Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[OH-].[Na+].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Cl>CN(C)C=O.C(OCC)(=O)C>[F:18][C:19]([F:28])([F:29])[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][S:15][C:13]1[O:14][C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)=[N:11][N:12]=1
Reactant: Sc1nnc(-c2ccc3[nH]ncc3c2)o1
Reactant: FC(F)(F)c1cccc(CCl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cccc(CSc2nnc(-c3ccc4[nH]ncc4c3)o2)c1
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a solution of 5-(1H-indazol-5-yl)-1,3,4-oxadiazole-2-thiol (218 mg, 1.00 mmol) and 1 M aqueous sodium hydroxide solution (1.00 mL, 1.00 mmol) in N,N-dimethylformamide (5 mL) was added 3-(trifluoromethyl)benzyl chloride (0.155 mL, 1.00 mmol) at room temperature, and the resulting mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (tetrahydrofuran) and recrystallized from methanol to give the title compound (279 mg, yield 74%) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:36]1[NH:41][CH2:40][CH2:39][N:38]2[CH2:42][CH2:43][CH2:44][CH:37]12.C(=O)([O-])[O-].[K+].[K+].CN=C=O>CS(C)=O.ClCCl>[F:34][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:41]3[CH2:40][CH2:39][N:38]4[CH2:42][CH2:43][CH2:44][C@H:37]4[CH2:36]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: C1CC2CNCCN2C1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1-c1ccccc1Cl
Agent: CN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2CCN3CCC[C@H]3C2)cc1-c1ccccc1Cl
Temperature: 150 °C
Reaction time: 12 h

Procedure:
To a solution of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(2-chlorophenyl)-3-pyridinyl]-N,2-dimethylpropanamide (WO 2005/002577; 0.11 mmol) in dry DMSO (1 ml) S -octahydropyrrolo[1,2-a]pyrazine, (0.22 mmol) and potassium carbonate (0.22 mmol) were added and the resulting mixture was shaken for 12 hours at 150° C. After cooling the dichloromethane was added (2 ml) and then isocyanate polymer bound was added (2.0 mmol), and the resulting mixture was shaken at room temperature overnight. Then the resin was filtered and the filtrate was concentrated under reduced pressure. Purifications were carried out using mass directed HPLC:
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].ClC1C=CC=CC=1.C1(=[O:25])CCCCC1>C(O)(=O)C.C([O-])(=O)C.[Co+2].C([O-])(=O)C>[C:3]1([CH3:8])[CH:4]=[C:5]([CH3:7])[CH:6]=[C:1]([CH3:11])[C:2]=1[C:9]([OH:25])=[O:10]
Reactant: O=C1CCCCC1
Reactant: Cc1cc(C)c(C=O)c(C)c1
Agent: [Co+2]
Agent: CC(=O)[O-]
Solvent: Clc1ccccc1
Solvent: CC(=O)O
Product: Cc1cc(C)c(C(=O)O)c(C)c1
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To a flask equipped with a stirrer, condenser and an oxygen inlet were added mesitaldehyde (20.0 g, 0.135 mol), 15 mL of chlorobenzene, 15 mL (0.145 mol) of cyclohexanone and 10 mg of cobalt (II) acetate dissolved in 1 mL of acetic acid. Oxygen was bubbled in slowly while the solution was stirred overnight. The reaction temperature was raised to 50° and the oxidation was continued for an additional 4 hr. The flask was cooled to 0° and the reaction product was removed by filtration and washed with petroleum ether. A total of 12.0 g (55% yield) of crystalline mesitoic acid was obtained. Additional mesitoic acid (2.4 g) was obtained from the filtrate by evaporation, dissolution of the residue in ether, extraction of the ether solution with aqueous sodium bicarbonate and acidification of the aqueous extract. The total yield of product was 65%. The identity of the product was confirmed by its nmr spectrum (CDCl3).
Reaction SMILES: Br[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH:36]=[C:35](B(O)O)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[S:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:3]2[C:2]([C:35]3[CH2:36][CH2:37][N:32]([C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:33][CH:34]=3)=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B(O)O)CC1
Reactant: Brc1cccnc1Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2cccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round-bottomed flask was added N-(4-(3-bromopyridin-2-yloxy)phenyl)benzo[d]thiazol-2-amine (0.5770 g, 1.449 mmol), 1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-ylboronic acid (0.987 g, 4.35 mmol), PdCl2(dppf) (0.080 g, 0.145 mmol), and sodium carbonate (0.768 g, 7.24 mmol) in DME (3.62 mL) and Water (1.207 mL) at 80° C. to stir overnight. Reaction allowed to cool to room temperature. Solvent was removed. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 5% to 80% EtOAc in hexane, to provide tert-butyl 4-(2-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate. MS (ESI, pos. ion) m/z: 501.0 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)[S:6][CH:7]=1.[NH:23]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:21][O:20][C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([O:16][CH3:17])[C:13]=1[O:18][CH3:19])[C:9]([NH:8][C:5]1[S:6][CH:7]=[C:3]([CH2:2][N:23]2[CH2:29][CH2:28][CH2:27][N:26]([CH2:2][C:3]3[N:4]=[C:5]([NH:8][C:9](=[O:22])[C:10]4[CH:11]=[C:12]([O:20][CH3:21])[C:13]([O:18][CH3:19])=[C:14]([O:16][CH3:17])[CH:15]=4)[S:6][CH:7]=3)[CH2:25][CH2:24]2)[N:4]=1)=[O:22]
Reactant: C1CNCCNC1
Reactant: COc1cc(C(=O)Nc2nc(CCl)cs2)cc(OC)c1OC
Product: COc1cc(C(=O)Nc2nc(CN3CCCN(Cc4csc(NC(=O)c5cc(OC)c(OC)c(OC)c5)n4)CC3)cs2)cc(OC)c1OC

