Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]=1[N+:16]([O-])=O)(O)=[O:2].[H][H].O>C(O)(=O)C.[C].[Pd]>[O:2]=[C:1]1[CH2:4][C:5]2[C:6](=[CH:7][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][CH:15]=2)[NH:16]1
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(CC(=O)O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)NC(=O)C2

Procedure:
4 g (15.8 mmol) of the thus obtained ethyl 4-(carboxymethyl)-3-nitrobenzoate and 0.45 g of 10% palladium-carbon were suspended in 15 mL of acetic acid, and the resulting mixture was stirred at room temperature in a hydrogen gas atmosphere for 23 hours. After completion of the reaction, water was added to the reaction mixture and the mixture was filtered to remove insoluble matter, and the filtrate was subjected to extraction with chloroform. The obtained chloroform layer was evaporated to dryness under reduced pressure, and water was added to the residue. Precipitated ethyl 2-oxoindoline-6-carboxylate was then obtained by filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15](=O)[CH3:16])=[N:9]2)=[CH:4][CH:3]=1.C(OP([CH2:26]/[C:27](=[N:32]\[O:33][CH3:34])/[C:28]([O:30][CH3:31])=[O:29])(OCC)=O)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][C:10]([O:13][CH2:14]/[C:15](/[CH3:16])=[CH:26]\[C:27](=[N:32]/[O:33][CH3:34])\[C:28]([O:30][CH3:31])=[O:29])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(=O)COc1ccn(-c2ccc(Cl)cc2)n1
Reactant: CCOP(=O)(C/C(=N\OC)C(=O)OC)OCC
Solvent: C1CCOC1
Product: CO/N=C(\C=C(\C)COc1ccn(-c2ccc(Cl)cc2)n1)C(=O)OC

Procedure:
To 5.26 g (21.0 mmol) 1-[1-(4-chlorophenyl)pyrazol-3-yl]oxypropan-2-one and 7.20 g (26.9 mmol) methyl (2Z)-3-diethoxyphosphoryl-2-methoxyimino-propanoate (which can be prepared as described for the dimethoxy derivative [(Tetrahedron Let 29, 3361-3364 (1988)] in 100 ml THF have been added at ambient temperature with stirring 2.59 g (23.1 mmol) potassium tert.-butylate. Stirring was continued over night. After removal of the solvent in vacuo the mixture was purified by chromatography on silica with heptane/ethyl acetate. 1.07 g of a 80:20 E:Z-mixture have been collected. This has been used directly for the next step.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.C(N(CC)CC)C.Cl.Cl[CH2:17][C:18]([NH2:20])=[NH:19]>CN(C=O)C>[C:18]([CH2:17][S:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1)(=[NH:19])[NH2:20]
Reactant: Sc1nnc(S)s1
Reactant: N=C(N)CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N=C(N)CSc1nnc(S)s1
Yield: 36.7 %

