Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:13](=[S:14])[NH:12][N:11]=[C:10]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:7][CH:8]=1.Br[CH2:22][C:23]#[N:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:11][NH:12][C:13]=2[S:14][CH2:22][C:23]#[N:24])[CH:6]=[CH:7][CH:8]=1
Reactant: N#CCBr
Reactant: COc1cccc(C2C(=S)NN=C2c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2c(-c3ccccc3)n[nH]c2SCC#N)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.4 %

Procedure:
To a solution of 4-(3-methoxyphenyl)-3-phenyl-1H-pyrazole-5(4H)-thione (0.200 g, 0.708 mmol) in DMF (5.0 mL) was added 2-bromoacetonitrile (0.047 mL, 0.708 mmol) and K2CO3 (0.098 g, 0.708 mmol). The mixture was stirred at 25° C. for 72 h, quenched with water (40.0 mL), extracted with EtOAc (4×50.0 mL) and washed with brine. The combined organics were dried over MgSO4, filtered, and concentrated to give a brown oil. This brown oil was purified by silica gel flash chromatography to give the title compound as a white solid (0.158 g). LCMS m/z=332.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 3.67 (s, 2H), 3.74 (s, 3H), 6.82-6.89 (m, 3H), 7.23-7.29 (m, 1H), 7.34 (s, 5H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17]O)=[CH:13][CH:12]=1.S(Cl)([Cl:21])=O>C(Cl)Cl>[Cl:21][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[CH:12][CH:13]=1
Reactant: OCc1ccc(Cc2nc3ccccc3s2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1ccc(Cc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 117.2 %

Procedure:
To a solution of (4-benzothiazol-2-ylmethyl-phenyl)-methanol (2.1 g, 8.1 mmol) in CH2Cl2 (90 mL) was added thionyl chloride (0.65 mL, 8.9 mmol) and the mixture was stirred at rt for 4 h. The reaction mixture was concentrated to afford the title compound as a tan solid (2.6 g, 100%). MS (ESI): mass calcd. for C15H12ClNS, 273.04; m/z found, 274.0 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.34 (d, J=8.2 Hz, 1H), 7.89 (d, J=8.2 Hz, 1H), 7.71-7.67 (m, 1H), 7.61-7.58 (m, 1H), 7.50-7.48 (m, 2H), 7.45-7.44 (m, 2H), 4.84 (s, 2H), 4.60 (s, 2H).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH2:5]([O:12][C:13]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(C)[C:14](O)=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O.C1(C)C=CC=CC=1>[CH2:5]([O:12][CH:13]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:14][C:1]([Cl:4])=[O:2])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Cl)Cl
Reactant: CC(OCc1ccccc1)(Oc1ccccc1)C(=O)O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)CC(OCc1ccccc1)Oc1ccccc1
Temperature: 80 °C

Procedure:
A three-liter, round-bottom flask was obtained and fitted with an overhead stirrer, a thermocouple, a temperature controller, an addition funnel with a cold trap overhead, and a line leading to a phosgene cyclinder. Also it was fitted with an exit line to a nitrogen/vacuum source, a heating mantle, and a catch basin. The exit line went to a condenser and a caustic scrubber. Into this flask was placed 183.2 g (0.67 mole) benzyloxyphenoxypropionic acid, 900 ml of toluene, and 2.9 g (0.04 mole) dimethylformamide. The phosgene cyclinder was turned on and 75 ml (1.05 moles) phosgene was allowed to accumulate in the funnel. The reactants were heated to 80° C. with stirring while the phosgene was added thereto. During the course of the phosgene addition, solids formed in the flask; however, ultimately they went into solution. After the phosgene addition, nitrogen was slowly added to the flask. The reaction was stopped, and a vacuum pulled on the flask to boil off the excess phosgene. The flask was then placed under a nitrogen atmosphere. The solvent was stripped off, leaving 233.2 g of yellow solids, which were identified by suitable analytical techniques as being the subject compound.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][N:17]([CH:19]4[CH2:22][O:21][CH2:20]4)[CH:18]=3)=[CH:11][CH:12]=2)[N:7]([C:23](Cl)=[O:24])[CH2:6][C@@H:5]1[CH3:26])(=[O:3])[CH3:2].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=1.N1C=CC=CC=1>ClCCCl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][N:17]([CH:19]4[CH2:22][O:21][CH2:20]4)[CH:18]=3)=[CH:11][CH:12]=2)[N:7]([C:23]([O:33][C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)=[O:24])[CH2:6][C@@H:5]1[CH3:26])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3cnn(C4COC4)c3)cc2N(C(=O)Cl)C[C@@H]1C
Reactant: Oc1cccnc1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(=O)N1c2ccc(-c3cnn(C4COC4)c3)cc2N(C(=O)Oc2cccnc2)C[C@@H]1C
Temperature: 50 °C
Reaction time: 6 h
Yield: 0 %