Procedure:
4-Chloromethyl-2-(3,4,5-trimethoxybenzamido)-thiazole (140 mg) and homopiperazine (20 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][C:10](=[O:12])[CH:9]=[CH:8][O:7]1)=[O:5])[CH3:2].[H][H]>CCOC(C)=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][C:10](=[O:12])[CH2:9][CH2:8][O:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CC(=O)C=CO1
Reactant: [H][H]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CC(=O)CCO1
Yield: 33.1 %

Procedure:
A mixture of 4-oxo-3,4-dihydro-2H-pyran-2-carboxylic acid ethyl ester (8.0 g, 46.0 mmol) and PdlC (10%, 0.20 g,) in EtOAc (70 mL) was shaken in a Parr bottle with hydrogen at 50 psi overnight and filtered through a pad of Celite. The filtrate was concentrated and the residue was distilled to give 2.62 g (33%) of yellowish oil: 1H NMR (CDCl3) δ 1.29 (t, 3H), 2.40 (d, 1H), 2.58-2.75 (m 3H), 3.79 (tt, 1H), 4.23 (q, 2H), 4.28 (m 1H), 4.40 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[C:8]([O:10][CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:7]=[CH:6][N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=O)=[CH:29][CH:28]=2)[N:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:60]1([NH2:67])[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=1[NH2:66].CCN(C(C)C)C(C)C>CN(C=O)C.O.C(#N)C>[NH2:66][C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][C:60]=1[NH:67][C:31](=[O:33])[C:30]1[CH:34]=[CH:35][C:27]([NH:26][C:22]2[N:21]=[C:20]([C:19]3[N:5]4[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH2:12][N:13]5[CH2:18][CH2:17][O:16][CH2:15][CH2:14]5)=[CH:9][C:4]4=[N:3][C:2]=3[CH3:1])[CH:25]=[CH:24][N:23]=2)=[CH:28][CH:29]=1
Reactant: Cc1nc2cc(OCCN3CCOCC3)ccn2c1-c1ccnc(Nc2ccc(C(=O)O)cc2)n1
Reactant: Nc1ccccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cc(OCCN3CCOCC3)ccn2c1-c1ccnc(Nc2ccc(C(=O)Nc3ccccc3N)cc2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of methyl 4-(4-(7-chloro-2-methylH-imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-ylamino)benzoate (100 mg, 0.25 mmol), KOtBu (86 mg, 0.76 mmol) in NMP (2 mL), and 2-morpholin-4-yl-ethanol (0.16 mL, 1.3 mmol) were added and heated in a microwave (Emry's Optimizer) at 170° C. for 10 minutes. The reaction mixture was then diluted with water and acetonitrile and purified by preparative HPLC affording 4-{4-[2-methyl-7-(2-morpholin-4-yl-ethoxy)-imidazo[1,2-a]pyridin-3-yl]-pyrimidin-2-ylamino}-benzoic acid after lyophilization. MS found for C25H26N6O4 as (M+H)+ 475.05. To the above carboxylic acid (59 mg, 0.124 mmol) in DMF (3 mL), were added HATU (71 mg, 0.186 mmol), 1,2-phenylenediamine (27 mg, 0.25 mmol), and DIPEA (0.07 mL, 0.372 mmol) and stirred at room temperature for 16 hours. Additional 1,2-phenylenediamine (50 mg, 0.46 mmol), HATU (150 mg, 0.39 mmol) and DIPEA (0.2 mL) were added and stirred at room temperature for 4 hours. The reaction mixture was diluted with water and acetonitrile and directly purified by preparative HPLC affording the title compound, after lyophilization. MS found for C31H32N8O3 as (M+H)+ 565.08. 1H NMR (400 MHz, dmso-d6): δ 10.04 (brs, 1H); 9.62 (m, 2H); 8.61 (d, J=4.8 Hz, 1H); 7.92 (d, J=8.8 Hz, 2H); 7.84 (d, J=8.8 Hz, 2H); 7.23 (s, 1H); 7.15 (d, J=6.0 Hz, 2H); 6.98-6.69 (m, 5H); 4.51 (m, 2H); 3.74-3.38 (m, 10H); 2.62 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[C:17](O)(=[O:26])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:17](=[O:26])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)CCc1ccccc1
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Product: O=C(CCc1ccccc1)Nc1ccccc1-c1cc2ccccc2[nH]1
Yield: 54 %

