Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]3[N:30]=[C:31]4[C:36](=[C:37]5[C:42]=3[CH:41]=[CH:40][CH:39]=[CH:38]5)[CH:35]=[CH:34][CH:33]=[CH:32]4)[CH2:27][C@H:21]2[C:20](=[O:43])[NH:19][C@:18]2([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:44][C@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:50].O1CCOCC1>C(OCC)(=O)C>[NH2:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]3[N:30]=[C:31]4[C:36](=[C:37]5[C:42]=3[CH:41]=[CH:40][CH:39]=[CH:38]5)[CH:35]=[CH:34][CH:33]=[CH:32]4)[CH2:27][C@H:21]2[C:20](=[O:43])[NH:19][C@:18]2([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:44][C@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[ClH:50]
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3nc4ccccc4c4ccccc34)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](N)C(=O)N1C[C@H](Oc3nc4ccccc4c4ccccc34)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3nc4ccccc4c4ccccc34)C[C@H]1C(=O)N2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](N)C(=O)N1C[C@H](Oc3nc4ccccc4c4ccccc34)C[C@H]1C(=O)N2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (2R,6S,13aS,14aR,16aS,Z)-ethyl 6-(tert-butoxycarbonylamino)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (Example 18a, 6.25 g, 9.32 mmol) dissolved in Ethyl acetate (50 ml) was added 4 N hydrogen chloride in dioxane (44.3 ml, 177 mmol) and the reaction mixture was stirred at rt for 6 h. The solvent was evaporated under reduced pressure to give a white solid which was rinsed with ethyl acetate. The filtered solid was dried to give (2R,6S,13aS,14aR,16aS,Z)-ethyl 6-amino-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxylate, Hydrochloric Acid (5.52 g, 98% yield)
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].[N:21]1[NH:22][C:23](=[O:27])[CH:24]=[CH:25][CH:26]=1.O>CN(C=O)C>[O:27]=[C:23]1[N:22]([CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[N:21]=[CH:26][CH:25]=[CH:24]1
Reactant: CC(C)(C)OC(=O)N1CCC(Br)CC1
Reactant: O=c1cccn[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncccc2=O)CC1
Temperature: 45 °C
Yield: 17 %

Procedure:
tert-Butyl 4-bromo-1-piperidinecarboxylate (1.00 g, 3.78 mmol) in DMF (20 mL) was treated with K2CO3 (523 mg, 3.78 mmol) and 3(2H)-pyridazinone (340 mg, 3.78 mmol) and then heated at 45° C. for 60 hours. The reaction mixture was allowed to cool to room temperature, poured into water (80 mL) and extracted with ethyl acetate (80 mL). The organic layer was washed with brine (3×50 mL), dried over MgSO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (elution with hexanes:ethyl acetate, 3:1) to provide the title compound (180 mg, 17% yield). 1H NMR (300 MHz, DMSO-d6) δ 1.41 (s, 9H), 1.66 (m, 4H), 2.91 (m, 2H), 4.05 (m, 2H), 4.96 (m, 1H), 6.93 (dd, 1H, J=1.5, 9.0 Hz), 7.39 (dd, 1H, J=3.0, 9.0 Hz), 7.95 (dd, 1H, J=3.0, 9.0 Hz); (MS (DCI/NH3) m/e 280 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:25](Cl)(Cl)=[S:26]>O1CCCC1>[N:1]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[N:9]=2)=[CH:4][CH:3]=1)=[C:25]=[S:26]
Reactant: Nc1ccc(-c2nc(-c3cccs3)no2)cc1
Reactant: S=C(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: S=C=Nc1ccc(-c2nc(-c3cccs3)no2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.1 %