Procedure:
A solution of (S)-4-acetyl-3-methyl-7-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-carbonyl chloride (0.050 g, 0.13 mmol) in 1,2-dichloroethane (1 mL) was added dropwise to a 50° C. solution of pyridine-3-ol (0.053 g, 0.26 mmol) and pyridine (1 mL) in 1,2-dichloroethane (20 mL). The resulting solution was stirred for 6 h at 50° C. and then concentrated under vacuum. The residue was purified by preparative thin layer chromatography (eluting with 1-20% methanol-dichloromethane) and then by preparative-HPLC (conditions: Column, SunFire™Prep C18OBD™, 19×150 nm; Mobile phase, A: 0.05% ammonium carbonate, B: acetonitrile; Detector, 220 and 254 nm) to afford (S)-pyridin-3-yl 4-acetyl-3-methyl-7-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.026 mg, 46%) as a white solid. 1H NMR (300 MHz, CD3OD) 1.17 (d, J=6.60 Hz, 3H), 2.27 (s, 3H), 3.50-3.79 (m, 1H), 4.35-4.45 (m, 1H), 5.02-5.25 (m, 5H), 5.55-5.65 (m, 1H), 7.39-7.49 (m, 2H), 7.51-7.57 (m, 1H), 7.78-7.83 (m, 1H), 7.97 (s, 1H), 8.10-8.19 (m, 2H), 8.47-8.50 (m, 1H), 8.52-8.56 (m, 1H). MS (ESI, pos. ion) m/z 434 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[CH:6])[CH3:2].[Li]CCCC.[CH:15](=[O:18])[CH2:16][CH3:17]>C1COCC1>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[C:6][CH:15]([OH:18])[CH2:16][CH3:17])[CH3:2]
Reactant: CCC=O
Reactant: C#CC(OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(C#CC(O)CC)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3,3-Diethoxy-propyne (2.73 g, 21.3 mmol) in THF (40 ml) was cooled to −78 C under N2. A solution of n-BuLi (2.0M in cyclohexane, 14 mL, 28 mmol) was added. After 30 min., Propionaldehyde (1.61 g, 27.7 mmol) in THF (10 ml) was added. After 15 h, the reaction was quenched by dilution with 1N HCl, warmed to room temperature and extracted into EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated to give product, 4.30 g (83%).
Reaction SMILES: S(=O)(=O)(O)O.O.[Cl:7][C:8]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([SH:17])=[CH:11][C:9]=1[NH2:10].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26](O)([CH3:28])[CH3:27]>O1CCCC1>[Cl:7][C:8]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([S:17][C:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][CH3:18])([CH3:28])[CH3:27])=[CH:11][C:9]=1[NH2:10]
Reactant: COc1ccccc1C(C)(C)O
Reactant: COc1cc(Cl)c(N)cc1S
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Cl)c(N)cc1SC(C)(C)c1ccccc1OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 33.7 %

