Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[CH2:10][CH2:11][C:12]([NH2:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](OCC)(=[O:18])C.C=O.[OH-].[K+]>CCCCCC>[OH:18][CH2:16][NH:14][C:12](=[O:13])[CH2:11][CH2:10][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:15]
Reactant: CCOC(C)=O
Reactant: NC(=O)CCC(=O)OCc1ccccc1
Agent: C=O
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Product: O=C(CCC(=O)OCc1ccccc1)NCO
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 20.7 g. (0.10 mole) of benzylsuccinamate in 150 ml. ethyl acetate at 25° C. is added 3.0 g. of paraformaldehyde and 1 ml. of a 20% (by weight) solution of ethanolic potassium hydroxide. After stirring at 25° C. for 20 hours, hexane is added to the cloudpoint and the mixture is cooled at 5° C. for 24 hours. Solvents are decanted off and the residue is washed with 25 ml. hexane to give benzyl N-hydroxymethylsuccinamate.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([N:18]([CH2:20][C:21]([N:23]1[CH2:30][CH2:29][CH2:28][C@H:24]1[C:25]([OH:27])=[O:26])=[O:22])[CH3:19])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].O[N:32]1[C:36](=[O:37])[CH2:35][CH2:34][C:33]1=[O:38].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.O1CCCC1>[C:33]1(=[O:38])[N:32]([O:26][C:25](=[O:27])[C@@H:24]2[CH2:28][CH2:29][CH2:30][N:23]2[C:21](=[O:22])[CH2:20][N:18]([C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])[CH3:19])[C:36](=[O:37])[CH2:35][CH2:34]1
Reactant: CN(CC(=O)N1CCC[C@H]1C(=O)O)C(=O)OCc1ccccc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(CC(=O)N1CCC[C@H]1C(=O)ON1C(=O)CCC1=O)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
4.5 g of CBZ-sarcosine is dissolved in 100 ml tetrahydrofuran and 2.4 ml of n-methylmorpholine is added. The reaction mixture is cooled to -10° C. and stirred while 2.6 ml of isobutylchloroformate is added. After 5 minutes of additional stirring at -10° C. 4.15 g L-proline-t-butylester hydrochloride in 100 ml of tetrahydrofuran and 3.0 ml of n-methylmorpholine are added to the reaction mixture. The reaction mixture is stirred overnight and slowly warmed to room temperature. The solvent is evaporated under reduced pressure at 30° C. and the residue is dissolved in 600 ml ethylacetate. The ethylacetate layer is washed with (3×150 ml), lN sodium hydroxide, water (1×200 ml) 10% citric acid (3×150 ml), and water (3×150 ml). The organic layer is dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to provide carbobenzoxysarcosyl-proline-t-butyl ester (CBZ-Sar-L-Pro-O-t-But). 6.5 g of this material is dissolved in 15 ml of methylene chloride and 25 ml of trifluoroacetic acid is then added. The reaction mixture is kept at room temperature for 45 minutes and then the solvent is evaporated under reduced pressure at 30° C. The residue is triturated with hexane (3×50 ml) and the hexane removed by decantation. The residue is evaporated from (2×50 ml) of benzene to provide an oily residue which is carbobenzoxysarcosyl-L-proline (CBZ-Sar-L-Pro). 5.4 g of this material and 3.45 g of N-hydroxysuccinimide are dissolved in 100 ml of tetrahydrofuran and cooled to 0° C. To this cooled reaction mixture is added 4.12 g of dicyclohexylcarbodiimide. The reaction mixture is stirred overnight at 4° C. and the solvent is evaporated under reduced pressure. The residue is dissolved in 400 ml of ethylacetate and the dicyclohexyl urea is filtered off. The filtrate is washed with lN-hydrochloric acid (3×100 ml), water (1×100 ml), saturated sodium bicarbonate solution (2×100 ml) and water (2×100 ml). The organic layer is dried over anhydrous magnesium sulfate, filtered and the solvent is evaporated under reduced pressure to provide carbobenzoxy-sarcosyl-L-proline-succinimidyl ester.
Reaction SMILES: [Br-].[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:3].CC(C)([O-])C.[K+].C(OC(N[C@@H:41]1[C@H:46]([CH2:47][CH:48]=O)[CH2:45][C@H:44]2[CH2:50][C@H:42]1[C:43]2([CH3:52])[CH3:51])=O)(C)(C)C.O>O1CCCC1>[C:2]([CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:48]\[CH2:47][CH:46]1[CH2:41][CH:42]2[CH2:50][CH:44]([C:43]2([CH3:51])[CH3:52])[CH2:45]1)#[N:3]
Reactant: N#CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1[C@H](CC=O)C[C@H]2C[C@H]1C2(C)C
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)C2CC(C/C=C\CCCC#N)CC1C2
Yield: 41.8 %