Procedure:
Prepared from 2-(2-aminophenyl) indole and hydrocinnamic acid in 54% yield following procedure 1. The product was crystallized from methanol. 99% Purity by LC/MS (230 DAD), Mass-spec [M+H+]=341, 1H NMR (DMSO-d6): 2.65 t, 7.5 Hz (2H), 2.91 t, 7.5 Hz (2H), 6.50 s (1H), 7.00 t, 7 Hz (1H), 7.10 t, 7 Hz (1H), 7.19–7.34 m (7H), 7.39 d, 8 Hz (1H), 7.51 d, 8 Hz (1H), 7.60–7.62 m (2H), 9.39 s (1H), 11.32 s (1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9](O)=[O:10])=[CH:4][CH:3]=1.C(OCC)(=O)CC(O)=O.CN.BrC1C=CC([C@H:32]([NH2:34])C)=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:34][CH3:32])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C(=O)O)c1ccc(Br)cc1
Reactant: C[C@@H](N)c1ccc(Br)cc1
Agent: CCOC(=O)CC(=O)O
Agent: CN
Product: CNC(=O)C(C)(C)c1ccc(Br)cc1
Yield: 84 %

Procedure:
The title compound was prepared as described in Step 1 of Example A(39), where 2-(4-bromophenyl)-2-methyl propionic acid was substituted for ethyl hydrogen malonate and methyl amine was substituted instead of (R)-(+)-1-(4-bromophenyl)ethylamine on that example. Yield 84%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:31]([OH:36])(=[O:35])[C:32]([CH3:34])=O.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:11][O:10][C:8]([C:5]1[N:6]=[C:7]2[CH:34]=[C:32]([C:31]([OH:36])=[O:35])[NH:1][C:2]2=[CH:3][CH:4]=1)=[O:9]
Reactant: COC(=O)c1ccc(N)cn1
Reactant: CC(=O)C(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2[nH]c(C(=O)O)cc2n1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
Methyl 5-aminopyridine-2-carboxylate (1.2 g, 5.2 mmol) and triphenylphosphine (1.5 g, 5.7 mmol) were initially charged in 10 ml of DMF, and pyruvic acid (1.83 g, 20.8 mmol), palladium(II) acetate (279 mg, 1.2 mmol) and triethylamine (2.6 g, 26 mmol) were added. The reaction mixture was stirred at a temperature of 100° C. for four hours, then cooled, concentrated on a rotary evaporator and taken up in ethyl acetate, water was added and the mixture was shaken. The aqueous phase was concentrated on a rotary evaporator and then triturated with a little cyclohexane. This gave 0.5 g (38% of theory) of 5-(methoxycarbonyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid. HPLC-MS: log P=0.44; mass (m/z): 221.0 (M+H)+; 1HNMR (D6-DMSO): δ 3.89 (s, 3H), 7.20 (s, 1H), 7.90-7.98 (m, 2H), 10 (broad, 1H), 12.24 (s, 1H).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[NH2:18][C:19]1[CH:28]=[CH:27][C:26]([CH2:29][NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O>[CH3:36][C:34]([CH3:37])([O:33][C:31]([NH:30][CH2:29][C:26]1[CH:27]=[CH:28][C:19]([NH:18][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]2)=[C:20]([C:21]([O:23][CH3:24])=[O:22])[CH:25]=1)=[O:32])[CH3:35]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: COC(=O)c1cc(CNC(=O)OC(C)(C)C)ccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1cc(CNC(=O)OC(C)(C)C)ccc1NC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 15 h
Yield: 90.1 %

