Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([NH:9][C:10]1[CH:11]=[C:12]([O:34][CH3:35])[C:13]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[C:14]2[C:19]=1[N:18]=[C:17]([O:20][CH3:21])[CH:16]=[C:15]2[CH3:22])[CH2:3][CH2:4][CH2:5][N+:6]([O-])=O.[H][H].[C:38]([OH:45])(=[O:44])[CH2:39][CH2:40][C:41]([OH:43])=[O:42]>[Pd].C(O)C>[C:38]([OH:45])(=[O:44])[CH2:39][CH2:40][C:41]([OH:43])=[O:42].[NH2:6][CH2:5][CH2:4][CH2:3][CH:2]([NH:9][C:10]1[CH:11]=[C:12]([O:34][CH3:35])[C:13]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=2)=[C:14]2[C:19]=1[N:18]=[C:17]([O:20][CH3:21])[CH:16]=[C:15]2[CH3:22])[CH3:1]
Reactant: [H][H]
Reactant: COc1cc(C)c2c(Oc3cccc(C(F)(F)F)c3)c(OC)cc(NC(C)CCC[N+](=O)[O-])c2n1
Agent: [Pd]
Agent: O=C(O)CCC(=O)O
Solvent: CCO
Product: COc1cc(C)c2c(Oc3cccc(C(F)(F)F)c3)c(OC)cc(NC(C)CCCN)c2n1
Reaction time: 2 h
Yield: 67.9 %

Procedure:
A mixture of the product from example 2.2 (7.5 g, 15.2 mmol), ethanol (150 ml) and 5% Pd—C (2 g) was stirred under ca. 1 bar hydrogen for 24 hours at ambient temperature. The catalyst was filtered off and the solvent evaporated to leave a volume of ca. 25 ml. Succinic acid (2.3 g, 19.8 mmol) was added, and the mixture heated under reflux for 30 minutes. The solution was then cooled to 0–5° C., seeded with authentic target compound, and stirred for 2 hours. The crystalline product was filtered off, washed with ethanol (15 ml) and dried in vacuo at 50° C. for 24 hours to give 8-[(4-amino-1-methylbutyl)amino]-2,6-dimethoxy-4-methyl-5-(3-trifluoromethylphenoxy)quinoline succinate as an off-white crystalline solid (6.0 g, 68%).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([F:11])[F:10])=[CH:5][CH:4]=1.[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15]([CH:45]=[O:46])=[CH:16][N:17]2[C@@H:22]1[O:39][C@H:38]([CH2:40][O:41][C:42](=[O:44])[CH3:43])[C@@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:23]1[O:24][C:25](=[O:27])[CH3:26].[Cl-].[NH4+]>O1CCCC1.BrCCBr>[F:10][CH:9]([F:11])[C:6]1[CH:7]=[CH:8][C:3]([CH:45]([C:15]2[C:14]3[C:18](=[CH:19][CH:20]=[CH:21][C:13]=3[F:12])[N:17]([C@@H:22]3[O:39][C@H:38]([CH2:40][O:41][C:42](=[O:44])[CH3:43])[C@@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:23]3[O:24][C:25](=[O:27])[CH3:26])[CH:16]=2)[OH:46])=[CH:4][CH:5]=1
Reactant: FC(F)c1ccc(Br)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C=O)c3c(F)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C(O)c3ccc(C(F)F)cc3)c3c(F)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
To a mixture of magnesium turnings (71 mg) in tetrahydrofuran (2 ml) was added dropwise a solution of 1-bromo-4-difluoromethylbenzene (587 mg) in tetrahydrofuran (1.5 ml) under being stirred vigorously. The mixture was warmed with a dryer, and thereto was added 1,2-dibromoethane (4 drops). The resultant mixture was vigorously stirred at room temperature till a disappearance of magnesium turnings, and then dropwise added to a solution of the above 4-fluoro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole-3-carboxaldehyde (350 mg) in tetrahydrofuran (4 ml) over 10 minutes at −78° C. under argon atmosphere. The mixture was stirred at same temperature for 1 hour, and thereto was added a saturated aqueous ammonium chloride solution (20 ml). The resultant mixture was extracted with ethyl acetate (50 ml) 3 times, and the combined organic layer was dried over magnesium sulfate. The insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure to give crude 4-(difluoromethyl)phenyl 4-fluoro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indol-3-yl methanol, which was used in the subsequent step without further purification.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[C:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:8]([CH3:17])=[CH:7][C:6]=1[NH:18][C:19]1[N:24]=[C:23]2[NH:25][N:26]=[CH:27][C:22]2=[C:21]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([CH:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])[N:20]=1)([CH3:3])[CH3:2].Cl.[CH3:42][N:43]([CH3:48])[CH2:44][C:45](Cl)=[O:46].C(N(CC)CC)C>ClCCl>[CH3:42][N:43]([CH3:48])[CH2:44][C:45]([N:14]1[CH2:15][CH2:16][CH:11]([C:9]2[CH:10]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[C:6]([NH:18][C:19]3[N:24]=[C:23]4[NH:25][N:26]=[CH:27][C:22]4=[C:21]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[S:35]([CH:38]([CH3:40])[CH3:39])(=[O:36])=[O:37])[N:20]=3)=[CH:7][C:8]=2[CH3:17])[CH2:12][CH2:13]1)=[O:46]
Reactant: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3cn[nH]c3n2)c(OC(C)C)cc1C1CCNCC1
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3cn[nH]c3n2)c(OC(C)C)cc1C1CCN(C(=O)CN(C)C)CC1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
N6-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (56 mg) was dissolved in 3 mL of dichloromethane. The solution was cooled to 5° C. and 2-(dimethylamino)acetyl chloride hydrochloride (24 mg) was added to the solution followed by triethylamine (15 mg). The solution was stirred at room temperature for approximately 30 minutes. After Prep-LC-MS, the final product is obtained. MS (ES+): 649.32 (M+1)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].Br[CH2:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:21]=1[O:22][CH2:23][C:24]#[N:25]>>[CH3:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][O:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[C:21]=1[O:22][CH2:23][C:24]#[N:25]
Reactant: Cc1cccc(CBr)c1OCC#N
Reactant: OCCCCOCc1ccc2ccccc2n1
Product: Cc1cccc(COCCCCOCc2ccc3ccccc3n2)c1OCC#N

