Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:4][C:5]1[S:9][C:8]([SH:10])=[N:7][N:6]=1)[CH:2]=[CH2:3].[H-].[Na+].Cl[C:14]1[C:15]([C:20]#[N:21])=[N:16][CH:17]=[CH:18][N:19]=1>CN(C=O)C.C1C=CC=CC=1>[CH2:1]([S:4][C:5]1[S:9][C:8]([S:10][C:14]2[C:15]([C:20]#[N:21])=[N:16][CH:17]=[CH:18][N:19]=2)=[N:7][N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCSc1nnc(S)s1
Reactant: N#Cc1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: C=CCSc1nnc(Sc2nccnc2C#N)s1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
The title compound was prepared according to the procedure described in Example 1 by using 5-(allylthio)-1,3,4-thiadiazole-2-thiol (460 mg, 2.42 mmol), NaH (60% dispersion in mineral oil, 107 mg, 2.66 mmol), and 3-chloropyrazine-2-carbonitrile (338 mg, 2.42 mmol) in DMF and benzene (8 ml, 1/1) by stirring at 85° C. under nitrogen atmosphere overnight.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21](O)=[O:22])[NH:6]2.[CH2:24]([S:31][CH:32]([CH:35]([O:38][CH3:39])[O:36][CH3:37])[CH2:33][NH2:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[CH2:24]([S:31][CH:32]([CH:35]([O:36][CH3:37])[O:38][CH3:39])[CH2:33][NH:34][C:21]([C:5]1[NH:6][C:7]2[C:3]([CH:4]=1)=[C:2]([CH3:1])[CH:10]=[CH:9][C:8]=2[N:11]([CH3:20])[S:12]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)(=[O:13])=[O:14])=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(=O)O)cc12
Reactant: COC(OC)C(CN)SCc1ccccc1
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: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(OC)C(CNC(=O)c1cc2c(C)ccc(N(C)S(=O)(=O)c3cccs3)c2[nH]1)SCc1ccccc1
Yield: 96.7 %

Procedure:
A solution of 4-methyl-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (3.0 g), 2-(benzylthio)-3,3-dimethoxypropan-1-amine (2.4 g), N-ethyldiisopropylamine (3.7 mL) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (4.2 g) in N,N-dimethylformamide (40 mL) was stirred at room temperature for 8 hr. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=2:3-3:2) to give the title compound (4.75 g, yield: 97%) as a pale-yellow oil. MS: 542 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:13]2=[C:14]3[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18]CC)=[O:17])=[CH:8][N:9]3[CH:10]([CH3:15])[CH2:11][O:12]2)=[CH:4][N:3]=1.O.S(=O)(=O)(O)O>C(O)(=O)C>[Cl:1][C:2]1[C:13]2=[C:14]3[C:5]([C:6](=[O:21])[C:7]([C:16]([OH:18])=[O:17])=[CH:8][N:9]3[CH:10]([CH3:15])[CH2:11][O:12]2)=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cn2c3c(c(Cl)ncc3c1=O)OCC2C
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CC1COc2c(Cl)ncc3c(=O)c(C(=O)O)cn1c23
Temperature: 0 °C

Procedure:
0.95 g (3.1 mmol) of ethyl 9-chloro-3-methyl-6-oxo-3,6-dihydro-2H-1-oxa-3a,8-diazaphenalene-5-carboxylate are heated at reflux in a mixture of 4 ml of acetic acid, 4 ml of water and 0.4 ml of concentrated sulphuric acid for four hours. The cooled mixture is put into ice-water, the product is isolated and washed with water.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:13].[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]([C:24](O)=[O:25])=[CH:18]2.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C.O1CCCC1>[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]([C:24]([NH:2][C@@H:3]1[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]1=[O:13])=[O:25])=[CH:18]2
Reactant: N[C@@H]1Cc2ccccc2NC1=O
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(N[C@@H]1Cc2ccccc2NC1=O)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 2 h
Yield: 81.2 %

