Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([CH2:34][OH:35])[CH2:3][C@H:4]([NH:15][C:16]([C:18]1[C:19]2[CH:26]=[N:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:20]=2[CH:21]=[N:22][CH:23]=1)=[O:17])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:6]=1.C1N=CN([C:41](N2C=NC=C2)=[O:42])C=1.O>CN(C=O)C>[CH3:14][S:11]([C:7]1[CH:6]=[C:5]([C@@H:4]([NH:15][C:16]([C:18]2[C:19]3[CH:26]=[N:25][N:24]([C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)[C:20]=3[CH:21]=[N:22][CH:23]=2)=[O:17])[CH2:3][CH:2]2[CH2:34][O:35][C:41](=[O:42])[O:1]2)[CH:10]=[CH:9][N:8]=1)(=[O:12])=[O:13]
Reactant: CS(=O)(=O)c1cc([C@H](C[C@H](O)CO)NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1cc([C@H](CC2COC(=O)O2)NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a chilled (0° C.) solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(1S,3S)-3,4-dihydroxy-1-(2-methanesulfonyl-pyridin-4-yl)-butyl]-amide (50.0 mg, 0.100 mmol) in DMF (1 mL) was added CDI (32.4 mg, 0.200 mmol). The mixture was then allowed to warm to room temperature. After 12 hours, the reaction was poured in to water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with aqueous ammonium chloride (3×10 mL) and brine (10 mL), dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-6% methanol in methylene chloride. The solid from the column chromatography was crystallized from methylene chloride to afford the title compound as white needle-shaped crystals. MS m/z 526.64 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH:22]=[CH2:23].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(C(C)C)C(C)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:26]([O:25][C:21](=[O:24])/[CH:22]=[CH:23]/[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1)[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cn2)CC1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C=C/c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 93.5 %

Procedure:
tert-Butyl 4-(5-bromopyridin-2-yl)piperazine-1-carboxylate (800 mg) was dissolved in DMF (4 ml), and ethyl acrylate (368 mg), palladium(II) acetate (27 mg), tris(2-methylphenyl)phosphine (290 mg), and DIPEA (1.26 g) were added thereto, followed by stirring at 100° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and then EtOAc was added thereto. The insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and then the obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain tert-butyl 4-{5-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]pyridin-2-yl}piperazine-1-carboxylate (790 mg).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([Cl:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:26]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=1>>[Cl:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:26]4[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1
Reactant: Cc1cccnc1Br
Product: Cc1cccnc1C(=O)c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1

Procedure:
This compound is prepared by method C using compound 12l and 2-bromo-3-methylpyridine
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[S:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=1)([O-])=O>CCO.C1COCC1>[NH2:1][C:4]1[CH:9]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:7]=[CH:6][C:5]=1[S:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=1
Reactant: CC(=O)Nc1ccc(Sc2ccc(C(F)(F)F)cc2[N+](=O)[O-])cc1
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Sc2ccc(C(F)(F)F)cc2N)cc1
Reaction time: 8 h
Yield: 80.9 %

Procedure:
The product from Example 183a (350 mg, 0.985 mmol), and Pt(IV)O2 (4 mg, 0.2 mmol) were placed in a 50 ml round bottom flask and dissolved in 1 ml of EtOH and 1 ml of THF. Reaction mixture placed under vacuum and backfilled with H2 using a balloon. Balloon was left on overnight and the next day the reaction mixture was purged and backfilled with N2, filtered and concentrated under vacuum giving the title compound (260 mg, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:14](=[O:25])OC2C=CC([N+]([O-])=O)=CC=2)[CH2:7]1.[CH2:30]([NH2:33])[C:31]#[CH:32].ClCCl>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:14]([NH:33][CH2:30][C:31]#[CH:32])=[O:25])[CH2:7]1
Reactant: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Oc1ccc([N+](=O)[O-])cc1
Reactant: C#CCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCNC(=O)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 86.5 %

