Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[C:3]1([S:9]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O1CCCC1>C(OCC)(=O)C>[C:3]1([S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH2:16][OH:17])=[CH:18][CH:19]=2)(=[O:10])=[O:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(S(=O)(=O)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.3 %

Procedure:
Sodium borohydride (777 mg, 20.5 mmol) was added slowly in portions to a 0° C. solution of 4-(benzenesulfonyl)-benzaldehyde (4.29 g, 18.6 mmol) and tetrahydrofuran (60 mL). The reaction mixture was allowed to warm to room temperature, then stirred at room temperature for 4 hours. The reaction mixture was then cooled over an ice-water bath, diluted with ethyl acetate (80 mL), then carefully quenched with a saturated aqueous solution of ammonium chloride (10 mL). The mixture was washed with water (80 mL), then the organic phase was dried over MgSO4, filtered, and concentrated to afford 2.83 g (61%) of (4-benzenesulfonyl-phenyl)-methanol as a white solid. This product was used in subsequent steps without further purification.
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Br:31][C:32]1[CH:37]=[C:36]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:35]=[CH:34][C:33]=1[CH2:42]Br.Cl>CN(C)C=O>[Br:31][C:32]1[CH:37]=[C:36]([C:38]([CH3:40])([CH3:39])[CH3:41])[CH:35]=[CH:34][C:33]=1[CH2:42][N:9]1[C:10](=[O:23])[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])=[C:12]([OH:13])[N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]1=[O:24]
Reactant: CC(C)(C)c1ccc(CBr)c(Br)c1
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(Cn2c(=O)c(C(=O)NCC(=O)O)c(O)n(C3CCCCC3)c2=O)c(Br)c1
Reaction time: 8 h
Yield: 7.5 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. potassium carbonate (740 mg, 5.35 mmoles) and 2-bromo-1-(bromomethyl)-4-(1,1-dimethylethyl)benzene (612 mg, 2.0 mmoles) in dimethylformamide (5 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The combined organic solutions were washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (1.0 mL) and 6 molar sodium hydroxide (1.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated. Preparative HPLC (50-90% acetonitrile-water-0.1% TFA) gave the title compound (40 mg, 7.5%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.17 (br. s., 1 H), 10.14 (br. s., 1 H), 7.59 (d, J=1.52 Hz, 1H), 7.33 (dd, J=8.08, 1.52 Hz, 1 H), 6.92 (d, J=8.08 Hz, 1 H), 4.96 (s, 2 H), 4.65 (t, J=11.75 Hz, 1H), 4.13 (d, J=5.56 Hz, 2 H), 2.25 (q, J=11.54 Hz, 2 H), 1.79 (d, J=12.13 Hz, 2 H), 1.53-1.73 (m, 3 H), 1.20-1.38 (m, 11 H), 1.11 (q, 1 H)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2].[Cl:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[C:38]([Cl:40])[CH:39]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:36]3[CH:35]=[C:34]([Cl:33])[CH:39]=[C:38]([Cl:40])[CH:37]=3)[CH:13]=2)[N:8]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]([F:26])([F:24])[F:25])=[CH:20][CH:21]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2]
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(OC(F)(F)F)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3cc(Cl)cc(Cl)c3)ccc2n1-c1ccc(OC(F)(F)F)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-trifluoromethoxyphenyl)indole-3-carboxylic acid ethyl ester (160 mg, 0.36 mmol, see step (b) Example 9) and 3,5-dichlorobenzeneboronic acid (140 mg, 0.72 mmol). Yield 100 mg (45%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]([C:17]2[CH:41]=[CH:40][C:20]3[N:21]([CH3:39])[C:22]([NH:24][C:25]4[S:26][C:27]5[CH:33]=[C:32]([O:34][C:35]([F:38])([F:37])[F:36])[CH:31]=[CH:30][C:28]=5[N:29]=4)=[N:23][C:19]=3[CH:18]=2)=[O:16])[CH2:9]1)=O)(C)(C)C.[ClH:42]>>[ClH:42].[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]([C:17]2[CH:41]=[CH:40][C:20]3[N:21]([CH3:39])[C:22]([NH:24][C:25]4[S:26][C:27]5[CH:33]=[C:32]([O:34][C:35]([F:36])([F:38])[F:37])[CH:31]=[CH:30][C:28]=5[N:29]=4)=[N:23][C:19]=3[CH:18]=2)=[O:16])[CH2:9]1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NC3CCCN(C(=O)OC(C)(C)C)C3)ccc21
Agent: Cl
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NC3CCCNC3)ccc21

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid piperidin-3-ylamide hydrochloride (13 mg) was prepared by following General Procedure L using 3-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (30 mg), and hydrochloric acid (0.1 ml, 4.0 N solution dioxane). LC/MS: m/z 492.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:19])OC2C=CC([N+]([O-])=O)=CC=2)=[CH:3][CH:2]=1.Cl.[NH2:21][C:22]1[C:23]2[C:33]([O:34][CH2:35][C@H:36]3[CH2:41][CH2:40][CH2:39][NH2+:38][CH2:37]3)=[CH:32][CH:31]=[CH:30][C:24]=2[NH:25][S:26](=[O:29])(=[O:28])[N:27]=1>>[NH2:21][C:22]1[C:23]2[C:33]([O:34][CH2:35][C@H:36]3[CH2:41][CH2:40][CH2:39][N:38]([C:8]([NH:7][C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[O:19])[CH2:37]3)=[CH:32][CH:31]=[CH:30][C:24]=2[NH:25][S:26](=[O:28])(=[O:29])[N:27]=1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCC[NH2+]C3)c21
Reactant: O=C(Nc1ccncc1)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCN(C(=O)Nc4ccncc4)C3)c21

Procedure:
Prepared as in Example 29 from 4-nitrophenyl pyridin-4-ylcarbamate (Example 28a) and (S)-3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 2a). MS=431 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([OH:16])=[CH:14][C:13]([CH3:17])=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:25](Cl)(=[O:27])[CH3:26].O>O1CCCC1>[C:25]([O:16][C:15]1[N:11]([C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:9]=2)[N:12]=[C:13]([CH3:17])[CH:14]=1)(=[O:27])[CH3:26]
Reactant: Cc1cc(O)n(-c2ccc(C(C)(C)C)cc2)n1
Reactant: CC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cc(C)nn1-c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 86.6 %

Procedure:
1-(4-t-Butylphenyl)-5-hydroxy-3-methyl-1H-pyrazole (21.7 g, 94.1 mmol) in tetrahydrofuran (600 mL) was mixed with triethylamine (26.2 mL, 188 mmol.) and acetyl chloride (7.4 mL, 104 mmol) at 0° C. and stirred at room temperature for 45 minutes. The reaction solution was mixed with water (300 mL), and the aqueous layer and the organic layer were separated. The solvent was removed from the organic layer by distillation, and the residue was mixed with ethyl acetate. The aqueous layer was extracted with ethyl acetate twice, and the extract was combined with the organic layer. The combined organic layer was washed with saturated aqueous sodium hydrogen carbonate once, with water twice and with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give 22.2 g of the desired product (87% yield).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:29](=[O:30])[N:7]2[CH:8]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:31])[C:5]1=[O:32])=[CH:15][C:14]([O:19][CH2:20][CH3:21])=[CH:13][CH:12]=4.[CH3:33][NH:34][CH3:35].O>C(#N)C.O1CCCC1.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:33][N:34]([CH3:35])[CH2:2][CH2:3][N:4]1[C:29](=[O:30])[N:7]2[CH:8]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:31])[C:5]1=[O:32])=[CH:15][C:14]([O:19][CH2:20][CH3:21])=[CH:13][CH:12]=4
Reactant: CCOc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCBr)C(=O)N1C3c1cccc(O)c1
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCN(C)C)C(=O)N1C3c1cccc(O)c1
Yield: 44 %

Procedure:
To a suspension of 200 mg (3aSR,10RS)-2-(2-Bromo-ethyl)-6-ethoxy-10-(3-hydroxy-phenyl)-3a-methyl-3a,4,9,10-tetrahydro-2,9,10a-triaza-cyclopenta[b]fluorene-1,3-dione (example 22) in 10 ml acetonitrile are added 200 μl of a 2 M solution of dimethyl amine in tetrahydrofurane and 85 mg sodium carbonate. The mixture is heated to reflux and additional 1 ml of the 2 m solution of dimethyl amine in THF are added. After additional 2 h heating to reflux, another 600 μl of the solution of dimethyl amine in THF are added. The mixture is heated to reflux for 15 h. Water is added and the mixture is extracted with ethyl acetate. The combined organic layers are washed with brine and dried with magnesium sulfate. After removal of the solvent under reduced pressure, the residue is triturated with diisopropyl ether. 82 mg (44%) of title compound are obtained as a colorless solid. MS: m/z (MH+)=463.2
Reaction SMILES: O.[OH-].[Li+].O.[CH3:5][C:6]1[CH:15]=[C:14]([N:16]2[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[C:18]([C:25]([O:27]C)=[O:26])=[CH:17]2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1>O1CCCC1>[CH3:5][C:6]1[CH:15]=[C:14]([N:16]2[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[C:18]([C:25]([OH:27])=[O:26])=[CH:17]2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: COC(=O)c1cn(-c2cc(C)nc3ccccc23)c2ncccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-n2cc(C(=O)O)c3cccnc32)c2ccccc2n1
Yield: 72.5 %

Procedure:
0.62 g (15 mmol) of lithium hydroxide monohydrate and 18 cm3 of water were added, at a temperature in the region of 20° C., to 1.6 g (5.0 mmol) of methyl 1-(2-methylquinolin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate in solution in 18 cm3 of tetrahydrofuran. After stirring at reflux of the solvent for 4 h, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa) and the residue was taken up in 80 cm3 of water. The mixture was extracted with 30 cm3 of ethyl acetate and then the pH was adjusted to 3 by addition of 14 cm3 of a 1N hydrochloric acid solution. The precipitate obtained was filtered off, washed twice with 10 cm3 of water, pulled dry and then dried in a desiccator under reduced pressure at a temperature in the region of 20° C. for 4 days and under reduced pressure (2.7 kPa) at a temperature in the region of 50° C. for 12 h. 1.1 g of 1-(2-methylquinolin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid were thus obtained in the form of a yellow crystalline powder melting at a temperature of greater than 260° C. used directly in the following stage.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][N:15]3[CH2:21][C:22]2[C:30]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[NH:24][N:23]=2)[CH:9]=1)[C:5]#[N:6].C1C=C(Cl)C=C(C(OO)=[O:39])C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][N:15]3[CH2:21][C:22]2[C:30]3[C:25](=[N+:26]([O-:39])[CH:27]=[CH:28][CH:29]=3)[NH:24][N:23]=2)[CH:9]=1)[C:5]#[N:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3c2cnn3Cc2n[nH]c3ncccc23)c1
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3c2cnn3Cc2n[nH]c3c2ccc[n+]3[O-])c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 3-chloro-5-{[5-chloro-1-(1H-pyrazolo[3,4-b]pyridin-3-ylmethyl)-1H-indazol-4-yl]oxy}benzonitrile (96 mg, 0.221 mmol) was added mCPBA (59.8 mg, 0.243 mmol) and stirred at room temperature for 18 hours. The suspension was concentrated in vacuo and then resuspended in DMF (5 mL). This suspension was filtered and then purified by reverse phase HPLC (Luna column, 10μ, C18, 250×21.2 cm) eluting with 5-95% ACN/water with 0.1% TFA). The desired fractions were concentrated to dryness and the resulting solid was suspended in MeOH (1 mL) and filtered to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[Br:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1[S:28](Cl)(=[O:30])=[O:29]>CN(C)C1C=CN=CC=1.ClCCl>[Br:17][C:18]1[CH:23]=[C:22]([C:24]([F:26])([F:25])[F:27])[CH:21]=[CH:20][C:19]=1[S:28]([NH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:30])=[O:29]
Reactant: COC(=O)c1sccc1N
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Br
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(F)(F)F)cc1Br
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 24 %

Procedure:
To a cooled (0° C.) solution of methyl 3-aminothiophene-2-carboxylate (534.0 mg; 3.4 mmol), 4-dimethylaminopyridine (94.3 mg; 0.77 mmol) and pyridine (2.5 mL; 30.9 mmol) in anhydrous dichloromethane (60 mL) was added 2-bromo-4-(trifluoromethyl)benzene-1-sulfonyl chloride (1.0 g; 3.09 mmol) portion-wise. After addition was complete the reaction mixture was stirred at 0° C. for 20 minutes, gradually allowed to war to room temperature, stirred for 16 hours, and then washed with aqueous hydrochloric acid (50 mL; 2N). The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by automated silica gel column chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 30% v/v over 400 mL gradient elution) to give the title product as a white solid (330 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]([CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:11](=[O:14])[CH:12]=[CH2:13])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH:28]=[O:29].C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:10]([CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:11](=[O:14])[CH2:12][CH2:13][C:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=2)=[O:29])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9]
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(SC)c(F)c1
Reactant: O=Cc1ccccn1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CSc1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ccccn2)cc1F
Temperature: 25 °C
Yield: 42 %

Procedure:
To a solution of 4-[3-fluoro-4-(methylsulfanyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (225 mg) in ethanol (3.6 mL) were added pyridine-2-carbaldehyde (83.2 μL), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (21.6 mg) and triethylamine (43.7 μL), and the mixture was stirred with heating under reflux for 2 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (127 mg, yield 42%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:12]1(=O)[O:17][C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12>>[CH3:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[N:4]1[C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]2[C:12]1=[O:17]
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Reactant: O=C1OC(=O)c2ccccc21
Product: Cc1cc([N+](=O)[O-])ccc1N1C(=O)c2ccccc2C1=O
Yield: 83 %

Procedure:
A mixture of 10.0 g (65.7 mmole) of 2-methyl-4-nitroaniline and 10.7 g (72.3 mmole) of phthalic anhydride was heated in an oil bath with an initial temperature of 150°. As the temperature was raised slowly to 165°, the mixture melted and resolidified. The cooled mixture was triturated with 200 ml of dichloromethane and filtered, and the filtrate was washed successively with 3N aqueous hydrochloric acid, water, and 5% aqueous sodium hydroxide. The organic phase was dried over calcium chloride, treated with activated charcoal, filtered, and the filtrate concentrated in vacuo. The resultant solid was suspended in hot ethanol and, after cooling, was collected and dried, giving 15.4 g of N-(2-methyl-4-nitrophenyl)phthalimide. A portion (10.0 g) of the intermediate was hydrogenated in tetrahydrofuran containing 4 ml of concentrated aqueous hydrochloric acid using 5 psi hydrogen gas over 5% palladium on carbon. The filtered solution was concentrated to dryness and the resultant solid washed with methanol, giving 8.3 g of the title compound. The product thus isolated was used in subsequent reactions without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([C:19]2[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=2)[CH:3]=1.[C:25](Cl)(=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=1.C(N(CC)CC)C>ClCCl>[CH3:33][O:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[C:25]([NH:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[C:4]([C:19]2[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=2)[CH:3]=1)=[O:34]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: Cn1nccc1-c1cc(N)ccc1OCCNC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(C(=O)Nc2ccc(OCCNC(=O)OC(C)(C)C)c(-c3ccnn3C)c2)c1
Temperature: 22 °C
Reaction time: 18 h
Yield: 73.9 %

Procedure:
Tert-butyl 2-(4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethylcarbamate (265 mg, 797.2 μmol), m-anisoyl chloride (168.0 μl, 1.5 eq) and triethylamine (266.7 μl, 2.4 eq) were taken up in 20 mL of dichloromethane in a round bottomed flask and stirred at 22° C. for 18 hr. The reaction was then concentrated and purified by column chromatography (40-75% ethyl acetate in hexane) to afford the title compound as a pale yellow oil in 73.9% yield LCMS m/z (%)=467 (M+H, 100). 1H NMR (400 MHz, CDCl3) δ ppm 1.43 (s, 9 H), 3.42 (q, J=5.56 Hz, 2H), 3.78 (s, 3 H), 3.88 (s, 3 H), 4.04 (t, J=4.80 Hz, 2 H), 6.28 (d, 1 H), 7.01 (d, J=9.09 Hz, 1 H), 7.10 (dt, J=4.55, 2.53 Hz, 1 H), 7.38-7.41 (m, 2 H), 7.43-7.45 (m, J=3.03 Hz, 1 H), 7.54 (d, J=2.02 Hz, 1 H), 7.66-7.71 (m, 1 H), 7.76 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=O)[CH2:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[C:13]([F:18])[C:12]=1[F:19].[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.B(F)(F)F.CCOCC>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1/[C:9](=[N:25]\[NH:24][C:21](=[NH:22])[NH2:23])/[CH2:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[C:13]([F:18])[C:12]=1[F:19]
Reactant: N=C(N)NN
Reactant: O=C(Cc1c(F)ccc(F)c1F)c1cc(Cl)ccc1Br
Agent: Cl
Agent: FB(F)F
Solvent: CO
Solvent: CCOCC
Product: N=C(N)N/N=C(/Cc1c(F)ccc(F)c1F)c1cc(Cl)ccc1Br
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a screw cap pressure vessel was added the intermediate from Step A (800 mg, 2.20 mmol), aminoguanidine hydrochloride (280 mg, 2.53 mmol), methanol (20 mL) and boron trifluoride diethyl etherate (0.63 mL, 4.95 mmol). After stirring at 100° C. for 1 hour, boron trifluoride diethyl etherate (1 mL) and aminoguanidine hydrochloride (200 mg) were added and the reaction solution heated at 100° C. for 3 hours. The solution was concentrated and the residue partitioned between EtOAc and aqueous 1N NaOH. The organic phase was washed with aqueous 1N NaOH (2×), brine and dried over anhydrous sodium sulfate. The solution was then filtered and concentrated to give the indicated product. m/z=419 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[C:11]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:12][N:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=23)=O)=[CH:4][CH:3]=1.O1CCCC1>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:10]2[C:11]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:12][N:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=23)=[CH:6][CH:7]=1
Reactant: CCCCc1nn2ccccc2c1C(=O)c1ccc(Br)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1nn2ccccc2c1Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.1 %

Procedure:
3.7 g of the product obtained in Example 1 were then introduced at ambient temperature and the mixture was stirred at ambient temperature for about 2 hours. Tetrahydrofuran with 20% water was introduced at a temperature of about 0° to 10° C., and the mixture was taken up in water, filtered, decanted and extracted with ethyl acetate. The organic phase was dried, filtered and the solvents were eliminated under reduced pressure at a temperature of about 50° C. to obtain 3.7 g of the expected product melting at <50° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:25](=[O:40])[CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])[CH2:27][CH2:28][C:29]([O:31]C)=[O:30])[CH:12]=[C:13]([O:15]CC2C=CC(OC)=CC=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl.P([O-])([O-])([O-])=O.C(O)(C)(C)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:25](=[O:40])[CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH:12]=[C:13]([OH:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCC(C(=O)c1cc(OCc2ccccc2)cc(OCc2ccc(OC)cc2)c1)c1ccccc1C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1ccccc1C(CCC(=O)O)C(=O)c1cc(O)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of methyl (RS)-5-[3-benzyloxy-5-(4-methoxybenzyloxy)phenyl]-4-(2-methylphenyl)-5-oxopentanoate (0.54 g) in dichloromethane (10 mL), pH 7.3 phosphate buffer and tert-butanol (0.1 mL) is treated at 0° C. with 2,3-dichloro-5,6-dicyanobenzoquinone (0.34 g) and stirred at ambient temperature for 48 hours. It is then diluted with water (100 mL) and extracted with dichloromethane (3×30 mL). The combined organic extracts are washed with brine (50 mL), dried over magnesium sulphate and concentrated. The resulting oil (0.4 g) is dissolved in a solution of potassium hydroxide in methanol (20 mL; 15% w/v) and heated at reflux for 5 hours and is then allowed to cool. The mixture is concentrated, diluted with water (30 mL) and acidified to pH1 by treatment with concentrated hydrochloric acid. The mixture is extracted with ethyl acetate (3×50 mL) and the combined organic extracts are washed with brine and dried over magnesium sulphate, and concentrated. The resulting residue is chromatographed on silica gel, eluting with a mixture of ethyl acetate and pentane (1:1 v/v). The resulting oil is triturated with a mixture of diisopropyl ether and pentane, to give (RS)-5-(3-benzyloxy-5-hydroxyphenyl)-4-(2-methylphenyl)-5-oxopentanoic acid in the form of a white solid (80 mg), m.p. 116-117° C. [Elemental analysis:- C,73.80; H,5.90%; Calculated:- C,74.24;H,5.98%].