Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:9]([NH2:10])=[C:8]([NH2:11])[C:6](=[O:7])[N:5]([CH3:12])[C:3]1=[O:4].[NH2:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=1[C:16](O)=O>CO>[NH2:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=1[C:16]1[NH:11][C:8]2[C:6](=[O:7])[N:5]([CH3:12])[C:3](=[O:4])[N:2]([CH3:1])[C:9]=2[N:10]=1
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Reactant: Nc1cc(Cl)ccc1C(=O)O
Solvent: CO
Product: Cn1c(=O)c2[nH]c(-c3ccc(Cl)cc3N)nc2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 12.5 %

Procedure:
1,3-dimethyl-5,6-diaminouracil (0.01 mol) was suspended in 50 ml methanol. 2-amino-4-chlorobenzoic acid (0.01 mol) was added, followed by 0.01 mol of DICD. The reactants were stirred at room temperature for 15 min, then filtered and washed with methanol. The solid was boiled in 40 ml 1 2.5N NaOH for five min, filtered hot, and the eluate was left to cool for three hours. The material which precipitated on cooling was filtered without washing, redissolved in 40 ml water, and precipitated by neutralization with concentrated HCl. The solid was collected by filtration, washed with H2O, and dried. The product was purified by suspending in 100 ml water, adding NaOH until the compound was dissolved, filtering, precipitating the solid with HCl, filtering, washing with H2O, and drying. The product was identified by chemical ionization mass spectrometry and elemental analysis. Yield 12.5%.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]1.[Cl:10][C:11]1[CH:12]=[C:13]([S:18]Cl)[CH:14]=[CH:15][C:16]=1[Cl:17]>>[Cl:10][C:11]1[CH:12]=[C:13]([S:18][C:5]2[NH:1][CH:2]=[C:3]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=2)[CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: ClSc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1cc[nH]c1
Product: COC(=O)c1c[nH]c(Sc2ccc(Cl)c(Cl)c2)c1
Yield: 104.2 %

Procedure:
By the procedure of Example 23, methyl pyrrole-3-carboxylate (2.5 g., 20 mmoles) was reacted with 3,4-dichlorobenzenesulfenyl chloride (4.24 g., 20 mmoles) to yield crude product (6.3 g., oil). The crude was chromatographed on 250 g. of silica gel, with 125 ml. fractions of the ethyl acetate-1/hexane-5/5% acetic acid eluant collected. Fractions 2 to 6 were combined and evaporated to dryness to afford purified methyl 5-(3,4-dichlorophenylthio)pyrrole-3-carboxylate (2.76 g., m.p. 93°-96° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][N:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][CH:19]=1)[CH2:6][CH2:7][CH2:8][CH2:9][N:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13].C(OC)(OC)OC.[C:34]([BH3-])#[N:35].[Na+].[CH3:38][N:39]1[CH:43]=[CH:42][N:41]=[C:40]1[CH:44]=O>CO.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][N:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH2:7][C:6]2[N:35]([CH3:34])[CH:3]=[CH:4][N:5]=2)[CH2:44][C:40]2[N:39]([CH3:38])[CH:43]=[CH:42][N:41]=2)=[CH:20][CH:19]=1)[CH2:6][CH2:7][CH2:8][CH2:9][N:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13]
Reactant: Cn1ccnc1C=O
Reactant: [BH3-]C#N
Reactant: CCCN(CCC)CCCCN(CC(=O)OC)Cc1ccc(CN)cc1
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCN(CC(=O)OC)Cc1ccc(CN(Cc2nccn2C)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