Procedure:
To a suspension of 30.3 g of (4-cyanobutyl)triphenylphosphonium bromide in 140 ml of tetrahydrofuran is added 8.07 g of potassium-tert-butoxide under stirring in an nitrogen atmosphere and the mixture is stirred at room temperature for 1.5 hours. A solution of the above prepared crude aldehyde 3c in 50 ml of tetrahydrofuran is dropwise added at 0° C. and the resulting mixture is stirred at the same temperature for 1 hour. Water is added to the reaction mixture, then which is extracted with ether. The organic layer is washed with water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue is purified by flash chromatography on 200 g of silica gel (hexane:ethyl acetate=6:1) to give 6.9 g of the titled compound 7a in 41.8% yield.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18]O.C1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH3:12])=[O:10]
Reactant: O=C(O)CCCCCCCBr
Reactant: COCCOCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COCCOCCOC(=O)CCCCCCCBr
Yield: 78.4 %

Procedure:
8-Bromooctanoic acid (22.3 g), 2-(2-methoxyethoxy)-ethanol (14.08 g) and p-toluenesulphonic acid (0.1 g) were added to toluene (250 ml) and the resulting solution heated at reflux temperature for 16 hours. Ethyl acetate (500 ml) was then added and the solution washed with aqueous K2CO3 solution and water, dried and evaporated. The residual oil was distilled to give 2-(2-methoxyethoxy)-ethyl 8-bromooctanoate (25.5 g), 77%) as a colourless oil, b.p. 126°-128° C./0.08 mm Hg.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:8][C@@H:7]([OH:9])[CH2:6]1)=[O:4].N1C=CC=CC=1.[O:16](S(C1C=CC(C)=CC=1)(=O)=O)[S:17]([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=O)=[O:18].[O-][Mn](=O)(=O)=O.[K+]>CCOC(C)=O.C(Cl)Cl>[CH3:1][O:2][C:3]([C@H:5]1[CH2:8][C@@H:7]([O:9][S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:18])=[O:16])[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@H]1C[C@@H](O)C1
Reactant: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)C1
Reaction time: 0.75 h

Procedure:
An ice bath cooled methylene chloride (80.0 mL) solution of cis-3-hydroxy-cyclobutanecarboxylic acid methyl ester (4.00 g, 31.0 mmol; predominantly cis) was charged with pyridine (3.00 mL, 37.0 mmol) and Ts2O (11.1 g, 34.0 mmol). After 45 min, TLC analysis (EtOAc) revealed no starting material (KMnO4 stain for alcohol sm). The reaction mixture was concentrated in vacuo, resuspended in ether (50.0 mL) and washed with 0.5 N HCl (2×25 mL), saturated bicarbonate (2×25 mL), water (2×25 mL), brine (1×25 mL), and then dried over Na2SO4, filtered and concentrated to yield the title compound as colorless oil, predominantly cis. 1H NMR (400 MHz, CDCl3): δ=2.44-2.55 (m, 7H), 2.56-2.65 (m, 1H), 3.65 (s, 3H), 4.59-4.77 (m, 1H), 7.33 (d, 2H, J=8.0 Hz), 7.77 (d, 2H, J=8.0 Hz).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[C:9](I)[CH:10]=2)[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[C:15]([NH:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[O:16].[F:26][C:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[CH:29][N:28]=1>>[F:26][C:27]1[CH:32]=[C:31]([C:9]2[CH:10]=[C:11]3[C:6](=[N:7][CH:8]=2)[N:5]([CH3:13])[C:4](=[O:14])[C:3]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])=[C:2]3[OH:1])[CH:30]=[CH:29][N:28]=1
Reactant: Cn1c(=O)c(C(=O)NCC(=O)OC(C)(C)C)c(O)c2cc(I)cnc21
Reactant: OB(O)c1ccnc(F)c1
Product: Cn1c(=O)c(C(=O)NCC(=O)O)c(O)c2cc(-c3ccnc(F)c3)cnc21

