Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]1([NH2:7])[CH2:5][CH2:4][CH2:3][C@@H:2]1[NH2:6].C(N(CC)CC)C.ClC1C=C2C(=CC=1)N(C1C=CC=CC=1)C(S(Cl)(=O)=O)C2=S(=O)=O.[Cl:38][C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[N:44]([S:48]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)(=[O:50])=[O:49])[C:43]([S:57](Cl)(=[O:59])=[O:58])=[CH:42]2>ClCCl.O>[Cl:38][C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[N:44]([S:48]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)(=[O:49])=[O:50])[C:43]([S:57]([NH:6][C@@H:2]1[CH2:3][CH2:4][CH2:5][C@@H:1]1[NH2:7])(=[O:59])=[O:58])=[CH:42]2
Reactant: O=S(=O)(Cl)c1cc2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reactant: N[C@@H]1CCC[C@@H]1N
Agent: O=S(=O)=C1c2cc(Cl)ccc2N(c2ccccc2)C1S(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N[C@H]1CCC[C@H]1NS(=O)(=O)c1cc2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reaction time: 0.25 h
Yield: 407.2 %

Procedure:
cis-1,2-Cyclopentanediamine (WO98/30574) (348 mg) was dissolved in dichloromethane (10 ml), and to the solution triethylamine (1 ml) and 5-chloro-1-phenyl-sulfonylindole-2-sulfonyl chloride (390 mg) were added at 0° C. with stirring. After 15 minutes and 1 hour, 5-chloro-1-phenylsulfonylindole-2-sulfonyl chloride (156 mg) was additionally added. After stirring for 15 minutes, 5-chloro-1-phenylsulfonylindole-2-sulfonyl chloride (78 mg) was further added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture to separate an organic layer. The resultant organic layer was washed with a saturated solution of sodium hydrogencarbonate and dried over anhydrous sodium sulfate. The residue was purified by flash column chromatography on silica gel (chloroform:methanol=23:2) to obtain the title compound (739 mg) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[N:12][C:13]3[CH:14]=[C:15]4[CH:22]=[N:21][NH:20][C:16]4=[CH:17][C:18]=3[N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[H-].[Na+].[CH2:25](I)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[CH2:25]([N:20]1[C:16]2=[CH:17][C:18]3[N:19]=[C:10]([C:4]4[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=4)[CH:11]=[N:12][C:13]=3[CH:14]=[C:15]2[CH:22]=[N:21]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH2:25]([N:21]1[CH:22]=[C:15]2[C:16]([CH:17]=[C:18]3[C:13](=[CH:14]2)[N:12]=[CH:11][C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)=[N:19]3)=[N:20]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: ICc1ccccc1
Reactant: COc1ccc(-c2cnc3cc4cn[nH]c4cc3n2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-c2cnc3cc4cn(Cc5ccccc5)nc4cc3n2)cc1F
Product: COc1ccc(-c2cnc3cc4cnn(Cc5ccccc5)c4cc3n2)cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 0.50 g of 7-(3-fluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-g]quinoxaline, 30 ml of anhydrous THF is added 0.061 g of 60% NaH. The red-orange mixture is stirred at room temperature for 10 minutes, then 0.265 g of benzyl iodide is added and is stirred at room temperature overnight. The mixture is filtered, washed with CH2Cl2. The filtrate and the CH2Cl2 wash are combined and mixed with water, extracted with CH2Cl2, separated, dried (Na2SO4) and concentrated in vacuo to give yellow crude solid. This is purified by silica-gel column chromatography using the combination of ethylacetate: hexane: methylene chloride as solvent to obtain 1-benzyl-7-(3-fluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-g]quinoxaline (m.p. 149°-155° C.) and 2-benzyl-7-(3-fluoro-4-methoxyphenyl)-2H-pyrazolo[3,4-g]quinoxaline (m.p. 225°-227° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Br[C:12]1[CH:13]=[C:14]([CH:18]([CH:25]2[CH2:27][CH2:26]2)[NH:19][S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH:15]=[N:16][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[CH:13]=[C:14]([CH:18]([CH:25]2[CH2:27][CH2:26]2)[NH:19][S:20]([CH2:23][CH3:24])(=[O:21])=[O:22])[CH:15]=[N:16][CH:17]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: CCS(=O)(=O)NC(c1cncc(Br)c1)C1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)NC(c1cncc(-c2ccccc2Cl)c1)C1CC1
Temperature: 100 °C
Yield: 21.4 %