The compound (1.78 g) obtained in Example 64-1 was dissolved in methanol (30 ml) and added with trimethyl orthoformate (1.8 ml), acetic acid (1.0 ml), and sodium cyanoborohydride (0.324 g). The mixture was gradually added with a methanol solution (5.0 ml) containing 1-methyl-2-imidazole carboxaldehyde (0.550 g) and the whole was stirred at room temperature for 1 hour. Further, sodium cyanoborohydride (0.486 g) and a methanol solution (6.0 ml) containing 1-methyl-2-imidazole carboxaldehyde (0.660 g) were added thereto and the whole was stirred at room temperature for 63 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform and washed with a saturated aqueous sodium hydrogen carbonate solution and then the whole was subjected to extraction with chloroform. The organic layer was a saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (1.18 g) as a colorless oily substance.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)CCC.[Cl:19][C:20]1[C:24](Cl)=[N:23][S:22][N:21]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:19][C:20]1[C:24]([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)=[N:23][S:22][N:21]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: Clc1nsnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Clc1nsnc1-c1cccs1
Yield: 54 %

Procedure:
0.92 g (0.00246 mol) of 2-(tributylstannyl)thiophene and 0.12 g (0.0001 mol) of tetrakis(triphenylphosphine)palladium(0) were added to a solution of 0.33 g (0.00213 mol) of 3,4-dichloro-1,2,5-thiadiazole in 4 mL of toluene under nitrogen and heated at reflux. After 3 and 6 h respectively, 0.04 g (2 times 2.5×10−5 mol) of tetrakis (triphenylphosphine)palladium(0) were added. After 24 h of reflux (quantitative HPLC: 54% of product formed, all the stannane was consumed), the reaction medium was diluted with 5 mL of ethyl acetate and vigorously stirred with 10 mL of a 1M aqueous solution of KF for 2 h. After filtration through celite, the aqueous phase was re-extracted with ethyl acetate, the combined organic phases were dried over magnesium sulfate and concentrated.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=[S:34])[NH:18][C:19](=[O:33])[N:20]([CH2:22][C:23]4[N:28]=[C:27]([C:29]([O:31]C)=[O:30])[CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+]>CO.O>[CH:12]1[C:8]2[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([C:16]3[C:17](=[S:34])[NH:18][C:19](=[O:33])[N:20]([CH2:22][C:23]4[N:28]=[C:27]([C:29]([OH:31])=[O:30])[CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1cccc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=S)[nH]c2=O)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=S)[nH]c2=O)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of the product from step (vi) (1.37 g) and lithium hydroxide monohydrate (0.588 g) in methanol (20 ml) and water (15 ml) was stirred at room temperature for 3 hours. A precipitate formed which was filtered off and partitioned between ethyl acetate and 1N HCl. The organic phase was dried (MgSO4) and concentrated under reduced pressure to 10 ml. The product was precipitated by the addition of diethyl ether. Yield 0.56 g.
Reaction SMILES: OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:6].[CH2:16]([C:18]1[N:19]=[N+:20]([O-:34])[C:21]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])=[CH:24][C:22]=2[N:23]=1)[CH3:17].FC(F)(F)C(O)=O>C(Cl)Cl.N>[CH2:16]([C:18]1[N:19]=[N+:20]([O-:34])[C:21]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]([CH3:32])[CH3:33])=[CH:24][C:22]=2[N+:23]=1[O-:6])[CH3:17]
Reactant: CCc1nc2cc(OCCN(C)C)ccc2[n+]([O-])n1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1n[n+]([O-])c2ccc(OCCN(C)C)cc2[n+]1[O-]
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 32.4 %