Procedure:
Alternatively, (R)-3-amino-3,4-dihydrocarbostyril hydrochloride (95 mg) was added to a mixture of tetrahydrofuran (10 mL), 5-chloroindole-2-carboxylic acid (103 mg), 1-hydroxy-7-azabenzotriazole (85 mg), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (120 mg) at room temperature. Diisopropylethylamine (186 mg) was added, and the resulting yellow suspension was stirred for 2 h, during which a solution formed. The solution was diluted with ethyl acetate (50 mL) and washed sequentially with 1.0 M aqueous hydrochloric acid (25 mL), 1.0 M aqueous sodium hydroxide (25 mL), and brine (25 mL), dried over anhydrous sodium sulfate, and evaporated under vacuum. The resulting solid crude product was triturated with diethyl ether (5 mL twice), then 50% methanol in diethyl ether (5 mL twice). Drying under vacuum provided pure title compound (132 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:30])[C:10](=[O:29])[C@@H:11]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[CH2:20])[CH:14]=2)=[CH:5][CH:4]=1.[C:31]([OH:34])(=[S:33])[CH3:32].N(C(C)(C)C#N)=NC(C)(C)C#N>C1(C)C=CC=CC=1>[C:31](=[O:34])([S:33][CH2:20][CH2:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][C@H:11]([NH:21][C:22]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:28])[C:10]([N:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH3:30])=[O:29])[CH:14]=1)[CH3:32]
Reactant: CC(O)=S
Reactant: C=Cc1cccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)c2ccc(OC)cc2)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Cc1ccccc1
Product: COc1ccc(N(C)C(=O)[C@H](Cc2cccc(CCSC(C)=O)c2)NC(=O)OC(C)(C)C)cc1
Temperature: 100 °C

Procedure:
To a solution of (5)-tert-butyl 1-((4-methoxyphenyl)(methyl)amino)-1-oxo-3-(3-vinylphenyl)propan-2-ylcarbamate (2.9 g, 7.06 mmol) and thioacetic acid (5 ml) in toluene (30 ml), was added azobisisobutyronitrile, (3.2 ml, 0.2M in toluene) dropwise. The solution was degassed for 30 minutes by purging with nitrogen. After purging was complete, the reaction was heated at 100° C. for 2 hours. The reaction was cooled to room temperature and then diluted with EtOAc (100 ml). The organics were washed with sodium bicarbonate (3×). The organic layer was dried with Na2SO4, filtered and concentrated. The crude product was introduced to a silica gel loading column and purified by column chromatography (20-50% EtOAc/hexanes) to provide the desired product (2.8 g, 5.74 mmol), 81.4%. MS (m/z) 487 [M+H]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([CH2:15][OH:16])=[CH:13][O:12][N:11]=2)=[CH:6][CH:5]=1.Cl[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=1.[Cl-].[Na+]>C1COCC1>[CH3:25][O:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][C:18]([O:16][CH2:15][C:14]2[C:10]([C:7]3[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=3)=[N:11][O:12][CH:13]=2)=[N:19][CH:20]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: OCc1conc1-c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a suspension of sodium hydride (55% dispersion in mineral oil, 1.16 g, 26.5 mmol) in THF (30 mL) was added a solution of [3-(4-chloro-phenyl)-isoxazol-4-yl]-methanol (24.1 mmol) in THF (60 mL) at 0° C. and the reaction mixture warmed to room temperature over 30 min. Then a solution of methyl 6-chloronicotinate (4.65 g, 26.5 mmol) in THF (60 mL) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=4:1 to 2:1) afforded 6-[3-(4-Chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (72%) which was obtained as a light yellow solid. To a suspension of 6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (1.0 mmol) in THF (3 mL) and methanol (3 mL) was added a solution of lithium hydroxide monohydrate (85.1 mg, 2.0 mmol) in water (3 mL) and the resulting mixture stirred at room temperature overnight. The mixture was acidified to pH 4 with HCl (1 N, 30 mL) and the resulting mixture was filtered. The solid was dried to afford the title compound (100%) which was obtained as a light yellow solid. MS: m/e=331.1 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][N:6]=[C:7]([CH2:11][S+:12]([O-:26])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH:23]([F:25])[F:24])=[CH:19][C:20]=3[N:21]=2)[C:8]=1[O:9][CH3:10].[OH-].[Na+:28]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][N:6]=[C:7]([CH2:11][S+:12]([O-:26])[C:13]2[N-:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH:23]([F:24])[F:25])=[CH:19][C:20]=3[N:21]=2)[C:8]=1[O:9][CH3:10].[Na+:28]
Reactant: COc1ccnc(C[S+]([O-])c2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccnc(C[S+]([O-])c2nc3cc(OC(F)F)ccc3[n-]2)c1OC

