Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](OC)=[O:14])=[C:11]([OH:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:20]>C(O)C.CO>[OH:19][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:18]=[CH:17][C:12]=1[C:13]([NH2:20])=[O:14]
Reactant: N
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1O
Solvent: CO
Solvent: CCO
Product: NC(=O)c1ccc(OCc2ccccc2)cc1O

Procedure:
A mixture of methyl 4-benzyloxy-2-hydroxybenzoate (20 g) and concentrated aqueous ammonia (30 mL) in ethanol (100 mL) is heated on the steam bath in a sealed pressure vessel overnight. The contents of the pressure vessel are dissolved in methanol and the solution is evaporated to dryness. The residue is subjected to flash chromatography, eluting first with dichloromethane to remove unreacted starting material, and then with a mixture of ethyl acetate and dichloromethane (3:7 v/v), to obtain 2-hydroxy-4-benzyloxybenzamide (4 g), in the form of a white solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][N:10]([C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[CH2:11][C@H:12]([O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C:3]([OH:5])=[O:4].N[C@@H](CCCCN(C(OCC1C=CC=CC=1)=O)C[C@@H](O)CCNC(OCC1C=CC=CC=1)=O)C(O)=O.FC(F)(F)C(O)=O.O1C=CCCC1>C(Cl)Cl>[NH2:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][N:10]([C:33]([O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:34])[CH2:11][C@@H:12]([O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])[C:3]([OH:5])=[O:4]
Reactant: N[C@@H](CCCCN(C[C@@H](CCNC(=O)OCc1ccccc1)OC1CCCCO1)C(=O)OCc1ccccc1)C(=O)O
Agent: C1=COCCC1
Agent: N[C@@H](CCCCN(C[C@@H](O)CCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CCCCN(C[C@H](CCNC(=O)OCc1ccccc1)OC1CCCCO1)C(=O)OCc1ccccc1)C(=O)O
Yield: 58 %

Procedure:
According to the method described for the preparation of 18a, 17b (37 mg, 73.8 μmol) was reacted with trifluoroacetic acid (17 mg, 0.15 mmol) and 3,4-dihydro-2H-pyran (46 mg, 50 μL, 0.55 mmol) in CH2Cl2 (2 mL) to give 18b (25 mg, 58%) as a colorless oil: 1H NMR δ 1.26-1.96 (m, 14H), 3.02-4.04 (m, 10H), 4.32-4.63 (m, 1H), 5.06 (s, 2H), 5.11 (s br, 2H), 7.22-7.40 (m, 10H); HRMS m/z calcd for C31H44N3O8 586.3128, found 586.3137.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[O:13][C:14]([O:16][CH3:17])=[O:15]>S(=O)(=O)(O)O>[F:12][C:10]1[CH:11]=[C:6]([F:5])[C:7]([O:13][C:14]([O:16][CH3:17])=[O:15])=[CH:8][C:9]=1[N+:1]([O-:4])=[O:2]
Reactant: COC(=O)Oc1ccc(F)cc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1F
Temperature: 0 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
A mixture of concentrated nitric acid (4 ml) and concentrated sulphuric acid (4 ml) was added slowly to a cooled mixture of 2,4-difluoro-1-methoxycarbonyloxybenzene (50 g, 0.027 mol) in concentrated sulphuric acid (4 ml) such that the reaction temperature was maintained below 30° C. The mixture was stirred for a further 3 hours, diluted with ice/water and the precipitated product collected by filtration washed with water and dried to give 2,4-difluoro-5-methoxycarbonyloxy-1-nitrobenzene (2.8 g, 45%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:15][CH3:16])[CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[N:9]=1.C(N(CCN[C:33]([C:35]1[CH:44]=[N:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([I:45])[CH:41]=2)[N:36]=1)=[O:34])CCOC1C(F)=NC=CC=1)C>>[CH2:15]([N:4]([CH2:3][CH2:2][NH:1][C:33]([C:35]1[CH:44]=[N:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([I:45])[CH:41]=2)[N:36]=1)=[O:34])[CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[N:9]=1)[CH3:16]
Reactant: CCN(CCNC(=O)c1cnc2cc(I)ccc2n1)CCOc1cccnc1F
Reactant: CCN(CCN)CCNc1cccc(F)n1
Product: CCN(CCNC(=O)c1cnc2cc(I)ccc2n1)CCNc1cccc(F)n1
Yield: 97 %

