Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40][CH:41]([C:45](O)=[O:46])[C:42](O)=[O:43])([CH3:33])[CH3:32]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[O:11][C:42](=[O:43])[C:41]([S:40][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[CH:31]([CH3:32])[CH3:33])=[C:45]([OH:46])[CH:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Reactant: CC(=O)c1cc(C)cc(C)c1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(-c2cc(O)c(Sc3ccccc3C(C)C)c(=O)o2)c1

Procedure:
The title compound was prepared by Method A using 3',5'-dimethylacetophenone (0.714 g, 4.83 mmol), trimethylsilyl triflate (1.12 mL, 5.79 mmol), triethylamine (1.34 mL, 9.66 mmol), methylene chloride (17 mL), and diethyl ester of [(2-isopropylphenyl)thio]propanedioic acid (1.00 g, 3.22 mmol) m.p. 154°-155° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.24 (d, 6H), 2.35 (s, 6H), 3.40 (m, 1H), 6.90 (d, 1H), 7.05 (t, 1H), 7.11 (dt, 2H), 7.20 (s, 1H), 7.27 (d, 1H), 7.45 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1.Cl>CN(C=O)C.CCOCC.O>[OH:1][C:2]1[CH:9]=[C:8]([O:10][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: N#Cc1ccc(O)cc1O
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1O
Temperature: 110 °C
Yield: 117.3 %

Procedure:
In a vial 2,4-dihydroxybenzonitrile (300 mg, 2.2 mmol), 2-chloro-5-nitropyridine (351.96 mg, 2.22 mmol) and K2 CO3 (920 mg, 6.62 mmol) were dissolved in DMF (5 mL). The reaction was heated for 1 hour under microwave irradiations (Set Temperature: 110° C.). The reaction mixture was diluted with Et2O and water, acidified with aqueous 1N HCl until pH=2, the phases were separated and the organics were dried over Na2SO4. The solid was filtered out and the solvent was removed affording crude 2-hydroxy-4-[(5-nitro-2-pyridinyl)oxy]benzonitrile (664 mg) as a brown solid. To a solution of this crude in dry DMF (5 mL) potassium carbonate (460 mg, 3.33 mmol) and isopropyl bromide (313 μL, 3.33 mmol) were added and the reaction mixture was stirred overnight at 50° C. The reaction was diluted with brine (10 mL) and extracted with ethyl acetate (2×20 mL). The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography on silica gel (SNAP 25 g) eluting from 100:0 to 75:25 cyclohexane/ethyl acetate affording the title compound (260 mg) as white solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][NH:5][C:4](=[S:7])[CH:3]1[C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9].C([O-])(=O)C.[Na+].Br[CH2:20][C:21](=O)[CH2:22][C:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:24].C(Cl)(Cl)Cl>C1C=CC=CC=1>[CH:11]([O:10][C:8]([C:3]1[CH:2]([CH3:1])[CH2:6][N:5]2[C:21](=[CH:22][C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[O:24])[CH2:20][S:7][C:4]=12)=[O:9])([CH3:13])[CH3:12]
Reactant: CC(C)OC(=O)C1C(=S)NCC1C
Reactant: O=C(CBr)CC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)OC(=O)C1=C2SCC(=CC(=O)Oc3ccc([N+](=O)[O-])cc3)N2CC1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
8.9 g of isopropyl 4-methyl-2-thioxopyrrolidine-3-carboxylate was dissolved in 200 ml of benzene and 5.1 g of anhydrous sodium acetate and 16.7 g of 4-nitrophenyl 4-bromoacetoacetate were added thereto. The obtained mixture was stirred at room temperature for 8 hours. Then 500 ml of chloroform was added and the mixture was washed with water and a saturated aqueous solution of sodium chloride. After drying and distilling off the solvent, the obtained residue was purified by silica gel column chromatography. A fraction eluted with dichloromethane was crystallized from a mixture of ether and n-hexane. Thus 11.9 g of the title compound was obtained.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C@H:32]2[CH2:37][CH2:36][C@H:35]([CH2:38][CH:39]=O)[CH2:34][CH2:33]2)=[CH:28][CH:27]=1)#[N:25].O>COC(C)(C)C>[CH3:2][O:3][CH:4]=[CH:39][CH2:38][C@H:35]1[CH2:34][CH2:33][C@H:32]([C:29]2[CH:28]=[CH:27][C:26]([C:24]#[N:25])=[CH:31][CH:30]=2)[CH2:37][CH2:36]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc([C@H]2CC[C@H](CC=O)CC2)cc1
Agent: [Cl-]
Solvent: COC(C)(C)C
Solvent: O
Product: COC=CC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Reaction time: 1 h

