Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[C:6]([C:9]1[CH:10]=[CH:11][C:12](Br)=[N:13][CH:14]=1)(=[O:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:6]([C:9]1[CH:10]=[CH:11][C:12]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[N:13][CH:14]=1)(=[O:8])[CH3:7]
Reactant: c1cn[nH]c1
Reactant: CC(=O)c1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(-n2cccn2)nc1
Temperature: 100 °C
Yield: 81.4 %

Procedure:
407.9 mg (corresponding to 5.99 mmol) of pyrazole was dissolved in 10 mL of dimethylformamide. Then, 400.0 mg (corresponding to 1.99 mmol) of 5-acetyl-2-bromopyridine and 827.9 mg (corresponding to 5.99 mmol) of potassium carbonate were added thereto. The resulting solution was heated at 100° C. for 5 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, supplemented with water, and extracted twice with dichloromethane. The combined dichloromethane layer was washed with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (elution solvent: dichloromethane/ethyl acetate=50/1), to obtain 304.0 mg (corresponding to 1.62 mmol) of 5-acetyl-2-(pyrazole-1-yl)pyridine (FIG. 5, step 1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH:13]=[CH2:14])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])(=[O:3])[CH3:2].C(Cl)(Cl)Cl.C(OO)(=[O:24])C>CO>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:12][CH:13]=[CH2:14])=[O:24])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)OO
Reactant: C=CCSc1ccc(NC(C)=O)c([N+](=O)[O-])c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C=CCS(=O)c1ccc(NC(C)=O)c([N+](=O)[O-])c1

Procedure:
3.0 G. of 1-acetamido-2-nitro-4-(prop-2-en-1-yl-thio)benzene, prepared according to Example I, in 30 ml. chloroform is cooled to -15° C. and treated with a solution of 2.5 g. of 40% peracetic acid in 4 ml. methanol. After the addition, the temperature is allowed to rise slowly to 20° C whereupon the solution is washed with sodium bisulfite solution and then with sodium bicarbonate solution. The product is isolated by evaporation of the solvent and purified to afford 1-acetamido-2-nitro-4-(prop-2-en-1-ylsulfinyl)benzene. This is treated with 20 ml. methanol and 10 ml. 5N aqueous sodium hydroxide at 20°-25° C. for one hour. The mixture is diluted with water and the crude product filtered off. Recrystallization yields 1-amino-2-nitro-4-(prop-2-en-1-ylsulfinyl)benzene.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[O:32])[N:19]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH:20]=[N:21]2)=[CH:16][C:15]=1[O:33][CH3:34].[Br:35][CH2:36][CH2:37][CH2:38]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:35][CH2:36][CH2:37][CH2:38][O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[O:32])[N:19]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:28])([CH3:29])[CH3:30])[CH:20]=[N:21]2)=[CH:16][C:15]=1[O:33][CH3:34]
Reactant: OCCCBr
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCCBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
Diethyl azodicarboxylate (3.9 ml, 24.5 mmol) was added in portions to a suspension of 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (5 g, 16.3 mmol), (prepared as described for the starting material in Example 12), 3-bromo-1-propanol (2.21 ml, 24.5 mmol) and triphenylphosphine (6.42 g, 24.5 mmol) in methylene chloride (50 ml). After stirring for 2 hours at ambient temperature, the volatiles were removed under vacuum and the residue was purified by column chromatography eluting with methylene chloride followed by methylene chloride/methanol (95/5) to give 7-(3-bromopropoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (6 g, 86%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:11][CH:12]1[C:17](=[O:18])[N:16]2[CH:19]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[C:20](=[O:26])[N:21]([CH:23]([CH3:25])[CH3:24])[CH2:22][CH:15]2[N:14]([S:35]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:39]=2[Cl:45])(=[O:37])=[O:36])[CH2:13]1>>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][CH:19]2[N:16]3[C:17](=[O:18])[CH:12]([NH:11][C:8]([C:5]4[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=4)=[O:10])[CH2:13][N:14]([S:35]([C:38]4[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:39]=4[Cl:45])(=[O:37])=[O:36])[CH:15]3[CH2:22][N:21]([CH:23]([CH3:25])[CH3:24])[C:20]2=[O:26])=[CH:29][CH:30]=1
Reactant: Cc1cnc(C(=O)O)cn1
Reactant: CC(C)N1CC2N(C(=O)C(N)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Product: Cc1cnc(C(=O)NC2CN(S(=O)(=O)c3ccc(Cl)cc3Cl)C3CN(C(C)C)C(=O)C(Cc4ccc(Cl)cc4)N3C2=O)cn1