Procedure:
Hydrogen peroxide (70%; 0.30 mL, ca. 6.1 mmol) was added dropwise to a stirred solution of trifluoroacetic anhydride (0.85 mL, 6.1 mmol) in DCM (15 mL) at 5° C. The solution was stirred at 20° C. for 10 min, then cooled to 5° C., added to a solution of 1-oxide 29 (160 mg, 0.61 mmol) and trifluoroactic acid (0.10 mL, 1.31 mmol) in DCM (15 mL) at 5° C. The solution was stirred at 20° C. for 16 h, diluted with dilute aqueous NH3 solution (40 mL) and extracted with CHCl3 (4×40 mL). The combined organic fraction was dried (Na2SO4) and the solvent evaporated. The residue was purified by column chromatography, eluting with a gradient (0-8%) MeOH/CH2Cl2 to give 1,4-dioxide 30 (55 mg, 32%) as a bright yellow solid, mp (MeOH, EtOAc) 146-149° C.; 1H NMR δ 8.33 (d, J=9.6 Hz, 1 H, H-8), 7.78 (d, J=2.6 Hz, 1 H, H-5), 7.42 (dd, J=9.6, 2.6 Hz, 1 H, H-7), 4.30 (t, J=5.4 Hz, 2 H, OCH2), 3.21 (q, J=7.5 Hz, 2 H, CH2), 2.83 (t, J=5.4 Hz, 2 H, NCH2), 2.37 [s, 6 H N(CH3)2], 1.43 (t, J=7.4 Hz, 3 H, CH3); 13C δ 164.9, 157.1, 141.5, 129.7, 124.7, 123.4, 98.0, 67.9, 57.7, 45.8 (2), 24.1, 9.3. Anal. Calcd for C13H18N4O3.¼MeOH: C, 55.6; H, 6.7; N, 19.6. Found: C, 55.5; H, 6.4; N, 19.5%.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].C[Al](C)C.CO[C:11](=O)[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([N:22]3[CH:27]=[CH:26][C:25]4[O:28][C:29]([C:31]5[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=5)=[CH:30][C:24]=4[C:23]3=[O:38])=[CH:19][CH:20]=2)[CH:15]=[N:14]1>C1(C)C=CC=CC=1.O>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C:29]2[O:28][C:25]3[CH:26]=[CH:27][N:22]([C:18]4[CH:17]=[C:16]5[C:21](=[CH:20][CH:19]=4)[N:13]([CH2:12][C:11]4[NH:3][CH2:2][CH2:1][N:4]=4)[N:14]=[CH:15]5)[C:23](=[O:38])[C:24]=3[CH:30]=2)=[CH:32][CH:33]=1
Reactant: COC(=O)Cn1ncc2cc(-n3ccc4oc(-c5ccc(Cl)cc5)cc4c3=O)ccc21
Reactant: NCCN
Agent: C[Al](C)C
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1c2cc(-c3ccc(Cl)cc3)oc2ccn1-c1ccc2c(cnn2CC2=NCCN2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 21.4 %

Procedure:
To a 0° C. solution of ethylenediamine (68 mL, 1.0 mmol) in toluene (0.36 mL) was slowly added trimethyl aluminium (0.50 mL, 10 M in toluene) over ten minutes. The solution was allowed to stir at 0° C. for 5 minutes; then a suspension of methyl-2-(5-(2-(4-chlorophenyl)-4-oxofuro[3,2-c]pyridin-5(4H)-yl)-1H-indazol-1-yl)acetate (0.22 g, 0.50 mmol) in toluene (7.27 mL) was added and the reaction mixture was heated to reflux. The reaction mixture was stirred at reflux for 18 h; then the reaction mixture was diluted with H2O (2 mL) and the solids were removed by filtration. The filtrate was extracted with CH2Cl2 (3×20 mL) and the extracts were dried (Na2SO4), filtered and concentrated. Purification by flash chromatography (silica gel, CH2Cl2/9:1 EtOH with NH4OH, 100:0 to 90:10) yielded the title compound (47.6 mg, 21%) as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.91 (d, J=9.0 Hz, 1H), 7.83 (d, J=1.5 Hz, 1H), 7.74 (d, J=9.0 Hz, 1H), 7.69 (d, J=7.5 Hz, 1H), 7.64 (s, 1H), 7.57-7.55 (m, 2H), 7.42 (dd, J=9.0, 2.0 Hz, 2H), 6.89 (d, J=7.0 Hz, 1H), 5.21 (s, 2H) 3.51 (br s, 1H), 3.30 (s, 4H); ESI MS m/z 444 [M+H]+; HPLC (Method A) 95.7% (AUC), tR=15.8 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:19]OS(C)(=O)=O)[C:11](=[O:18])[N:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:13]=2)=[CH:4][C:3]=1[CH3:25].[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>>[CH2:26]([N:28]([CH2:19][C:10]1[C:11](=[O:18])[N:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:25])[CH:4]=2)[CH:9]=1)[CH2:29][CH3:30])[CH3:27]