Procedure:
To concentrated sulfuric acid (6 mL) was added water (6 mL) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. To the mixture was added a solution of 2-chloro-5-mercapto-4-methoxyaniline (0.5 g) and 2-(2-methoxyphenyl)-2-propanol (0.88 g) in tetrahydrofuran (6 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, a saturated aqueous sodium hydrogen carbonate solution and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=4/1) to give the title compound (0.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=[O:17])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[Cl:47][C:48]1[CH:61]=[CH:60][C:51]2[NH:52][C:53]([C@@H:55]([NH2:59])[CH2:56][O:57][CH3:58])=[N:54][C:50]=2[CH:49]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=[O:17])[C:5]([NH:59][C@H:55]([C:53]1[NH:52][C:51]2[CH:60]=[CH:61][C:48]([Cl:47])=[CH:49][C:50]=2[N:54]=1)[CH2:56][O:57][CH3:58])=[O:7]
Reactant: O=C(O)c1ccc(N2CCCCC2=O)c(Cl)c1
Reactant: COC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC[C@H](NC(=O)c1ccc(N2CCCCC2=O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1f from 3-chloro-4-(piperidin-2-on-1-yl)-benzoic acid, TBTU, NMM and (1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxy-ethylamine in DMF and subsequent purification by chromatography on silica gel (eluting gradient: ethyl acetate/ethanol 95:5->90:10).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]([NH2:10])=O)[C:5]([CH3:11])=[N:4]1)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8](=[S:21])[NH2:10])[C:5]([CH3:11])=[N:4]1)[CH3:2]
Reactant: CCn1cc(C(N)=O)c(C)n1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCn1cc(C(N)=S)c(C)n1
Temperature: 25 °C
Yield: 23.9 %

Procedure:
To a suspension of 1-ethyl-3-methyl-1H-pyrazole-4-carboxamide (1.7 g, 11 mmol) produced in the above in toluene (80 mL) was added Lawesson's reagent (7.0 g, 17 mmol), and the mixture was heated under reflux for 1.5 hr. The reaction solution was cooled to room temperature and purified by basic silica gel column chromatography (ethyl acetate/hexane=0/100→20/80) to give the title compound (445 mg, 24%) as a yellow oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)(=[O:13])=[O:12].[Cl:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([Cl:28])[C:26]=1Cl>>[Cl:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([Cl:28])[C:26]=1[N:17]1[CH2:18][CH2:19][CH:14]([S:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)(=[O:12])=[O:13])[CH2:15][CH2:16]1
Reactant: Clc1cncc(Cl)c1Cl
Reactant: O=S(=O)(c1ccc2ccccc2c1)C1CCNCC1
Product: O=S(=O)(c1ccc2ccccc2c1)C1CCN(c2c(Cl)cncc2Cl)CC1
Yield: 12.1 %

Procedure:
Using the procedure from Example 7A, Step 7E, 4-(2-naphthylsulfonyl)piperidine (130 mg, 0.51 mmol) was reacted with 3,4,5-trichloropyridine (182 mg, 1.0 mmol) to afford the title compound (26 mg), a white solid, in 12% yield.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[C:4]([CH3:8])[NH:3]1.[OH-].[Ca+2].[OH-].[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13].Cl>O1CCOCC1>[CH3:1][N:2]1[C:6]([OH:7])=[C:5]([C:19](=[O:20])[C:18]2[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:23][CH:22]=2)[C:4]([CH3:8])=[N:3]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc(=O)n(C)[nH]1
Agent: Cl
Agent: [Ca+2]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1nn(C)c(O)c1C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 69.3 %