Procedure:
Synthesis took place in analogy to Example 29e using 5-methylpyrazine-2-carboxylic acid and 3-amino-6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW=678.10 (calculated, monoisotopic); measured value (M+H)+: 679.06
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29](=[O:49])[CH2:30][C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)[CH3:27]>>[CH2:26]([O:28][C:29](=[O:49])[CH2:30][C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)[CH3:27]
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1cccc(F)c1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4cccc(F)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[3-(3-fluoro-phenyl)-1-methyl-propyl]-amine and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:6][CH:5]([CH2:7][NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH2:4][O:3]1.[H-].[Na+].[Cl:16][C:17]1[N:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[C:19](Cl)[N:18]=1.O>CN(C=O)C>[Cl:16][C:17]1[N:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[C:19]([N:8]([CH2:7][CH:5]2[CH2:4][O:3][C:2]([CH3:13])([CH3:1])[O:6]2)[S:9]([CH3:12])(=[O:10])=[O:11])[N:18]=1
Reactant: CC1(C)OCC(CNS(C)(=O)=O)O1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N(CC2COC(C)(C)O2)S(C)(=O)=O)nc(Cl)n1
Reaction time: 0.17 h
Yield: 57.4 %

Procedure:
To a solution of N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)methane sulfonamide (0.875 g, 4.18 mmol) in DMF (25 mL) was added 60% NaH in mineral oil (0.193 g, 4.83 mmol). After 10 minutes, methyl 2,6-dichloropyrimidine-4-carboxylate (0.871 g, 4.21 mmol) was added. After stirring for 30 minutes, the reaction mixture was diluted into 100 mL water and extracted three times with 50 mL EtOAc. The combined organic layers were washed once with 25 mL brine, dried over MgSO4, filtered, and evaporated to a residue. The residue was chromatographed over silica gel with 30-60% EtOAc in hexanes. The product fractions were concentrated in vacuo. After sitting overnight a crystalline solid formed. The solid was decanted and dried under vacuum to give methyl 2-chloro-6-(N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)methylsulfonamido)pyrimidine-4-carboxylate as a cream-colored powder (0.911 g, 2.40 mmol, 57% yield). LC/MS: m/z=380.2 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[OH:15].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.S([O-])(O)(=O)=O.[K+]>CN(C=O)C>[CH2:16]([O:15][C:9]1[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=1[Br:7])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cc(F)ccc1Br
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(Br)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.7 %

Procedure:
Potassium carbonate (2.61 g, 18.8 mmol) was added to a solution of 2-bromo-5-fluorophenol (3.0 g, 15.7 mmol) in DMF (15.7 mL) and the mixture was stirred in a nitrogen stream at room temperature for 15 minutes. To this solution, benzyl bromide (2.69 g, 15.7 mmol) was added dropwise at the same temperature and the mixture solution was stirred at the same temperature overnight. To the reaction mixture was added a potassium hydrogensulfate aqueous solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduce pressure. The obtained residue was purified by silica gel column chromatography (developing solution=n-hexane) to obtain the title compound (4.31 g, 98%) as a colorless oil.
Reaction SMILES: N(C([O:10][CH2:11][CH3:12])=O)=NC(OCC)=O.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)C[C:14]1=O.CO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:14][N:13]1[C:21]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][C:11]1=[O:10]
Reactant: O=C1Cc2ccccc2N1
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CN1C(=O)Cc2ccccc21
Yield: 58.9 %

Procedure:
Add diethyl azodicarboxylate (DEAD, 8.0 g, 44.9 mmol) dropwise to a solution of indolin-2-one (4.0 g, 30.0 mmol), methanol (1.4 g, 44.9 mmol) and triphenylphosphine (12.0 g, 44.9 mmol) in THF (40 mL) at 0° C., stir the reaction at room temperature overnight. Concentrate under reduced pressure, purify the resulting residue with flash chromatography (silica gel, EtOAc:PE=1:3) to afford the title compound (2.6 g, 59.1%). MS: (M+1): 148.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21]([C:25]2NN=[N:27][N:26]=2)[CH:22]=[CH:23][CH:24]=1.C1(N=C=NC2CCCCC2)CCCCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]1[O:17][C:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[CH:20]=2)=[N:26][N:27]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1cccc(-c2nnn[nH]2)c1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CC(C)(C)OC(=O)N1CCCCC1Cc1nnc(-c2cccc(Cl)c2)o1
Yield: 57.8 %