Procedure:
The title compound was prepared similarly to the procedures described for Example 64 (a, b) from tert-butyl 2-(4-hydroxy-6-iodo-1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamido)acetate (Example 26 (g)) and 2-fluoro-4-pyridinylboronic acid. MS (ESI, pos. ion) m/z: 373 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm: 12.99 (s, 1 H), 10.34-10.48 (m, 1 H), 9.31 (s, 1 H), 8.80 (s, 1 H), 8.30-8.41 (m, 1 H), 7.84-7.96 (m, 1 H), 7.78 (s, 1 H), 4.04-4.25 (m, 2 H), 3.72 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][NH:15]3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([OH:22])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn].O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][C:14](=[O:22])[NH:15]3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCO
Reactant: COc1ccc(-c2cccc3[nH]ccc23)cc1OC
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(-c2cccc3c2CC(=O)N3)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
To the suspension of 4-(3,4-dimethoxy-phenyl)-1H-indole (14.7 g, 58 mmol) in t-BuOH:ethanol:acetic acid (367 mL:217 mL:113 mL) was added pyridinium tribromide (55.68 g, 174 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added more acetic acid (287 mL). Zinc dust (18.95 g, 290 mmol) was added to the reaction mixture portionwise. After stirring for one hour, water was added to the reaction. The unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water (6×), sat. NaHCO3 (2×), brine (3×), dried over Na2SO4, concentrated and triturated with ether to give 10.14 g (65%) of 4-(3,4-dimethoxy-phenyl)-1,3-dihydro-indol-2-one as an earth colored solid.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[NH2:13][C:9]1[C:8]([N+:14]([O-:16])=[O:15])=[C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([NH:1][C:26]([NH:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:27])=[CH:3][CH:4]=2)[CH:12]=[CH:11][N:10]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc(Oc2ccnc(N)c2[N+](=O)[O-])cc1
Product: Nc1nccc(Oc2ccc(NC(=O)Nc3ccccc3)cc2)c1[N+](=O)[O-]
Yield: 73.9 %

Procedure:
Method H3 was used with 4-(4-aminophenoxy)-3-nitropyridin-2-amine (50 mg, 0.2 mol) and phenyl isocyanate (22 μL, 0.2 mmol) to afford the title compound (54 mg, 74%). 1H-NMR (δ, ppm, DMSO-d6): 5.96 (d, 1H, HPy,5, J=5.72 Hz), 6.99 (t, 1H, Harom,Ph′,4), 7.13-7.16 (m, 4H, NH2,Py+Harom,Ph,3+5), 7.30 (t, 2H, Harom,Ph′,3+5, J=7.90 Hz), 7.48 (d, 2H, Harom,Ph′,2+6′J=7.69 Hz), 7.55 (d, 2H, Harom,Ph,2+6, J=8.93 Hz), 8.00 (d, 1H, HPy,6, J=5.78 Hz), 8.69 (s, 1H, NHurea,1), 8.81 (s, 1H, NHurea,3); LC-MS (m/z): 366 (M+H, 100).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=1[CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)([OH:3])=[O:2].[S:26]1[CH2:32][C:30](=[O:31])[NH:29][C:27]1=[S:28]>>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=1[CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([CH:18]=[C:32]2[S:26][C:27](=[S:28])[NH:29][C:30]2=[O:31])=[CH:20][CH:21]=1)([OH:3])=[O:2]
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1ccc(OCc2ccccc2-c2ccccc2C(=O)O)cc1
Product: O=C1NC(=S)SC1=Cc1ccc(OCc2ccccc2-c2ccccc2C(=O)O)cc1
Yield: 79085.6 %