Procedure:
A solution of 1.66 g of benzyl 4-oxopiperidine-1-carboxylate and 1 g of methyl 2-amino-5-({[(1,1-dimethylethoxy)carbonyl]amino}methyl)benzoate obtained in stage 5.1 in 20 ml of DCM is added dropwise at AT to a suspension of 2.04 g of NaBH(OAc)3 in a mixture of 20 ml of DCM and 0.41 ml of AcOH. The mixture is stirred at AT for 15 h 00 and then a further 2.04 g of NaBH(OAc)3 are added. After stirring for 6 h 00, 1.66 g of benzyl 4-oxopiperidine-1-carboxylate are added and the mixture is stirred at AT for 48 h 00. A saturated NaHCO3 solution is added and extraction is carried out with DCM. The organic phase is washed with a saturated NaHCO3 solution and twice with a saturated NH4Cl solution. It is dried over Na2SO4 and filtered, and the filtrate is evaporated under reduced pressure. The residue is chromatographed on silica gel, elution being carried out with an AcOEt/heptane mixture, (5/95, v/v) as far as (40/60, v/v), to give 1.6 g of the expected product.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[C:14]([C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:28]2[CH:33]=[C:32]([F:34])[C:31]([Cl:35])=[CH:30][C:29]=2[C:36]([NH:38][NH2:39])=[O:37])(=[O:26])=[O:25])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[C:14]([C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:28]2[CH:33]=[C:32]([F:34])[C:31]([Cl:35])=[CH:30][C:29]=2[C:36]([NH:38][NH:39][C:5](=[O:7])[CH2:4][CH2:3][S:2][CH3:1])=[O:37])(=[O:25])=[O:26])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(F)c(Cl)cc2C(=O)NN)cc1
Reactant: CSCCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSCCC(=O)NNC(=O)c1cc(Cl)c(F)cc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
To a stirred solution of 3-methylsulfanyl-propionic acid (120 mg, 1.0 mmol) under an inert atmosphere in 6 mL of anhydrous DCM and DMF (200 μL) was added oxalyl chloride (89 μL, 1.0 mmol). The resultant solution was stirred at room temperature overnight and then added to a solution of 4-tert-butyl-N-(4-chloro-5-fluoro-2-hydrazinocarbonyl-phenyl)-benzenesulfonamide (400 mg, 1.0 mmol) and Et3N (0.35 mL, 2.5 mmol) at 0° C. The resultant solution was stirred at room temperature for 4 hours and the solvent was removed in vacuo. The residue was purified via automated silica gel chromatography to afford 4-tert-butyl-N-{4-chloro-5-fluoro-2-[N′-(3-methylsulfanyl-propionyl)-hydrazinocarbonyl]-phenyl}-benzenesulfonamide as an oil: MS (ES) M+H expected 502.1, found 502.0.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:20])=[C:6]([CH:8]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[O:11][C:10]([CH3:18])([CH3:17])[C:9]2=[O:19])[CH:7]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.[F-].[Cs+]>COCCOC>[Cl:20][C:5]1[CH:4]=[CH:3][C:2]([C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=2)=[CH:7][C:6]=1[CH:8]1[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[O:11][C:10]([CH3:18])([CH3:17])[C:9]1=[O:19]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC1(C)OC(C)(C)C(=O)C(c2cc(Br)ccc2Cl)C1=O
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: CC1(C)OC(C)(C)C(=O)C(c2cc(-c3ccc(Cl)cc3)ccc2Cl)C1=O
Temperature: 80 °C
Yield: 34.1 %