Procedure:
A suspension of 4.5 g of methoxymethyl-triphenylphosphonium chloride in 40 ml of t-butyl methyl ether was treated within 3 minutes with 1.5 g of potassium t-butylate while gassing with argon at -10° C. and the solution was stirred for a further 1 hour at 0°-5° C. The suspension was then treated dropwise within 5 minutes at 0° C. with a solution of 2.0 g of [trans-4-(p-cyanophenyl)cyclohexyl]acetaldehyde in 20 ml of t-butyl methyl ether and the mixture was stirred for a further 2 hours at room temperature. The reaction mixture was subsequently poured into 100 ml of water and extracted three times with 100 ml of diethyl ether each time. The organic phased were washed twice with 100 ml of water each time, dried over magnesium sulphate and concentrated. The resulting, viscous oil was dissolved in 15 ml of ethyl acetate and the clear solution was treated with 250 ml of petroleum ether. After leaving to stand for 10 minutes at -20° C. the precipitated triphenylphosphine oxide was filtered off and the filtrate was concentrated to dryness. Low-pressure chromatography (0.5 bar) of the residue (3.3 g) on silica gel with ethyl acetate/petroleum ether (vol. 5:95) gave 2.04 g (91%) of p-[trans-4-(3-methoxy-2-propenyl)cyclohexyl]benzonitrile as a colourless oil; Rf-value (ethyl acetate/petroleum ether vol. 10:90) 0.33.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:5]2[C:6]([C@@H:10]3[CH2:12][C@H:11]3[CH2:13][NH2:14])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1.C(=O)([O-])O.[Na+]>[CH3:1][C:2]1[CH:15]=[C:5]2[C:6]([C@@H:10]3[CH2:12][C@H:11]3[CH2:13][NH:14][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc2c([C@@H]3C[C@H]3CN)cccn2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc2c([C@@H]3C[C@H]3CNC(=O)c3ccccc3)cccn2n1
Yield: 67.3 %

Procedure:
To a solution of trans-1-[2-(2-methylpyrazolo[1,5-a]pyridin-4-yl)cyclopropyl]methanamine (50.0 mg, 0.248 mmol) and triethylamine (41.6 μL, 0.298 mmol) in tetrahydrofuran (2.5 mL) was added benzoyl chloride (31.7 μL, 0.273 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 5 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) 15 and silica gel column chromatography (NH, methanol/ethyl acetate=0/100→5/95) to give the title compound (51.0 mg, yield 67%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.[H-].[Na+].[CH2:14]([O:16]C(=O)OCC)C.Cl>C1(C)C=CC=CC=1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:5]([C:8]([OH:10])=[CH:9][C:14](=[O:16])[O:11]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1ccc(F)cc1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=c1cc(O)c2ccc(F)cc2o1
Temperature: 115 °C
Reaction time: 6 h

Procedure:
A solution of 1-(4-fluoro-2-hydroxyphenyl)ethanone (50 g, 0.33 mol) in toluene was added over 30 min to a suspension of NaH (60% oil, 65 g, 1.63 mol) in toluene. Then diethylcarbonate (59 mL, 0.49 mol) was added over 15 min and the reaction mixture was stirred at 115° C. for 6 h. The mixture was cooled to rt followed by the addition of HCl 2N and diluted with EtOAc. The organic phase was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by trituration in hexane and Et2O to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[C:13]([F:15])([F:14])[C:12]([CH3:17])([CH3:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[Cl:21][C:22]1[CH:23]=[C:24]([F:31])[C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1>>[NH2:18][C:10]1[O:11][C:12]([CH3:16])([CH3:17])[C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28]([C:25]3[C:24]([F:31])=[CH:23][C:22]([Cl:21])=[CH:27][N:26]=3)=[O:29])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: O=C(O)c1ncc(Cl)cc1F
Reactant: CC1(C)OC(N)=N[C@](C)(c2cc(N)ccc2F)C1(F)F
Product: CC1(C)OC(N)=N[C@](C)(c2cc(NC(=O)c3ncc(Cl)cc3F)ccc2F)C1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-2) and 5-chloro-3-fluoro-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white foam. MS (ISP): m/z=445.2 [M+H]+, 447.2 [M+2+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O>CS(C)=O>[CH:2]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:7][CH:8]=1)=[O:1]
Reactant: NC(=O)c1cc(-c2ccc(CO)cc2)no1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1cc(-c2ccc(C=O)cc2)no1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 50.3 %

Procedure:
To a solution of 3-(4-hydroxymethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 19; 100 mg, 0.46 mmol) in DMSO (1.5 mL) was added Dess-Martin periodinane (214 mg, 0.5 mmol). The mixture was stirred at room temperature for 2.5 h. Water (5 mL) was added and the mixture was filtered to give a white solid. The filtrate was extracted three times with EtOAc and the combined extracts were dried (Na2SO4), filtered and evaporated to give a residue. The white solid from the first filtration was triturated with MeOH and the mixture was filtered. The filtrate was evaporated to give a second residue. The two residues were combined and purified by chromatography (25% acetone/CH2Cl2) to give 3-(4-formyl-phenyl)-isoxazole-5-carboxylic acid amide (50 mg, 50%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[F:11][C:12]([F:23])([F:22])[O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.CC[O:26][C:27]([C:29]([CH2:31][C:32]([CH3:34])=[O:33])=[O:30])=O>>[C:32]([CH:31]1[CH:18]([C:17]2[CH:20]=[CH:21][C:14]([O:13][C:12]([F:23])([F:22])[F:11])=[CH:15][CH:16]=2)[N:1]([C:2]2[CH:3]=[C:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)[C:27](=[O:26])[C:29]1=[O:30])(=[O:33])[CH3:34]
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: Cc1cc(N)cn(C)c1=O
Reactant: CCOC(=O)C(=O)CC(C)=O
Product: CC(=O)C1C(=O)C(=O)N(c2cc(C)c(=O)n(C)c2)C1c1ccc(OC(F)(F)F)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 57.1 using 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2), 4-trifluoromethoxy-benzaldehyde and ethyl acetopyruvate. tR: 0.79 min (LC-MS 2); ESI-MS: 423 [M+H]+ (LC-MS 2); ESI-MS: 421 [M−H]− (LC-MS 2).
Reaction SMILES: [CH:1]([C:4]1[CH2:8][C:7](=[O:9])[NH:6][N:5]=1)([CH3:3])[CH3:2].[Cl:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N+:14]([O-])=[CH:13][CH:12]=1>C(OC(=O)C)(=O)C>[Cl:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14]/[C:13](=[C:8]2/[C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][NH:6][C:7]/2=[O:9])/[CH:12]=1
Reactant: CC(C)C1=NNC(=O)C1
Reactant: [O-][n+]1ccc(Cl)c2ccccc21
Solvent: CC(=O)OC(C)=O
Product: CC(C)C1=NNC(=O)/C1=C1/C=C(Cl)c2ccccc2N1

Procedure:
Methyl isobutyrylacetate (0.5 g, 3.47 mmol) was stirred in ethanol and acetic acid (10:1, 2:0.2 mL) and treated with hydrazine (0.13 mL, 4.16 mmol). After 24 hrs, the resulting solid was filtered off and washed with a minimum amount of ethanol to yield 3-isopropyl-1H-pyrazol-5(4H)-one. Then, the 3-isopropyl-1H-pyrazol-5(4H)-one (0.169 g, 1.34 mmol) and 4-chloroquinoline N-oxide (0.24 g, 1.34 mmol) were stirred in acetic anhydride (1.5 mL) at ambient temperature for 20-30 minutes. The reaction mixture was concentrated and the resulting solid was filtered off and washed with a minimum amount of ether to yield Example 18. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.30 (d, J=6.82 Hz, 6H) 3.98 (bs, 1H) 7.61 (t, J=7.58 Hz, 1H) 7.76-7.82 (m, 1H) 7.93 (d, J=8.34 Hz, 1H) 8.08-8.18 (m, 2H); ESI-MS: m/z calc'd for C15H14ClN3O 287.74. found 288.2 (M+H)+.
Reaction SMILES: C(OC1C=C(B(O)O)C=C(OC(C)C)C=1OC)(C)C.[CH:20]([O:23][C:24]1[CH:25]=[C:26]([CH:31]=[C:32]([O:36][CH:37](C)C)[C:33]=1[O:34]C)[C:27]([O:29][CH3:30])=[O:28])(C)C>>[CH3:20][O:23][C:24]1[CH:25]=[C:26]([CH:31]=[C:32]2[O:36][CH2:37][O:34][C:33]=12)[C:27]([O:29][CH3:30])=[O:28].[CH3:20][O:23][C:24]1[CH:25]=[C:26]([CH:31]=[C:32]2[O:36][CH2:37][O:34][C:33]=12)[C:27]([OH:29])=[O:28]
Reactant: COC(=O)c1cc(OC(C)C)c(OC)c(OC(C)C)c1
Agent: COc1c(OC(C)C)cc(B(O)O)cc1OC(C)C
Product: COC(=O)c1cc(OC)c2c(c1)OCO2
Product: COc1cc(C(=O)O)cc2c1OCO2

Procedure:
Synthesis of the title compound from methyl 3-methoxy-4,5-methylenedioxybenzoate was carried out by applying the synthetic procedure of 3,5-diisopropoxy-4-methoxyphenylboronic acid from methyl 3,5-diisopropoxy-4-methoxybenzoate in Reference Example 6. From methyl 3-methoxy-4,5-methylenedioxybenzoate (4.30 g, 20.5 mmol), 3-methoxy-4,5-methylenedioxybenzoic acid (3.00 g) was obtained as colorless prisms (melting point: 215.0-216.0° C.) (yield: 71%). From 3-methoxy-4,5-methylenedioxybenzoic acid (2.50 g, 12.7 mmol), 3-methoxy-4,5-methylenedioxy-1-nitrobenzene was obtained as a pale yellow amorphous powder (1.26 g, yield: 50%). From 3-methoxy-4,5-methylenedioxy-1-nitrobenzene (1.26 g, 16.4 mmol), 1-iodo-3-methoxy-4,5-methylenedioxybenzene was obtained as pale yellow needles (melting point: 71.0-72.0° C.) (1.08 g, yield: 61%). From 1-iodo-3-methoxy-4,5-methylenedioxybenzene (750.0 mg, 2.70 mmol), the title compound was obtained as a colorless crystalline powder (melting point: 279.0-281.0° C.) (347.0 mg, yield: 66%).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[OH-].[Na+].[NH2:12][C:13]1[C:14]([OH:47])=[C:15]([N:23]=[N:24][C:25]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[N:26][NH:27][C:28]2[CH:33]=[C:32]([S:34]([OH:37])(=[O:36])=[O:35])[CH:31]=[CH:30][C:29]=2[C:38]([OH:40])=[O:39])[CH:16]=[C:17]([S:19]([OH:22])(=[O:21])=[O:20])[CH:18]=1>O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:12][C:13]2[C:14]([OH:47])=[C:15]([N:23]=[N:24][C:25]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[N:26][NH:27][C:28]3[CH:33]=[C:32]([S:34]([OH:37])(=[O:35])=[O:36])[CH:31]=[CH:30][C:29]=3[C:38]([OH:40])=[O:39])[CH:16]=[C:17]([S:19]([OH:22])(=[O:21])=[O:20])[CH:18]=2)[N:7]=1
Reactant: Nc1cc(S(=O)(=O)O)cc(N=NC(=NNc2cc(S(=O)(=O)O)ccc2C(=O)O)c2ccccc2)c1O
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(S(=O)(=O)O)cc1NN=C(N=Nc1cc(S(=O)(=O)O)cc(Nc2nc(Cl)nc(Cl)n2)c1O)c1ccccc1
Temperature: 1.5 °C

Procedure:
9.22 parts of cyanuric chloride are suspended in 150 parts of ice-water. The pH is brought to 5 with 1 N sodium hydroxide solution and the temperature is kept at 0 to 2° C. A neutral solution of 29.80 parts of the copper complex of 5-amino-3-[3-phenyl-5-(2-carboxy-5-sulfophenyl)-1-formazano]-4-hydroxybenzenesulfonic acid in 250 parts of water is added to this suspension at 0 to 3° C. During the addition the pH is kept at 5 with a 2 N sodium hydroxide solution. After the addition the mixture is stirred at 0 to 3° C. and pH 5 for about a further 2 hours. A solution of 5-[4,6-dichloro-1,3,5-triazin-2-ylamino]-3-(3-phenyl-5-(2-carboxy-5-sulfophenyl)-1-formazano]4-hydroxybenzenesulfonic acid is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([Cl:30])[CH:29]=1)[O:5][C:6]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:19]3[NH:26][CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)=[CH:13][C:7]=1[C:8]([O:10]CC)=[O:9].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([Cl:30])[CH:29]=1)[O:5][C:6]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:19]3[NH:26][CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)=[CH:13][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)c1cc(Nc2ncnc3cc[nH]c23)ccc1Oc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(Nc2ncnc3cc[nH]c23)ccc1Oc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.1 %

Procedure:
To a solution of ethyl 2-(3,5-dichlorophenoxy)-5-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoate (100 mg) in a mixed solvent of tetrahydrofuran (0.68 mL) and ethanol (0.68 mL) was added 1N aqueous sodium hydroxide solution (0.68 mL), and the mixture was stirred at room temperature for 16 hrs. 1N Hydrochloric acid (0.68 mL) and water (5 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The resultant precipitate was collected by filtration, washed with water (10 mL×3) and diisopropyl ether (10 mL×3) and dried under reduced pressure (80° C.) to give the title compound (76 mg) as white powder crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=C(C=C[CH:25]=1)OC1CN([C@@H](CC2CCCCC2)C(O)=O)C(=O)C=1.Cl.[CH3:27]N(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.Cl.[OH:58][C@@H:59]([CH2:89]O)[CH2:60][N:61]1[CH:65]=[CH:64][C:63]([NH:66][C:67](=[O:88])[C@@H:68]([N:73]2[CH2:77][C:76]([O:78][C:79]3[CH:84]=[CH:83][CH:82]=[C:81]([Cl:85])[C:80]=3Cl)=[CH:75][C:74]2=[O:87])[CH2:69][CH:70]([CH3:72])[CH3:71])=[N:62]1>ClCCl.C(OCC)(=O)C>[Cl:85][C:81]1[CH:80]=[C:79]([CH:84]=[CH:83][CH:82]=1)[O:78][C:76]1[CH2:77][N:73]([C@@H:68]([CH2:69][CH:70]2[CH2:71][CH2:3][CH2:2][CH2:25][CH2:72]2)[C:67]([NH:66][C:63]2[CH:64]=[CH:65][N:61]([CH2:60][C:59]([OH:58])([CH3:27])[CH3:89])[N:62]=2)=[O:88])[C:74](=[O:87])[CH:75]=1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Reactant: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(Cl)c2)=CC1=O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3cccc(Cl)c3)=CC2=O)n1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 29.9 %

Procedure:
To a stirred solution of (S)-2-[4-(3-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid (200 mg, 0.6 mmol) in dichloromethane (10 mL) was gradually added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (115 mg, 0.6 mmol) and N,N-diisopropylethylamine (213 mg, 1.7 mmol) at room temperature, under nitrogen. After 15 min,, 1-hydroxybenzotriazole (0.092 g, 0.625 mmol) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 85 mg, 0.5 mmol) were added to the reaction mixture. The reaction mixture was then stirred at 23° C. for 48 h. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous ammonium chloride solution followed by a saturated aqueous sodium bicarbonate solution. The organic layer was then washed with a saturated aqueous sodium chloride solution, separated, dried over sodium sulfate and concentrated in vacuo to afford the crude product, which was purified by flash column chromatography (silica gel (100-200 mesh)) which afforded (S)-2-[4-(3-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (0.075 g, 27%) as a white solid: 1H NMR (400 MHz, CDCl3) δ ppm 0.84-1.11 (m, 2H), 1.16 (s, 3H), 1.19-1.35 (m, 3H), 1.27 (s, 3H), 1.60-1.98 (m, 8H), 3.39 (br. s., 1H), 3.95 (s, 2H), 4.09 (d, J=18.0 Hz, 1H), 4.28 (d, J=18.0 Hz, 1H), 4.89 (dd, J=9.2, 6.5 Hz, 1H), 5.03 (s, 1H), 6.69 (d, J=2.2 Hz, 1H), 7.09 (dd, J=8.2, 1.8 Hz, 1H), 7.21 (t, J=1.8 Hz, 1H), 7.27 (m, 1H), 7.30 (d, J=2.2 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 8.49 (br. s., 1H).
Reaction SMILES: C([CH2:4][O:5][C:6]1[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[C:7]=1[C:8](=O)[CH:9]=[CH:10][CH:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:13][CH2:12]1)(O)=O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C.O>C(O)(=O)C>[OH:27][C:23]1[C:7]2[C:8]([CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:15][CH:16]=3)=[CH:4][O:5][C:6]=2[CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)COc1cccc(O)c1C(=O)C=CC1C=CC(OCCCO)=CC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: OCCCOc1ccc(CCc2coc3cccc(O)c23)cc1
Temperature: 115 °C
Reaction time: 8 h
Yield: 19.3 %

Procedure:
To a solution of 2′-carboxymethoxy-6′-hydroxy-4-(3-hydroxypropoxy)dihydrochalcone (2.8 g) in acetic acid (39.4 mL) were added sodium acetate (17.8 g) and acetic anhydride (17.9 mL), and the mixture was stirred at 115° C. overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethylether. The extract was washed with water twice, a saturated aqueous sodium hydrogen carbonate solution, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in methanol (10 mL). To the solution was added 2 mol/L aqueous sodium hydroxide solution (26 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was acidified by addition of 2 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1-1/1) to give the title compound (0.45 g).
Reaction SMILES: B.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1[N:11]=[C:12]([N:16]([CH:20]([CH2:30][CH2:31][CH3:32])[C:21]2[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][CH:22]=2)[CH2:17][CH2:18][CH3:19])[S:13][C:14]=1[CH3:15].O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CO>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1[N:11]=[C:12]([N:16]([CH:20]([CH:30]2[CH2:32][CH2:31]2)[C:21]2[CH:22]=[CH:23][C:24]([CH2:27][OH:28])=[CH:25][CH:26]=2)[CH2:17][CH2:18][CH3:19])[S:13][C:14]=1[CH3:15]
Reactant: CCCC(c1ccc(C(=O)O)cc1)N(CCC)c1nc(-c2ccc(Cl)cc2Cl)c(C)s1
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCN(c1nc(-c2ccc(Cl)cc2Cl)c(C)s1)C(c1ccc(CO)cc1)C1CC1
Reaction time: 8 h

Procedure:
2 ml of 1N borane solution in tetrahydrofuran are added, at -7° C., to 403 mg of the compound of Example 1 in 15 ml of anhydrous tetrahyrofuran, and the mixture is then left stirring overnight. 10 ml of water and 2 ml of methanol are then added in the presence of potassium carbonate. The reaction mixture is evaporated to dryness under vacuum.