Procedure:
A mixture of 2-chlorophenylboronic acid (24 mg, 0.16 mmol), N-((5-bromopyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide (50 mg, 0.16 mmol), PdCl2(PPh3)2 (9 mg, 0.01 mmol) and Na2CO3 (2 M in water, 0.16 mL, 0.32 mmol) in DMF(1.5 mL) was heated at 100° C. for 2 h. After concentration, the residue was dissolved in DCM and filtered. The filtrates were concentrated and purified by flash column (EtOAc/Heptane, v/v, 0-40%) to give the title compound (12 mg, 23%); ESI-MS m/z: 351 [M+1]+, 1H-NMR (MeOD, 400 MHz) δ 8.65 (1H, d, J=2.0 Hz), 8.55 (1H, d, J=2.0 Hz), 8.04 (1H, t, J=2.0 Hz), 7.61-7.58 (1H, m), 7.48-7.44 (3H, m), 4.29 (1H, d, 0.1=8.8 Hz), 3.02-2.89 (2H, m), 1.34-1.28 (1H, m), 1.28 (1H, t, J=7.2 Hz), 0.80-0.75 (1H, m), 0.67-0.60 (2H, m), 0.51-0.47 (1H, m)
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]([Cl:12])=[C:4]([NH2:13])[N:3]=1.Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O.[I-].[Na+]>>[NH2:13][C:4]1[N:3]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:1]=[C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[Cl:12]
Reactant: O=C(CBr)c1ccccc1
Reactant: COC(=O)c1cc(Cl)c(N)nc1N
Agent: [I-]
Agent: [Na+]
Product: COC(=O)c1cc(Cl)c(N)n2cc(-c3ccccc3)nc12