Reactant: Cc1cc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)ccc1F
Reactant: CCNCC
Product: CCN(CC)Cc1cc(-c2ccc(F)c(C)c2)nn(CC(C)C)c1=O

Procedure:
Following the procedure of Example 9(4), 6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and diethylamine were reacted to yield the title compound as a slightly yellow oil (yield: 94.7%).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([NH:5][C:6]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]2[C:7]=1[CH:8]=[N:9][NH:10]2)=[O:4].[C:18]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19].N12CCCN=C1CCCCC2>CC#N>[C:18]([C:22]1[CH:23]=[CH:24][C:25]([CH2:26][NH:27][C:3]([NH:5][C:6]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]3[C:7]=2[CH:8]=[N:9][NH:10]3)=[O:4])=[CH:28][CH:29]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: Cc1ccc(NC(=O)C(Cl)(Cl)Cl)c2cn[nH]c12
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(NC(=O)NCc2ccc(C(C)(C)C)cc2)c2cn[nH]c12
Temperature: 25 °C

Procedure:
2,2,2-Trichloro-N-(7-methyl-1H-indazol-4-yl)acetamide (72 mg, 0.25 mmol), 4-tert-butylbenzylamine (55 mg, 0.34 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.09 mL, 0.60 mmol) were combined in CH3CN (6 mL) and refluxed overnight. The mixture was allowed to cool to ambient temperature and was concentrated under reduced pressure. The residue was taken up in ethyl acetate and washed twice with saturated aqueous NH4Cl solution. The organic layer was dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure. The residue was triturated with ethyl acetate to provide the title compound. The corresponding hydrochloride salt was prepared with methanolic HCl. 1H NMR (300 MHz, d6-DMSO) δ 12.90 (br s, 1H), 7.94 (d, J=1.3 Hz, 1H), 7.91 (s, 1H), 7.47 (m, 2H), 7.37 (m, 2H), 7.25 (m, 2H), 6.84 (t, J=5.8 Hz, 1H), 4.26 (d, J=5.7 Hz, 2H), 2.35 (s, 3H), 1.27 (s, 9H); MS (ESI+) m/z 337 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[C:11]([OH:16])[C:10]=3[CH2:9][CH2:8][C@@H:7]2[CH3:17])=[O:5])[CH2:3][CH2:2]1.[Br:18]N1C(=O)CCC1=O>C(#N)C.ClCCl>[Br:18][C:12]1[CH:13]=[CH:14][C:15]2[N:6]([C:4]([CH:1]3[CH2:2][CH2:3]3)=[O:5])[C@@H:7]([CH3:17])[CH2:8][CH2:9][C:10]=2[C:11]=1[OH:16]
Reactant: C[C@H]1CCc2c(O)cccc2N1C(=O)C1CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: ClCCl
Product: C[C@H]1CCc2c(ccc(Br)c2O)N1C(=O)C1CC1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
Into a 1000-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed (2S)-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-5-ol (4.0 g, 17.3 mmol) in acetonitrile (600 mL) and dichloromethane (150 mL). The solution was cooled to −10° C., and a solution of N-bromosuccinimide (3.08 g, 17.3 mmol) in acetonitrile (50 mL) was added dropwise over 3 h. The resulting solution stirred for 30 minutes at −10° C., and was then concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 0-20% ethyl acetate/petroleum ether) to afford (2S)-6-bromo-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-5-ol (3.6 g, 68%) as a light yellow solid. MS: (ES, m/z): 310, 312 [M+H]+
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.N1C=C(B(O)O)C=NC=1>>[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:12][C@H:11]([N:13]5[CH2:17][CH2:16][CH2:15][CH2:14][CH2:18]5)[CH2:10]4)[S:8][C:4]=3[CH:3]=2)=[CH:25][CH:24]=1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: COc1ccc(B(O)O)cn1
Agent: OB(O)c1cncnc1