Procedure:
The title compound (1.21 g) was prepared from 2-carboxymethyl-piperidine-1-carboxylic acid tert butyl ester (1.35 g), 5-(3-chlorophenyl)tetrazole (1.0 g) and dicyclohexylcarbodiimide (1.15 g) according to the method of description 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)([CH:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)O)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)(=O)C.S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)=[C:10]2[CH2:11][CH2:12][N:13]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)N1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=S(=O)(c1ccccc1)N1CCC(=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 64.3 %

Procedure:
A solution of 5.23 g (0.0118 mole) of α,α-bis(4-fluorophenyl)-1-(phenylsulfonyl)-4-piperidinemethanol in 100 ml of acetic acid and 20 ml of 2M sulfuric acid was heated at reflux for 2.5 hours and then poured over ice. The mixture was made basic with 50% sodium hydroxide, and the basic mixture was extracted with methylene chloride. The methylene chloride solution was dried (anhydrous sodium sulfate), and the solvent was removed in vacuo. The residue was recrystallized from ether-hexane to give 3.23 g (64.4%) of white crystalline solid, mp 90°-92.5° C.
Reaction SMILES: [OH:1][C@:2]1([C:13]2[S:14][C:15]([C:18]3[CH:23]=[C:22]([NH:24][C:25]4[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=4)[CH:21]=[C:20]([CH3:35])[CH:19]=3)=[CH:16][N:17]=2)[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[C:4]([CH3:12])([CH3:11])[CH2:3]1.[OH-].[K+:37]>C(#N)C.O>[OH:1][C@:2]1([C:13]2[S:14][C:15]([C:18]3[CH:23]=[C:22]([NH:24][C:25]4[N:30]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:28]=[CH:27][N:26]=4)[CH:21]=[C:20]([CH3:35])[CH:19]=3)=[CH:16][N:17]=2)[CH2:7][CH2:6][C@H:5]([C:8]([O-:10])=[O:9])[C:4]([CH3:11])([CH3:12])[CH2:3]1.[K+:37]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc([C@@]3(O)CC[C@H](C(=O)O)C(C)(C)C3)s2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc([C@@]3(O)CC[C@H](C(=O)[O-])C(C)(C)C3)s2)c1
Temperature: 35 °C

Procedure:
(1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid (9.8 mg, 0.019 mmol) was dissolved in acetonitrile (20 μL) and water (20 μL). Potassium hydroxide (19 μL, 0.019 mmol) was added, and the mixture was heated to 35° C. for 10 min. The mixture was allowed to cool to room temperature, diluted with water, froze to a solid, and lyophilized to dryness to afford potassium (1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylate. MS ESI: [M+H]+ m/z 507.1. 1H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.83 (d, J=4.9, 1H), 7.91 (s, 1H), 7.88 (s, 1H), 7.46 (s, 1H), 7.27 (d, J=4.9, 1H), 7.12 (s, 1H), 5.97 (s, 2H), 2.31 (s, 3H), 1.92-1.82 (m, 2H), 1.81-1.65 (m, J=13.8, 5H), 1.54-1.48 (m, 1H), 1.47-1.39 (m, 1H), 1.05 (s, 3H), 0.95 (s, 3H). rhSYK activity=+++
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:36]([CH3:37])=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][C:5]=1[CH3:38].[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([N:46]=[C:47]=[S:48])=[CH:42][CH:41]=1.C(N(CC)CC)C>O1CCCC1>[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([NH:46][C:47]([NH:3][C:4]2[C:5]([CH3:38])=[CH:6][C:7]([O:8][C:9]3[CH:10]=[CH:11][C:12]4[N:16]=[C:15]([CH2:17][O:18][C:19]5[CH:20]=[CH:21][C:22]([CH2:23][CH:24]6[S:28][C:27](=[O:29])[NH:26][C:25]6=[O:30])=[CH:31][CH:32]=5)[N:14]([CH3:33])[C:13]=4[CH:34]=3)=[CH:35][C:36]=2[CH3:37])=[S:48])=[CH:42][CH:41]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: Cc1cc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc(C)c1N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc(C)c1NC(=S)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 63.9 %