Procedure:
In 22 ml. of dry dioxane is dissolved 2.24 g. of 1,3-dimethyl-5-pyrazolone and then 2.96 g. of calcium hydroxide is added thereto. 3.71 g. of p-nitrobenzoyl chloride is added dropwise thereto while stirring at room temperature. After completion of the dropwise addition, the mixture is heated under reflux for 1 hour. After completion of the reaction, the reaction mixture is allowed to cool and then 40 ml. of a 2N hydrochloric acid solution is added thereto. Crystalline substances thus separated are recovered by filtration and washed with water to give 4.38 g. of crude crystals. This product is recrystallized from methanol to give 3.62 g. of the desired product as pale yellow columns having a melting point of 234°-235° C. Yield 69.3%
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][O:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[S:19]([N:22]=[C:23]=[O:24])(=[O:21])=[O:20])=[O:13]>C(Cl)Cl>[CH3:9][C:4]1[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH:1][C:23]([NH:22][S:19]([C:18]2[CH:17]=[CH:16][S:15][C:14]=2[C:12]([O:11][CH3:10])=[O:13])(=[O:20])=[O:21])=[O:24])[N:3]=1
Reactant: COC(=O)c1sccc1S(=O)(=O)N=C=O
Reactant: Cc1nc(C)nc(N)n1
Solvent: ClCCl
Product: COC(=O)c1sccc1S(=O)(=O)NC(=O)Nc1nc(C)nc(C)n1
Temperature: 25 °C
Yield: 62.5 %

Procedure:
To 1.23 g of 2-amino-4,6-dimethyl-1,3,5-triazine in 30 ml of anhydrous methylene chloride was added with stirring 2.7 g of 2-methoxycarbonyl-3-thiophenesulfonylisocyanate. The mixture was heated to the boiling point and allowed to cool and stir at ambient temperature for sixteen hours. The solid thus obtained was removed by filtration to yield 2.3 g of the crude desired product melting at 158°-178°. The product showed peaks at 1720 and 1700 cm-1, by infrared absorption spectroscopy, consistent for the desired product.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[N:2]1.C(N(C(C)C)CC)(C)C.[CH2:18]([O:25][C:26](=[O:47])[C@H:27]([CH3:46])[CH2:28][C@H:29]([N:43]=[C:44]=[O:45])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:33][CH:32]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([O:25][C:26]([C@H:27]([CH3:46])[CH2:28][C@H:29]([NH:43][C:44]([N:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[N:2]1)=[O:45])[CH2:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[CH:35][CH:36]=1)=[O:47])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)N=C=O)C(=O)OCc1ccccc1
Reactant: O=C(O)c1cc[nH]n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)n1ccc(C(=O)O)n1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Next, to a solution of 1H-pyrazole-3-carboxylic acid (20.5 mg, 0.183 mmol) in DMF (1 mL) is added diisopropylethylamine (0.032 mL, 0.183 mmol). After 15 min a solution of the above (2R,4S)-5-biphenyl-4-yl-4-isocyanato-2-methyl-pentanoic acid benzyl ester in DMF (1 mL) is added dropwise and the mixture is stirred at room temperature for 18 hours. The mixture is purified by preparative HPLC using a gradient of 10% MeCN to 100% MeCN (0.1% TFA). Lyophilization of the appropriate fractions furnishes 1-((1S,3R)-3-benzyloxycarbonyl-1-biphenyl-4-ylmethyl-butylcarbamoyl)-1H-pyrazole-3-carboxylic acid.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH:21]([C:30]1[C:34](I)=[C:33]([CH:36]2[CH2:39][CH:38]([CH2:40][CH:41]([CH2:44][CH3:45])[CH2:42][CH3:43])[CH2:37]2)[O:32][N:31]=1)[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:46]1(B2OC(C)(C)C(C)(C)O2)[CH2:48][CH2:47]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)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.C(OCC)(=O)C>[Si:1]([O:18][CH2:19][CH2:20][CH:21]([C:30]1[C:34]([CH:46]2[CH2:48][CH2:47]2)=[C:33]([CH:36]2[CH2:39][CH:38]([CH2:40][CH:41]([CH2:44][CH3:45])[CH2:42][CH3:43])[CH2:37]2)[O:32][N:31]=1)[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(C2CC2)OC1(C)C
Reactant: CCC(CC)CC1CC(c2onc(C(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC(=O)OC(C)(C)C)c2I)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCC(CC)CC1CC(c2onc(C(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC(=O)OC(C)(C)C)c2C2CC2)C1
Temperature: 80 °C
Reaction time: 5 h
Yield: 65.2 %