Procedure:
To a solution of 1.50 g of 2,5-dimercapto-1,3,4-thiadiazole and 4.2 ml of triethylamine in 30 ml of DMF was added 1.29 g of α-chloroacetamidine hydrochloride at room temperature under stirring. Further, the mixture was stirred for 2.5 hours at room temperature and concentrated under reduced pressure. The residue was subjected to a column chromatography on silica gel (100 g), eluting with a (4:1) mixture of acetonitrile and water. The pertinent fractions were collected and concentrated under reduced pressure, and the concentrate was subjected to a column chromatography on XAD-II (450 ml) being washed with water, and eluted with 10% aqueous ethanol. After concentrating, the precipitating crystals were filtered to give 755mg of 2-amidinomethylthio-5-mercapto-1,3,4-thiadiazole as colorless crystals, mp: 184°-187° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([C:18]([F:21])([F:20])[F:19])[C@H:14]1[CH2:13][S:12][C:11]([NH2:22])=[N:10]2.S(=O)(=O)(O)O.[N+:28]([O-])([OH:30])=[O:29].[OH-].[Na+]>C(O)(C(F)(F)F)=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:28]([O-:30])=[O:29])=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([C:18]([F:19])([F:21])[F:20])[C@H:14]1[CH2:13][S:12][C:11]([NH2:22])=[N:10]2
Reactant: O=[N+]([O-])O
Reactant: NC1=N[C@@]2(c3cccc(F)c3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@@]2(c3cc([N+](=O)[O-])cc(F)c3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(4aS,5S,7aS)-7a-(2,3-Difluorophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine (1.42 g) was dissolved in TFA (6 mL), and the solution was cooled to 0° C. Sulfuric acid (conc., 1 mL) was added, followed by fuming nitric acid (0.30 mL) dropwise over 20 mins. After stirring at 0° C. for 1 h, the reaction mixture was poured onto ice (50 g) and basified to pH 12 with 2 N NaOH (aq.). After allowing the ice to melt, the mixture was extracted with EtOAc (3×75 mL), and the combined organic portions dried over MgSO4 and evaporated to afford the title compound (1.91 g, purity approx. 80%) which was used in the subsequent step without purification. 1H NMR (400 MHz, CDCl3) δ ppm 2.88 (dd, J=13.8, 3.9 Hz, 1H), 3.11 (dd, J=13.6, 2.8 Hz, 1H), 3.37 (dt, J=7.4, 3.5 Hz, 1H), 3.93 (d, J=7.8 Hz, 1H), 4.53-4.83 (m, 4H), 8.09 (ddd, J=9.0, 6.3, 2.9 Hz, 1H), 8.27 (dt, J=5.2, 2.6 Hz, 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]2([C:33]3[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:32]=3[O:31][CH2:30]2)[CH2:26][CH2:25]1)=[O:23].[CH2:39]([S:41]([NH2:44])(=[O:43])=[O:42])[CH3:40]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:44][S:41]([CH2:39][CH3:40])(=[O:43])=[O:42])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]2([C:33]3[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:32]=3[O:31][CH2:30]2)[CH2:26][CH2:25]1)=[O:23]
Reactant: Cc1ccc(Cl)c(Nc2c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc3c(C(=O)O)cnn23)c1
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3Cl)c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc12
Yield: 43.2 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-chloro-5-methylphenylamino)-6-(6-fluoro-2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.140 g, 0.262 mmol) obtained in step 2 and ethanesulfonamide (0.142 g, 1.31 mmol), the title compound (0.071 g, 43%) was obtained.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH:5]=[CH:4][N:3]=[CH:2]1.[N:19]1[C:27]2[C:22]3[C:23](=[CH:28][CH:29]=[CH:30][C:21]=3[C:20]=1S)[CH:24]=[CH:25][CH:26]=2>C(O)C>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:20]2[C:21]3[CH:30]=[CH:29][CH:28]=[C:23]4[C:22]=3[C:27](=[CH:26][CH:25]=[CH:24]4)[N:19]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NCCCCCCCCCCCCn1ccnc1
Reactant: SC1=Nc2cccc3cccc1c23
Solvent: CCO
Product: c1cc2c3c(cccc3c1)C(NCCCCCCCCCCCCn1ccnc1)=N2

Procedure:
A mixture of 2.5 g of 12-(1H-imidazol-l-yl)dodecanamine, 1.9 g of benz(cd)indole-2-thiol, 3.4 g of mercuric acetate and 400 ml of ethanol was reacted as described in Example 1. The crude product was purified by dissolved it in chloroform and chromatographing it on a silica gel column, eluting with 10% methanol in chloroform giving 490 mg of the desired product, mp 95° C.-97° C.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[CH:7].[C:10]([C:14]1([CH2:18]O)[CH2:17][O:16][CH2:15]1)([CH3:13])([CH3:12])[CH3:11].C(C(CO)(CO)CO)(C)(C)C>>[C:10]([C:14]12[CH2:15][O:16][C:1]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[CH:7])([O:9][CH2:18]1)[O:8][CH2:17]2)([CH3:13])([CH3:12])[CH3:11]
Reactant: C#CCCCCC(=O)O
Reactant: CC(C)(C)C1(CO)COC1
Agent: CC(C)(C)C(CO)(CO)CO
Product: C#CCCCCC12OCC(C(C)(C)C)(CO1)CO2

Procedure:
Using the procedure described in stage (vi) of Example I and starting from hept-6-ynoic acid and 3-t-butyl-3-hydroxymethyloxetane (2-t-butyl-2-hydroxymethylpropan-1,3-diol was prepared by the method of Y. Ozoe and M. Eto Agric. Biol. Chem. 1982, 46, 411), 4-t-butyl-1-(hex-5-ynyl)-2,6,7-trioxabicyclo[2.2.2]octane was prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[CH3:14][C:15]([OH:24])([CH3:23])[CH2:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:20]1[CH2:21][CH2:22][CH:17]([CH2:16][C:15]([CH3:23])([OH:24])[CH3:14])[CH2:18][CH2:19]1)=[O:13])=[CH:5]2
Reactant: CC(C)(O)CC1CCNCC1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(O)CC1CCN(C(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.3 %