Procedure:
To a solution of 1.2 g (0.005 mole) of 5-(4-aminophenyl)-3-(2-thienyl)-1,2,4-oxadiazole in 150 ml of dry tetrahydrofuran containing 0.49 g of triethylamine, 0.56 g (0.005 mole) of thiophosgene is added and the mixture stirred at room temperature for 3 hours. After filtration, the solution is evaporated in vacuo to give the crude product. It is crystallized from petroleum ether to give 0.7 g (50%) of the title compound, m.p. 161°-162°.
Reaction SMILES: [OH-].[K+].C[O:4][C:5]([C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][CH2:12][N:13]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[C:9]([O:23][CH3:24])[CH:8]=1)=[O:6].CO>O1CCCC1>[C:19]([O:18][C:16]([N:13]1[C:14]2[C:10](=[C:9]([O:23][CH3:24])[CH:8]=[C:7]([C:5]([OH:6])=[O:4])[CH:15]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COC(=O)c1cc(OC)c2c(c1)N(C(=O)OC(C)(C)C)CC2
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(=O)O)cc2c1CCN2C(=O)OC(C)(C)C
Yield: 88 %

Procedure:
A 3 N aqueous KOH solution (6.5 mL, 19.5 mmol, 3 equiv.) was added to a solution of 4-methoxy-2,3-dihydro-indole-1,6-dicarboxylic acid 1-tert-butyl ester 6-methyl ester (2 g, 6.5 mmol, 1 equiv.) in a 1:4 MeOH:tetrahydrofuran solution (20 mL) and the mixture was shaken for 16 hours. The methanol was removed under vacuum and the pH was adjusted to 3 with 3 N aqueous HCl solution. The resulting slurry was diluted with ethyl acetate (20 mL), the organic layer was separated and the aqueous phase was extracted with EtOAc (2×20 mL). The organic layers were combined, dried over Na2SO4 and the solvent was removed under vacuum to afford 4-methoxy-2,3-dihydro-indole-1,6-dicarboxylic acid 1-tert-butyl ester, 1.68 g (88% yield). LC @215 nm; Rt 1.44: 83%, m/z (ES+): 238 (M-Boc+MeCN+H+.); δH (400 MHz; d6-DMSO) 12.58 (1H, br.s) 7.97 (1H, br.s), 6.94 (1H, d), 3.70 (2H, t), 3.61 (3H, s), 2.75 (2H, t), 1.28 (9H, s).
Reaction SMILES: C[S:2][C:3](=S)[NH:4][N:5]=[CH:6][C:7]1[N:8]=[C:9]([CH2:13][CH2:14][CH3:15])[NH:10][C:11]=1[CH3:12].C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:12][C:11]1[N:10]=[C:9]([CH2:13][CH2:14][CH3:15])[N:8]2[C:7]=1[CH:6]=[N:5][NH:4][C:3]2=[S:2]
Reactant: CCCc1nc(C=NNC(=S)SC)c(C)[nH]1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCc1nc(C)c2cn[nH]c(=S)n12

Procedure:
A mixture of 32.12 gm. of 3-[(5-methyl-2-n-propyl-4-imidazolyl)methylene]dithiocarbazic acid methyl ester and 200 ml. of diphenyl ether is reacted as described in Example 58 giving the desired product, m.p. 183°-186° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([C:22]3[N:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[CH:24][N:23]=3)=[O:21])[CH:16]([CH2:34][CH3:35])[CH2:15]1)(=[O:13])=[O:12])=[CH:5]2.ClC1C=CC=C(C(OO)=[O:44])C=1.S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(O)C.C(OCC)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([C:22]3[N:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N+:29]=4[O-:44])=[CH:24][N:23]=3)=[O:21])[CH:16]([CH2:34][CH3:35])[CH2:15]1)(=[O:13])=[O:12])=[CH:5]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCC1CN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CCN1C(=O)c1ncc(-c2ccccn2)cn1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: CCOCC
Product: CCC1CN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CCN1C(=O)c1ncc(-c2cccc[n+]2[O-])cn1
Reaction time: 5 h
Yield: 18.3 %