Procedure:
A 100 ml flask was charged with toluene (50.0 ml). Pantoprazole (5.0 g, 12.8 mmol) and 47% aqueous NaOH (1.2 g) were added to the stirred solvent at room temperature. The mixture was stirred until dissolution and then overnight until precipitation. The solid was filtered giving pantoprazole sodium. The sample was dried at 45° C. under 10 mm Hg vacuum overnight, giving 4.21 g of amorphous pantoprazole sodium.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:14]([C@H:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:32])[C@@H:15]([C:24]1[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=1)[CH2:16][C:17](OC(C)(C)C)=[O:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([N:14]([C@H:31]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH3:32])[C@@H:15]([C:24]1[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=1)[CH2:16][CH2:17][OH:18])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1ccc([C@@H](CC(=O)OC(C)(C)C)N(Cc2ccccc2)[C@@H](C)c2ccccc2)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc([C@@H](CCO)N(Cc2ccccc2)[C@@H](C)c2ccccc2)cn1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
To a solution of LiAlH4 (1.24 g, 32.79 mmol) in THF (80 mL) at 0° C., was added dropwise a solution of (R)-tert-butyl 3-(benzyl((S)-1-phenylethyl)amino)-3-(6-methylpyridin-3-yl)propanoate (4.7 g, 10.93 mmol) in THF and was heated to 75° C. After 4 h, the reaction mixture was quenched with EtOAc and filtered. The filtrate was washed with excess EtOAc and dried under high vacuum to afford a residue. Purification of the residue by column chromatography (neutral Al2O3, Et2O/Pet ether 15:85) afforded the title compound. MS: 361.5 ([M−H]+);
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([OH:14])=[C:9]([F:15])[CH:8]=1)[CH3:2].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:28][C:29]([CH3:35])=[C:30]([CH2:32][CH2:33]O)[N:31]=2)=[CH:23][CH:22]=1.COC(=O)CC(=O)C(Br)C.ClC1C=CC(C(N)=S)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]([F:15])[C:10]([O:14][CH2:33][CH2:32][C:30]2[N:31]=[C:27]([C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=3)[S:28][C:29]=2[CH3:35])=[C:11]([F:13])[CH:12]=1)[CH3:2]
Reactant: Cc1sc(-c2ccc(Cl)cc2)nc1CCO
Reactant: CCOC(=O)C(Cc1cc(F)c(O)c(F)c1)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: COC(=O)CC(=O)C(C)Br
Agent: NC(=S)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1cc(F)c(OCCc2nc(-c3ccc(Cl)cc3)sc2C)c(F)c1)OCC

Procedure:
In analogy to the procedure described in example 4 d], [rac]-3-(3,5-difluoro-4-hydroxy-phenyl)-2-ethoxy-propionic acid ethyl ester [example 70 a]] was reacted with 2-[2-(4-chloro-phenyl)-5-methyl-thiazol-4-yl]-ethanol (prepared from [rac]-4-bromo-3-oxo-pentanoic acid methyl ester [PCT Int. Appl. (2001), WO 01/79202] and 4-chloro-thiobenzamide in analogy to the procedures described in examples 12 a] and 12 b]) in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-3-(4-{2-[2-(4-chloro-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-3,5-difluoro-phenyl)-2-ethoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-3-(4-{2-[2-(4-chloro-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-3,5-difluoro-phenyl)-2-ethoxy-propionic acid as light yellow amporphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17]CC)=[O:16])=[CH:7][C:6]=2[CH:20]=1.[OH-].[Li+].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([F:13])([F:12])[F:14])[C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]=2[CH:20]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)ccc2OC1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1=Cc2cc(Cl)ccc2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.5 %