Procedure:
A mixture of 4-(5-bromo-2-chlorophenyl)-2,2,6,6-tetramethylpyran-3,5-dione (0.22 g, 0.6 mmol), 4-chlorophenylboronic acid (0.14 g, 0.9 mmol), and cesium fluoride (0.28 g, 1.8 mmol) are stirred together in 1,2-dimethoxyethane (2.4 ml) under an atmosphere of nitrogen at room temperature for 45 minutes. [1,1′-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) (80 mg, 0.098 mmol) is added and the reaction mixture is heated at 80° C. overnight. The reaction mixture is filtered through diatomaceous earth, washing the filter cake with dichloromethane (7 ml) and water (3 ml). The mixture is acidified to pH1 by addition of 2M aqueous hydrochloric acid, and the organic phase is separated. The aqueous phase is extracted with dichloromethane, and all organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated. The residue is dissolved in N,N-dimethylformamide (approximately 1 ml) and purified by preparative reverse phase HPLC to give 4-(4,4′-dichlorobiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione (80 mg).
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)#[CH:11]>C(N(CC)CC)C.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>[F:18][C:14]1[CH:13]=[C:12]([C:10]#[C:11][C:2]2[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Cc1ccc(N)c(Br)n1
Reactant: C#Cc1cccc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(N)c(C#Cc2cccc(F)c2)n1
Yield: 59.8 %

Procedure:
Following the same procedure as described in Example 1, (2-bromo-6-methyl-pyridin-3-yl)amine (200 mg, 1.07 mmol) reacted with (PPh3)2PdCl2 (36 mg, 0.05 mmol), Cul (10 mg, 0.05 mmol) and 1-ethynyl-3-fluorobenzene (148 μl, 1.28 mmol) in triethylamine (5 ml). The crude residue was purified by flash chromatography (hexane/ethyl acetate 4:1) to yield 145 mg (0.64 mmol, 60%) of (2-(3-fluoro-phenylethynyl)-6-methyl-pyridin-3-yl)amine as a pale yellow solid. The hydrochloride of (2-(3-fluoro-phenylethynyl)-6-methyl-pyridin-3-yl)amine was prepared as described in Example 1 to yield 148 mg (0.56 mmol, 88%) of the title hydrochloride as a yellow solid.
Reaction SMILES: [C:1]([NH:8][C@:9](N1C(=O)CCC1=O)([C:18]([OH:20])=[O:19])[CH:10](C(C)(C)C)[C:11]([OH:13])=[O:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>CN(C=O)C>[NH:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11](=[O:12])[O:13][C:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@](C(=O)O)(C(C(=O)O)C(C)(C)C)N1C(=O)CCC1=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
FIG. 12 illustrates the synthesis of Mass Tag (3). To a mixture of N-Boc-β-tert-butyl-α-succinimido-aspartic acid (Boc-Asp(But)-OSu) (Bacchem, 0.1 mmol) in DMF (1 ml) was added hexamethyleneimine (Aldrich, 0.4 mmol). More DMF (2 ml) was added. The mixture was shaken at room temperature for 2 hours to form Boc-Asp(But)-HMI. Boc-Asp(But)-HMI was purified with preparative HPLC, and characterized with MS ([M+H]+: 371.3, calculated; 371.1, found).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]2[CH:15]=[C:16]([CH:31]=[CH:32][CH:33]=2)[CH:17]=[C:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)=[N:11][CH:12]=1)[CH2:2][CH2:3][C:4]#[CH:5].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]2[CH:33]=[CH:32][CH:31]=[C:16]([CH:17]=[C:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:15]=2)=[N:11][CH:12]=1)[CH2:2][CH2:3][C:4]#[CH:5]
Reactant: C#CCCCOc1ccc(Oc2cccc(C=C3CCN(C(=O)OC(C)(C)C)CC3)c2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C#CCCCOc1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reaction time: 0.5 h
Yield: 114.4 %

Procedure:
To a solution of tert-butyl 4-(3-(5-(pent-4-ynyloxy)pyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (0.68 g, 1.33 mmol) in dry CH2Cl2 (3 mL) cooled to 0° C. was added TFA (1 mL, 13.3 mmol) dropwise. The mixture was stirred for 30 min. The reaction was concentrated and then partitioned between saturated NaHCO3 solution and CH2Cl2. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the title compound (0.53 g, 99%). m/z (421.2, MH+).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:16]=1.O[CH:26]([C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30].Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C1C=CN=CC=1)C.CN(C)C=O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][C:22]([O:24][CH:26]([C:33](=[O:40])[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:23])=[CH:19][CH:20]=1
Reactant: COC(=O)CCC(O)C(=O)c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)CCC(OC(=O)Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.3 %

Procedure:
A mixture of [4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]acetic acid (1.00 g), methyl 4-hydroxy-5-oxo-5-phenylpentanoate (687 mg), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (water-soluble carbodiimide; hereinafter to be referred to as WSC) (711 mg), 4-(N,N-dimethylamino)pyridine (75.5 mg) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 18 hrs, and the reaction mixture was poured into 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]acetoxy-5-oxo-5-phenylpentanoate (1.44 g, yield 88%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio).