Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[C:11]([F:32])[C:10]=2[F:33])[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[C:41](OC(=O)C)(=[O:43])[CH3:42]>>[C:41]([NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[C:11]([F:32])[C:10]=2[F:33])[CH:5]=[CH:4][N:3]=1)(=[O:43])[CH3:42]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)c(F)c2F)c(=O)n(-c2ccccc2)n1C
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cc(Oc2ccc(NC(=O)c3c(C)n(C)n(-c4ccccc4)c3=O)c(F)c2F)ccn1
Temperature: 35 °C
Reaction time: 4 h
Yield: 68.9 %

Procedure:
To a suspension of N-(4-((2-aminopyridin-4-yl)oxy)-2,3-difluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (135 mg, 0.3 mmol) in acetic anhydride (6 mL) was added Et3N (0.4 mL, 2.9 mmol). The reaction mixture was stirred at 35° C. for 4 hours, then filtered, and the filter cake washed with PE (5 mL), EtOAc (5 mL) and CH3OH (2 mL) respectively to give the title compound as a beige solid (102 mg, 68.9%).
Reaction SMILES: [CH2:1]([C:4]1[C:9]([Cl:10])=[C:8]([Cl:11])[CH:7]=[CH:6][C:5]=1[OH:12])[CH2:2][CH3:3].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(C(C)=O)C>[CH2:1]([C:4]1[C:9]([Cl:10])=[C:8]([Cl:11])[CH:7]=[CH:6][C:5]=1[O:12][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH2:2][CH3:3]
Reactant: O=C(O)CCCCCCBr
Reactant: CCCc1c(O)ccc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCCCCC(=O)O)ccc(Cl)c1Cl
Temperature: 25 °C

Procedure:
A solution of 3.09 g. of 2-propyl-3,4-dichlorophenol, 3.1 g. of 7-bromoheptanoic acid, 3.1 g. of potassium carbonate, and 2.0 g. of potassium iodide in 50 ml. of methyl ethyl ketone was heated at reflux overnight. The reaction mixture was cooled to room temperature and evaporated in vacuo. Ethyl acetate and water were added to the residue and the layers were separated. Fresh water was added to the organic layer, the pH was adjusted to 2.0 with acid, and the layers were separated. The organic layer was washed with a saturated sodium chloride solution, filtered through sodium sulfate, and evaporated to dryness to give 4.68 g. of the desired title product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:7])[S:5][CH:6]=1.[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O)=[O:9].C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH3:7][C:4]1[S:5][CH:6]=[C:2]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:8]=[O:9])[CH:3]=1
Reactant: O=Cc1ccccc1B(O)O
Reactant: Cc1cc(Br)cs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccccc2C=O)cs1
Temperature: 150 °C
Yield: 80.9 %

Procedure:
In a microwave vial, 4-bromo-2-methyl-thiophene (653 mg, 3.69 mmol), 2-formyl phenylboronic acid (500 mg, 3.36 mmol) and 7 ml of actonitrile were mixed. 6.7 ml of 1N aqueous sodium carbonate was added to above solution, followed by 5 mole percent of dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated at 150° C. for 5 minutes with microwave irradiation. After cooling, 50 ml of ethyl acetate was added, the organic layer was separated, washed with water, dried with sodium sulfate, the organic solvent was evaporated and the residue was purified by ISCO to give 550 mg of 2-(5-methyl-thiophen-3-yl)benzaldehyde, yield 81%.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:25][C@H:26]1[CH2:31][CH2:30][CH2:29][C@H:28]([OH:32])[CH2:27]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:2]([NH:25][C@H:26]4[CH2:31][CH2:30][CH2:29][C@H:28]([OH:32])[CH2:27]4)=[N:7][CH:6]=[N:5][C:4]=3[O:8][C:9]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Reactant: N[C@H]1CCC[C@H](O)C1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(N[C@H]4CCC[C@H](O)C4)c23)cc1
Temperature: 120 °C

