55 mmol) were combined in CH2Cl2 (8 mL) and stirred overnight. The mixture was concentrated and purified by preparative HPLC to give the title compound.
Reaction SMILES: [CH2:1]([N:5]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:7]=[N:6]1)[CH2:2][C:3]#[CH:4].Br[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][F:25])[N:19]=1>>[F:25][CH2:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:4]#[C:3][CH2:2][CH2:1][N:5]2[N:9]=[C:8]([C:10]3[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=3)[CH:7]=[N:6]2)[N:19]=1
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCn1ncc(-c2ccc(F)cc2)n1
Product: FCc1cccc(C#CCCn2ncc(-c3ccc(F)cc3)n2)n1
Yield: 44.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-(but-3-ynyl)-4-(4-fluorophenyl)-2H-1,2,3-triazole (150 mg, 0.70 mmol, Example 254(B)) and 2-bromo-6-(fluoromethyl)pyridine (146 mg, 0.77 mmol, Example 190(E)). The crude residue was purified by flash chromatography (DCM/MeOH 99.5:0.5 to 99:1) to yield 101 mg (0.31 mmol, 45%) of 2-(fluoromethyl)-6-(4-(4-(4-fluorophenyl)-2H-1,2,3-triazol-2-yl)but-1-ynyl)pyridine as a yellow solid (M.P.=84-86° C.).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.Cl.[CH2:12]([O:19][NH2:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.CN(C)CCCN=C=NCC.O>CN(C)C1C=CN=CC=1.ClCCl>[CH2:12]([O:19][NH:20][C:6](=[O:8])[C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=C(NOCc1ccccc1)c1ccc(O)cc1
Yield: 45.3 %

Procedure:
To a mixture of 4-hydroxybenzoic acid (16) (0.424 g, 3.07 mmol), O-benzylhydroxylamine hydrochloride (0.490 g, 3.07 mmol), and 4-dimethylaminopyridine (0.414 g, 3.39 mmol) in dichloromethane (30 ml) under argon atmosphere 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.643 g, 3.35 mmol) was added and the resultant mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into a mixture of saturated NaH2PO4 (30 ml) and water (70 ml), and extracted with ethyl acetate (2×75 ml). The extract was washed with a mixture of saturated NaH2PO4 (15 ml) and water (35 ml), brine (50 ml), and dried (MgSO4). The solvent was evaporated and the residue was chromatographed on silica gel (50 g) with benzene-ethyl acetate-acetic acid (75:25:1, 100 ml) and benzene-ethyl acetate-acetic acid (50:50:1, 300 ml) as eluents to give the title compound (0.338 g, 45%) as a white solid. 1H NMR (DMSO-d6, HMDSO), δ: 4.88 (2H, s); 6.79 (2H, d, J=8.8 Hz); 7.23-7.55 (5H, m); 7.59 (2H, d, J=8.8 Hz); 10.02 (1H, br s); 11.48 (1H, s).
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[CH:17]1[C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[CH:20]=[C:19]([NH2:27])[N:18]=1>ClCCl.C(OCC)(=O)C.CCCCCC>[N:27]([C:19]1[N:18]=[CH:17][C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[CH:20]=1)=[C:1]=[S:2]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: Nc1cc2c(cn1)CCCC2
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: S=C=Nc1cc2c(cn1)CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (222 mg, 0.956 mmol) in dchloromethane (5 mL) was added a solution of 5,6,7,8-tetrahydroisoquinolin-3-amine (139 mg, 0.938 mmol) in dichloromethane (1.5 mL) and the resulting solution was stirred at room temperature overnight. The reaction mixture was applied directly to a Biotage column in 20-25% ethyl acetate/hexane, collecting the first major peak. Yield 141.8 mg (79%) 3-iothiocyanato-5,6,7,8-tetrahydroisoquinoline. NMR 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.10 (1H, s), 6.84 (1H, s), 2.74 (4H, t, J=6.3 Hz), 1.81 (4H, dd, J=4.0, 2.7 Hz).
Reaction SMILES: Cl.CS[C:4]1[N:9]=[C:8]([C:10]2[C:11]([O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[C:27]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[N:26][N:25]=4)=[CH:19][CH:18]=3)=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:6][N:5]=1.O[O:41][S:42]([O-:44])=O.[K+].[C:46]([O-])(O)=O.[Na+]>CO>[CH3:46][S:42]([C:4]1[N:9]=[C:8]([C:10]2[C:11]([O:16][C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[C:27]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[N:26][N:25]=4)=[CH:21][CH:22]=3)=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:6][N:5]=1)(=[O:44])=[O:41]
Reactant: O=S([O-])OO
Reactant: O=C([O-])O
Reactant: CSc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(-c4ccccc4)c4ccccc34)cc2)n1
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)c1nccc(-c2cccnc2Oc2ccc(Nc3nnc(-c4ccccc4)c4ccccc34)cc2)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 100 ml dried round bottom flask was charged with N-(4-(3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-phenylphthalazin-1-amine hydrochloride (1.25 g, 2.27 mmol) and sonicated in methanol (20.6 ml, 0.11 M) for 20 minutes. To this was added oxone (4.18 g, 6.81 mmol) and the mixture was stirred at RT for 2 days. The mixture was cooled to 0° C. and basified with aq. NaHCO3. The solids were filtered, washed with water, and dried under high vacuum to provide N-(4-(3-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-phenylphthalazin-1-amine as a light yellow solid. MS m/z=547 [M+H]+. Calc'd for C30H22N6O3S: 546.60.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29].[Br:39][C:40]1[CH:41]=[N:42][C:43](Cl)=[N:44][CH:45]=1.C(N(CC)C(C)C)(C)C.O>C1(C)C=CC=CC=1>[F:1][C:2]([F:37])([F:38])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=1)[CH2:6][N:7]([C:43]1[N:44]=[CH:45][C:40]([Br:39])=[CH:41][N:42]=1)[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([CH:25]([CH3:26])[CH3:27])[CH:22]=[CH:21][C:20]=1[O:28][CH3:29]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Clc1ncc(Br)cn1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Temperature: 25 °C
Yield: 67.4 %