Product: COc1ccc(-c2ccc3nc([C@H]4C[C@H](N5CCCCC5)C4)sc3c2)cn1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, substituting the product of Example 44A for the product of Example 1E, and substituting 6-methoxypyridine-3-boronic acid for pyrimidine-5-boronic acid. 1H NMR (500 MHz, CDCl3) δ ppm 8.43 (d, J=2.44 Hz, 1H) 8.03 (d, J=8.54 Hz, 1H) 7.97 (d, J=1.53 Hz, 1H) 7.84 (dd, J=8.70, 2.59 Hz, 1H) 7.62 (dd, J=8.54, 1.83 Hz, 1H) 6.85 (d, J=8.54 Hz, 1H) 4.00 (s, 3H) 3.82-3.93 (m, 1H) 3.36-3.48 (m, 1H) 2.87-2.98 (m, 2H) 2.52-2.71 (m, 4H) 2.08 (s, 2H) 1.67-1.82 (m, 4H) 1.48-1.58 (m, 2H). MS: (M+H)+=380.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([S:17]([CH2:20][C@@H:21]([N:25]1[C@H:30]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[C@@H:29]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=2)[CH2:28][C@@:27]([CH2:46][C:47]([OH:49])=O)([CH3:45])[C:26]1=[O:50])[CH:22]1[CH2:24][CH2:23]1)(=[O:19])=[O:18])([CH3:16])([CH3:15])[CH3:14].[NH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>>[C:13]([S:17]([CH2:20][C@@H:21]([N:25]1[C@H:30]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[C@@H:29]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=2)[CH2:28][C@@:27]([CH2:46][C:47]([NH:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[O:49])([CH3:45])[C:26]1=[O:50])[CH:22]1[CH2:23][CH2:24]1)(=[O:18])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)S(=O)(=O)C[C@H](C1CC1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CC(C)(C)S(=O)(=O)C[C@H](C1CC1)N1C(=O)[C@@](C)(CC(=O)Nc2ccccc2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC, 0.117 g, 0.612 mmol) was added to a solution of 2-((3R,5R,6S)-1-((S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (0.118 g, 0.204 mmol, Example 1, Step H) and aniline (0.020 mL, 0.225 mmol) at 0° C. After the addition was complete, the reaction mixture was removed from the ice bath and stirred at room temperature for 19 hours. The reaction mixture was diluted with ice-cold 1 M hydrochloric acid to adjust the pH to 1 and the solution was extracted twice with ether. The combined organic layer was washed with brine, dried over sodium sulfate, decanted and concentrated under a vacuum to provide an orange oil. Purification by flash chromatography (12 g SiO2 column, gradient elution of 15% to 100% ethyl acetate in hexanes provided the title compound as a white foam.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[Li].C([Li])CCC.[O:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1.[Cl:17]CCCCCO.[Cl-].[NH4+]>CCOCC.CCCCCC>[Cl:17][CH2:16][CH2:15][CH2:14][CH:13]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[OH:12]
Reactant: c1ccoc1
Reactant: OCCCCCCl
Reactant: [Li]c1ccco1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: OC(CCCCl)c1ccco1
Reaction time: 0.25 h

Procedure:
To a stirred suspension of 2-furyllithium (prepared from 0.53 moles of n-butyllithium and 39.5 g of furan by the procedure of J. Org. Chem., 27, 1216 (1962)) in 350 ml of ether and ca. 200 ml of hexane at -78° is added a solution of 57.9 g of 4-chlorobutanol (Chem. Abstr., 59, 7579F (1963)) in 80 ml of ether during 25 minutes. The mixture is warmed to 0° during 20 minutes, stirred at 0° for 15 minutes, and treated with 140 ml of saturated ammonium chloride. The ether phase is washed with water and brine, dried over magnesium sulfate and potassium carbonate mixture, and concentrated to give a liquid, pmr spectrum (CDCl3): δ3.59 (triplet, CH2Cl) and 4.70 (triplet, CH2CHOH).