Procedure:
The 4-[2-(2-carboxyphenyl)benzoxy]benzaldehyde (93.7 mg, 0.28 mmol) was then coupled with rhodanine (37.5 mg, 0.28 mmol) as described supra to yield the title product (99.1 g, 79%). mp >225° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH:34]1([CH2:40][C:41](Cl)=[O:42])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH:34]1([CH2:40][C:41]([N:29]2[CH2:28][CH2:27][CH:26]([N:23]3[C:19]4=[N:20][CH:21]=[N:22][C:17]([O:16][C:15]5[CH:14]=[CH:13][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:33][CH:32]=5)=[C:18]4[CH:25]=[N:24]3)[CH2:31][CH2:30]2)=[O:42])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Reactant: O=C(Cl)CC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)CC3CCCCC3)CC2)cc1

Procedure:
2-Cyclohexyl-1-{4-[4-(4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-yl}-ethanone was prepared according to General Procedure I by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with cyclohexyl-acetyl chloride (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 0.90-0.98 (m, 2H), 1.05-1.19 (m, 4H), 1.65-1.78 (m, 7H), 1.95-2.09 (m, 5H), 2.25-2.27 (m, 2H), 2.79-2.85 (m, 1H), 3.30 (methyl sulfonyl and water peak), 4.04-4.08 (m, 1H), 4.54-4.58 (m, 1H), 5.06-5.11 (m, 1H), 7.63-7.65 (m, 2H), 8.05-8.07 (m, 2H), 8.40 (s, 1H), 8.57 (s, 1H). Mass spectrum MH+=498.5.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:7][CH:6](CS([O-])(=O)=O)[CH2:5][O:4]2)[CH2:2]1.[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([O:24][C:25]3[CH:26]=[CH:27][C:28]([N:31]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:32]([C:34]4([C:37]([NH2:39])=[O:38])[CH2:36][CH2:35]4)=[O:33])=[N:29][CH:30]=3)=[CH:19][CH:20]=[N:21]2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH2:2]1[C:3]2([CH2:7][CH:6]([O:13][C:14]3[CH:23]=[C:22]4[C:17]([C:18]([O:24][C:25]5[CH:26]=[CH:27][C:28]([N:31]([C:40]6[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=6)[C:32]([C:34]6([C:37]([NH2:39])=[O:38])[CH2:36][CH2:35]6)=[O:33])=[N:29][CH:30]=5)=[CH:19][CH:20]=[N:21]4)=[CH:16][CH:15]=3)[CH2:5][O:4]2)[CH2:1]1
Reactant: O=S(=O)([O-])CC1COC2(CC2)C1
Reactant: NC(=O)C1(C(=O)N(c2ccccc2)c2ccc(Oc3ccnc4cc(O)ccc34)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: NC(=O)C1(C(=O)N(c2ccccc2)c2ccc(Oc3ccnc4cc(OC5COC6(CC6)C5)ccc34)cn2)CC1
Temperature: 25 °C
Reaction time: 36 h
Yield: 19.9 %

Procedure:
To a mixture of (4-oxaspiro[2.4]heptane-6-yl)methanesulfonate (168 mg, 0.877 mmol) and N-(5-(7-hydroxyquinolin-4-yloxy)pyridin-2-yl)-N-phenylcyclopropane-1,1-dicarboxamide (300 mg, 0.682 mmol) in 5 mL of N,N-dimethylacetamide was added cesium carbonate (893 mg, 2.74 mmol). After stirring at room temperature for 36 hrs, then the reaction mixture was warmed up to 40° C. for 8 hrs. The reaction mixture was concentrated in vacuo and the residue was chromatographed with a silica gel column (2:1 (v/v) EtOAc/n-hexane) to afford the title compound as a white solid (73 mg, 20%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].S(=O)(=O)(O)O.C(Cl)(Cl)Cl.[CH:22]1[CH:27]=CC=CC=1.C[OH:29]>C(OC(=O)C)(=O)C>[CH3:1][NH:2][C:3](=[O:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[O:5][C:27](=[O:29])[CH3:22]
Reactant: CNC(=O)C(O)c1ccccc1
Reactant: c1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: CNC(=O)C(OC(C)=O)c1ccccc1
Temperature: 92.5 °C
Reaction time: 5 h