Procedure:
A mixture of 5-[4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (288 mg), 4-chlorophenyl isothiocyanate (102 mg), triethylamine (121 mg) and anhydrous tetrahydrofuran (10 ml) was stirred at room temperature for 23 hours. The reaction mixture was concentrated and diluted with water. The precipitate was isolated by filtration and then chromatographed on a silica gel column using ethyl acetate:n-hexane=3:1 as the eluant to afford the title compound (215 mg, mp 160-162° C.).
Reaction SMILES: Cl[CH:2]([CH2:6][CH2:7][Cl:8])[C:3](=[O:5])C.[SH:9][CH2:10][CH2:11]O.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:8][CH2:7][CH2:6][C:2]1[S:9][CH2:10][CH2:11][O:5][CH:3]=1
Reactant: CC(=O)C(Cl)CCCl
Reactant: OCCS
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: ClCCC1=COCCS1
Yield: 60 %

Procedure:
A mixture of the 3,5-dichloro-2-pentanone (39 g., 0.24 mole) and 2-mercaptoethanol (20 g., 0.26 mole) in toluene (250 ml) was stirred, and triethylamine (27 g., 0.27 mole) added dropwise thereto. After stirring overnight at ambient temperature, the mixture was washed with dilute hydrochloric acid and subsequently refluxed with p-toluenesulfonic acid (0.5 g.) with azeotropic removal of water for 4 hours. Upon cooling, the reaction mixture was washed with aqueous sodium bicarbonate, dried (magnesium sulfate), and the toluene removed to leave the product 3-(2-chloroethyl)-5,6-dihydro-1,4-oxathiin (bp. 62°-70°/0.025 mm) in 60% yield and 98% purity (G.C.). N.M.R. spectrum (Deuterchloroform) gave lambda values: 1.85 (3H,S) 2.3-2.65 (2H,t); 2.9-3.5 (2H,t); 3.95-3.7 (2H,t); 4.1-4.25 (2H,t).
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:9]([NH:11][CH2:12][CH3:13])[CH3:10]>>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([N:11]([CH2:12][CH3:13])[CH2:9][CH3:10])[CH3:8])[CH3:7]
Reactant: CCNCC
Reactant: CCOC(=O)C(C)Br
Product: CCOC(=O)C(C)N(CC)CC
Temperature: 25 °C
Reaction time: 10 h
Yield: 80 %

Procedure:
To ethyl 2-bromopropionate (0.15 moles), diethylamine (0.4 moles) was added, followed by stirring for 10 hours at room temperature. White solid was removed by filtration, and then the filtrate was distilled to obtain 2-diethylaminopropionic acid ethyl ester (0.120 moles).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.O[CH2:28][C:29]1[CH:30]=[C:31]([CH:41]=[CH:42][CH:43]=1)[O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][N:40]=1)[C:36]#[N:37]>ClCCl.C(OCC)(=O)C>[I:25][CH2:28][C:29]1[CH:30]=[C:31]([CH:41]=[CH:42][CH:43]=1)[O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][N:40]=1)[C:36]#[N:37]
Reactant: II
Reactant: N#Cc1ccnc(Oc2cccc(CO)c2)c1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1ccnc(Oc2cccc(CI)c2)c1
Reaction time: 0.17 h
Yield: 55.9 %

