Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[I:43][C:44]1[CH:45]=[C:46]([CH:48]=[CH:49][C:50]=1[CH3:51])[NH2:47].CCN(C(C)C)C(C)C>CN(C=O)C>[I:43][C:44]1[CH:45]=[C:46]([NH:47][C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[O:8])[CH:48]=[CH:49][C:50]=1[CH3:51]
Reactant: Cc1ccc(N)cc1I
Reactant: O=C(O)c1ccoc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2ccoc2)cc1I
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Furoic acid (2.4 g, 21.45 mmol) and HATU (8.15 g, 21.45 mmol) in DMF (25 ml) were stirred at room temperature for 15 mins. HOBT (2.9 g, 21.45 mmol), 3-iodo-4-methylaniline (5.0 g, 21.45 mmol) and DIPEA (11.2 ml, 64.35 mmol) were added and the reaction stirred at room temperature for 16 hrs. The solvent was evaporated under vacuum and the residue partitioned between ethyl acetate (100 ml) and aqueous sodium carbonate (10%, 100 ml). The aqueous layer was extracted with ethyl acetate (50 ml) and the combined organic phases washed with hydrochloric acid (2N, 75 ml), water (75 ml) and brine (75 ml). The organic phase was dried (magnesium sulphate) and absorbed onto silica. The silica was applied to a flash silica column and eluted with cyclohexane/ethyl acetate (3:1). The solvent was evaporated from the product fractions under vacuum to give N-(3-iodo-4-methylphenyl)-3-furamide. LCMS: retention time 3.52 min, MH+ 328. NMR: δH [2H6]-DMSO 9.92,(1H, b), 8.36,(1H, d), 8.23,(1H, d), 7.80,(1H, t), 7.66,(1H, dd), 7.29,(1H, d), 6.98,(1H, d), 2.33,(3H, s).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH2:12][CH3:13])[N:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27](=[O:30])(=[O:29])[NH2:28])=[CH:17][CH:16]=2)[N:7]=1)=[O:5])C.C(Cl)Cl.Cl[C:35]([O:37][CH3:38])=[O:36].CCN(C(C)C)C(C)C.[Li+].[OH-].O>C1COCC1.CCO>[CH3:38][O:37][C:35]([NH:28][S:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:8]2[C:9]([CH2:11][CH2:12][CH3:13])=[CH:10][C:6]([C:4]([OH:3])=[O:5])=[N:7]2)=[CH:16][CH:17]=1)(=[O:30])=[O:29])=[O:36]
Reactant: CCCc1cc(C(=O)OCC)nn1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reactant: COC(=O)Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(C(=O)O)nn1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Propyl-1-(2′-sulfamoylbiphenyl-4-ylmethyl)-1H-pyrazole-3-carboxylic acid ethyl ester (80 mg, 0.2 mmol) was dissolved in methylene chloride (2.0 mL, 30.6 mmol). Methyl chloroformate (17.4 μL, 224 μmol) was added, along with DIPEA (81.5 μL, 468 μmol). The mixture was stirred at room temperature for 2 hours. 1 M LiOH in water (1.5 mL, 1.50 mmol) and THF:EtOH 2:1 mL were added and the resulting mixture was stirred for 2 hours. The reaction was quenched with 1 N HCl and DCM (4 mL) was added. The organics were extracted and dried under vacuum to yield the title compound.