Procedure:
tert-Butyl 5-(tert-butyldiphenylsilanyloxy)-3-{5-[3-(2-ethylbutyl)cyclobutyl]-4-iodoisoxazol-3-yl}valerate (4.96 g), 2-cyclopropyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1.68 g), tripotassium phosphate (5.66 g), PdCl2(PPh3)2 (468 mg) and N,N-dimethylacetamide (50 mL) were mixed. The mixture was stirred at 80° C. for 5 hr. To the reaction mixture were added ethyl acetate (50 mL) and Celite at RT, and the mixture was filtered. The collected solid was washed with ethyl acetate (50 mL×2). The filtrate was washed with water/brine=1/1 (100 mL×2) and brine (50 mL), then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo. The resultant residue was purified by silica gel column chromatography (Eluent: ethyl acetate/hexane=1/50→1/40→1/30→1/20) to give the title compound (2.86 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[C:23]([CH:28]=O)=[CH:24][CH:25]=[CH:26][CH:27]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[CH3:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: Cc1ccccc1-c1ccccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: COc1ccccc1N1CCN(Cc2ccccc2-c2ccccc2C)CC1

Procedure:
186 mg of the target compound (0.50 mmol, 97.9%) was obtained using 1-(2-methoxyphenyl)piperazine (196 mg, 1.02 mmol), 2′-methylbiphenyl-2-carbaldehyde (100 mg, 0.51 mmol) and NaBH(OAc)3 (329 mg, 1.53 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@@H:8]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[C:16](=[O:27])[NH:17][C:18]1[N:19]=[C:20]2[N:24]([CH:25]=1)[CH:23]=[C:22](Br)[S:21]2)=[O:10])([CH3:4])([CH3:3])[CH3:2].[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:1]([O:5][C:6](=[O:34])[NH:7][C@@H:8]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:9](=[O:10])[N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[C:16](=[O:27])[NH:17][C:18]1[N:19]=[C:20]2[N:24]([CH:25]=1)[CH:23]=[C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[S:21]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@@H]1C(=O)Nc1cn2cc(Br)sc2n1)c1ccccc1
Reactant: OB(O)c1ccccc1
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@@H]1C(=O)Nc1cn2cc(-c3ccccc3)sc2n1)c1ccccc1
Yield: 6 %