Procedure:
N-methyl mandelic amide 100 g, synthesized as above is dissolved in acetic anhydride 200 ml at 60 degrees C. and concentrated sulfuric acid 0.5 ml is added. The mixture is heated at 90-95 degrees C. for 5 hours to complete the acetylation. The reaction mixture is then evaporated at 70 degrees C. in vacuum and the syrupy residue thus obtained is mixed with 1 liter of ice water. Chloroform 200 ml is added to extract the oily product and the chloroform layer is washed with 5% aqueous sodium bicarbonate, 200 ml and 0.2N HCL 200 ml, and dried with anhydrous sodium sulfate. On evaporation of the chloroform solution at 40 degrees C. in vacuum white crystalline product is formed from the syrupy residue. The crystals are washed with n-hexane. N-methyl phenyl alpha-acetoxyacetamide 66 g thus synthesized is identified by infrared spectroscopy, high performance liquid chromatography and thin-layer chromatography with a mobility of 0.65 on a solvent system of benzene:methanol 1:1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[SH:6].[CH:7](O)([CH3:9])[CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH:7]([S:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)([CH3:9])[CH3:8]
Reactant: CC(C)O
Reactant: Sc1nccs1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)Sc1nccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.8 %

Procedure:
To a solution of thiazole-2-thiol (300 mg, 2.56 mmol), isopropanol (154 mg, 2.56 mmol) and triphenylphosphine (671.5 mg, 2.56 mmol) in THF (5 mL) was added DEAD (445.8 mg, 2.56 mmol) dropwise at room temperature. The mixture was stirred at room temperature for 3 hours. Reaction was completed according to t.l.c. The reaction mixture was allowed to stir over the weekend then concentrated and the residue was subjected to flash column chromatography using 10% ethyl acetate/hexane as solvent to give a colorless oil (260 mg, 64% yield).
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[Si:19]([O:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][C:28]=1[CH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].CCCCCC>CCOCC.CCOC(C)=O>[Si:19]([O:26][C:27]1[CH:34]=[CH:33][C:30](/[CH:31]=[CH:9]/[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[CH:29][C:28]=1[CH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)([C:22]([CH3:24])([CH3:25])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1C1CCCC1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)/C=C/c1ccc(O[Si](C)(C)C(C)(C)C)c(C2CCCC2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 100 mL 3-necked flask equipped with a magnetic stirrer, a nitrogen inlet and a reflux condenser were added 1.57 g of tert-butyl diethylphosphonoacetate (Aldrich) and 20 mL of anhydrous ethyl ether. This was followed by addition of 0.40 g of 60% NaH mineral oil dispersion. The resulting cloudy solution was heated at reflux for 25 min, cooled to 0° C. and treated with a solution of 1.52 g of 4((tert-butyldimethylsilyl)oxy)-3-cyclopentylbenzaldehyde in 10 mL of ether. A thick yellow gel resulted which was broken up with a spatula. The mixture was allowed to warm to RT and stirring was continued for an additional 1 h Analysis by tic (SiO2, 95:5 hexane:EtOAc) indicated a major new component at Rf=0.48 and minor components at Rf=0.06, 0.41 and 0.98. The mixture was diluted with 70 mL of ether, washed with saturated brine, and dried over anhydrous MgSO4. The drying agent was removed by filtration and the filtrate concentrated to give a yellow oil. This material was purified by flash chromatography on silica gel (97:3 hexaneEtOAc) to afford 1.53 g (77%) of tert-butyl trans-4-((tert-butyldimethylsilyl)oxy)-3-cyclopentylcinramate as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1.C(O[CH:14](OCC)[CH2:15][NH2:16])C.[C:20]([S-:22])#[N:21].[K+].Cl>C(O)C.[Pd].O.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][N:16]2[CH:15]=[CH:14][N:21]=[C:20]2[SH:22])=[CH:7][CH:8]=1
Reactant: CCOC(CN)OCC
Reactant: N#C[S-]
Reactant: COc1ccc(C=O)cc1
Agent: [Pd]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CO
Product: COc1ccc(Cn2ccnc2S)cc1
Reaction time: 0.75 h