Procedure:
To a methylene chloride solution (50 ml) of 4-[(5-chloroindol-2-yl)sulfonyl]-2-(ethyl)-1-[(5-(pyridin-2-yl)pyrimidin-2-yl]carbonyl]piperazine (234 mg) was added metachloroperbenzoic acid (1.58 g) at room temperature. The resulting mixture was stirred for 5 hours. An aqueous solution (20 ml) of sodium sulfite was added, followed by stirring for 1 hour. To the reaction mixture were added a saturated aqueous solution of sodium bicarbonate and methylene chloride. The water layer was extracted thrice with methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was subjected to chromatography on a silica gel column (methanol:methylene chloride=1:50). The oil thus obtained was solidified from ethanol-diethyl ether, whereby the title compound (44.1 mg) was obtained as a pale yellow solid. MS (FAB) m/z: 527 [(M+H)+, Cl35], 529 [(M+H)+, Cl37].
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH2:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:19])[C:13]3[NH:20][CH:21]=[CH:22][C:12]=3[C:11]=2[CH:10]=1)=O.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24].C(N(CC)CC)C>C(O)C>[NH2:1][C:2]1[S:3][CH:6]=[C:7]([C:9]2[CH:18]=[CH:17][C:16]3[NH:15][C:14](=[O:19])[C:13]4[NH:20][CH:21]=[CH:22][C:12]=4[C:11]=3[CH:10]=2)[N:4]=1.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24]
Reactant: O=C(CBr)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Reactant: NC(N)=S
Agent: CCC(=O)[O-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1nc(-c2ccc3[nH]c(=O)c4[nH]ccc4c3c2)cs1
Temperature: 90 °C
Reaction time: 3 h
Yield: 16.9 %

Procedure:
17 mg (1.5 mmol) of thiourea is added to a suspension of 57 mg (0.15 mmol) of 8-(2-bromo-acetyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 3 mL of ethanol. The mixture is stirred at 90° C. for 3 hours then the mixture is cooled to room temperature. Triethylamine (2 mmol) is added then the solvent is evaporated and the product is purified by chromatography on silica (chloroform/methanol/triethylamine 8/2/1). After drying, 9 mg (17%) of 8-(2-amino-thiazol-4-yl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a beige solid.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][N:13]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:14](=[O:25])[CH2:15][CH2:16][N:17]=[CH:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>CO.[Pd]>[C:1]12([CH2:11][CH2:12][N:13]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:14](=[O:25])[CH2:15][CH2:16][NH:17][CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: CCCCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)CCN=Cc1ccncc1
Agent: [Pd]
Solvent: CO
Product: CCCCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)CCNCc1ccncc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 36.1 %

Procedure:
3-(4-Pyridylmethylideneamino)propionic acid N-[2-(1-adamantyl)ethyl]-N-pentylamide (Compound No. 21-1) (1.6 g, 3.9 mmol) was dissolved in methanol, 10% palladium on carbon (catalytic amount) was added to the solution, and the mixture was stirred under hydrogen at 1 atm and room temperature for seven hours. The 10% palladium on carbon was filtered out, the filtrate was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography to give 0.58 g (36%) of the titled compound as an oily matter.
Reaction SMILES: [OH:1][CH:2]1[CH2:9][CH2:8][CH:7]2[CH:3]1[CH2:4][CH2:5][CH2:6]2.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH:7]12[CH2:8][CH2:9][C:2](=[O:1])[CH:3]1[CH2:4][CH2:5][CH2:6]2
Reactant: OC1CCC2CCCC12
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C1CCC2CCCC12
Reaction time: 3.5 h