Procedure:
Initially charge 1.0 g (2.97 mmol) of 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine and 513 mg (approx. 4.5 mmol) of (+/−)-cis/trans-3-aminocyclohexanol (approx. 3:1 cis/trans mixture; prepared according to J. Chem: Soc. Perkin Trans. I, 1994, 537) in 2.7 ml of DMF. After adding 1.03 ml (5.94 mmol) of DIEA, heat the mixture to 120° C. for 2 h. After cooling, add to ice-water. Filter off the precipitated solid with suction, wash with water and dry under reduced pressure. Purify the crude product by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 2:1→1:2). 1.05 g (85.1% of theory) of the target product are obtained as a cis/trans mixture.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C@@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])=[O:17])=[CH:11][CH:10]=1)=O)(C)(C)C.O1CCOCC1.Cl>O1CCOCC1>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C@@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])=[O:17])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(NC(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccc(NC(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of the Product from Example 3A (0.245 g, 0.56 mmol) in dioxane (5 mL) was added 4M HCl dioxane (2.8 mL, 11.2 mol) and the mixture was stirred at ambient temperature for 17 hours. The mixture was concentrated and azeotroped with toluene to five a tan solid (0.18 g, 86%).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:28]4[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]5[CH2:27][CH2:26][CH2:25][CH2:24]5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:35](Br)[CH:36]=[CH2:37].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:37]([O:34][C:31]1[CH:30]=[CH:29][C:28]([C:14]2[C:15]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]4[CH2:24][CH2:25][CH2:26][CH2:27]4)[N:17]=3)=[C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([NH:6][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[N:12]3[N:13]=2)=[CH:33][CH:32]=1)[CH:36]=[CH2:35]
Reactant: Oc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 25 °C
Yield: 61.6 %

Procedure:
To a solution of 4-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenol (100 mg, 0.22 mmol) in N,N-dimethylformamide (5 mL) was added allyl bromide (21 μL, 0.24 mmol) and potassium carbonate (122 mg, 0.88 mmol). The mixture was heated at reflux for 3 hours. The mixture was allowed to cool to room temperature and water was added. The mixture was extracted with ethyl acetate. The ethyl acetate phase was dried (magnesium sulfate), filtered and concentrated to a solid. The residue was purified by flash chromatography (1:1 ethyl acetate:hexanes) to give 2-[4-(allyloxy)phenyl]-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine (67 mg, 61%) as a yellow solid. 1H NMR (CDCl3): δ 7.94 (d, 1H), 7.73 (d, 1H), 7.53 (d, 2H), 7.24 (t, 1H), 6.95 (d, 2H), 6.28 (d, 1H), 6.08–5.96 (m, 3H), 5.41 (dd, 1H), 5.27 (dd, 1H), 5.10 (d, 1H), 4.56 (d, 2H), 4.32 (m, 1H), 3.95 (m, 1H), 2.10–2.00 (m, 4H), 1.76–1.45 (m, 12H); MS m/z 495 (M+1); Anal. Calcd for C30H34N6O: C, 72.86; H, 6.93; N16.99. Found: C, 72.47; H, 7.05; N, 16.75.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([OH:18])[C:11]3[S:17][CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[F:26][C:27]([F:33])([F:32])[S:28](O)(=[O:30])=[O:29]>C(Cl)Cl>[F:26][C:27]([F:33])([F:32])[S:28]([O:18][C:10]1[C:11]2[S:17][CH2:16][CH2:15][CH2:14][C:12]=2[N:13]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:9]=1)(=[O:30])=[O:29]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: Oc1nc(-c2cccc(Cl)c2)nc2c1SCCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(Oc1nc(-c2cccc(Cl)c2)nc2c1SCCC2)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.4 %

Procedure:
To a suspension of 2-(3-chlorophenyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-ol (5.2 g, 18.6 mmol) in methylene chloride (200 mL) at 0° C. was added N,N-dimethylaminopyridine (0.020 g, cat.), triethylamine (5.2 mL, 37.3 mmol) and trifluoromethanesulfonic acid (3.7 mL, 22.4 mmol). The suspension was warmed to rt and stirred for 3 h. The mixture was cooled to 0° C. and the reaction was quenched with a saturated solution of NaHCO3. The organic layer was washed a saturated solution of NaHCO3 and brine. The organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by column chromatography (silica, methylene chloride) to afford title compound (6.6 g, 86%) as a white solid. MW=410.82. 1H NMR (CDCl3, 300 MHz) δ 8.35-8.31 (m, 1H), 8.25-8.18 (m, 1H), 7.48-7.36 (m, 2H), 3.18-3.05 (m, 4H), 2.38-2.27 (m, 2H); APCI MS m/z 411 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[O:12]1[CH2:17][CH2:16][N:15]([S:18]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([CH:30]=2)[C:26]([NH:28][NH2:29])=[O:27])(=[O:20])=[O:19])[CH2:14][CH2:13]1>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6](/[C:8](=[N:29]/[NH:28][C:26](=[O:27])[C:25]2[CH:30]=[C:21]([S:18]([N:15]3[CH2:14][CH2:13][O:12][CH2:17][CH2:16]3)(=[O:20])=[O:19])[CH:22]=[N:23][CH:24]=2)/[CH3:9])[CH:7]=1
Reactant: NNC(=O)c1cncc(S(=O)(=O)N2CCOCC2)c1
Reactant: CC(=O)c1cc(Cl)ccc1O
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1cncc(S(=O)(=O)N2CCOCC2)c1)c1cc(Cl)ccc1O
Temperature: 70 °C
Yield: 65.7 %