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amine (3.0 g) is dissolved in toluene (20 ml) and thereto are added 5-bromo-2-chloropyrimidine (1.6 g) and N,N-diisopropylethylamine (1.4 ml) and the mixture is heated under reflux overnight. The reaction solution is allowed to cool to room temperature, and thereto is added water and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=40:1) to give (3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amine (2.6 g). MS (m/z): 708/706 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[C:7]3[C:12]([CH:13]=[CH:14][C:4]=2[N:3]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[H-].[Na+].[CH3:17]I.Cl>O1CCCC1.O>[CH3:1][C:2]1[N:3]([CH3:17])[C:4]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:5]=2[N:6]=1
Reactant: Cc1nc2ccc3ccccc3c2[nH]1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2c3ccccc3ccc2n1C
Reaction time: 0.33 h

Procedure:
To a solution of 8.56 g of 2-methyl-1H-naphth[1,2-d]imidazole in 100 ml of tetrahydrofuran was added over a period of 15 minutes 2.25 g of 50% sodium hydride in oil and the mixture allowed to stir for 20 minutes. Methyl iodide (2.93 ml) was added over a 5-minute period and the reaction mixture allowed to stir at room temperature overnight. The reaction mixture was poured into water and the pH adjusted to 2 with 12N hydrochloric acid. The aqueous acid was extracted with chloroform (2×100 ml) and the pH adjusted to 10 with ammonium hydroxide. The aqueous base was extracted with chloroform (2×100 ml) and the combined extracts dried and concentrated to give 7.75 g of the isomers as a tan solid.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:60]/[CH:61]=[CH:62]/[CH3:63].FC(F)(F)S(O)(=O)=O.C(=O)(O)[O-].[Na+]>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH2:60]/[CH:61]=[CH:62]/[CH3:63])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: C/C=C/COC(=N)C(Cl)(Cl)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Product: C/C=C/COC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1O
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (115 mg in 3 ml 33% methylene chloride in cyclohexane) trans-2-butenyl trichloroacetimidate (48 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 35 minutes the reaction was quenchedby the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×8 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel (ethyl acetate:hexane (1:1)+1% methanol) gave the title compounds (14 mg 4"-ether; 12 mg 3"-ether).
Reaction SMILES: Cl[C:2](OC1C=CC([N+]([O-])=O)=CC=1)=[O:3].N1C=CC=CC=1.[NH2:20][C:21]1[CH:31]=[CH:30][C:24]2[O:25][C:26]([F:29])([F:28])[O:27][C:23]=2[CH:22]=1.CCN(C(C1C=CC=C(C)C=1)=O)CC.[CH3:46][N:47]([CH3:65])[CH2:48][CH2:49][CH2:50][O:51][C:52]1[CH:57]=[CH:56][C:55]([NH2:58])=[CH:54][C:53]=1[C:59]1[N:60]([CH3:64])[N:61]=[CH:62][CH:63]=1>ClCCCl>[F:28][C:26]1([F:29])[O:25][C:24]2[CH:30]=[CH:31][C:21]([NH:20][C:2]([NH:58][C:55]3[CH:56]=[CH:57][C:52]([O:51][CH2:50][CH2:49][CH2:48][N:47]([CH3:46])[CH3:65])=[C:53]([C:59]4[N:60]([CH3:64])[N:61]=[CH:62][CH:63]=4)[CH:54]=3)=[O:3])=[CH:22][C:23]=2[O:27]1
Reactant: Nc1ccc2c(c1)OC(F)(F)O2
Reactant: CN(C)CCCOc1ccc(N)cc1-c1ccnn1C
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CCN(CC)C(=O)c1cccc(C)c1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CN(C)CCCOc1ccc(NC(=O)Nc2ccc3c(c2)OC(F)(F)O3)cc1-c1ccnn1C
Reaction time: 1 h
Yield: 33.8 %