Procedure:
This compound was prepared, starting from compound 15 (55 mg, 0.24 mmol), according to the procedure developed for compound 10. Reaction time under reflux: 6 h, to give compound 16 (84 mg, 0.16 mmol) as an orange-coloured oil. Yield 97%; Rf (Al2O3, CH2Cl2/EtOH, 98/2, v/v) 0.70; IR (CCl4) ν 1521, 1619, 1685, 2760-3000, 3405 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.09 (t, 3H, J=7.1 Hz), 2.72 (q, 2H, J=7.1 Hz), 2.82 (m, 2H), 3.35 (q, 2H, J=5.7 Hz), 3.63 (q, 2H, J=5.9 Hz), 5.40 (se, 1H), 6.01 (dd, 1H, J=2.3, 8.0 Hz), 6.11 (dd, 1H, J=2.3, 8.0 Hz), 7.30 (q, 1H, 4JH-F=8.0 Hz, J=8.0 Hz), 7.90 (d, 1H, J=8.8 Hz), 8.06 (dd, 1H, J=1.8, 8.8 Hz), 8.34 (se, 1H), 8.58 (d, 1H, J=1.8 Hz), 9.61 (s, 1H); ESI-MS m/z 508.9 [M+H]+.
Reaction SMILES: C([Li])CCC.[Br-].[N:7]1([CH2:12][CH2:13][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:11][CH2:10][CH2:9][CH2:8]1.C(OC[N:37]1[CH:41]=[CH:40][N:39]=[C:38]1[C:42]([C:44]1[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=1)=O)C>CCCCCC.C1COCC1>[NH:37]1[CH:41]=[CH:40][N:39]=[C:38]1[CH:42]([C:44]1[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=1)[CH2:13][CH2:12][N:7]1[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CCOCn1ccnc1C(=O)c1ccc(C)cc1
Reactant: c1ccc([P+](CCN2CCCC2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(CCN2CCCC2)c2ncc[nH]2)cc1
Reaction time: 0.08 h
Yield: 106.4 %

Procedure:
A solution of n-butyl lithium in hexane (1.6 M, 7.7 ml) was added dropwise under nitrogen with stirring to a suspension of 2-(1-pyrrolidyl)ethyltriphenylphosphonium bromide (5.41 g) in dry THF (75 ml) keeping the temperature at -10° to -5°. The addition was complete after 5 min. The mixture was then stirred at 0° for 20 min. then cooled to -5° and treated with a solution of (1-ethoxymethylimidazol-2-yl)-4-methylphenylmethanone (3.0 g) in dry THF (30 ml). The mixture was stirred at room temperature for 16 h. and then the precipitated triphenylphosphine oxide was filtered off and washed with a little THF (10 ml). The filtrate and washings were combined and concentrated in vacuo to a yellow syrup. This was absorbed from chloroform (3 ml) onto a column of silica gel (Merck Kieselgel 60, 200 g). Removal of the solvent afforded isomers of the title compound as a thick yellow brown syrup (3.52 g) which was used in the next stage without further purification.
Reaction SMILES: O=P(Cl)(Cl)Cl.[Cl:6][C:7]1[CH:12]=[C:11]([CH:13]=[N:14]O)[C:10]([Cl:16])=[CH:9][N:8]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:6][C:7]1[CH:12]=[C:11]([C:13]#[N:14])[C:10]([Cl:16])=[CH:9][N:8]=1
Reactant: ON=Cc1cc(Cl)ncc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: N#Cc1cc(Cl)ncc1Cl
Temperature: 0 °C
Yield: 77.4 %