Procedure:
Mix polymer-supported triphenylphosphine (2.33 mmol/g load capacity, 0.85 g, 1.99 mmol), imidazole (0.14 g, 1.99 mmol) and iodine (0.51 g, 1.99 mmol) in dichloromethane (8 mL) in a vial (0.75 oz). Seal and shake for 10 minutes. Add a solution of 2-(3-hydroxymethyl-phenoxy)-isonicotinonitrile (0.30 g, 1.33 mmol) in dichloromethane (3 mL) and shake for 2 hrs. Filter the resin and wash with dichloromethane (50 mL). Concentrate the filtrate under reduced pressure to give a residue. Dissolve the residue in ethyl acetate (25 mL), wash with saturated sodium thiosulfate solution (2×25 mL) and dry over sodium sulfate. Filter and concentrate to give 2-(3-iodomethyl-phenoxy)-isonicotinonitrile as a yellow solid (0.25 g, 53%). Mix the yellow solid (0.25 g, 0.70 mmol), 1-(2,4-dihydroxy-3-methyl-phenyl)-propan-1-one (0.14 g, 0.77 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in acetone (7 mL). Heat to 50° C. for 2.5 hrs. Allow the reaction to cool to ambient temperature and concentrate under reduced pressure to give a solid. Dilute with ethyl acetate (25 mL) and filter. Concentrate the filtrate under reduced pressure to give an oil. Triturate with methanol (50 mL) and filter to give a solid. Purification by flash chromatography using 5% ethyl acetate/hexanes to 20% ethyl acetate/hexanes as gradient eluent yields the title compound (0.16 g, 60%): MS (m/z): 387.2 (M−1). 1H NMR (CDCl3) 12.91 (s, 1H), 8.34 (d, J=5.1 Hz, 1H), 7.65 (d, J=9.0 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.31-7.24 (m, 2H), 7.21 (s, 1H), 7.15 (d, J=8.0 Hz, 1H), 6.51 (d, J=9.0 Hz, 1H), 5.23 (s, 2H), 3.00 (q, J=7.5 Hz, 2H), 2.19 (s, 3H), 1.26 (t, J=7.5 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]([N:26]1[CH2:31][CH2:30][N:29]([C:32](=[O:43])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([F:42])([F:41])[F:40])[CH2:28][CH2:27]1)[CH2:3][NH:4][C:5]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18]CC3C=CC=CC=3)[CH:13]=2)[O:9][N:8]=1)=[O:6]>CO.[Pd]>[O:1]=[C:2]([N:26]1[CH2:27][CH2:28][N:29]([C:32](=[O:43])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([F:40])([F:42])[F:41])[CH2:30][CH2:31]1)[CH2:3][NH:4][C:5]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[O:9][N:8]=1)=[O:6]
Reactant: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cc(-c2cccc(OCc3ccccc3)c2)on1
Agent: [Pd]
Solvent: CO
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cc(-c2cccc(O)c2)on1
Yield: 43.1 %

Procedure:
10% Pd/c (40 mg) was added to a stirred solution of 5-(3-benzyloxy-phenyl)-isoxazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide (74 mg, 0.12 mmol) (prepared by the method as described above) in MeOH (30 mL) and stirred under hydrogen atmosphere. The reaction mixture was then stirred for 6 hrs. The mixture was filtered over a bed of celite. The celite was washed with MeOH and the filtrate was concentrated under reduced pressure to afford 26 mg (41.9% yield) of 5-(3-hydroxy-phenyl)-isoxazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 99.07%. 1H NMR (CD3OD): δ 7.64 (m, 4H), 7.5 (d, 1H), 7.32 (m, 1H), 7.24 (s, 1H), 6.98 (m, 2H), 4.26 (m, 2H), 3.7 (m, 4H), 3.5 (m, 2H), 3.38 (m, 1H), 3.24 (m, 1H).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[C:16]([NH:19][CH2:20][CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1)(=[O:18])[CH3:17].[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C.CN(C)C=O>[C:16]([NH:19][CH2:20][CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:4](=[O:6])[CH2:3][CH2:2][C:1]([O:8][CH3:9])=[O:7])[CH:27]=2)[CH2:22]1)(=[O:18])[CH3:17]
Reactant: CC(=O)NCC1Cc2ccccc2C1
Reactant: COC(=O)CCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: COC(=O)CCC(=O)c1ccc2c(c1)CC(CNC(C)=O)C2
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.4 %

Procedure:
To 48.3 g of methyl hydrogen succinate dissolved in 840 ml of dichloroethane were added 46.4 g of oxalyl chloride and 2 drops of dimethylformamide. The mixture was stirred at room temperature for 5 hours. Then, under ice cooling, 34.6 g of 2-(acetylaminomethyl)indane dissolved in 280 ml of dichloroethane and 97.6 g of anhydrous aluminum chloride were added to the reaction mixture. After the mixture was stirred for 1 hour, the reaction mixture was poured into ice water. The organic layer was collected by separation, washed with water and dried, and the solvent was removed to obtain 51.8 g of 2-(acetylamino) methyl-5-(3methoxycarbonylpropionyl) indane.
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[C:31]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)#[N:32]>>[C:31]([C:33]1[CH:38]=[C:37]([C:18]2[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=2)[CH:36]=[CH:35][CH:34]=1)#[N:32]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOC=C1c1cccc(C#N)c1
Yield: 63 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and 3-cyanophenylboronic acid using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as an off-white solid (63% yield); 1H-NMR (d6-DMSO) 1.08 (9H, s), 3.69 (2H, t), 4.12 (2H, t), 6.61 (1H, s), 7.50-7.52 (2H, m), 7.62-7.66 (2H, m); MS ES(+) 231.0 (M+-tBu). IR λmax=2225, 1697 cm−1