Reaction SMILES: C(OC[S:6]([C:9]1[C:14]([F:15])=[CH:13][C:12]([C:16]2[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:18][O:19][C:20]=2[CH3:21])=[CH:11][C:10]=1[F:28])(=[O:8])=[O:7])(=O)C.[OH-].[Li+].[NH:31](S(O)(=O)=O)O>C1COCC1.CO.O>[F:28][C:10]1[CH:11]=[C:12]([C:16]2[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:18][O:19][C:20]=2[CH3:21])[CH:13]=[C:14]([F:15])[C:9]=1[S:6]([NH2:31])(=[O:8])=[O:7]
Reactant: CC(=O)OCS(=O)(=O)c1c(F)cc(-c2c(-c3ccccc3)noc2C)cc1F
Reactant: O=S(=O)(O)NO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1onc(-c2ccccc2)c1-c1cc(F)c(S(N)(=O)=O)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of {[2,6-difluoro-4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl}methyl acetate (1.5 g, 3.9 mmol) in THF (25 mL) and methanol (25 mL) was added a solution of lithium hydroxide (0.50 g, 12 mmol) in water (4 mL). The resulting solution was stirred at room temperature for 1 hour. Additional solution of lithium hydroxide (0.60 g, 14 mmol) in water (8 mL) was added, followed by solid hydroxylamine sulfonic acid (1.6 g, 14.1 mmol) and methanol (5 mL). The reaction mixture was stirred overnight and poured into water (250 mL). The 2,6-difluoro-4-(5-methyl-3-phenyl-isoxazol-4-yl)benzenesulfonamide was isolated as a white solid (1.08 g, 85%). MP 226.1-226.2° C. 1H NMR (CD3OD/400 MHz) 7.36-7.46 (m, 5H), 6.95 (d, 2H, J=9.4), 2.51 (s, 3H). ESHRMS m/z 351.0621 (M+H+, Calcd 351.0615). Anal. Calcd for C16H12F2N2O3S: C, 54.85; H, 3.45; N, 8.00. Found: C, 54.95; H, 3.51; N, 7.81.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)[N:5]=[C:4]2[N:17]([CH3:20])[N:18]=[CH:19][C:3]=12.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1[OH:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1[O:29][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)[N:5]=[C:4]2[N:17]([CH3:20])[N:18]=[CH:19][C:3]=12
Reactant: Cc1cccc(C)c1O
Reactant: Cn1ncc2c(Cl)cc(-c3cccc4[nH]ncc34)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1Oc1cc(-c2cccc3[nH]ncc23)nc2c1cnn2C
Temperature: 155 °C
Yield: 19.2 %

Procedure:
4-Chloro-6-(1H-indazol-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine 7 (0.040 g, 0.141 mmol) was dissolved in 2 mL DMF. 2,6-Dimethylphenol 8b (0.034 g, 0.281 mmol) was added followed by the addition of potassium carbonate (0.2 g, 1.41 mmol) and the resultant reaction mixture was heated in a microwave at 155° C. for 30 minutes. The reaction mixture was diluted with ethyl acetate and filtered and the organic portions were washed with saturated sodium bicarbonate solution followed by brine, dried over anhydrous sodium sulfate and solvent removed and purified to obtain 106 as a white solid (10 mg, 20%). 1H NMR (400 MHz, CDCl3) δ 10.13 (s, 1H), 8.77 (s, 1H), 7.58 (t, J=7.2, 2H), 7.48 (dd, J=11.8, 19.0, 2H), 7.18 (s, 3H), 6.97 (d, J=23.8, 1H), 4.22 (s, 3H), 2.19 (s, 6H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:19][C:18]3[C:13](=[N:14][C:15]([C:20]([OH:22])=O)=[CH:16][CH:17]=3)[C:12]=2[NH:23][C:24]([C@H:26]2[CH2:31][CH2:30][C@H:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][C:33]3=[O:38])[CH2:28][CH2:27]2)=[O:25])=[O:10])=[N:6][CH:7]=1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:19][C:18]3[C:13](=[N:14][C:15]([C:20]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[O:22])=[CH:16][CH:17]=3)[C:12]=2[NH:23][C:24]([C@H:26]2[CH2:27][CH2:28][C@H:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][C:33]3=[O:38])[CH2:30][CH2:31]2)=[O:25])=[O:10])=[N:6][CH:7]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N4CCOCC4=O)CC3)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Cl)cn1)c1oc2ccc(C(=O)N3CCOCC3)nc2c1NC(=O)[C@H]1CC[C@H](N2CCOCC2=O)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2-{[(5-Chloropyridin-2-yl)amino]carbonyl}-3-({[trans-4-(3-oxomorpholin-4-yl)cyclohexyl]carbonyl}amino)furo[3,2-b]pyridine-5-carboxylic acid (100 mg) obtained in Example 79 is dissolved in N,N-dimethylformamide (3 ml), and thereto are added successively morpholine (32 μl), 1-hydroxybenzotriazole (50 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (71 mg), and the mixture is stirred at room temperature for 15 hours. The reaction solution is diluted with ethyl acetate-tetrahydrofuran, and the solution is washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over sodium sulfate. The solvent is evaporated under reduced pressure and the resulting residue is suspended in ethyl acetate-diethyl ether. The solid precipitates are collected by filtration to give the title compound (109 mg).