Reaction SMILES: [C:1]([C@:11]([C:28]([OH:30])=[O:29])([OH:27])[C@:12]([C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)([OH:16])[C:13]([OH:15])=[O:14])(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.Cl.[Cl:32][C:33]1[CH:34]=[C:35]([C:40]2([CH2:45][CH2:46][OH:47])[CH2:44][CH2:43][NH:42][CH2:41]2)[CH:36]=[CH:37][C:38]=1[Cl:39]>O.CO.CO>[C:17]([C@:12]([C:13]([OH:15])=[O:14])([OH:16])[C@:11]([C:1](=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)([OH:27])[C:28]([OH:30])=[O:29])(=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.[Cl:32][C:33]1[CH:34]=[C:35]([C@@:40]2([CH2:45][CH2:46][OH:47])[CH2:44][CH2:43][NH:42][CH2:41]2)[CH:36]=[CH:37][C:38]=1[Cl:39]
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Agent: COc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(OC)cc2)cc1
Agent: Cl
Solvent: O
Solvent: CO
Product: OCC[C@]1(c2ccc(Cl)c(Cl)c2)CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Combine (R,R)-di-p-anisoyltartaric acid (0.8 g, 19 mmol) and aqueous 12M hydrochloric acid solution (0.16 mL, 19 mmol) in water/methanol (10 mL)/(10 mL). Heat to reflux. Add dropwise, a solution of 2-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (1.0 g, 38.5 mmol) in methanol (10 mL). After 15 minutes, slowly cool to ambient temperature. Filter the solid that forms and rinse with water to give (S)-2-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (R,R)-di-p-anisoyltartaric acid: mp; 201°-204° C. (dec). Analysis by HPLC, as described in Example 106.1.1 indicates an enantiomeric excess of 97%, (97% ee).
Reaction SMILES: [CH2:1]([N:5]([CH2:22][C:23]1[CH:34]=[CH:33][C:26]([O:27][CH2:28][C:29]([O:31]C)=[O:30])=[C:25]([CH3:35])[CH:24]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:7]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.O1CCCC1>[CH2:1]([N:5]([CH2:22][C:23]1[CH:34]=[CH:33][C:26]([O:27][CH2:28][C:29]([OH:31])=[O:30])=[C:25]([CH3:35])[CH:24]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:16][CH:17]=2)[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(Cc1ccc(OCC(=O)OC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a solution of methyl {4-[(butyl{6-[4-(trifluoromethyl)phenyl]pyridin-2-yl}amino)methyl]-2-methylphenoxy}acetate (40 mg, 0.082 mmol) in methanol (2 mL) and tetrahydrofuran (2 mL), was added 2M NaOH aq. (2 mL). After stirring for 1 h at room temperature the solvent was removed in vacuo and the residue acidified with 2M HCl, before extraction into ethyl acetate (2×15 mL). The organic solution was dried (MgSO4) and the solvents removed in vacuo to afford the title compound as a white solid (35 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:12][C:13]3[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[C:7]([CH3:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:23][O:24][CH2:25][CH2:26]Br>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:12][C:13]3[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[C:7]([CH3:11])[N:8]2[CH2:26][CH2:25][O:24][CH3:23])=[CH:4][CH:3]=1
Reactant: COCCBr
Reactant: Cc1[nH]c2cc(Cl)ccc2c1Sc1cccc(CC(=O)O)c1
Product: COCCn1c(C)c(Sc2cccc(CC(=O)O)c2)c2ccc(Cl)cc21

Procedure:
Prepared according to the procedure described in Example 4, Step 1, using the following starting materials: [3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid and 2-bromethyl methyl ether.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([NH:24][CH3:25])=[O:23])=[C:20]([F:28])[CH:19]=3)[C:10]2=S)=[CH:5][C:4]=1[C:30]([F:33])([F:32])[F:31])#[N:2].FC1C=C(N2C(=S)N(C3C=C(C(F)(F)F)C(C#N)=NC=3)C(=O)C32CCC3)C=CC=1[OH:41].C(C1(NC2C=CC(C(NC)=O)=C(F)C=2)CCC1)#N.OO>CO.CCOC(C)=O>[C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([NH:24][CH3:25])=[O:23])=[C:20]([F:28])[CH:19]=3)[C:10]2=[O:41])=[CH:5][C:4]=1[C:30]([F:33])([F:32])[F:31])#[N:2]
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(O)c(F)c3)C2=S)cc1C(F)(F)F
Reactant: CNC(=O)c1ccc(N2C(=S)N(c3cnc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1F