Procedure:
The title compounds were prepared according to the procedure described in the step 2 in EXAMPLE 1 (METHOD B) using methyl 2,6-diamino-5-chloro-3-pyridinecarboxylate (EXAMPLE 1, METHOD B, Step 1), 2-bromoacetophenone and sodium iodide.
Reaction SMILES: [CH3:1][Si:2]([CH3:28])([C:24]([CH3:27])([CH3:26])[CH3:25])[O:3][CH2:4][C@@H:5]1[C@@H:14]2[C@@H:8]([O:9][C@@H:10]([CH2:15]O)[CH2:11][CH:12]=[CH:13]2)[CH2:7][C@H:6]1[O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1.OI1(=O)C2C=CC=CC=2[C:32](=O)O1.[C:41]([O:44][CH2:45][CH3:46])(=[O:43])[CH3:42].O>CS(C)=O>[CH3:28][Si:2]([CH3:1])([C:24]([CH3:25])([CH3:26])[CH3:27])[O:3][CH2:4][C@@H:5]1[C@@H:14]2[C@@H:8]([O:9][C@@H:10](/[CH:15]=[CH:42]/[C:41]([O:44][CH:45]([CH3:32])[CH3:46])=[O:43])[CH2:11][CH:12]=[CH:13]2)[CH2:7][C@H:6]1[O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1
Reactant: CCOC(C)=O
Reactant: O=C1OI(=O)(O)c2ccccc21
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1[C@H]2C=CC[C@H](CO)O[C@H]2C[C@H]1OC1CCCCO1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)OC(=O)/C=C/[C@H]1CC=C[C@@H]2[C@@H](CO[Si](C)(C)C(C)(C)C)[C@H](OC3CCCCO3)C[C@@H]2O1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
The compound (165 mg) produced in Example 55 was dissolved in DMSO (2 mL), a Wittig reagent (carboisopropoxymethylenetriphenylphosphorane, 218 mg) and 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide (IBX, 168 mg) were added, followed by stirring at 50° C. for 5 hours. Ethyl acetate and water were added to the reaction mixture, and insolubles were filtered. Extraction with ethyl acetate, and washing with an aqueous saturated sodium bicarbonate solution and a saline, and drying with anhydrous magnesium sulfate were carried out, followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=97:3→80:20) to obtain a titled compound (174 mg) having the following physical property values.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([OH:7])[OH:6].[CH:8]([C:10]([CH3:12])=[O:11])=[CH2:9].[ClH:13]>C[Si](C)(C)N[Si](C)(C)C.O>[ClH:13].[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:9][CH2:8][C:10](=[O:11])[CH3:12])(=[O:7])[OH:6]
Reactant: NCCCP(O)O
Reactant: C=CC(C)=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: O
Product: CC(=O)CCP(=O)(O)CCCN
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 2.46 g of 3-aminopropylphosphonous acid in 20 ml of hexamethyldisilazane is heated to reflux under an inert gas for 24 hours. The resulting clear solution is cooled to room temperature and 14.4 g of freshly distilled methyl vinyl ketone are added. An exothermic reaction ensues, the reaction temperature rising to approximately 60° C. The reaction mixture is stirred for 1 hour at a temperature between 50° and 60°. After cooling to room temperature, the volatile materials are removed in vacuo to yield a colourless oil. This oil is dissolved in water and stirred at room temperature for 1 hour and the aqueous layer is evaporated to dryness at 55°. A semi-solid residue is obtained which is dissolved in 50 ml of 2.0M aqueous hydrochloric acid and washed with dichloromethane, (3×100 ml), and ether (1×100 ml). After removal of the water, the white solid is co-evaporated with water (10×50 ml) and then with absolute ethanol (10×50 ml). Crystallisation of the residue form ethanol yields 3-aminopropyl(3-oxobutyl)phosphinic acid hydrochloride. Treatment of the hydrochloride with propylene oxide/ethanol or passage through a DOWEX® 50 W×8 (14-40 mesh) ion-exchange column gives 3-aminopropyl(3-oxobutyl)phosphinic acid, m.p. 163°-5° (decomp.), as a white solid.
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>C(OCC)(=O)C>[CH3:46][C:43]1[CH:42]=[CH:41][C:40]([CH2:39][C:28]2[CH:29]=[C:30]([OH:31])[C:25](=[O:24])[NH:26][N:27]=2)=[CH:45][CH:44]=1
Reactant: Cc1ccc(Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(Cc2cc(O)c(=O)[nH]n2)cc1

Procedure:
Prepared in the same way as 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(4-methylphenyl)methyl]pyridazine (Intermediate 56) except that the solvent mixture used for the hydrogenation was made up of tetrahydrofuran and ethyl acetate and the product was recrystallised from a mixture of ethyl acetate and heptanes.
Reaction SMILES: [OH-].[Na+].[C:3]([CH2:11][C:12]([O:14]CC)=[O:13])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O>[C:3]([CH2:11][C:12]([OH:14])=[O:13])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydroxide (0.4 g) was dissolved in water (10 ml) and ethyl benzoylacetate (manufactured by Aldrich, 2.14 g: purity 90%) was added thereto and stirred at room temperature overnight. The reaction product was washed with ether and ether extraction was performed by adding a 10%-dilute sulfuric acid (4.9 g). An excess of anhydrous sodium sulfate was added to the ether extract, drying was performed thereon, and the anhydrous sodium sulfate was removed by filtering. In addition, the ether was removed using a rotary evaporator and a benzoylacetic acid was obtained (yield: 1.05 g).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13](Cl)[C:8]=2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[C:15]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>CN1C(=O)CCC1.C(OCC)(=O)C>[C:1]([O:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13]([N:25]3[CH2:24][CH2:23][N:22]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:27][CH2:26]3)[C:8]=2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c(Cl)ncnc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(=O)OC1CCc2c1ncnc2N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 75.1 %

Procedure:
To a solution of 4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl acetate (1.15 g, 5.4 mmol) in NMP (4 mL) and TEA (0.5 mL) was added 1-Boc-piperazine (1.05 g, 5.64 mmol). The mixture was microwaved at 100° C. for 30 minutes and then diluted with ethyl acetate (200 mL) and washed with water (6×100 mL). The organic phase was dried and concentrated. The residue was subject to chromatography on silica gel, eluting by hexanes/ethyl acetate (2:1-1:1) to afford the tert-butyl 4-(7-acetoxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (1.47 g, 75%). 1H NMR (CDCl3, 400 MHz) δ 8.56 (s, 1H), 5.99-5.96 (m, 1H), 3.78-3.73 (m, 2H), 3.53-3.50 (m, 2H), 3.15-3.07 (m, 1H), 2.99-2.92 (m, 1H), 2.63-2.54 (m, 1H), 2.04-1.93 (m, 1H), 1.48 (s, 9H). MS (APCI+) [M+H]+363.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[N:21]1([CH2:20][CH2:19][O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:27]=[CH:28][CH:29]=[C:2]([N:36]4[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]4)[CH:3]=3)=[CH:9][CH:10]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: C1CCNCC1
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(Br)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(N2CCCCC2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 3-bromo-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-benzamide (200 μmol, 1 eq.), cesium carbonate (300 μmol, 1.5 eq), and piperidine (300 μmol, 1.5 eq.) is suspended in anhydrous dioxane (2 ml) in a 2-dram vial. To the heterogeneous mixture is added bis(tri-t-butylphosphine)palladium(0) (5 mg, 5 mol %). The mixture is heated and agitated for 12 hours. The mixture is cooled to room temperature, filtered and concentrated. The residue is purified using reverse phase conditions (5:95; AcCN:H2O) to give N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-3-piperidin-1-yl-benzamide. Mp: 147-148° C. 1H NMR (300 MHz, DMSO-d6): δ 10.16 (s, 1H), 8.22 (m, 1H), 7.87 (m, 1H), 7.60 (s, 1H), 7.55 (m, 2H), 7.47 (m, 3H), 7.17 (d, 1H), 7.04 (d, 1H, J=8.7), 4.33 (t, 2H, J=5.7), 3.62 (t, 4H, J=4.5), 3.32 (m, 4H), 2.90 (t, 2H, J=5.7), 2.58 (m, 4H), 1.65 (m, 4H), 1.57 (m, 2H). MS: 460.2 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)(=[O:3])[CH3:2].[F:14][C:15]([F:25])([F:24])[C:16]([F:23])([F:22])[C:17](OCC)=[O:18]>>[F:22][C:16]([F:23])([C:15]([F:25])([F:24])[F:14])[C:17](=[O:18])[CH2:2][C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc2ccccc2c1
Reactant: CCOC(=O)C(F)(F)C(F)(F)F
Product: O=C(CC(=O)C(F)(F)C(F)(F)F)c1ccc2ccccc2c1

Procedure:
The compound was synthesized according to example 1 using 2-acetylnaphthalene and ethyl pentafluoropropionate as starting materials. The product was crystallized from petroleum ether. 1H NMR (CDCl3): 6.79 (s, 1 H); 7.57-7.67 (m, 2H); 7.90 (bd, 1 H); 7.94-7.95 (m, 2H); 7.99 (bd, 1H); 8.53 (s, 1 H). IR (film): 1602 (C═O); 1201 (C—F).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][C:21]=1[OH:30])(=[O:19])=[O:18])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[N:32]1([CH2:41][C@H:42]([CH3:44])O)[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[N:33]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>CO.O1CCCC1>[C:1]([O:5][C:6](=[O:31])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][C:21]=1[O:30][C@H:42]([CH3:44])[CH2:41][N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[N:33]1)(=[O:19])=[O:18])[CH:9]([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])([CH3:3])([CH3:4])[CH3:2]
Reactant: C[C@H](O)Cn1ncc2ccccc21
Reactant: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(C)=O)cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(C)=O)cc1O[C@H](C)Cn1ncc2ccccc21
Temperature: 25 °C
Yield: 88.9 %