Procedure:
To a solution of 4-nitrophenyl chloroformate (55.1 mg, 0.273 mmol) in 1,2-dichloroethane (7 mL) and pyridine (22 μL, 0.272 mmol) was added 5-amino-2,2-difluoro-1,3-benzodioxole (28 μL, 0.241 mmol) and stirred for one hour. A spatula of StratoSpheres PL-DETA resin was added and stirring continued for an additional hour. The resulting mix was filtered (washing with 3 mL 1,2-dichloroethane) into a flask containing 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (49.7 mg, 0.181 mmol) and stirring continued overnight. The resulting material was purified by HPLC. The product was dried in vacuo to afford Compound 129 as a white solid (29.0 mg, 34%). LCMS m/z (%)=474 (M+H, 100), 1H NMR (400 MHz, DMSO-d6) δ: 8.91 (bs, 1H), 8.61 (bs, 1H), 7.65 (d, J=2.09 Hz, 1H), 7.44 (d, J=1.86 Hz, 1H), 7.44 (dd, J=8.88, 2.82 Hz, 1H), 7.37 (d, J=2.71 Hz, 1H), 7.29 (d, J=8.75 Hz, 1H), 7.09 (d, J=8.95 Hz, 1H), 7.07 (dd, J=8.78, 2.18 Hz, 1H), 6.23 (d, J=1.81 Hz, 1H), 3.97 (t, J=6.35 Hz, 2H), 3.65 (s, 3H), 2.19 (t, J=7.03 Hz, 2H), 2.07 (s, 6H), 1.77-1.67 (m, 2H).
Reaction SMILES: Cl[CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].[CH:8]([OH:11])([CH3:10])[CH3:9].N1C=CC=CC=1>ClCCl>[CH:8]([O:11][S:4]([CH:3]=[CH2:2])(=[O:6])=[O:5])([CH3:10])[CH3:9]
Reactant: CC(C)O
Reactant: O=S(=O)(Cl)CCCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CS(=O)(=O)OC(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Chloroethylsulfonyl chloride (2 g, 12.3 mmol), isopropanol (1 mL), and pyridine (2.7 mL) were dissolved in dichloromethane (20 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was washed successively with 1N hydrochloric acid and water, and the organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered, and the solvent was evaporated to give the title compound (1.06 g).
Reaction SMILES: [C:1]1(C)[C:2]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH2:12](N(CC)CC)C.[OH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:31]=[C:32]([C:36]([NH2:38])=[O:37])[CH:33]=[CH:34][CH:35]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:12][C:5]1[CH:6]=[CH:1][C:2]([S:7]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([NH2:38])=[O:37])[CH:31]=2)(=[O:8])=[O:9])=[CH:3][CH:4]=1
Reactant: NC(=O)c1cccc(OCCCCCCCCCO)c1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: CCN(CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCCCCCCCOc2cccc(C(N)=O)c2)cc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 69 %