Procedure:
1-(5-chloro-2-hydroxyphenyl)ethanone (6.55 mg, 0.038 mmol) and 5-(morpholinosulfonyl)nicotinohydrazide (10 mg, 0.035 mmol) was dissolved in Methanol (3 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was refluxed for 12 h at 70° C. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the title compound (E)-N′-(1-(5-chloro-2-hydroxyphenyl)ethylidene)-5-(morpholinosulfonyl)nicotinohydrazide (10 mg, 0.023 mmol, 65.2% yield) as a solid. 1HNMR (400 MHz, DMSO-d6): δ 11.82 (bs, 1H), 9.35 (s, 1H), 9.08 (s, 1H), 8.52 (s, 1H), 7.66 (s, 1H), 7.34 (d, 1H, J=8.4 Hz), 6.94 (d, 1H, J=8.8 Hz), 3.63 (m, 4H), 2.99 (m, 4H), 2.50 (s, 3H). ESI-MS: 439.1 [M+H]+
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[C:12]([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[K+].[K+].[CH3:22][CH2:23][CH2:24][CH2:25][CH2:26]Br>CN(C=O)C>[CH2:22]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[C:12]([O:14][CH3:15])=[O:13])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCBr
Reactant: COC(=O)c1cccc(O)c1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCOc1cccc(C(=O)OC)c1C(=O)OC
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
3-Hydroxyphthalic anhydride (1.0 g, 6.6 mmol) was dissolved in methanol (20 ml), and a catalytic amount of p-toluene sulfonic acid was added to this solution. The mixture was stirred with refluxing under heating for 5 hours, and concentrated under reduced pressure to give a crude product of dimethyl 3-hydroxyphthalate. The crude product of dimethyl 3-hydroxyphthalate was dissolved in DMF (20 ml), and potassium carbonate (6 g, 43 mmol) and n-amyl bromide (3 ml, 24 mmol) were added to this solution. The mixture was stirred at 90° C. for 1.5 hours, and solids were removed by filtration through Celite. The filtrate was concentrated under reduced pressure to give a crude product of dimethyl 3-pentyloxyphthalate. The crude product of dimethyl 3-pentyloxyphthalate was dissolved in methanol (10 ml), and a 1N aqueous sodium hydroxide solution (20 ml) was added to this solution. The mixture was stirred at 90° C. for 2 hours, and a 3N aqueous hydrochloric acid solution (15 ml) was added to the reaction nixture. The mixture was extracted with ethyl acetate (30 ml×3), and washed with saturated brine (20 ml). The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give a crude product of 3-pentyloxyphthalic acid. The crude product of 3-pentyloxyphthalic acid was dissolved in acetic acid (20 ml), and a mine hydrochloride (1.0 g, 7.3 mmol) was added. The mixture was stirred at 90° C. for 2 hours and concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (hexane/ethyl acetate=4/1) to give N-2-(4-hydroxyphenyl)ethyl-3-pentyloxyphthalimide (0.8 g, 2.3 mmol, 35%) as colorless crystals.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[CH2:12][CH2:13][CH2:14][N:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][CH2:18][C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]1=2)=[O:5])C.[OH-].[Na+].[ClH:32]>C(O)C.O>[ClH:32].[CH:26]1[C:17]2[CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:15]([CH2:14][CH2:13][CH2:12][N:7]3[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]3[C:4]([OH:5])=[O:3])[C:16]=2[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)C1CCCCN1CCCN1c2ccccc2CCc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1CCCCN1CCCN1c2ccccc2CCc2ccccc21
Temperature: 50 °C
Reaction time: 5 h
Yield: 73 %