Procedure:
A mixture of 0.25 g (0.54 mmol) (S)-3-(4-acetylamino-2-hydroxy-benzenesulfonylamino)-4,4-diethoxy-butyric acid tert-butyl ester, 0.096 g (0.54 mmol) (S)-2-indazol-1-yl-1-methyl-ethanol, 0.285 g (1.08 mmol) triphenylphosphine, and 40 mL dry tetrahydrofuran was stirred at room temperature. Diethyl azodicarboxylate 0.2 mL (1.08 mmol) was added dropwise and the resulting yellow solution was stirred 18 h at room temperature. TLC analysis indicated complete reaction. The reaction mixture was concentrated in vacuo to give a deep yellow oil. The product ether was purified over silica eluting with ethyl acetate to 9:1 ethyl acetate:methanol to yield 0.298 g (0.48 mmol, 89%) of (S)-3-[4-acetylamino-2-((R)-2-indazol-1-yl-1-methyl-ethoxy)-benzenesulfonylamino]-4,4-diethoxy-butyric acid tert-butyl ester as a colorless foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CC(C)=O.[I-].[K+].CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:5]#[N:6]
Reactant: N#Cc1ccc(O)c(Br)c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOCC
Product: N#Cc1ccc(OCc2ccccc2)c(Br)c1
Temperature: 48 °C
Yield: 86.1 %

Procedure:
To a solution of 3-bromo-4-hydroxybenzonitrile (60 g, 303 mmol) in acetone (600 mL) under nitrogen, potassium carbonate (62.8 g, 455 mmol) was added followed by potassium iodide (0.503 g, 3.03 mmol). To the mixture benzyl chloride (49.3 mL, 424 mmol) was added dropwise and the mixture was heated at 50° C. (48° C. internal temp) for 16 h. Reaction mixture was cooled down to room temperature, taken up with water (500 mL)/Et2O (1 L). Phases were separated and the aqueous phase back extracted with Et2O (2×500 mL). Combined organics were washed with NaHCO3 saturated solution (400 mL), then with 1M HCl solution (400 mL) and brine. Crude solution was then dried over Na2SO4 and evaporated under reduced pressure to give crude material (110 g) as brown solid that was triturated with c-hex (500 mL) for 30 min. The solid was collected by filtration and washed with c-hex/EtOAc 9/1 (200 mL). Evaporation of residual solvents under high vacuum afforded title material (75.5 g; 261 mmol; 86%) as pale brown solid.
Reaction SMILES: [Cl-].[CH:2]1([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([CH2:15][NH:16][C:17]([C@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[C:24]([C@@H:26]3[CH2:30][C@@H:29]([OH:31])[CH2:28][N:27]3[C:32](=[O:53])[CH2:33][C:34]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:25])=[O:18])[CH2:10]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C>ClCCl.CS(C)=O>[CH:2]1([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([CH2:15][NH:16][C:17]([C@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[C:24]([C@@H:26]3[CH2:30][C:29](=[O:31])[CH2:28][N:27]3[C:32](=[O:53])[CH2:33][C:34]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:25])=[O:18])[CH2:10]2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C(NC[C@H]1CCCN(CC2CCCCC2)C1)[C@H]1CCCN1C(=O)[C@@H]1C[C@@H](O)CN1C(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1C[C@@H](C(=O)N2CCC[C@@H]2C(=O)NC[C@H]2CCCN(CC3CCCCC3)C2)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reaction time: 0.33 h
Yield: 72.2 %