Agent: CNC(=O)c1ccc(NC2(C#N)CCC2)cc1F
Agent: OO
Solvent: CO
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(N2C(=O)N(c3cnc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1F
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-methylbenzamide (synthesized as described for Example 1 using 5-amino-3-(trifluoromethyl)picolinonitrile (Intermediate 1) and of 4-((1-cyanocyclobutyl)amino)-2-fluoro-N-methylbenzamide (Intermediate 21) as starting materials) (90 mg, 0.19 mmol) and H2O2 (30%, 0.72 mL) in MeOH (8 mL) was stirred at room temperature for 5 days. The reaction mixture was diluted with EtOAc (10 mL) and the organic layer was washed with water, brine, and dried over magnesium sulfate. The residue obtained was purified by reverse phase HPLC (acetonitrile/water:TFA) to obtain 10 mg of 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-6,8-dioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-methylbenzamide as a white solid. 1H NMR (500 MHz, CDCl3) δ 9.28 (d, 1H), 8.54 (d, 1H), 8.23 (t, 1H), 7.33 (m, 1H), 7.27 (m, 1H), 6.93 (m, 1H), 3.07 (d, 3H), 2.71 (m, 2H), 2.57 (m, 2H), 2.28 (m, 1H), 1.82 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC(C)=O.Cl>O>[C:2]1([NH:1][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccccc1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: O=C(Nc1ccccc1)c1ccccc1
Reaction time: 1.5 h

Procedure:
N-phenylbenzamide (Structure II) is synthesized from aniline and benzoyl chloride using acetone as a reaction media and an aqueous solution of NAOH to neutralize the HCl generated. A 20 ml aqueous solution of NAOH (2.57 grams, 0.064 moles) and 6.0 grams (0.064 moles) of aniline are first added to a stirred 250 ml flask containing 75 ml of acetone. Benzoyl chloride (9.06 grams, 0.064 moles) is next added over a five minute period. This reaction mixture which now contains a white precipitate is stirred for 1.5 hours and then diluted with 50 ml of deionized water. This solution is next filtered and the filter cake obtained is sequentially washed with 50 ml of deionized water (two times) followed by 50 ml of methanol. The washed filter cake is recovered and DSC analysis of this product showed a sharp melting endotherm at 169° C. ##STR10##
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH2:5][C:6]([N:8]([CH2:18][C:19]1([C:32]([O:34]C)=O)[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=[O:7])C.C[O-].[Na+]>CO>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:8]2[C:6](=[O:7])[CH:5]([C:4]([O:3][CH3:1])=[O:36])[C:32](=[O:34])[C:19]3([CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:23][CH2:24]3)[CH2:18]2)=[CH:15][CH:14]=1
Reactant: CCOC(=O)CC(=O)N(Cc1ccc(OC)cc1)CC1(C(=O)OC)CCN(C(=O)OC(C)(C)C)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1C(=O)N(Cc2ccc(OC)cc2)CC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: 60 °C
Reaction time: 15 h

Procedure:
The mixture from Step 2 was dissolved in anhydrous MeOH (50 mL), sodium methoxide (25.6 mmol, 1.384 g) was added and then the suspension was stirred for 15 h at 60° C. The reaction mixture was concentrated in vacuo, taken up in 2 N HCl and extracted with DCM. The organic layer was dried over MgSO4, filtered and concentrated in vacuo yielding the desired product A3 (2.02 g) as an oil. MS (ES) C24H32N2O7 requires: 460. found: 461.2 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH:7](/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27])[CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1)#[N:2].[C:28]([C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1)([CH3:31])([CH3:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:28]([C:32]1[CH:33]=[CH:34][C:35]([CH2:36][O:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2/[CH:20]=[CH:19]/[CH:7]([CH2:6][CH2:5][CH2:4][CH2:3][C:1]#[N:2])[CH2:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[CH:38][CH:39]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2O)CCCCC#N)cc1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)CCCCC#N)cc1