Procedure:
To 100 ml of acetonitrile was added 24.5 g of POCl3, followed by 27.1 g of 2,5-dichloro-4-pyridinecarboxaldehyde oxime (prepared as described in Example 4). The reaction mixture was heated at reflux temperature for 1 hour, then cooled and poured onto 300 g of ice. The pH of the mixture was adjusted to about pH 6 with K2CO3 and filtered. The filtrate was extracted with 100 ml of CH2Cl2. The filter cake and the CH2Cl2 solution were combined, diluted with equal volumes of hexane, treated with charcoal, dried, and concentrated. The residue was purified by distillation on a Kugelrohr distillation apparatus (boiling point 80° C. at 0.2 mm pressure) to give 19.0 g (77%) of the desired 2,5-dichloro-4-pyridinecarbonitrile as a white solid, m.p. 58°-60° C.
Reaction SMILES: [Si:1]([O:18][C@@H:19]1[C@@H:23]([CH2:24]I)[O:22][C@@H:21]([N:26]2[CH:34]=[C:32]([CH3:33])[C:30](=[O:31])[NH:29][C:27]2=[O:28])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.[CH3:35][C:36](N=NC(C#N)(C)C)(C#N)[CH3:37]>C1(C)C=CC=CC=1>[Si:1]([O:18][C@@H:19]1[C@@H:23]([CH2:24][CH2:37][CH:36]=[CH2:35])[O:22][C@@H:21]([N:26]2[CH:34]=[C:32]([CH3:33])[C:30](=[O:31])[NH:29][C:27]2=[O:28])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Reactant: Cc1cn([C@H]2C[C@H](O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@@H](CI)O2)c(=O)[nH]c1=O
Solvent: Cc1ccccc1
Product: C=CCC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 65 °C

Procedure:
A stirred solution of 3'-O-(t-butyldiphenylsilyl)-5'-deoxy-5'-iododthymidine (12, 1.77 g, 3 mmol), allytributyltin (2.97 g, 9 mmol) and AIBN (0.54 g, 3.3 mmol) in dry toluene (30 ml) was degassed completely and heated at 65° C. for 6 hr. The solution was cooled and concentrated under vacuo. The residue was purified by silica gel column chromatography and on elution with hexanes:EtOAc (1:1, v/v) furnished the title compound as homogeneous material. Appropriate fractions were pooled and evaporated to furnish 46, 0.75 g of a white foam, 50% yield. The structure was confirmed by 1H NMR.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:3].[NH:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][C:11]1=[O:17]>O>[CH3:1][N:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH:3][C:13]1[CH2:14][CH2:15][NH:10][C:11](=[O:17])[CH:12]=1
Reactant: CN(N)c1ccccc1
Reactant: O=C1CCNC(=O)C1
Solvent: O
Product: CN(NC1=CC(=O)NCC1)c1ccccc1
Yield: 89.6 %

Procedure:
1-Methyl-1-phenylhydrazine (21.6 g) was added to a suspension of 2,4-piperidinedione (20.0 g) in industrial methylated spirit (100 ml) at 20°-25° under nitrogen. The resultant solution was stirred for 3 h at room temperature. Water (300 ml) was added and the resulting suspension was filtered to give the title compound (34.4 g) as a solid, m.p. 180.5°-182°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][C:11](=[O:13])[NH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([N:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]1)=[O:16])[CH2:10][C:11](=[O:13])[NH2:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)O
Product: CN1CCN(C(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)CC1
Yield: 81.3 %

Procedure:
In the same manner as in Reference Example 2, N-tert-butoxycarbonyl-L-asparagine (5.0 g) and 1-methylpiperazine (2.2 g) were condensed to obtain colorless crystal 1-(N-tert-butoxycarbonyl-L-asparaginyl)-4-methylpiperazine (5.5 g).
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:36]([C:40]1[CH:44]=[C:43]([NH:45][C:46](=[O:61])[C:47]([CH3:60])([S:51]([CH:54]2[CH2:59][CH2:58][O:57][CH2:56][CH2:55]2)(=[O:53])=[O:52])[CH2:48][CH2:49]O)[O:42][N:41]=1)([CH3:39])([CH3:38])[CH3:37]>C(Cl)Cl>[C:36]([C:40]1[CH:44]=[C:43]([N:45]2[CH2:49][CH2:48][C:47]([CH3:60])([S:51]([CH:54]3[CH2:55][CH2:56][O:57][CH2:58][CH2:59]3)(=[O:52])=[O:53])[C:46]2=[O:61])[O:42][N:41]=1)([CH3:37])([CH3:39])[CH3:38]
Reactant: CC(C)(C)c1cc(NC(=O)C(C)(CCO)S(=O)(=O)C2CCOCC2)on1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)c1cc(N2CCC(C)(S(=O)(=O)C3CCOCC3)C2=O)on1
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
To a solution of di-tert-butyl azodicarboxylate (0.126 g; 0.546 mmol) in methylene chloride (2.5 mL) was added triphenylphosphine (0.143 g; 0.546 mmol). The mixture was stirred 30 minutes and N-(3-tert-butyl-isoxazol-5-yl)-4-hydroxy-2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-butyramide (0.212 g; 0.546 mmol) was added. After 3 hours the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using ethyl acetate and hexanes as the eluent. Removal of the volatiles from the product-rich fractions provided 0.105 g of the solid product. 1H NMR (CDCl3) δ 6.41 (s, 1H), 4.09 (m, 4H), 3.85 (m, 1H), 3.49 (m, 2H), 3.24 (m, 1H), 2.25-1.86 (m, 5H), 1.75 (s, 3H), 1.35 (s, 9H). MS (ESI): m/e 371 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([C:16]#[N:17])=[C:14]([S:18][CH3:19])[S:13][C:12]=2[C:20]([NH2:22])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C=O.C(O)=O>CC#N>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([C:16]#[N:17])=[C:14]([S:18][CH3:19])[S:13][C:12]=2[C:20]#[N:22])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1sc(C(N)=O)c(-c2ccc(C(C)(C)C)cc2)c1C#N
Agent: C=O
Solvent: CC#N
Solvent: O=CO
Product: CSc1sc(C#N)c(-c2ccc(C(C)(C)C)cc2)c1C#N