Procedure:
A stirred solution of crude (E)-2-[(mixture of 3α and 3β)-tert-butyldimethylsilyloxy-3-cyclohexylprop-1-enyl]-6-hydroxybicyclo[3,3,0]octane (0.36 g; prepared as described in Reference Example 32 and predominantly in the 2β-configuration) in dichloromethane (15 ml) was treated with pyridinium chlorochromate (0.42 g) at 20° C. under an argon atmosphere and stirred for a further period of 3.5 hours. The mixture was then treated with silica gel (2 g) and carefully concentrated in vacuo. The resulting powder was placed onto a column of silica gel and eluted with a mixture of ethyl acetate and hexane (1:4 v/v), to give (E)-2-[(mixture of 3α and 3β)-tert-butyldimethylsilyloxy-3-cyclohexylprop-1-enyl]bicyclo[3,3,0]octan-6-one (0.22 g), predominantly in the 2β-configuration.
Reaction SMILES: C1COCC1.[Cl:6][C:7]1[C:11]([Cl:12])=[C:10]([CH3:13])[NH:9][C:8]=1[C:14]([NH:16][C@H:17]1[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C@H:18]1[C:30]([O:32]C)=[O:31])=[O:15].[OH-].[Li+].Cl>O.O1CCOCC1.CO>[ClH:6].[Cl:6][C:7]1[C:11]([Cl:12])=[C:10]([CH3:13])[NH:9][C:8]=1[C:14]([NH:16][C@H:17]1[CH2:22][CH2:21][NH:20][CH2:19][C@H:18]1[C:30]([OH:32])=[O:31])=[O:15]
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: O
Product: Cc1[nH]c(C(=O)N[C@H]2CCNC[C@H]2C(=O)O)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
THF (10 ml) and MeOH (8 ml) were added to cis(±)1-tert-butyl 3-methyl 4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidine-1,3-dicarboxylate (Intermediate 46; 2.24 g). The resultant mixture was cooled to 0° C., and a solution of lithium hydroxide (0.37 g) in water (5 ml) at 0° C. was added dropwise via pipette, producing a clear, lightly yellow solution. The reaction was stirred at 0° C. for 2 h, stored overnight in a freezer without stirring, then stirred again at 0° C. for six hours. The reaction was acidified to pH 3 with 2N HCl 9-7 ml), and was concentrated in vacuo. The resultant mixture was dissolved in EtOAc (125 ml) and a saturated aqueous sodium chloride solution (40 ml), followed by the addition of 2N HCl (˜1 ml) to acidify the aqueous layer to pH 1. The phases were separated and the aqueous layer was washed with EtOAc (2×60 ml). The combined EtOAc layers were dried over anhydrous MgSO4 and concentrated in vacuo. The resultant white solid was suspended in anhydrous THF (35 ml) under an argon atmosphere, cooled to 0° C., followed by the addition of 4 M HCl in 1,4-dioxane (10 ml, 40 mmol). The reaction was warmed to room temperature, producing a clear orange-red solution. The reaction was stirred overnight at room temperature, followed by the addition of 5 ml of 4 M HCl in 1,4-dioxane. The reaction was stirred for two days at room temperature, then heated to 50° C. for two hours, and allowed to slowly cool to room temperature overnight. The reaction was concentrated in vacuo, and carried on to the next reaction without further purification (5.16 mmol). MS (ES)(M+H)): 320, 322 for C12H15Cl2N3O3.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]1[C:14]([N:15]=O)=[C:13]([CH3:17])[N:12]=[C:7]12.C(O)(=O)C>O.[Zn]>[NH2:15][C:14]1[N:6]2[CH:5]=[CH:4][C:3]3[C:8]([C:7]2=[N:12][C:13]=1[CH3:17])=[CH:9][CH:10]=[CH:11][C:2]=3[Cl:1]
Reactant: Cc1nc2c3cccc(Cl)c3ccn2c1N=O
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc2c3cccc(Cl)c3ccn2c1N
Yield: 80.6 %

Procedure:
Zinc powder (10.2 g) was added portionwise to a mixture of 7-chloro-2-methyl-3-nitrosoimidazo[2,1-a]isoquinoline (7.7 g) and acetic acid (100 ml) in water (77 ml) over a period of 7 hours and then the mixture was filtered by suction. The filtrate was evaporated in vacuo and the residue was extracted with chloroform after an addition of aqueous sodium bicarbonte to it. The extract was washed with water and evaporated in vacuo. The residual solid was washed with ethyl acetate and dried in a desiccator to give 3-amino-7-chloro-2-methylimidazo[2,1-a]isoquinoline (5.85 g).
Reaction SMILES: C[O:2][C:3](=[O:32])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:31])[N:25]([CH3:30])[CH:26]=[C:27]([Cl:29])[CH:28]=2)=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[O:7].O.[OH-].[Li+].C(OCC)(=O)C>C1COCC1.O>[Cl:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:8]=1[C:6]([NH:5][C@H:4]([C:3]([OH:32])=[O:2])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:31])[N:25]([CH3:30])[CH:26]=[C:27]([Cl:29])[CH:28]=2)=[CH:19][CH:18]=1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(-c2cc(Cl)cn(C)c2=O)cc1)NC(=O)c1c(C)cccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cccc(Cl)c1C(=O)N[C@@H](Cc1ccc(-c2cc(Cl)cn(C)c2=O)cc1)C(=O)O
Reaction time: 1 h
Yield: 80.6 %