Procedure:
Toluenesulfonyl chloride (410 mg, 2.15 mmol, 1.5 equiv.) and triethylamine (0.40 ml, 2.88 mmol, 2 equiv.) were added to a solution of 3-[(9-hydroxynonyl)oxy]benzenecarboxamide (400 mg, 1.43 mmol, 1 equiv.) in CH2Cl2 (4 ml) and the reaction mixture was stirred at r.t. for 6 days. Saturated NaHCO3 solution (40 ml) was added and the mixture was extracted with CH2Cl2 (3×30 ml). The combined organic extracts were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with CH3OH/CH2Cl2 (2%), to give the desired compound as white solid (428 mg, 69%), mp 78-80° C. HPLC-MS (method 1): m/z 434 [M+H]+, Rt=4.90 min.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]([C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)[CH2:14][O:15][C:16](=[O:18])[CH3:17])(=O)=O)=CC=1.[C:26]1([C@H:32]([NH2:34])[CH3:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C=O>[C:16]([O:15][CH2:14][CH:13]([C:19]1[CH:20]=[CH:21][C:22]([Br:25])=[CH:23][CH:24]=1)[CH2:12][NH:34][C@@H:32]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:33])(=[O:18])[CH3:17]
Reactant: C[C@@H](N)c1ccccc1
Reactant: CC(=O)OCC(COS(=O)(=O)c1ccc(C)cc1)c1ccc(Br)cc1
Solvent: CN(C)C=O
Product: CC(=O)OCC(CN[C@H](C)c1ccccc1)c1ccc(Br)cc1
Temperature: 120 °C
Reaction time: 7 h
Yield: 40.5 %

Procedure:
To a solution of (+)-3-acetoxy-2-(4-bromophenyl)propyl 4-methylbenzene-sulfonate (8.00 g, 18.7 mmol) in N,N-dimethylformamide (94.0 ml) was added (R)-(+)-1-phenylethylamine(11.3 g, 93.2 mmol) at room temperature. The mixture was stirred at 120° C. for 7 hours and concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluant: hexane/ethyl acetate=7/3) to afford diastereopure 3-((R)-1-phenylethylamino)-2-(4-bromophenyl)propyl acetate as pale yellow oil (2.85 g, 40%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[CH:10]([CH2:28][CH2:29][CH3:30])[CH2:9]1)=O)(C)(C)C.[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1>>[CH2:28]([CH:10]1[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:31][CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=3)[N:22]=2)[CH:18]=[CH:19][CH:20]=1)[CH2:29][CH3:30]
Reactant: CCCC1CN(C(=O)OC(C)(C)C)CCN1Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1ccc(O)cc1
Product: CCCC1CNCCN1Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 131 was coupled with tyramine following procedure F. The product was deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 432. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.35 (s, 1H) 8.29 (d, 2H) 8. 7.81 (d, 1H) 7.68 (t, 1H) 7.49 (d, 1H) 7.2-7.2 (m, 3H) 6.68 (d, 2H) 4.8 (d, 1H) 4.17 (d, 1H) 3.85 (br s, 2H) 3.68 (d, 1H) 3.1-3.6 (m, 6H) 2.9 (t, 2H) 2.2 (m, 1H) 1.9 (m, 1H) 1.38-1.65 (m, 1H) 1.05 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:22])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]=[N:19][N:18]=[C:17]1[CH3:21].[CH2:23]=[O:24]>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:22])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:17]([CH3:21])=[N:18][N:19]=[C:20]1[CH2:23][OH:24]
Reactant: C=O
Reactant: Cc1nncn1-c1ccc(Cl)cc1C(=O)c1ccccc1F
Solvent: Cc1ccccc1C
Product: Cc1nnc(CO)n1-c1ccc(Cl)cc1C(=O)c1ccccc1F
Temperature: 122 °C

Procedure:
In the manner given in Example 4, 2'-fluoro-5 -chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone, paraformaldehyde and xylene are warmed under nitrogen to about 122° C. to give 2'-fluoro-5-chloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1.[CH3:26][N:27]([CH2:29][CH2:30][CH2:31]Cl)[CH3:28]>>[Br:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([O:14][CH2:31][CH2:30][CH2:29][N:27]([CH3:28])[CH3:26])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1
Reactant: Cc1cccc(-c2nc3ccc(O)cc3n2Cc2ccccc2Br)c1
Reactant: CN(C)CCCCl
Product: Cc1cccc(-c2nc3ccc(OCCCN(C)C)cc3n2Cc2ccccc2Br)c1

Procedure:
The title compound was prepared essentially as described in Example 116 except that the compound of Example 126 was reacted with 3-(N,N-dimethylamino)propyl chloride. MS 479.