Procedure:
Add 3-(4-tert-butyl-phenyl)-4-cyano-5-methylsulfanyl-thiophene-2-carboxylic acid amide(0.121 mmol) to 0.5 ml of CH3CN and add 18 mg paraformaldehyde and formic acid (1.59 mmol). Heat for 6 hrs. Concentrate and purify by radial chromatography eluting with ethyl acetate/hexanes to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 7.39 (q, 4H, J=12.0 Hz), 2.80 (s, 3H) and 1.42 (s, 9H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([O:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:7][C:6]=1[OH:22])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:25](Cl)[C:26](=[CH2:28])[CH3:27]>CN(C)C=O>[C:1]([C:5]1[CH:10]=[C:9]([O:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:7][C:6]=1[O:22][CH2:27][C:26]([CH3:28])=[CH2:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C(=O)Oc1cc(C(C)(C)C)c(O)cc1C(C)(C)C
Reactant: C=C(C)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)COc1cc(C(C)(C)C)c(OC(=O)C(C)(C)C)cc1C(C)(C)C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Under a nitrogen stream, a solution of 0.50 g of 2,5-di-t-butyl-4-trimethylacetoxyphenol in 3 ml of dimethylformamide was added dropwise into a suspension of 0.08 g of oily sodium hydride in 3 ml of dimethylformamide. After stirring for 30 minutes, 0.19 ml of methallyl chloride was added dropwise and the mixture was stirred for 3 hours and allowed to attain room temperature. After the reaction was quenched with a saturated aqueous ammonium chloride solution, the mixture was extracted with water and n-hexane. The organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 1% ethyl acetate) to give 0.48 g of 2,5-di-t-butyl-4-trimethylacetoxy-1-(2-methyl-2-propenyloxy)benzene as a colorless oil (yield 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17]([NH2:24])=[CH:16][C:15]=1[NH2:25])[C:9](=O)[O:10]CC.[H-].[Na+].C(=O)(O)[O-].[Na+]>C(O)C>[NH2:24][C:17]1[CH:18]=[C:19]([C:20]([F:23])([F:22])[F:21])[C:14]2[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9](=[O:10])[NH:25][C:15]=2[CH:16]=1
Reactant: CCOC(=O)N(c1ccccc1Cl)c1c(N)cc(N)cc1C(F)(F)F
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: Nc1cc(C(F)(F)F)c2c(c1)[nH]c(=O)n2-c1ccccc1Cl
Yield: 76.6 %