Procedure:
To a solution of 370 mg of 5-chloroindole-2-carboxylic acid and 300 mg of 2-methyl-1-(piperidin-4-yl)-2-propanol in 8 mL of DMF were added 360 mg of 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride and 250 mg of 1-hydroxybenzotriazole, followed by stirring at room temperature for 1 day. 0.5M aqueous hydrochloric acid was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with 0.5 M aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform:methanol=1:0-10:1], and then crystallized from diisopropyl ether to obtain 268 mg of 1-{1-[(5-chloro-1H-indol-2-yl)carbonyl]piperidin-4-yl}-2-methylpropan-2-ol as a white crystal.
Reaction SMILES: O(C([N:10]1[CH2:15][CH2:14][C:13]([C:26]#[CH:27])([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N+:23]([O-:25])=[O:24])[CH2:12][CH2:11]1)=O)C1C=CC=CC=1.CO.[OH-].[Na+].[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]\[C:35]([OH:37])=[O:36]>O>[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]\[C:35]([OH:37])=[O:36].[C:26]([C:13]1([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N+:23]([O-:25])=[O:24])[CH2:14][CH2:15][NH:10][CH2:11][CH2:12]1)#[CH:27]
Reactant: C#CC1(Oc2ccccc2[N+](=O)[O-])CCN(C(=O)Oc2ccccc2)CC1
Agent: O=C(O)/C=C\C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C#CC1(Oc2ccccc2[N+](=O)[O-])CCNCC1
Temperature: 25 °C
Yield: 43 %

Procedure:
A suspension of 1.00 g of 1-phenoxycarbonyl-4-ethynyl-4-(2-nitrophenoxy)piperidine, 14 ml of methanol, and 6 ml of 15% sodium hydroxide solution was heated at reflux for 2.5 hrs under nitrogen and allowed to cool to room temperature. The mixture was poured into water, extracted twice with chloroform, washed with saturated sodium chloride solution and dried over anhydrous potassium carbonate. Evaporation of solvent provided an oil. Treatment of a solution of the oil which ethereal maleic acid provided 0.43 g (43%) of product, mp 155°-157°.
Reaction SMILES: C(O)C.[CH:4]1([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:14][C:13]=2[C:25]2[CH:30]=[C:29]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[CH:28]=[CH:27][C:26]=2[O:38][CH2:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[OH-].[Na+]>Cl>[CH:40]1([CH2:39][O:38][C:26]2[CH:27]=[CH:28][C:29]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:30][C:25]=2[C:13]2[CH:14]=[C:15]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: CCOC(=O)CCc1ccc(OCC2CCCCC2)c(-c2cc(CCC(=O)OCC)ccc2OCC2CCCCC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCc1ccc(OCC2CCCCC2)c(-c2cc(CCC(=O)O)ccc2OCC2CCCCC2)c1
Temperature: 25 °C
Yield: 96.9 %

Procedure:
To 3.6 ml of an ethanol solution containing 86.7 mg (0.1500 mmol) of 2,2'-dicyclohexylmethoxy-5,5'-bis(2-ethoxycarbonylethyl) biphenyl obtained in Reference Example 4, there was added 1.2 ml (1.2 mmol) of 1N sodium hydroxide solution and the mixture was agitated at room temperature. The solvent of the reaction mixture was evaporated off under reduced pressure and, to the resulting evaporated residue, water was added. The solution obtained was acidified adding IN hydrochloric acid to a pH of 1-2. The thus-formed precipitate was filtrated, washed with water and dried, whereby 75.9 mg (0.1454 mmol, 97%) of the title compound was obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].OS(O)(=O)=O>O>[C:12]([O:11][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:14])[CH3:13]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1ccc(Br)cc1C(=O)O
Yield: 88 %

Procedure:
To a well-stirred mixture of 5-bromosalicylic acid 29 (200 g, 0.92 mol) and acetic anhydride (210 mL) was added concentrated H2SO4 (0.5 mL). After a few minutes the reaction mixture solidified and was suspended in H2O (1 L). The solid was collected by filtration and washed with H2O. The white solid was dissolved in ethyl acetate (3 L), washed with brine, dried (Na2SO4) and concentrated to give 30 (210 g, 88% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:21])=[C:16]([F:20])[C:17]=3[Cl:19])[C:12](=[O:22])[C:11]([C:23]([O:25]CC)=[O:24])=[CH:10]2)[CH:5]=[N:6][C:7]=1[Cl:8].Cl>>[NH2:1][C:2]1[CH:3]=[C:4]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:21])=[C:16]([F:20])[C:17]=3[Cl:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]2)[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)c1cn(-c2cnc(Cl)c(N)c2)c2c(Cl)c(F)c(F)cc2c1=O
Agent: Cl
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)cnc1Cl
Yield: 92.2 %