Procedure:
A solution of N-[(2-chloro-6-methylphenyl)carbonyl]-4-(5-chloro-1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester (51 mg, 0.108 mmol) in THF (3 mL) was treated with a solution of lithium hydroxide monohydrate (18 mg, 0.43 mmol) in water (1.0 mL). Additional THF was added to effect a clear solution and the reaction mixture was stirred 1 hr. TLC (ethyl acetate) indicated starting material was consumed. A few drops of acetic were added and the entire reaction mixture was applied to a 4×30 cm, C-18 reversed phase HPLC column and eluted with a linear gradient of acetonitrile in water of 5 to 95% over 35 min. The product containing fraction was lyophillyzed to give N-[(2-chloro-6-methylphenyl)carbonyl]-4-(5-chloro-1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine (40 mg, 82%) as a white solid. LR-Electrospray: m/z positive ion, 481(M+Na), 459(M+H (2 Cl)); negative ion, 457 (M−H (2 Cl)).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][N:3]=1.[CH3:8][O:9][C:10]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[CH:13][C:11]=1[NH2:12]>>[CH3:8][O:9][C:10]1[CH:16]=[C:15]([C:2]2[N:6]([CH3:7])[N:5]=[CH:4][N:3]=2)[CH:14]=[CH:13][C:11]=1[NH2:12]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Reactant: Cn1ncnc1Br
Product: COc1cc(-c2ncnn2C)ccc1N

Procedure:
The title compound was prepared according to the method described for Preparation 158 using 5-bromo-1-methyl-1H-1,2,4-triazole and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. The residue was purified using Biotage silica gel column chromatography eluting with EtOAc.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:24]=3)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]3[N:40]=[CH:41][CH:42]=[C:16]23)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:43][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C(#N)C>[Si:1]([O:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]4[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:27][CH:28]=3)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]3[N:40]=[CH:41][C:42]([F:43])=[C:16]23)[CH2:13][CH2:14]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: F[B-](F)(F)F
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)CC2)c2ccnn12
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)CC2)c2c(F)cnn12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 4′-{[4-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1.76 g) in acetonitrile (15 mL) was added 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (1.1 g), and the mixture was stirred at 80° C. for 3 hr. To the reaction mixture were added ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.24 g, 13%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([CH3:8])[CH:7]=1.[Mg].II.[Br:14][C:15]1[CH:16]=[C:17]([C:22](=[O:24])[CH3:23])[CH:18]=[CH:19][C:20]=1[Cl:21]>O1CCCC1>[Br:14][C:15]1[CH:16]=[C:17]([C:22]([C:2]2[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([CH3:8])[CH:7]=2)([OH:24])[CH3:23])[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: COc1ccc(Br)cc1C
Reactant: CC(=O)c1ccc(Cl)c(Br)c1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(C(C)(O)c2ccc(Cl)c(Br)c2)cc1C
Temperature: 25 °C
Yield: 62.8 %