Procedure:
Compound A24 was synthesized from compound 12a (0.053 mmol) and phenylboronic acid (0.16 mmol), following the procedure as described for compound A1, to give compound A24 as a white solid in 6% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.40 (s, 9H), 1.82-1.91 (m, 1H), 2.01-2.13 (m, 1H), 2.35-2.42 (m, 1H), 3.13-3.21 (m, 1H), 3.77-3.84 (m, 1H), 4.70-4.72 (m, 1H), 5.46 (d, J=7.08 Hz, 1H), 6.04 (d, J=7.08 Hz, 1H), 7.31-7.46 (m, 11H), 7.63 (s, 1H), 7.89 (s, 1H), 9.88 (brs, 1H); and MS (ESI, EI+) m/z=546.23 (MH+)
Reaction SMILES: [CH2:1]([N:3]([CH2:27][CH3:28])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[CH2:13][C:14]([O:16]CC)=[O:15])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[OH-].[Na+]>CO.O>[CH2:27]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[CH2:13][C:14]([OH:16])=[O:15])=[CH:10][CH:11]=1)=[O:5])[CH3:28]
Reactant: CCOC(=O)CC(c1ccc(C(=O)N(CC)CC)cc1)c1cccc(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCN(CC)C(=O)c1ccc(C(CC(=O)O)c2cccc(OC)c2)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Ethyl 3-(4-diethylcarbamoylphenyl)-3-(3-methoxyphenyl)propionate (275 mg) was dissolved in a mixed solution of methanol (5.6 ml) and water (2.8 ml), added with 1 N aqueous sodium hydroxide (1.4 ml) and stirred at 50° C. for 1 hour. The solvent was evaporated under reduced pressure and added with 1 N aqueous hydrochloric acid (5 ml), and the reaction mixture was extracted twice with dichloromethane (5 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to obtain 3-(4-diethylcarbamoylphenyl)-3-(3-methoxyphenyl)propionic acid.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([S:19]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH2:32][CH2:33][O:34][S:35]([C:38]4[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=4)(=[O:37])=[O:36])[CH:29]=3)[NH:24][N:23]=2)(=[O:21])=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(C)=O>[CH2:1]([N:24]1[C:25]2[C:30](=[CH:29][C:28]([O:31][CH2:32][CH2:33][O:34][S:35]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=3)(=[O:37])=[O:36])=[CH:27][CH:26]=2)[C:22]([S:19]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)(=[O:20])=[O:21])=[N:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)c(S(=O)(=O)c2cccc4ccccc24)nn3Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Benzyl bromide (0.46 mL, 3.9 mmol) was added to a stirring suspension of toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (1.85 g, 3.54 mmol) and cesium carbonate (1.28 g, 3.93 mmol) in acetone (60 mL). The reaction mixture was stirred under nitrogen at ambient temperature for 1.5 hours. It was then poured into excess water and extracted with chloroform. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography with 40-50% ethyl acetate in hexane. Drying at 80° C. in vacuo for 30 minutes yielded toluene-4-sulfonic acid 2-[1-benzyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester as a light buff foam (1.39 g, 64.1%); Mass Spectrum (+EI, [M+H]+) m/z 613. 1HNMR (500 MHz, DMSO-d6): δ8.74-8.77 (m, 1H), 8.55-8.57 (m, 1H), 8.25-8.27 (m, 1H), 8.01-8.05 (m, 1H), 7.64-7.76 (m, 4H), 7.58-7.64 (m, 2H), 7.25 (d, 2H, J=7.93 Hz), 7.10-7.19 (m, 5H), 7.07 (d, 1H, J=2.19 Hz), 6.94-6.97 (m, 1H), 5.69 (s, 2H), 4.30-4.32 (m, 2H), 4.14-4.16 (m, 2H), 2.18 ppm (s, 3H). Elemental Analysis for C33H28N2O6S2.0.60 mol H2O: Calcd: C, 63.57; H, 4.72; N, 4.49; Found: C, 63.17; H, 4.63; N, 4.30.
Reaction SMILES: [H-].[Na+].FC1C(F)=CC=CC=1[CH2:11][S:12]([C:15]1[N:20]=[C:19]([N:21]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[S:22]([N:25]2[CH2:28][CH2:27][CH2:26]2)(=[O:24])=[O:23])[CH:18]=[C:17]([O:38][CH3:39])[N:16]=1)(=O)=O.[CH:40]1[CH:45]=[CH:44][C:43]([CH2:46]CS)=[CH:42][CH:41]=1>CN(C=O)C.CCOC(C)=O>[CH3:37][O:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][N:21]([C:19]2[CH:18]=[C:17]([O:38][CH3:39])[N:16]=[C:15]([S:12][CH2:11][CH2:46][C:43]3[CH:44]=[CH:45][CH:40]=[CH:41][CH:42]=3)[N:20]=2)[S:22]([N:25]2[CH2:28][CH2:27][CH2:26]2)(=[O:23])=[O:24])=[CH:35][CH:34]=1
Reactant: SCCc1ccccc1
Reactant: COc1ccc(CN(c2cc(OC)nc(S(=O)(=O)Cc3cccc(F)c3F)n2)S(=O)(=O)N2CCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2cc(OC)nc(SCCc3ccccc3)n2)S(=O)(=O)N2CCC2)cc1

Procedure:
60% Sodium hydride (29 mg) was added to a solution of the product of step ii) (0.36 g) and 2-phenylethylthiol (0.1 g) in anhydrous DMF (4 ml) stirred under nitrogen. The reaction mixture was stirred for 18 h, diluted with EtOAc and washed with H2O. The separated organic solution was dried (MgSO4), filtered and the solvent evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel using Et2O/isohexane (3:7) as eluent to give the product as a white solid. Yield: 0.17 g.