Procedure:
To 100 mg of ethyl 1-(5-amino-6-chloropyridin-3-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate was added 3 ml of concentrated hydrochloric acid, and the mixture was heated under reflux for 2 hours. The reaction solution was allowed to cool, and the solid precipitated was collected by filtration. The solid was washed with ethanol to obtain 86 mg of the title compound as a pale yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:14][CH2:15]Cl)[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)[CH2:15][CH2:14][CH2:13][N:12]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:24]
Reactant: COC(=O)C(c1ccc(F)cc1)N(CCCCl)C(=O)OC(C)(C)C
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Product: COC(=O)C1(c2ccc(F)cc2)CCCN1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 20 h

Procedure:
To a solution of [tert-butoxycarbonyl-(3-chloro-propyl)-amino]-(4-fluoro-phenyl)-acetic acid methyl ester (10.91 g) in acetonitrile (60 mL) was added benzyltriethylammoniumchloride (3.32 g) (see also Chemistry of Heterocyclic Compound, 36, 2000, 416-420) followed by solid potassium carbonate (12.1 g, finely ground). The reaction mixture was stirred at 50° C. for 20 hours. A further 1.6 g of benzyltriethylammoniumchloride and 4 g of potassium carbonate was added to push the reaction to completion. The reaction mixture was filtered and the filtrate was reduced in vacuo. The residue was diluted with water and extracted with chloroform (3×50 mL). The combined organic phases were washed with brine and dried over sodium sulfate. Filtration and evaporation of the volatiles in vacuo afforded a crude residue which was purified using flash column chromatography (EtOAc/Heptane 2:8) on silica gel to afford the desired 2-(4-Fluoro-phenyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (4.25, MS (ES+): 324.3 (MH+)) as a pale yellow oil.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:11])[NH:6][C:7](=[O:10])[NH:8][CH:9]=1)([CH3:3])[CH3:2].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.Cl[CH2:25][O:26][CH2:27][CH3:28]>ClCCl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:27]([O:26][CH2:25][N:8]1[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:11])[NH:6][C:7]1=[O:10])[CH3:28]
Reactant: CCOCCl
Reactant: CC(C)c1c[nH]c(=O)[nH]c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: [I-]
Solvent: ClCCl
Product: CCOCn1cc(C(C)C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-isopropyluracil (18 g) in dichloromethane (230 ml) was added bis-trimethylsilylacetamide (60.7 ml) and the mixture stirred for 1 hr at room temperature. To the solution were added tetra-n-butylammonium iodide (0.46 g) and chloromethylethyl ether (10.7 ml) at room temperature and the mixture stirred for 1.5 hr. The resultant mixture was washed and partitioned with cooled water (50 ml) (×2). The organic layer was concentrated under reduced pressure. The residue was crystallized at room temperature from n-heptane (100 ml) to yield 1-ethoxymethyl-5-isopropyluracil (22.2 g). M.p., 78.4° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:9][CH2:8][CH2:7][C@H:6]2[N:3]1[C:4](=[O:16])[C@@:5]2([C:12]([OH:15])([CH3:14])[CH3:13])[N+]#[C-].C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:17])[O:9][CH2:8][CH2:7][C@H:6]2[N:3]1[C:4](=[O:16])[C@@H:5]2[C:12]([OH:15])([CH3:13])[CH3:14]
Reactant: [C-]#[N+][C@]1(C(C)(C)O)C(=O)N2[C@@H]1CCOC2(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: CC(C)(O)[C@H]1C(=O)N2[C@@H]1CCOC2(C)C