Yield: 92.2 %

Procedure:
A solution of 2.976 g (8.19 mmol) of methyl E-4-{6-cyano-2-[2-(2-hydroxyphenyl)vinyl]hexyl}-benzoate from Example 119A in 100 ml of dry acetonitrile is mixed with 2.789 g (12.28 mmol) of 4-(tert-butyl)benzyl bromide and 1.697 g (12.28 mmol) of anhydrous potassium carbonate and heated to reflux for 12 hours. The mixture is then filtered and the filtrate is concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. The organic phase is concentrated. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 8:1→4:1). 3.85 g (92% yield) of a solid are obtained.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:12]=[CH:11][C:9]([OH:10])=[C:8]([CH2:13][CH2:14][CH3:15])[C:7]=2[OH:16])=O)[CH2:3]C1.[NH2:17][OH:18].Cl.C([O-])(=O)C.[Na+]>CO.O>[CH:4]1([CH:6]2[C:12](=[N:17][OH:18])[CH:11]=[C:9]([OH:10])[C:8]([CH2:13][CH2:14][CH3:15])=[C:7]2[OH:16])[CH2:1][CH2:3]1
Reactant: CCCc1c(O)ccc(C(=O)C2CC2)c1O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCC1=C(O)C(C2CC2)C(=NO)C=C1O

Procedure:
A solution of 4-cyclopropylcarbonyl-2-(n-propyl)resorcinol (1.0 g, 4.54 mmole) in methanol (10 mL) was treated with hydroxylamine.HCl (1.58g, 22.7 mmole) and sodium acetate (1.86g, 22.7 mmole) and the mixture refluxed for 7 hours. The cooled mixture was poured into water and extracted 3× with ethyl acetate. The combined extracts were washed with water (2×), 10% sodium bicarbonate, brine, dried over magnesium sulfate and concentrated in vacuo to give a solid. The crude product was chromatographed on silica gel eluting with methylene chloride followed by methanol:methylene chloride (5:95) to afford the title compound. NMR (CDCl3); δ 0.89 (m, 2H); 0.94 (t, 3H); 1.10 (m, 2H); 1.76 (m, 1H); 2.61 (t, 2H); 6.35 (d, 1H); 7.41 (d, 1H).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.O[CH2:17][C@H:18]([O:32][CH2:33][P:34]([OH:37])([OH:36])=[O:35])[CH2:19][O:20][N:21]1[CH:29]=[N:28][C:27]2[C:26](=[O:30])[NH:25][C:24]([NH2:31])=[N:23][C:22]1=2>C(O)(C)(C)C>[OH:36][P:34]1(=[O:35])[CH2:33][O:32][C@H:18]([CH2:19][O:20][N:21]2[CH:29]=[N:28][C:27]3[C:26](=[O:30])[NH:25][C:24]([NH2:31])=[N:23][C:22]2=3)[CH2:17][O:37]1
Reactant: Nc1nc2c(ncn2OC[C@H](CO)OCP(=O)(O)O)c(=O)[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(C)(C)O
Product: Nc1nc2c(ncn2OC[C@@H]2COP(=O)(O)CO2)c(=O)[nH]1
Temperature: 25 °C

Procedure:
A solution of dicyclohexylcarbodiimide (0.615 g, 3.0 mmol) in t-butanol (10 ml) was added dropwise over 30 minutes to a solution of (S)-9-[3-hydroxy-2-(phosphonomethoxy)propoxy]guanine (0.20 g, 0.6 mmol) and N,N-dicyclohexyl-4-morpholinocarboxamidine (0.175 g, 0.6 mmol) in 50% aqueous t-butanol (30 ml). The reaction mixture was heated under reflux for 4 hours, allowed to cool to ambient temperature and evaporated to dryness. Water was added to the residue and the mixture filtered through a glass fibre filter paper. The filtrate was evaporated to dryness and the solid obtained purified on DEAE-Sephadex (HCO3- form) eluting with a linear gradient of aqueous triethylammonium bicarbonate (pH 7.5) from 0.001M to 0.25M. Relevant fractions were combined and evaporated to dryness co-evaporating with ethanol/water, 3:1 (x2) to remove all traces of triethylamine. The product was converted into the sodium salt using DOWEX 50W-X8 (Na+ form). The title compound was obtained as a white solid (0.12 g, 59%) after lyophilisation. IR: νmax (KBr) 3400, 3140, 1690, 1610, 1475, 1380, 1240, 1208, 1079, 1040, 1010, 960, 790 cm-1. 1H NMR: δH [(CD3)2SO] 3.42 (1H, dd, J=13.2 Hz, J=3.3 Hz, OCHBP), 3.55 (1H, dd, J=13.2 Hz, J= 8 Hz, OCHAP), 3.79 (1H, m, CH), 3.92 (1H, m, CHBOP), 4.07-4.32 (3H, m, CHAOP, NOCH2), 6.86 (2H, br.s, D2O exchangeable NH2), 7.90 (1H, s, H-8), 10.97 (1H, br.s, D2O exchangeable NH). m/z: (FAB, thioglycerol) 318 (M-Na+2H+), 340 (MH+).