Procedure:
A solution of the ester from Step 1 (13.02 g, 42 mmole) was dissolved in 200 mL of methanol and 20 mL of water, treated with lithium hydroxide (5.36 g, 0.128 mole) and stirred at room temperature for 16 hours. The reaction mixture was acidified with 1.2 N HCl, whereupon a solid formed that was isolated by filtration. The solid was washed with 200 mL of water and 200 mL of hexanes and dried in vacuo to afford the title compound as a yellow solid (10.00 g, 85%): mp 181–184° C.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([NH:16][C:17]1[CH:29]=[C:28]([N:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32][CH2:31]2)[CH:27]=[CH:26][C:18]=1[C:19]([O:21]C(C)(C)C)=[O:20])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:8]([NH:16][C:17]1[CH:29]=[C:28]([N:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32][CH2:31]2)[CH:27]=[CH:26][C:18]=1[C:19]([OH:21])=[O:20])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N2CCc3ccccc32)cc1NC(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(N2CCc3ccccc32)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
5.0 mL of trifluoroacetic acid solution containing 75 mg of tert-butyl 2-(benzamido)-4-(indolin-1-yl)benzoate was stirred at room temperature for 1 hour and 30 minutes. The solvent was evaporated under reduced pressure, ethyl acetate and water were added and pH was adjusted to pH 6.5 with a saturated sodium hydrogen carbonate aqueous solution. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with water and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. Methanol was added to the obtained residue and a solid substance was separated by filtration to obtain 51 mg of 2-(benzamido)-4-(indolin-1-yl)benzoic acid a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1.N>Cl.C1COCC1>[NH2:1][C:2]1[C:24]([Cl:25])=[CH:23][C:5]([C:6]([O:8][CH2:9][CH:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[O:7])=[C:4]([O:26][CH3:27])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)OCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: N
Solvent: C1CCOC1
Product: COc1cc(N)c(Cl)cc1C(=O)OCC1CCNCC1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A mixture of intermediate 10 (18 g) in HCl (25 ml) and THF (250 ml) was stirred for 30 minutes at 70° C. The reaction mixture was cooled, alkalized with aqueous ammonia and the layers were separated. The aqueous layer was extracted twice with THF. The combined organic layers were dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (cluent: CH2Cl2/(CH3OH/NH3) 90/10). The pure fractions were collected and the solvent was evaporated. The residue (10 g) was dissolved in CHCl3, washed with aqueous ammonia, dried, filtered and the solvent was evaporated. The residue was suspended in DIPE, filtered off and dried, yielding 8.5 g (65%) 4-piperidinylmethyl 4-amino-5-chloro-2-methoxybenzoate (intermediate 11).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])[CH2:3][CH2:2]1.C[O:22][C:23](=[O:29])[C@H:24]([CH2:26][S:27][CH3:28])[NH2:25].C(=O)([O-])[O-].[K+].[K+]>O.CO>[O:1]1[CH2:6][CH2:5][N:4]([C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:8])[CH2:3][CH2:2]1.[CH3:28][S:27][CH2:26][C@@H:24]([C:23]([OH:29])=[O:22])[NH2:25]
Reactant: COC(=O)[C@@H](N)CSC
Agent: O=C(O)[C@H](Cc1ccccc1)NC(=O)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CSC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To an ice-cooled solution of 1.15 g N-(morpholinocarbonyl)-L-phenylalanine-S-methyl-L-cysteine methyl ester in 30 mL water and 60 mL methanol was added 3.5 g potassium carbonate. The resulting mixture was stirred at 0° for 15 min. and at ambient temperature for 4 h. The solution was concentrated in vacuo to an aqueous solution, which was acidified with conc. hydrochloric acid and extracted 3×50 mL methylene chloride. The combined extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to afford 1.0 g (89%) of the crude acid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH:11]=[N:10][C:9]([SH:12])=[N:8]1.CN(C)C=O.[C:18]([O:22][C:23]([NH:25][C@@:26]1([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[C@H:31]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=2)[C@H:30](OS(C)(=O)=O)[C@@H:29]2[C@H:27]1[C@H:28]2[C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[O:24])([CH3:21])([CH3:20])[CH3:19]>C(=O)(O)[O-].[Na+]>[C:18]([O:22][C:23]([NH:25][C@@:26]1([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[C@H:31]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=2)[C@@H:30]([S:12][C:9]2[N:10]=[CH:11][NH:7][N:8]=2)[C@@H:29]2[C@H:27]1[C@H:28]2[C:47]([O:49][C:50]([CH3:52])([CH3:51])[CH3:53])=[O:48])=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Sc1nc[nH]n1
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@@H](OS(C)(=O)=O)[C@H]1OCc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@H](Sc2nc[nH]n2)[C@H]1OCc1ccc(Cl)c(Cl)c1
Reaction time: 0.08 h
Yield: 69.5 %