Procedure:
To a mixture of (6R,7R)-2,2-dimethyl-7-(1-hydroxy-1-methylethyl)-7-isocyano-1-aza-3-oxabicyclo[4.2.0]octan-8-one and its (6R,7S)-isomer (2.5 g) in benzene (75 ml) were added tributyltinhydride (3.07 ml) and azobisisobutyronitrile (170 mg) at ambient temperature and the mixture was refluxed for 30 minutes. The reaction mixture was chromatographed on silica gel (65 g) eluting with a mixture of methylene chloride and acetone (10:1-2:1) to give a crude product, which was purified by silica gel (75 g) chromatography (hexane and ethyl acetate) to give (6R,7S)-2,2-dimethyl-7-(1-hydroxy-1-methylethyl)-1-aza-3-oxabicyclo[4,2,0]-octan-8-one (0.545 g) [(6R,7S)-isomer] and its (6R,7R)-isomer (1.406 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[CH2:46][CH2:45][CH2:44][C@H:43]([O:47][Si](C(C)C)(C(C)C)C(C)C)[CH2:42]5)=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[CH2:46][CH2:45][CH2:44][C@H:43]([OH:47])[CH2:42]5)=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC[C@H](O[Si](C(C)C)(C(C)C)C(C)C)C5)n4c3)c3ccccc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC[C@H](O)C5)n4c3)c3ccccc32)cc1

Procedure:
A solution of Intermediate 63d (123 mg, 0.156 mmol) and TBAF (1M in THF, 195 μL, 0.195 mmol) in THF (4 mL) was stirred at RT for 1 h. The mixture was diluted with water and extracted with DCM (4×15 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-12% [2M NH3 in MeOH] in DCM, to give the title compound as a white powder after freeze-drying (82 mg, 83%). LCMS (Method 5): Rt 4.27 min, m/z 635.2 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.38-1.47 (1H, m), 1.62-1.74 (1H, m), 1.79-1.98 (4H, m), 1.99-2.16 (2H, m), 2.36 (3H, s), 2.78-2.86 (1H, m), 2.89-2.98 (1H, m), 3.20-3.36 (2H, m, under water signal), 3.77-3.86 (1H, m), 4.77-4.86 (1H, m), 4.90 (1H, d, J 5.2), 5.53 (1H, t, J 4.3), 6.32 (1H, s), 7.08 (1H, d, J 8.7), 7.16 (1H, dd, J 10.1, 2.1), 7.26-7.41 (8H, m), 7.61 (1H, d, J 10.0), 7.69 (1H, d, J 1.4), 8.03 (1H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][CH:15]=[C:14]2[CH2:24][CH2:25][C:26](=O)[NH2:27])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCOCC1.N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:29])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:15]=[C:14]2[CH2:24][CH2:25][C:26]#[N:27])=[CH:9][CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc(-n2c(CCC(N)=O)ccc2-c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1ccc(-n2c(CCC#N)ccc2-c2ccccc2)cc1
Temperature: 25 °C
Yield: 62 %

Procedure:
A stirred solution of 4-[2-(2-carbamoyl-ethyl)-5-phenylpyrrol-1-yl]-benzoic acid tert-butyl ester (3.92 mmol, 1.0 eq.) in dioxane and pyridine was cooled in an ice bath. To the mixture was added Trifluoroacetic anhydride (TFA, 7.84 mmol, 2.0 eq.). After 10 minutes the ice bath was removed and the reaction was allowed to warm to room temperature overnight. The solvent was evaporated in vacuo and the residue treated with EtOAc (250 mL) and saturated NaHCO3 (150 mL). The organic layer was separated, dried (Na2SO4) and the solvent evaporated in vacuo. The residue was loaded onto a 40 g RediSep silica-gel column for purification. Gradient elution with ethyl acetate/hexane (0% to 10% ethyl acetate in hexane over 25 minutes) gave the product as a yellow solid after combination of the appropriate fractions and evaporation of the solvent in vacuo, 62% yield.
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C1COCC1.[C:14]1(=[O:20])[CH2:19][CH2:18][CH2:17][CH:16]=[CH:15]1.Cl>C(OCC)(=O)C>[OH:20][C:14]1([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:19][CH2:18][CH2:17][CH:16]=[CH:15]1
Reactant: CCOC(=O)C[Zn]Br
Reactant: O=C1C=CCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)C=CCCC1
Yield: 87 %

Procedure:
Under nitrogen atmosphere, 20 mL of ethyl acetate was added to 3.05 g (5 mmol, 1.0 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.48 g (5 mmol) of 2-cyclohexen-1-one in 5 mL of ethyl acetate was added dropwise while stirring at 0˜50C. The mixture was stirred at 0˜5° C. for 3 hours. 10 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 25 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL (×2) of an aqueous saturated sodium chloride solution, 10 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 10 mL of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 0.80 g of the desired product (yield 87%).