Procedure:
To a solution of 0.0037 ml of oxaryl chloride in 0.3 ml of dichloromethane, 0.0065 ml of dimethyl sulfoxide was added at −78° C., followed by 20 minutes' stirring at the same temperature. Then a solution of 25 mg of (2R)-N-{((3R)-1-cyclohexylmethyl-3-piperidyl)methyl}-1-{(2S,4R)-4-hydroxy-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonylpyrrolidine-2-carboxamide in 0.9 ml of dichloromethane was added at the same temperature, followed by 30 minutes' stirring, addition of 0.0024 ml of triethylamine at the same temperature, and 20 minutes' stirring at room temperature. The reaction liquid was diluted with chloroforom, washed with saturated brine and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the resulting residue was purified with a preparative thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (Merck); chloroform/methanol=9/1), to provide 18 mg of the title compound as a pale pink solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:15]2[CH:11]([N:12]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:13][CH:14]2[C:16]([OH:18])=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH2:31])=[N-].N(N(C)C(N)=O)=O.[OH-].[K+]>CCOC(C)=O.CCOCC>[CH3:31][O:17][C:16]([CH:14]1[CH2:13][N:12]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:15]12)=[O:18]
Reactant: CC(C)(C)OC(=O)N1CCC2C1C(C(=O)O)CN2C(=O)OCc1ccccc1
Reactant: C=[N+]=[N-]
Agent: CN(N=O)C(N)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)C2CCN(C(=O)OC(C)(C)C)C12

Procedure:
To a solution of crude 13 (0.47 g) in EtOAc (10 mL) and Et2O (10 mL) was added an ethereal solution of diazomethane that was prepared by treatment of N-nitroso-N-methyl urea (0.5 g) in Et2O (10 mL) with 1M KOH (10 mL). After consumption of starting material (monitored by TLC), the reaction mixture was diluted with HOAc. The solution was extracted with EtOAc, washed with saturated NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated to give a dark oil that was purified by HPLC (2″ Dynamax® SiO2, 10% EtOAc/hexane to 100% EtOAc over 30 min) to give 14 (0.19 g) as a yellow-colored oil. 1H NMR (CDCl3, 300 MHz): δ7.40-7.29 (m, 5H), 5.23-5.09 (m, 2H), 4.56-4.52 (m, 2H), 4.11-4.04 (m, 1H), 3.69 (s, 3H), 3.45-3.42 (m, 1H), 3.22-3.12 (m, 1H), 2.27-2.10 (m, 1H), 1.96 (m, 1H), 1.47 (s, 9H) ppm. Mass spectrum, m/z [405.2] (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=1>C(=O)([O-])[O-].[Ag+2].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>[C:18]1([CH3:17])[CH:23]=[CH:22][C:21]([C:5]2[S:1][C:2]([C:6]3[CH:7]=[CH:8][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:15][CH:16]=3)=[N:3][CH:4]=2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1ccc(-c2nccs2)cc1
Reactant: Cc1ccc(I)cc1
Agent: [Ag+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Product: CCOC(=O)c1ccc(-c2ncc(-c3ccc(C)cc3)s2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 83.3 %

Procedure:
In a sealed tub was added ethyl 4-(thiazol-2-yl)benzoate (100 mg, 0.43 mmol), 4-methyliodobenzene (111 mg, 0.51 mmol), silver carbonate (236 mg, 0.86 mmol) and tetrakis(triphenylphosphine)palladium (0) (11.2 mg, 0.86 mmol). The flask was purged with nitrogen three times and then was added acetonitrile (1.8 mL). The mixture was stirred under Ar atmosphere for 12 h at 60° C. When the reaction completed, the inorganic solids were filtered on (Celite®) and the residue was washed several times with dichloromethane, then filtered and evaporated. Flash chromatography of the residue on silica gel (SiO2, hexane:ethyl acetate, 9:1) afforded 115.8 mg of ethyl 4-(5-(p-tolyl)thiazol-2-yl)benzoate as a white crystalline solid (84% yield). EM (IE): m/z (%): 323.1; (M+, 100). HRMS (ESI): calculated for C19H18NO2S: 324.1053. found: 324.1055.