Procedure:
Ethyl 2-chlorophenyl[2,4-diamino-6-(trifluoromethyl)phenyl]carbamate (68.8 mg) was dissolved in ethanol (6 ml), and to the solution was added sodium hydride (14.7 mg). The reaction mixture was heated at reflux for 2 hours. After allowing to cool, to the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted 3 times with chloroform. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resultant residue was purified by preparative TLC (2 mm, 20×20 cm, CHCl3:methanol=5:1) to give the title compound (46.2 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([C:19]3[C:27]([O:28][CH3:29])=[CH:26][C:25]([CH3:30])=[C:24]4[C:20]=3[CH:21]=[CH:22][N:23]4C(OC(C)(C)C)=O)([CH2:13][CH2:14][C:15]([O:17]C)=[O:16])[CH3:12])=[N:8][C:7]=2[CH:38]=1)#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+]>CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([C:19]3[C:27]([O:28][CH3:29])=[CH:26][C:25]([CH3:30])=[C:24]4[C:20]=3[CH:21]=[CH:22][NH:23]4)([CH3:12])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[N:8][C:7]=2[CH:38]=1)#[N:2]
Reactant: COC(=O)CCC(C)(c1nc2cc(C#N)ccc2o1)c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: COc1cc(C)c2[nH]ccc2c1C(C)(CCC(=O)O)c1nc2cc(C#N)ccc2o1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of (±)-tert-Butyl 4-(2-(5-cyanobenzo[d]oxazol-2-yl)-5-methoxy-5-oxopentan-2-yl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 150-B) (83 mg, 0.160 mmol) and cesium carbonate (261 mg, 0.802 mmol) in MeOH (1.6 mL) was heated to 60° C. and stirred for 2 hrs. The reaction was cooled down to rt and quenched with a saturated solution of ammonium chloride, MeOH was then removed in vacuo. The residue was diluted with AcOEt and water. The layers were separated and the water layer was extracted with AcOEt. The combined organic layers were passed through a phase separator and purified by preparative HPLC (HC-B) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.05 (br. s., 1H) 8.32 (d, J=1.26 Hz, 1H) 7.66-7.89 (m, 2H) 7.30 (t, J=2.91 Hz, 1H) 6.69 (s, 1H) 6.38 (dd, J=3.03, 1.77 Hz, 1H) 3.51 (s, 3H) 2.58-2.65 (m, 2H) 2.44 (s, 3H) 2.15 (dd, J=9.73, 6.69 Hz, 2H) 1.91 (s, 3H). HRMS calcd. for C23H21N3O4 (M+H)+ 404.1610. found 404.1607.
Reaction SMILES: [OH:1][C@@H:2]([CH3:12])[C@H:3]([NH2:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1.C(=O)(O)[O-].[Na+].Cl[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:20]>O1CCCC1.O1CCOCC1>[CH2:22]([O:21][C:19]([NH:11][C@H:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1)[C@H:2]([CH3:12])[OH:1])=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: C[C@H](O)[C@H](N)c1cccc(O)c1
Reactant: CCCCCCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCCCCCOC(=O)N[C@H](c1cccc(O)c1)[C@H](C)O
Temperature: 0 °C
Yield: 96.3 %

Procedure:
To a solution of (1R,2S)-2-hydroxy-1-(3-hydroxyphenyl)propylamine (17.2 g) in tetrahydrofuran (500 ml) was added 0.5M aqueous solution of sodium bicarbonate (500 ml) and the mixture was stirred at 0° C. To the mixture was added a solution of hexyl chloroformate (14 g) in dioxane (20 ml) and the mixture was stirred for 30 minutes at 0° C. The reaction mixture was extracted with ethyl acetate (300 ml). The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1→2:1→3:2) to give the title compound (24.2 g) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[O:8][CH:7]([C:18]([F:21])([F:20])[F:19])[C:6]([C:22]([O:24]CC)=[O:23])=[CH:5]2.CC1C=C2C(C=CCO2)=CC=1Cl>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[O:8][CH:7]([C:18]([F:21])([F:20])[F:19])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(Cc3cccs3)cc2OC1C(F)(F)F
Agent: Cc1cc2c(cc1Cl)C=CCO2
Product: O=C(O)C1=Cc2cc(Cl)c(Cc3cccs3)cc2OC1C(F)(F)F