Procedure:
The above ester (0.83 g, 0.002 mol) was dissolved in a mixture of ethanol (8 ml), water (2 ml) and sodium hydroxide (0.58 g, 0.015 mol). The reaction mixture was stirred at room temperature for 50 h and at 50° C. for 5 h. Water. (50 ml) and concentrated hydrochloric acid (3 ml) were added, and the resulting mixture was extracted with dichloromethane (3×10 ml). The combined organic extracts were washed with brine (2×20 ml), dried (MgSO4) and concentrated in vacuo. The residue was re-dissolved in methanol (2 ml) and ethyl acetate (5 ml) and concentrated in vacuo. The solid residue was washed with a small amount of ethyl acetate and dried, affording 0.6 g (73%) of the title compound as a powder.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[CH2:9][C:10]1[CH:25]=[CH:24][C:13]([O:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:12][CH:11]=1.[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][CH:30]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][N:7]2[CH2:6][CH:5]3[CH:4]([CH2:3][N:2]([CH2:9][C:10]4[CH:11]=[CH:12][C:13]([O:14][C:15]5[S:16][C:17]6[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=6[N:19]=5)=[CH:24][CH:25]=4)[CH2:1]3)[CH2:8]2)=[CH:31][CH:30]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: c1ccc2sc(Oc3ccc(CN4CC5CNCC5C4)cc3)nc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccc(CN2CC3CN(Cc4ccc(Oc5nc6ccccc6s5)cc4)CC3C2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.7 %

Procedure:
To a solution of 2-[4-(hexahydro-pyrrolo[3,4-c]pyrrol-2-ylmethyl)-phenoxy]-benzothiazole (200 mg, 0.56 mmol) in CH2Cl2 (22 mL) was added 4-formyl-benzoic acid methyl ester (103 mg, 0.62 mmol) followed by the addition of acetic acid (28 μL, 0.48 mmol) then sodium triacetoxyborohydride (144 mg, 0.68 mmol). The reaction stirred at rt for 16 h. The reaction was then washed with satd. aq. NaHCO3 (2×20 mL). The organic layer was dried, filtered and concentrated. The resulting oil was purified by column chromatography (20% to 60% EtOAc in Hexanes) to afford the title compound (55 mg, 19%). MS (ESI): mass calcd. for C29H29N3O3S, 499.64; m/z found, 500.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.01 (d, J=8.3 Hz, 2H), 7.76 (d, J=8.1 Hz, 1H), 7.47-7.38 (m, 1H), 7.35-7.26 (m, 4H), 7.68 (d, J=7.9 Hz, 4H), 3.92 (s, 4H), 3.65 (d, J=12.2 Hz, 4H), 2.71-2.60 (m, 3H), 2.38 (d, J=7.2 Hz, 4H), 1.27 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:22]\[O:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)/[C:13]([NH:15][C:16]2C=CN(C)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH3:29][C:30]1N=C(N)[S:32][N:31]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:22]\[O:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)/[C:13]([NH:15][C:16]2[S:32][N:31]=[C:30]([CH3:29])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Cc1nsc(N)n1
Reactant: Cn1ccc(NC(=O)/C(=N/OC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nsc(NC(=O)/C(=N/OC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reaction time: 2 h
Yield: 50 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic (prepared as in Example 1, 96 mg, 0.28 mmol), 3-methyl-[1,2,4]thiadiazol-5-ylamine (32 mg, 0.28 mmol) and N,N-diisopropylethylamine (145 μL, 0.83 mmol) were combined in acetonitrile (1.25 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (106 mg, 0.28 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 40% ethyl acetate/hexanes) to afford (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-N-(3-methyl-[1,2,4]thiadiazol-5-yl)-acetamide (62 mg, 50%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C17H19ClN4O4S2 [M+] 442.05, found 443 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.67 (m, 4 H, 2×CH2), 1.90 (m, 4 H, 2×CH2), 2.60 (s, 3 H, ArCH3), 3.32 (s, 3 H, SO2CH3), 4.95 (m, 1 H, OCH), 7.60 (dd, Jo=8.3, Jm=1.6 Hz, 1 H, Ar), 7.70 (d, Jm=1.6 Hz, 1 H, Ar), 8.22 (d, Jo=8.3 Hz, 1 H, Ar), 10.35 (s, 1 H, NH).
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][C:5]=1[CH3:20])([O-])=O>O>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][C:5]=1[CH3:20]
Reactant: Cc1ccc2c(c1[N+](=O)[O-])C(=O)c1ccccc1C2=O
Solvent: O
Product: Cc1ccc2c(c1N)C(=O)c1ccccc1C2=O
Reaction time: 2 h

Procedure:
The wet filter cake of 1-nitro-2-methylanthraquinone (0.45 mole) was placed in a 5 l flask. To the flask was added 420 g (1.75 mole) of Na2S.9H2O dissolved in 2.5 l of H2O and the slurry was heated and then stirred at 95°-99° C. for 2 hours. The reaction mixture was filtered and the orangish-red solid 1-amino-2-methylanthraquinone product was washed with hot H2O until the filtrate was clear and dried in vacuo at 70° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:3]=1.[H-].[Na+].[CH3:16]I.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH3:16])=[C:4]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(Br)ccc1CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCc1ccc(Br)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.9 %

Procedure:
To a solution of (4-bromo-2-methanesulfonyl-phenyl)-methanol (preparation 112) (500 mg, 1.89 mmol) in DMF (10 mL) was added NaH (226 mg, 5.66 mmol, 60% in oil) at room temperature. After stirring at room temperature for 30 minutes, to above mixture was added MeI (230 mg, 10 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 hrs. TLC (petroleum ether:EtOAc 1:1) showed the reaction was complete. Then the mixture was poured into H2O (10 mL) and extracted with EtOAc (50 mL×3), washed with brine (10 mL×3), dried over sodium sulfate, concentrated in vacuo to give the residue, which was purified by a Biotage silica gel cartridge (petroleum ether/EtOAc 1:1, Rf˜0.5) to give the title compound (200 mg, 40%) as yellow oil.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:4]1.[CH2:16]([S:20][C:21]1[N:26]=[C:25](Cl)[CH:24]=[CH:23][N:22]=1)[CH2:17][CH2:18][CH3:19]>CN(C=O)C>[CH2:16]([S:20][C:21]1[N:22]=[C:23]([N:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:4]2)[CH:24]=[CH:25][N:26]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCSc1nccc(Cl)n1
Reactant: NS(=O)(=O)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCSc1nccc(-n2cc(S(N)(=O)=O)c3ccccc32)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.3 %

Procedure:
NaH (147 mg, 3.67 mmol, 60% dispersion) was added to a solution of 1H-indole-3-sulfonic acid amide (600 mg, 3.06 mmol) in DMF (5 mL) at 0° C., and stirred for 15 min. 2-Butylsulfanyl-4-chloro-pyrimidine (682 mg, 3.36 mmol) was added, and washed down with additional DMF (2 mL). The reaction mixture was allowed to warm to RT, and stirred overnight under N2. The reaction mixture was then poured into water, extracted with hot EtOAc, washed with water, brine, and filtered. The mixture was concentrated to half volume, heated on a steam bath, and allowed to crystallize. The resulting white solid was filtered off, washed with DCM, and air-dried to provide 1-(2-butylsulfanyl-pyrimidin-4-yl)-1H-indole-3-sulfonic acid amide (868 mg, 71.4% yield).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH:8]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][C:10]([OH:12])=[O:11])=[CH:3][CH:2]=1.[CH3:27][C:28](O)([CH3:30])[CH3:29].CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:2]=[CH:3][C:4]([CH2:7][CH:8]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH2:9][C:10]([O:12][C:28]([CH3:30])([CH3:29])[CH3:27])=[O:11])=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC(CC(=O)O)Cc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC(Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 62 h
Yield: 38 %

Procedure:
A solution of 4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoic acid (250 mg, 0.703 mmol), tBuOH (0.135 ml, 1.407 mmol), EDCl (270 mg, 1.407 mmol) and 4-dimethylaminopyridine (86.0 mg, 0.704 mmol) in DCM (7 ml) is allowed to stir at room temperature under nitrogen for 62 hours. The reaction is quenched with water, and the organic layer is separated and concentrated. The residue is purified by flash column chromatography on silica gel to give tert-butyl 4-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)butanoate (110 mg); HPLC retention time=1.77 minutes (condition B); MS (ES+)=412.1 (m+1) 300.0 (m-tBux2+3; 100%); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.41 (s, 9H) 1.47 (s, 9H) 2.36 (A of ABX, Jab=15.5 Hz, Jax=6.2 Hz, 1H) 2.44 (B of ABX, Jab=15.5 Hz, Jbx=5.6 Hz) 2.82-2.94 (m, 2H) 4.11-4.17 (m, 1H) 5.08-5.10 (m, 1H) 7.25-7.34 (m, 3H) 7.41-7.44 (m, 2H) 7.51-7.58 (m, 4H).