Reaction SMILES: ClC1C=CC(/C=[N:9]/[C:10]([CH3:22])([CH2:18][CH:19]2[CH2:21][CH2:20]2)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C1COCC1.O>C(OCC)(=O)C>[NH2:9][C:10]([CH3:22])([CH2:18][CH:19]1[CH2:21][CH2:20]1)[C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12]
Reactant: CC(C)(C)OC(=O)C(C)(CC1CC1)/N=C/c1ccc(Cl)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(C)(N)CC1CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 43 %

Procedure:
In a 250 mL round-bottomed flask, tert-butyl 2-[(E)-(4-chlorophenyl)methyleneamino]-3-cyclopropyl-2-methyl-propanoate (example 186a, 1.7 g, 5.28 mmol) and citric acid (1.8 g, 9.37 mmol) were combined with THF (30 ml) and water (5 ml) to give a yellow solution. The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was poured into 200 mL ethyl acetate and extracted with an iced 1 M aqueous solution of sodium hydroxide and brine. The aqueous layer was back-extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (452 mg, 43%). MS (ESI, m/z): 200.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:3].[Br:10]Br.O>CO>[Br:10][CH2:1][C:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:3]
Reactant: CC(=O)C1CCCCC1
Reactant: BrBr
Solvent: O
Solvent: CO
Product: O=C(CBr)C1CCCCC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 5.67 g (45 mmol) cyclohexyl methyl ketone in 27 mL anhydrous methanol was cooled to +10° C. in an ice bath and 9.58 g (60 mmol) bromine was added all at once. The reaction was stirred at +10° C. for 45 minutes, upon which time 7.5 mL of water was added. The reaction was stirred at room temperature for a further 2.5 hr and concentrated. The crude product was taken up in ether and washed with brine. The organic phase was dried over MgSO4 and concentrated to afford crude 2-bromo-1-cyclohexyl-ethanone. The product was used immediately in the next step without further purification.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15]CC3C=CC=CC=3)=[O:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([OH:15])=[O:14])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)n1ccc2cc(C(=O)OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N1CCc2cc(C(=O)O)ccc21
Yield: 46.8 %

Procedure:
The benzyl 1-acetyl-1H-indole-5-carboxylate (550 mg) obtained above was suspended in ethanol (9 ml). 10% Palladium on carbon was added thereto, and the mixture was stirred for 16 hours at room temperature in a hydrogen atmosphere. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. Precipitated crystals were collected by filtration, washed with ether and dried under reduced pressure to give the title compound (180 mg, Y.:48%).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.S(Cl)(Cl)=O.[C:16]([O:20][C:21](=[O:30])[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH2:29])([CH3:19])([CH3:18])[CH3:17].C(C1C=CC(C(Cl)=O)=CC=1)=O.C(N(C(C)C)CC)(C)C>ClCCl.CN(C=O)C>[C:16]([O:20][C:21](=[O:30])[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:1](=[O:3])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: O=Cc1ccc(C(=O)Cl)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.8 %

Procedure:
To a suspension of 4-carboxybenzaldehyde (6 g, 40 mmol) in dichloromethane (10 mL) was added thionyl chloride (4.1 mL, 56 mmol, 1.4 eq), followed by DMF (1 mL) dropwise. The mixture was refluxed for 4 hours and excess of thionyl chloride and DMF were removed under reduced pressure. To a solution of (2-aminophenyl)-carbamic acid tert-butyl ester (8.32 g, 40 mmol, 1 eq) in dichloromethane (80 mL), stirred at 0° C., was added a suspension of 4-formyl benzoyl chloride in dichloromethane (20 mL), followed by diisopropyl ethylamine (3.61 mL, 20 mmol, 1 eq). The mixture was stirred for 30 minutes at 0° C. then at room temperature for 30 minutes. The crude residue was diluted with dichloromethane (300 mL) and washed with water. The combined organic layers were dried (MgSO4), filtered and concentrated under vacuo. The crude residue was purified by column chromatography on silica gel (elution 20% ethyl acetate in hexane) to give 6.1 g (45% yield) of anilide 315. 1H NMR (CDCl3): δ 10.18 (s, 1H), 9.64 (brs, 1H), 8.20 (d, J=7.9 Hz, 2H), 8.06 (d, J=7.9 Hz, 2H), 7.96 (d, J=7.9 Hz, 1H), 7.28-7.38 (m, 1H), 7.24 (d, J=4.4 Hz, 1H), 6.84 (s, 1H), 6.81 (d, J=8.8 Hz, 1H), 1.58 (s, 9H).
Reaction SMILES: C(ON[C:10]([C@H:12]1[C@H:17]2[O:18]C(C)(C)[O:20][C@@H:16]2[C@H:15]([OH:23])[CH2:14][N:13]1[S:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:29][CH:28]=1)(=[O:26])=[O:25])=[O:11])C1C=CC=CC=1.C[OH:41]>>[OH:18][C@H:17]1[C@H:16]([OH:20])[C@H:15]([OH:23])[CH2:14][N:13]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:29][CH:28]=2)(=[O:25])=[O:26])[C@H:12]1[C:10]([OH:41])=[O:11]
Reactant: CO
Reactant: CC1(C)O[C@H]2[C@H](O1)[C@H](C(=O)NOCc1ccccc1)N(S(=O)(=O)c1ccc(Oc3ccccc3)cc1)C[C@H]2O
Product: O=C(O)[C@H]1[C@@H](O)[C@H](O)[C@H](O)CN1S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The above compound (5) (8.68 g) was dissolved in methanol (350 mL) and a cation exchange resin (Muromac, 19.0 g) was added, and then the mixture was stirred overnight at room temperature. The insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel medium pressure column chromatography (chloroform:methanol=1:0→30:1→20:1→10:1) to obtain the titled compound (7.35 g) as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10](=[O:23])[CH2:11][C:12](=[O:22])/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH:5]=[CH:6][CH:7]=1.CN(C)C1C=CC(/C=C/C(=O)CC(=O)/C=C/C2C=CC(O)=C(OC)C=2)=CC=1>>[OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10](=[O:23])[CH2:11][C:12](=[O:22])[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(/C=C/c1ccc(O)cc1)CC(=O)/C=C/c1cccc(O)c1
Agent: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(N(C)C)cc2)ccc1O
Product: O=C(CCc1ccc(O)cc1)CC(=O)CCc1cccc(O)c1

Procedure:
The title compound was synthesized using the same procedure employed for Example 372, but with (1E,6E)-1-(3-hydroxyphenyl)-7-(4-hydroxyphenyl)hepta-1,6-diene-3,5-dione (20 mg, 65 μmol, synthesized in Example 59) as the starting material instead of (1E,6E)-1-(4-dimethylaminophenyl)-7-(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione, and was purified by silica gel column chromatography eluting with hexane/ethyl acetate=70/30 to 60/40. The product was obtained as a gum (15.5 mg, 77%) having the following characteristics.