Procedure:
The ester obtained from Example 170 Step 3 was converted to the acid according to the procedure of Example 150 Step 4. The product (20 mg) contained a major impurity amounting to 14%, which was determined to be the 7-methyl-6-chlorochromene, which can be removed by reverse phase HPLC (column: Delta Pak 300×50 mm I.D. C18, 15 μM) using a H2O—CH3CN gradient (conditions: 90/10-50/50 over 30 minutes) which gave pure product. 1H NMR (MeOH-d4) 7.54 (s, 1H), 7.14 (s, 1H), 7.07 (d, 1H, J=4.3 Hz), 6.76-6.73 (3H), 5.55 (q, 1H, J=6.9 Hz), 4.15 (d, 1H, J=16.7 Hz), 4.05 (d, 1H, J=16.1 Hz).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42](C(O)=O)([CH3:44])[CH3:43])=[CH:33][CH:32]=2)=[C:28]([CH:49]([CH3:51])[CH3:50])[N:27]([CH2:52][CH2:53][CH2:54][O:55]C(=O)C2C=CC=CC=2)[N:26]=1)(=O)C.C(O[C:72]([N:74]1[CH2:79][CH2:78][NH:77][CH2:76][CH2:75]1)=[O:73])C1C=CC=CC=1.C(N1CCNCC1)C1C=CC=CC=1>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:72]([N:74]4[CH2:75][CH2:76][NH:77][CH2:78][CH2:79]4)=[O:73])([CH3:44])[CH3:43])=[CH:35][CH:36]=3)=[C:28]([CH:49]([CH3:50])[CH3:51])[N:27]([CH2:52][CH2:53][CH2:54][OH:55])[N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2nn(CCCOC(=O)c3ccccc3)c(C(C)C)c2Cc2ccc(CCCC(=O)NC(C)(C)C(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: c1ccc(CN2CCNCC2)cc1
Product: CC(C)c1c(Cc2ccc(CCCC(=O)NC(C)(C)C(=O)N3CCNCC3)cc2)c(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)nn1CCCO

Procedure:
The title compound was prepared in a similar manner to that described in Example 99 using 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-1-(3-benzoyloxypropyl)-4-[(4-{3-[1-carboxy-1-(methyl)ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole and 1-(benzyloxycarbonyl)piperazine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-1-(methyl)ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole and 1-benzyl-piperazine, respectively.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([CH2:8][NH:9]C(=O)OCC2C=CC=CC=2)=[N:5][C:4]2[CH2:20][CH2:21][O:22][CH2:23][C:3]1=2>CO.[Pd]>[NH2:9][CH2:8][C:6]1[NH:7][C:2](=[O:1])[C:3]2[CH2:23][O:22][CH2:21][CH2:20][C:4]=2[N:5]=1
Reactant: O=C(NCc1nc2c(c(=O)[nH]1)COCC2)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NCc1nc2c(c(=O)[nH]1)COCC2
Temperature: 25 °C
Yield: 100.3 %

Procedure:
A solution of benzyl (4-oxo-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)methylcarbamate (55.5 g, 176 mmol) in methanol (4 L) was degassed several times under nitrogen then palladium on carbon (1.87 g, 1.76 mmol, 10% on carbon) was added slowly under nitrogen atmosphere. The mixture was stirred under a hydrogen balloon at ambient temperature until TLC showed complete consumption of starting material. Filtration through a pad of Celite and evaporation of solvent provided the title compound (32 g, >99% yield). 1H NMR (400 MHz, CD3OD) δ 4.49 (s, 2H), 3.93 (t, J=5.5 Hz, 2H), 3.77 (s, 2H), 2.66 (t, J=5.5 Hz, 2H). MS m/z 182.2 (M+1), retention time=0.39 min.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14]([NH2:16])=[S:15])[CH:7]=2)[CH2:3][CH2:2]1.Br[CH2:19][C:20](=O)[C:21]([O:23]CC)=O>C(O)C>[C:8]1([NH:13][C:21]([C:20]2[N:16]=[C:14]([NH:13][C:8]3[CH:7]=[C:6]([C:5](=[O:17])[NH:4][CH:1]4[CH2:3][CH2:2]4)[CH:11]=[CH:10][C:9]=3[CH3:12])[S:15][CH:19]=2)=[O:23])[CH:9]=[CH:10][CH:11]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(N)=S
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1Nc1nc(C(=O)Nc2ccccc2)cs1
Temperature: 75 °C
Reaction time: 16 h
Yield: 79.6 %

Procedure:
To a stirred solution of N-Cyclopropyl-4-methyl-3-thioureido-benzamide 3A (100 mg, 0.48 mmol) in 10 mL of ethanol was added ethyl bromopyruvate (89 mg, 0.48 mmol) and the reaction was heated at 75° C. overnight. After 16 hours, the reaction was cooled and concentrated and the crude product was purified by flash chromatography on silica gel loaded with CH2Cl2 and eluted with 1:1 hexanes/ethyl acetate followed by 1:2 hexanes/ethyl acetate to provide the title compound as a solid (75 mg, 45%). HPLC, tR, 2.97 min. (4 minute method); MS, m/z 346.0 [M+1]+.