Procedure:
5-Bromo-2-methoxytoluene (6.4 g, 0.032 mol) was dissolved in tetrahydrofuran (100 mL) and 5 mL of the solution was added to a stirred mixture of magnesium turnings (0.90 g, 0.037 mol) and iodine (a catalytic amount) in tetrahydrofuran (10 mL). The mixture was heated to vigorous reflux until some of the iodine colour was lost. The flask was removed from the heat and the remainder of the bromide was added so as to maintain a gentle reflux. The flask was then returned to the heat and stirred at reflux for 2 hours. The flask was removed from the heat and a solution of 1-(3-bromo-4-chlorophenyl)-ethanone (7.1 g, 0.030 mol) in tetrahydrofuran (100 mL) was added so as to maintain a gentle reflux. The reaction mixture was returned to the heat and stirred at reflux for 3 hours then cooled to room temperature and poured into ice-water (300 mL). The mixture was stirred for 5 minutes then concentrated to remove tetrahydrofuran. The aqueous residue was diluted with aqueous ammonium chloride (100 mL), extracted with ethyl acetate (3 200 mL) and the combined organic extracts were washed with water (100 mL) and brine (100 mL), dried (sodium sulfate) and concentrated to give the crude product as a red oil which was purified by flash chromatography (5 to 10% ethyl acetate/hexane) to give the desired alcohol as a bright yellow oil (6.7 g, 71%). 1H NMR (300 MHz; CDCl3) 7.72 (1H, d, J 2.1, Ar), 7.35 (1H, d, 8.5, Ar), 7.23-7.13 (3H, m, Ar), 6.76 (1H, d, J 8.5, Ar), 3.82 (3H, s, OMe), 2.19 (3H, s, Me), 2.11 (1H, s, OH), 1.88 (3H, s, Me).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:24])[CH:13]([CH2:19][C:20]([O:22]C)=[O:21])[CH2:14][S:15][C:16](=[O:18])[CH3:17])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O>[C:1]([O:5][C:6](=[O:25])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:24])[CH:13]([CH2:19][C:20]([OH:22])=[O:21])[CH2:14][S:15][C:16](=[O:18])[CH3:17])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)CC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)SCC(CC(=O)O)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
To a solution of 1-[3-(acetylthio)-2-methoxycarbonylmethylpropanoyl]-L-proline tert-butyl ester (3.7 g) in methanol (60 ml), N sodium hydroxide (40 ml) is added. After four hours, the reaction mixture is diluted with water (100 ml) and extracted with ethyl acetate. The aqueous layer is acidified and extracted with ethyl acetate. This last ethyl acetate layer is dried and concentrated to dryness in vacuo. The residue is dissolved in a mixture of pyridine and acetic anhydride (3:1) and the solution is stored at room temperature overnight. The reaction mixture is diluted with ethyl acetate (200 ml) and washed with 10% potassium bisulfate. The organic layer is dried and concentrated to dryness in vacuo to yield 1-[3-(acetylthio)-2-carboxymethylpropanoyl]-L-proline tert-butyl ester.
Reaction SMILES: Cl.[OH:2][C@H:3]([C:15]1[CH:24]=[CH:23][C:18]2[C:19](=[O:22])[O:20][CH2:21][C:17]=2[C:16]=1[CH3:25])[CH2:4][NH:5][C:6]1([CH:10]2[CH2:14][CH2:13][NH:12][CH2:11]2)[CH2:9][CH2:8][CH2:7]1.[CH3:26][C:27]1[C:35]2[CH2:34][O:33][C:32](=[O:36])[C:31]=2[CH:30]=[CH:29][C:28]=1[C@@H:37]1[CH2:39][O:38]1>>[OH:38][C@H:37]([C:28]1[CH:29]=[CH:30][C:31]2[C:32](=[O:36])[O:33][CH2:34][C:35]=2[C:27]=1[CH3:26])[CH2:39][N:12]1[CH2:13][CH2:14][CH:10]([C:6]2([NH:5][CH2:4][C@H:3]([OH:2])[C:15]3[CH:24]=[CH:23][C:18]4[C:19](=[O:22])[O:20][CH2:21][C:17]=4[C:16]=3[CH3:25])[CH2:9][CH2:8][CH2:7]2)[CH2:11]1
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Reactant: Cc1c([C@@H](O)CNC2(C3CCNC3)CCC2)ccc2c1COC2=O
Agent: Cl
Product: Cc1c([C@@H](O)CNC2(C3CCN(C[C@H](O)c4ccc5c(c4C)COC5=O)C3)CCC2)ccc2c1COC2=O

Procedure:
5-{(1R)-1-Hydroxy-2-[3-(1-{[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]amino}cyclobutyl)pyrrolidin-1-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one was prepared in a similar fashion to that described for the synthesis of EXAMPLE 1 starting from 5-[(1R)-1-hydroxy-2-{[1-(pyrrolidin-3-yl)cyclobutyl]amino}ethyl]-4-methyl-2-benzofuran-1(3H)-one hydrochloride [INTERMEDIATE 5] and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one [INTERMEDIATE 2B].