Procedure:
A mixture of 13.6 g (0.1 mole) of anisaldehyde, 3.3 g (0.1 mole) of aminoacetaldehyde diethyl acetal and ml of CH3OH was heated at 95° for 10 minutes. A residue was dissolved in 150 ml of ethanol and hydrogenated over 10% Pd on carbon at 50 psi (0.34 MPa) until H2 uptake was complete. The catalyst was filtered and the filtrate was treated with 10.4 g (0.107 mole) of KSCN, 0 ml of 3N HCl and 40 ml of H2O. The mixture was refluxed, letting the solvent evaporate until the volume of the reaction mixture was 100 ml. After 45 minutes, the mixture was cooled, and a solid was filtered, washed with H2O and dried. Recrystallization from ethanol gave (1-(4-methoxybenzyl)-2-mercaptoimidazole, 15.0 g (68%), mp 140-142°.
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH:18](Br)[CH3:19].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH:1]([N:14]1[CH2:19][CH2:18][CH:17]1[CH3:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: CC(Br)CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC1CCN1C(c1ccccc1)c1ccccc1

Procedure:
Combine benzhydrylamine (27.5 g=0.15 ml), 1,3-dibromobutane (40.5 g=0.19 mol) and sodium carbonate (28 g=0.33 mol) in 250 ml acetonitrile. Reflux 24 hours, allow to cool, filter and concentrate. Dissolve the residue in ether and wash with 1% sodium carbonate solution. Dry, concentrate and distill to obtain the product, boiling point 110°-115° C./0.1 mm pressure.
Reaction SMILES: ClC(OCC)=O.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[CH2:16][C@H:15]2[C:17]([OH:19])=O)=[CH:10][CH:9]=1.CCN(CC)CC.[N-:27]=[N+:28]=[N-:29].[Na+]>CC(C)=O.O>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[CH2:16][C@H:15]2[C:17]([N:27]=[N+:28]=[N-:29])=[O:19])=[CH:10][CH:9]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc(Br)cc1
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)[C@@H]1C[C@H]1c1ccc(Br)cc1
Reaction time: 1 h
Yield: 91.1 %

Procedure:
Ethyl chloroformate (1.9 mL) was added to a solution of (trans)-2-(4-bromophenyl) cyclopropanecarboxylic acid (Intermediate J, 4 g, 0.0165 mol) and Et3N (2.51 mL, 0.0199 mol) in acetone (60 mL) at −20° C., stirred at same temperature for 1 h, then a solution of NaN3 (1.3 g, 0.0199 mol) in water (5 mL), was added and stirred for 30 mins at rt. After completion of reaction, checked by TLC, the solvent was evaporated and crude residue was dissolved in ethyl acetate (100 mL), washed with water (40 mL), dried over anhydrous Na2SO4, filtered and evaporated to get (trans)-2-(4-bromophenyl)cyclopropanecarbonyl azide (4 g). The crude residue is carried to next step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([NH:12][C:13]([C:15]1[CH:16]=[N:17][C:18]([O:21][CH2:22][C:23]2[C:24]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:25][O:26][C:27]=2[CH3:28])=[CH:19][CH:20]=1)=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[OH-].[Li+].Cl>C1COCC1.CO.O>[CH3:28][C:27]1[O:26][N:25]=[C:24]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]=1[CH2:22][O:21][C:18]1[N:17]=[CH:16][C:15]([C:13]([NH:12][C@@H:4]([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([OH:35])=[O:2])=[O:14])=[CH:20][CH:19]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N[C@@H](Cc2ccccc2)C(=O)O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
To a suspension of (S)-2-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-3-phenyl-propionic acid methyl ester (100 mg, 0.21 mmol) in THF (1 mL) and methanol (0.29 mL) was added a solution of lithium hydroxide monohydrate (25.4 mg, 1.0 mmol) in water (0.74 mL) added and the resulting mixture stirred at room temperature for 2 h. The mixture was acidified to pH 4 with HCl (1 N, 30 mL) and the resulting mixture extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated to afford the title compound (92 mg, 95%) which was obtained as a white solid. MS: m/e=470.1 [M−H]−.