Procedure:
Potassium carbonate (1.45 g, 10.50 mmol) is added to 1H-1,2,4-triazole-3-thiol (424.79 mg, 4.20 mmol) and dimethylformamide (10.50 mL, 9.93 g, 135.80 mmol) at room temperature and stirred. After 5 minutes, di-tert-butyl (1S,2R,3S,4R,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-[(3,4-dichlorobenzyl)oxy]-4-[(methylsulfonyl)oxy]bicyclo[3.1.0]hexane-2,6-dicarboxylate (1.40 g, 2.10 mmol) is added to the reaction and stirred at 85° C. After 2 days, cool the reaction to room temperature, dilute with saturated sodium bicarbonate, then extract with ethyl acetate (3×). The combined organics are washed with water, brine, filtered, and concentrated under reduced pressure to give a residue. The residue is purified by flash chromatography eluting with 5-75% ethyl acetate in hexanes to give the title compound (978.0 mg, 1.46 mmol, 69%). MS (m/z): 671/669 (M−1).
Reaction SMILES: [NH:1]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C@@H:2]([C:6]([N:8]([CH3:41])[C@H:9]([C:27]([NH:29][CH2:30][C:31]([O:33]CC1C=CC=CC=1)=[O:32])=[O:28])[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[NH:26])[NH:15][S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[O:7])[CH:3]([CH3:5])[CH3:4]>CO>[NH:1]([C:42]([O:44][C:45]([CH3:47])([CH3:46])[CH3:48])=[O:43])[C@@H:2]([C:6]([N:8]([CH3:41])[C@H:9]([C:27]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:28])[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[NH:26])[NH:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([CH3:23])=[CH:24][CH:25]=1)(=[O:18])=[O:17])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](C(=O)NCC(=O)OCc2ccccc2)N(C)C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)cc1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](C(=O)NCC(=O)O)N(C)C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)cc1
Reaction time: 0.5 h

Procedure:
4.50 g Boc-D-Val-NMeArg(Tos)-Gly-OBzl (4.44 mmol) dissolved in 80 ml methanol was purged with N2 for 10 min. 1.30 g Pd/C catalyst (10% Fluka lot #273890) was then added, and then H2 was passed directly over the surface of the reaction. TLC showed the reaction to be complete within approximately 0.5 hr. After 1 hr. the catalyst was removed by filtering through a bed of Celite, and the solvent removed at 40° under reduced pressure. The resulting solid was triturated well with 50 ml refluxing ether, filtered, and washed with petroleum ether: yield 3.05 g (78%); TLC Rf(CM) =0.03; Rf(CMA) =0.37; NMR is consistent with structure; FABMS M+H+ =599.45 (expected 599.29).
Reaction SMILES: C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[C:36]([NH:44][C:45]3[N:50]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:48]=[CH:47][N:46]=3)[CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=2)O1.Br[C:57]1[S:61][C:60]([C:62]2([OH:66])[CH2:65][CH2:64][CH2:63]2)=[N:59][CH:58]=1.[F-].[K+]>C1COCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[F:43][C:40]([F:42])([F:41])[C:38]1[CH:39]=[C:34]([C:57]2[S:61][C:60]([C:62]3([OH:66])[CH2:65][CH2:64][CH2:63]3)=[N:59][CH:58]=2)[CH:35]=[C:36]([NH:44][C:45]2[N:50]=[C:49]([C:51]([F:52])([F:54])[F:53])[CH:48]=[CH:47][N:46]=2)[CH:37]=1
Reactant: OC1(c2ncc(Br)s2)CCC1
Reactant: CC1(C)OB(c2cc(Nc3nccc(C(F)(F)F)n3)cc(C(F)(F)F)c2)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: OC1(c2ncc(-c3cc(Nc4nccc(C(F)(F)F)n4)cc(C(F)(F)F)c3)s2)CCC1
Temperature: 85 °C
Yield: 86.2 %

Procedure:
A solution of palladium(II) acetate (2.55 mg, 0.011 mmol) and butyldi-1-adamantyl phosphine (CataCXium A, 8.14 mg, 0.023 mmol) in THF (1.42 mL) was stirred for 10 min while nitrogen was bubbled through gently. Intermediate 13 (100 mg, 0.189 mmol), Intermediate 1 (51.0 mg, 0.218 mmol), potassium fluoride (33.0 mg, 0.568 mmol) and water (473 μl) were added. The tube was sealed (screw cap) and heated overnight at 85° C. The reaction was cooled to room temperature and diluted with ethyl acetate. After decanting the solids and extraction with ethyl acetate, the organic layer was washed with brine and dried over MgSO4. Filtration and subsequent solvent evaporation gave a residue which was purified by chromatography on silica gel (5-50% ethyl acetate in hexanes) to give 75 mg (86%) of 1-{5-[3-(trifluoromethyl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]-1,3-thiazol-2-yl}cyclobutanol as a grey solid. MS ESI [M+H]+ 461.1. 1H NMR (400 MHz, DMSO-d6): δ 10.67 (s, 1H); 8.93 (d, J=4.9 Hz, 1H); 8.33 (s, 1H); 8.24 (s, 1H); 8.17 (s, 1H); 7.68 (s, 1H); 7.41 (d, J=4.9 Hz, 1H); 6.62 (s, 1H); 2.59-2.48 (m, 2H); 2.42-2.31 (m, 2H); 1.98-1.87 (m, 2H). rhSYK activity=++