Procedure:
Example 56 was prepared in an analogous manner to Example 43 from Intermediate 10 (0.040 g) and propargylamine (0.006 g) using dichloromethane and triethylamine at a temperature of 22° C. to yield the title compound (0.028 g).
Reaction SMILES: [C:1]([Mg]Br)#[C:2][CH3:3].[OH:6][C:7]1[CH:23]=[CH:22][C:10]([CH:11]=[C:12]2[C:17](=[O:18])[O:16][C:15]([CH3:20])([CH3:19])[O:14][C:13]2=[O:21])=[CH:9][CH:8]=1>C1COCC1>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([CH:11]([CH:12]2[C:13](=[O:21])[O:14][C:15]([CH3:20])([CH3:19])[O:16][C:17]2=[O:18])[C:1]#[C:2][CH3:3])=[CH:22][CH:23]=1
Reactant: CC#C[Mg]Br
Reactant: CC1(C)OC(=O)C(=Cc2ccc(O)cc2)C(=O)O1
Solvent: C1CCOC1
Product: CC#CC(c1ccc(O)cc1)C1C(=O)OC(C)(C)OC1=O
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-propynyl magnesium bromide in THF (0.5 N, 322 mL, 161.28 mmol) is added a solution of 5-(4-hydroxy-benzylidene)-2,2-dimethyl-[1,3]dioxane-4,6-dione (20 g, 80.64 mmol) in THF (200 mL) by cannula under a nitrogen atmosphere. Over the course of the addition, the reaction mixture changed to a thick, yellow suspension. After addition is compete, the reaction mixture is stirred for 15 minutes at 50° C., quenched with aqueous NH4Cl, and acidified to pH ˜2 with 2 N HCl. The mixture is extracted with EtOAc (2×300 mL) and the combined extracts are washed with saturated brine, dried over MgSO4, filtered, and concentrated to a yellow solid (20 g, 86%). The product is carried on crude.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23]S(C)(=O)=O.[CH2:28](O)[CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][OH:36].CO>C(Cl)(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][OH:36]
Reactant: COCCOCCOCCOCCOCCOCCOCCOS(C)(=O)=O
Reactant: OCCOCCOCCO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO

Procedure:
Monodispersed compound 32 was prepared from compound 31 and monodispersed triethylene glycol using the procedure described above in Example 17. Oil; Rf 0.41 (methanol:chloroform=6:10); MS m/z calc'd for C21H44O11 472.29 (M++1), found 472.29.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[OH:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH2:29][CH:30]([CH2:35][CH2:36][CH3:37])[C:31]([O:33][CH3:34])=[O:32])=[CH:23]2.O[CH2:39][CH2:40][CH2:41][NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=1.C(P(CCCC)CCCC)CCC>O1CCCC1>[N:44]1[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=1[NH:42][CH2:41][CH2:40][CH2:39][O:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH2:29][CH:30]([CH2:35][CH2:36][CH3:37])[C:31]([O:33][CH3:34])=[O:32])=[CH:23]2
Reactant: CCCC(Cc1cc2cc(O)ccc2[nH]1)C(=O)OC
Reactant: OCCCNc1ccccn1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCC(Cc1cc2cc(OCCCNc3ccccn3)ccc2[nH]1)C(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.7 %

Procedure:
1,1′-(Azodicarbonyl)dipiperidine (0.12 g, 0.48 mmol) was added to the solution of methyl 2-[(5-hydroxyindolyl)methyl]pentanoate (0.03 g, 0.12 mmol), as prepared in the preceding step, 2-(3-hydroxypropyl)aminopyridine (0.026 g, 0.17 mmol), as prepared in step b of Example 1, and tri-n-butylphosphine (0.09 g, 0.46 mmol) in tetrahydrofuran (6.0 mL). After stirring at ambient temperature overnight (16 h), the reaction was concentrated and the residue was purified by flash chromatography on silica gel (10%–50% ethyl acetate in hexane) to give the title compound as a yellow oil (0.016 g, 36%). 1H-NMR (400 MHz, CDCl3) δ 8.08 (m, 1H), 7.39 (m, 1H), 7.20 (d, J=8.9 Hz, 1H), 7.07 (d, J=2.4 Hz, 1H), 7.02 (d, J=3.3 Hz, 1H), 6.88 (dd, J=8.9, 2.4 Hz, 1H), 6.53 (m, 1H), 6.40 (m, 2H), 4.32 (br s, 1H), 4.42 (m, 1H), 4.25 (m, 3H), 3.52 (m, 5H), 2.91 (m, 1H), 2.20 (m, 2H), 1.72 (m, 2H), 1.43 (m, 3H), 0.95 (t, J=7.2 Hz, 3H).
Reaction SMILES: O[C@H:2]1[C@@H:6]([CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][N:4]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:3]1.CCN(S(F)(F)[F:32])CC.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[F:32][C@@H:2]1[C@@H:6]([CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][N:4]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](CNC(=O)OCc2ccccc2)[C@H](O)C1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](CNC(=O)OCc2ccccc2)[C@@H](F)C1
Reaction time: 2 h
Yield: 85 %

Procedure:
To a stirred solution of (±)-1,1-dimethylethyl cis-3-hydroxy-4-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinecarboxylate (0.8 g, 2.29 mmole), in DCM (50 mL) at −78° C. was added DAST dropwise (0.59 mL, 4.80 mmole). After 2 h, Aqueous Na2CO3 was added to the reaction solution and the layers separated. The organic layer was dried over Na2SO4 and concentrated under vacuum. Purification on silica (hexanes/EtOAc, 1:1) provided the title compound (0.68 g, 85%) as a colorless oil: LC-MS (ES) m/e 353 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[N:10][C:11]2[C:16]([CH2:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:19][CH3:20])[CH3:9])[CH:5]=[CH:4][CH:3]=1.[CH3:21][Al](C)C.[OH-].[K+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[C:16]([CH2:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:19][CH3:20])([CH3:21])[CH3:9])[CH:5]=[CH:4][CH:3]=1
Reactant: CCc1cccc(CC)c1N=C(C)c1cccc(Br)n1
Reactant: C[Al](C)C
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCc1cccc(CC)c1NC(C)(C)c1cccc(Br)n1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
In argon atmosphere, to a mixture of 6.20 g (18.7 mmol) of N-[1-(6-bromopyridin-2-yl)ethylidene]-2,6-diethylaniline in 110 ml of dry toluene cooled to 0° C., a solution of 2.70 g (37.4 mmol) of AlMe3 in 40 ml of dry toluene was added dropwise for 10 min. The reaction mixture was slowly warmed to room temperature, stirred for 25 min at 40° C., and then cooled to 0° C. Further on, 150 ml of 5% KOH was added dropwise by vigorous stirring for 1 h at this temperature. The aqueous layer was separated, the organic layer was washed with 100 ml of water, 100 ml of brine, dried over Na2SO4, and then evaporated to dryness. Yield 6.40 g (98%) of yellow oil. Anal. Calc. for C18H23BrN2: C, 62.25; H, 6.68, N, 8.07. Found: C, 62.40; H, 6.82, N, 8.04. 1H NMR (CDCl3): δ 7.61 (dd, J=7.5 Hz, J=0.6 Hz, 1H, 5-H in pyridine), 7.51 (t, J=7.5 Hz, 1H, 4-H in pyridine), 7.34 (dd, J=7.5 Hz, J=0.6 Hz, 1H, 3-H in pyridine), 6.97-7.03 (m, 3H, 3, 4, 5-H in 2, 6-Et2C6H3), 3.97 (br.s, 1H, NH), 2.45 (q, J=7.5 Hz, 4H, CH2Me), 1.46 (s, 6H, Me2C), 1.11 (t, J=7.5 Hz, 6H, CH2Me).
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.O>[O:11]1[CH2:12][CH2:13][CH2:14][CH:8]([C:7]2[C:2]([O:28][C:25]3[CH:24]=[CH:23][C:22]([NH:21][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=4)=[CH:27][CH:26]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1
Reactant: Oc1ccc(Nc2ccccn2)cc1
Reactant: Fc1ncccc1C1CCCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: c1ccc(Nc2ccc(Oc3ncccc3C3CCCOCC3)cc2)nc1
Temperature: 120 °C
Reaction time: 17 h

Procedure:
2-Fluoro-3-(oxepan-4-yl)pyridine (0.061 g, 0.31 mmol), 4-(pyridin-2-ylamino)phenol (0.18 g, 0.94 mmol), and cesium carbonate (0.31 g, 0.94 mmol) were mixed in NMP (0.75 mL). The reaction mixture was placed under a nitrogen atmosphere and stirred at 120° C. for 17 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (2×). The combined organic layers were washed with 1 M aqueous sodium hydroxide, washed with sat. sodium chloride, dried over magnesium sulfate, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography to give N-(4-(3-(oxepan-4-yl)pyridin-2-yloxy)phenyl)pyridin-2-amine MS (ESI, pos. ion) m/z: 362.2 (M+1). IC50 (uM) 0.026.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH2:10][CH2:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:17]([O:19][C:20](=[O:26])[C@H:21]([C@@H:23]([CH3:25])[OH:24])[NH2:22])C>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([NH:22][C@H:21]([C:20]([O:19][CH3:17])=[O:26])[C@@H:23]([CH3:25])[OH:24])=[O:15])[CH2:10][CH2:11][CH3:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](N)[C@@H](C)O
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Product: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)OC)[C@@H](C)O

Procedure:
The preparation was performed in a similar manner as Example 1.001 (d) Method B from N-(tert-butoxycarbonyl)-L-norvaline (13.0 g, 59.8 mmol) and L-threonine ethyl ester hydrochloride (9.23 g, 54.4 mmol) to give methyl N-(tert-butoxycarbonyl)-L-norvalyl-L-threoninate. MS (APCI): m/z 333 (M+H).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([OH:12])=O)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH2:35][C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][C:45]=1[O:46][CH2:47][CH:48]1[CH2:50][CH2:49]1)[N:42]=[CH:41][N:40]=[C:39]2[NH:51][C:52]1[CH:57]=[CH:56][C:55]([F:58])=[C:54]([Cl:59])[CH:53]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:59][C:54]1[CH:53]=[C:52]([NH:51][C:39]2[C:38]3[C:43](=[CH:44][C:45]([O:46][CH2:47][CH:48]4[CH2:49][CH2:50]4)=[C:36]([NH:35][C:10](=[O:12])[CH2:9][P:4]([O:3][CH2:1][CH3:2])([O:6][CH2:7][CH3:8])=[O:5])[CH:37]=3)[N:42]=[CH:41][N:40]=2)[CH:57]=[CH:56][C:55]=1[F:58]
Reactant: CCOP(=O)(CC(=O)O)OCC
Reactant: Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOP(=O)(CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
137 mg (diethoxyphosphoryl)-acetic acid and 225 mg benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate are added subsequently to a solution of 200 mg 6-amino-4-[(3-chloro-4-fluoro-phenyl)amino]-7-cyclopropylmethoxy-quinazoline and 0.11 ml triethylamine in 1 ml of anhydrous N,N-dimethyl-formamide. The reaction mixture is stirred for one hour at room temperature, quenched with 10 ml of water, and extracted with ethyl acetate/methanol (10:1). The combined extracts are washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The crude product is recrystallized from diethyl ether. Yield: 190 mg (64% of theory), Melting point: 185-187° C. Mass spectrum (ESI*): m/z=537, 539 [M+H]*
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]([CH2:17][C:18]([OH:20])=O)[C:9]2[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:17][C:18]([N:31]([CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C:28]2[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=2)=[O:20])[C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[CH:15][CH:16]=2)=[O:7])=[CH:21][CH:22]=1
Reactant: COC(=O)CCCNc1ccc(OC)cc1
Reactant: COc1ccc(N(CC(=O)O)C(=O)c2ccc(Cl)cc2)cc1
Product: COC(=O)CCCN(C(=O)CN(C(=O)c1ccc(Cl)cc1)c1ccc(OC)cc1)c1ccc(OC)cc1

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-2-(p-anisidino)acetic acid and methyl 4-(p-anisidino)butyrate and suitable processing produces methyl N-[N-(p-chlorobenzoyl)-2-(p-anisidino)acetyl]-4-(p-anisidino)butyrate (oil), saponification of which and processing of the reaction product yields N-[N-(p-chlorobenzoyl)-2-(p-anisidino)acetyl]-4-(p-anisidino)butyric acid (M.P. 105° to 108°).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]([F:15])([F:14])[F:13])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:16][C:17]1[C:24]([F:25])=[C:23]([C:26]([F:29])([F:28])[F:27])[C:22]([F:30])=[C:21]([F:31])[C:18]=1[CH2:19]Br>CN(C=O)C>[F:16][C:17]1[C:24]([F:25])=[C:23]([C:26]([F:29])([F:27])[F:28])[C:22]([F:30])=[C:21]([F:31])[C:18]=1[CH2:19][NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]([F:13])([F:14])[F:15])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Fc1c(F)c(C(F)(F)F)c(F)c(F)c1CBr
Reactant: Nc1ccc(OC(F)(F)F)c(C(=O)O)c1
Solvent: CN(C)C=O
Product: O=C(O)c1cc(NCc2c(F)c(F)c(C(F)(F)F)c(F)c2F)ccc1OC(F)(F)F
Yield: 80 %

Procedure:
According to the similar procedure in Synthesis Example 1, by using 5-amino-2-trifluoromethoxybenzoic acid (1.35 g, 6.23 mmole), DMF (50 ml), TEA (6 ml), and 2,3,5,6-tetrafluoro-4-trifluoromethylbenzyl bromide (1.10 ml, 6.73 mmole), 2.25 g (81.0% yield) of 5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)-2-trifluoromethoxybenzoic acid was obtained as a yellow solid.:
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:48]([OH:50])=O)[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(C(C)C)C(C)C)C.[NH2:60][CH:61]([C:64]1[CH:69]=[CH:68][C:67]([Cl:70])=[CH:66][CH:65]=1)[CH2:62][OH:63]>CN1C(=O)CCC1>[Cl:70][C:67]1[CH:66]=[CH:65][C:64]([CH:61]([NH:60][C:48]([C:33]2([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:26])([CH3:27])[CH3:28])[CH2:38][CH2:37][N:36]([C:39]3[C:40]4[CH:47]=[CH:46][NH:45][C:41]=4[N:42]=[CH:43][N:44]=3)[CH2:35][CH2:34]2)=[O:50])[CH2:62][OH:63])=[CH:69][CH:68]=1
Reactant: NC(CO)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
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: CN1CCCC1=O
Product: CC(C)(C)OC(=O)NC1(C(=O)NC(CO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.8 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (148 mg, 0.39 mmol) was added in one portion to a stirred solution of 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (134 mg, 0.37 mmol) and N-ethyldiisopropylamine (0.077 mL, 0.44 mmol) in NMP (3 mL). The mixture was treated with 2-amino-2-(4-chlorophenyl)ethanol (70 mg, 0.41 mmol) (CAS™ no. 179811-64-4, see US2006/0004045 for preparation). The dark solution was stirred for 16 hours at room temperature. The mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was washed twice with water and then brine. The organic solution was dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash silica chromatography on silica using gradient elution (1% methanol/DCM to 15% methanol/DCM). Product containing fractions were combined to give tert-butyl 4-(1-(4-chlorophenyl)-2-hydroxyethylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (152 mg, 80%) as colourless solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[CH:13]=O>C(OC(=O)C)(=O)C>[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[CH:13]=[CH:1][C:2]1[N:3]=[N:4][C:5]([CH:8]=[CH:13][C:12]2[CH:15]=[CH:16][C:17]([N+:18]([O-:20])=[O:19])=[C:10]([Cl:9])[CH:11]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(C)nn1
Reactant: O=Cc1ccc([N+](=O)[O-])c(Cl)c1
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1ccc(C=Cc2ccc(C=Cc3ccc([N+](=O)[O-])c(Cl)c3)nn2)cc1Cl
Yield: 18.3 %

Procedure:
First, 28 g of 3,6-dimethylpyridazine and 98 g of 3-chloro-4-nitrobenzaldehyde were dissolved in 1.5 liters of acetic anhydride to produce 21 g of 3,6-di(3-chloro-4-nitrostyryl)-pyridazine.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]([C:13](=[O:16])[CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4]([CH2:18][CH2:19][CH3:20])=[CH:5][C:6](=[O:17])[O:7]2.CO[CH:23](OC)[CH2:24][C:25]([CH3:28])(O)[CH3:26]>>[OH:12][C:10]1[C:11]2[CH:23]=[CH:24][C:25]([CH3:28])([CH3:26])[O:1][C:2]=2[C:3]2[C:4]([CH2:18][CH2:19][CH3:20])=[CH:5][C:6](=[O:17])[O:7][C:8]=2[C:9]=1[C:13](=[O:16])[CH2:14][CH3:15]
Reactant: CCCc1cc(=O)oc2c(C(=O)CC)c(O)cc(O)c12
Reactant: COC(CC(C)(C)O)OC
Product: CCCc1cc(=O)oc2c(C(=O)CC)c(O)c3c(c12)OC(C)(C)C=C3

Procedure:
reacting 5,7-dihydroxy-8-propionyl-4-propylcoumarin with 4,4-dimethoxy-2-methylbutan-2-ol so as to produce 5-Hydroxy-2,2-dimethyl-6-propionyl-10-propyl -2H,8H-benzo[1,2-b: 3,4-b']-dipyran-8one;
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:21][CH2:20]2)=[CH:14][N:13]=1>CN(C=O)C.CCOC(C)=O>[CH2:3]([S:10][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([S:25]([CH3:28])(=[O:26])=[O:27])[CH2:21][CH2:20]2)=[CH:14][N:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: SCc1ccccc1
Reactant: CS(=O)(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCC(Oc2ccc(SCc3ccccc3)nc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.6 %

Procedure:
A suspension of NaH (60% dispersion in mineral oil, 413 mg, 10.32 mmol) in dry DMF (12 mL) at 0° C. was treated dropwise with benzyl mercaptan (1.21 mL, 10.32 mmol). After the addition the mixture was stirred at room temperature for 15 minutes. 2-Chloro-5-(1-methanesulfonyl-piperidin-4-yloxy)-pyridine (1.00 g, 3.44 mmol) was added and the mixture stirred at room temperature for 18 hours, heated at 80° C. for a further 8 hours and allowed to cool overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4 and concentrated under vacuum. Purified by silica gel column chromatography (30-50% EtOAc in cyclohexane) to give 2-benzylsulfanyl-5-(1-methanesulfonyl-piperidin-4-yloxy)-pyridine (659 mg, 51%). 1H NMR (300 MHz, CDCl3) δ 8.20 (br s, 1H), 7.40-7.34 (m, 2H), 7.32-7.18 (s, 4H), 7.14-7.05 (m, 2H), 4.52-4.43 (m, 1H), 4.39 (s, 2H), 3.36 (t, J=5.6 Hz, 4H), 2.82 (s, 3H), 2.08-1.91 (m, 4H). LCMS (m/z, Method A) ES+ 379.1 [M+1]+.
Reaction SMILES: C(S)[C@@H:2]([OH:7])[C@H:3](O)[CH2:4]S.[CH2:9]([C:17]1[C:18]([NH:20][C:21](=O)[CH:22]=1)=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13]CCC>CS(C)=O>[CH2:21]([N:20]1[C:18](=[O:19])[CH:4]=[CH:3][C:2]1=[O:7])[CH2:22][CH2:17][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: O[C@H](CS)[C@H](O)CS
Reactant: CCCCCCCCC1=CC(=O)NC1=O
Solvent: CS(C)=O
Product: CCCCCCCCN1C(=O)C=CC1=O

Procedure:
For a vehicle control, combine a solution of vehicle (5 mM NaPO4 pH 5.5, 150 mM NaCl, 0.5 mM DTT) with PBS (Gibco product #20012-027, pH 7.2) in a 1:10 ratio. Add 1/400 vol. of 20 mM Octylmaleimide in DMSO and a 1/400 vol. of DMSO to give a final concentration of 50 μM N-octylmaleimide and 0.5% DMSO. Finally, add 1:1000 vol. of 0.35 M DTT.