Procedure:
MS (ESI) 391 (M+H)+. Prepared from 4-(quinolin-2-ylmethoxy)-butan-1-ol (EXAMPLE 34b) and (2-bromomethyl-6-methyl-phenoxy)-acetonitrile
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.[F:27][C:28]([F:42])([F:41])[C:29]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:30]=1[CH2:31]Br>ClCCl>[F:27][C:28]([F:41])([F:42])[C:29]1[CH:36]=[C:35]([C:37]([F:40])([F:38])[F:39])[CH:34]=[CH:33][C:30]=1[CH2:31][NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:16][CH:17]=1
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Reactant: COC(=O)C(C)(C)Oc1ccc(CCN)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(C(F)(F)F)cc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
A solution of methyl 2-[4-(2-aminoethyl)phenoxy]-2-methylpropanoate (Biochim. Biophys. Acta 1997, 1339 (2), 321–330) (2 g; 8.44 mmol) in dichloromethane (20 ml) was treated with DIEA (1.47 ml; 8.44 mmol) and 2,4-bis-trifluoromethyl-benzyl bromide (2.59 g; 8.44 mmol). After stirring at rt overnight, the reaction mixture was concentrated and partitioned between ethyl acetate and saturated Na2CO3 solution. The organic phase was washed with Na2CO3 solution and brine, dried over sodium sulfate and concentrated. Purification by flash chromatography on silica gel using an ethyl acetate-hexane mixture (10–50%) afforded the title compound (2.0 g; 51% yield).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:27][O:28][CH2:29][CH2:30][OH:31]>O>[CH3:27][O:28][CH2:29][CH2:30][O:31][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: COCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COCCOc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 80 °C

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.27 g of potassium carbonate and 3 ml of 2-methoxyethanol was stirred while heating at 80° C. for 2.5 hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.23 g of 2-[3-(2-methoxyethoxy)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 120”).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH3:10])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(=O)Cc1ccc(Br)cc1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(Cc1ccc(Br)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(4-Bromophenyl)propan-2-one (2.03 g) was dissolved in CHCl3 (40 mL), and morpholine (1.24 mL) was added thereto, followed by stirring at room temperature overnight and then at 60° C. for 4 hours. NaBH(OAc)3 (4.03 g) and acetic acid (1.1 mL) were sequentially added thereto, followed by stirring overnight. The reaction was terminated by addition of water, and the reaction solution was separated between CHCl3 and a saturated aqueous NaHCO3 solution. The residue was purified by silica gel column chromatography (mobile phase: CHCl3/EtOAc=80/20 to 60/40 (v/v)) to yield the title compound (1.67 g, colorless oil).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8](=[O:10])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.O=[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.N1CCCC1.Cl>CO>[O:10]=[C:8]1[C:3]2=[N:4][CH:5]=[CH:6][CH:7]=[C:2]2[O:1][C:12]2([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH2:9]1
Reactant: CC(=O)c1ncccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Solvent: CO
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1ncccc1O2
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
A solution of 1-(3-hydroxy-2-pyridyl)ethanone (2.4 g, 18 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (3.5 g, 18 mmol) and pyrrolidine (1.5 mL, 18 mmol) in MeOH (12 mL) was stirred at 80° C. for 2 hours. After cooling to room temperature 1M aqueous HCl was added until pH 4 was reached and the reaction mixture was stirred for further 30 minutes. Methanol was evaporated, the remaining mixture was poured into water, and the pH adjusted to pH 7 with saturated aqueous sodium carbonate. The aqueous phase was extracted with ethyl acetate (3×), washed with brine (3×), dried over sodium sulfate and evaporated to dryness. Purification by silica gel chromatography (50-100% ethyl acetate in hexane) afforded tert-butyl 4′-oxo-3′,4′-dihydrospiro-[piperidine-4,2′-pyrano[3,2-b]pyridine]-1-carboxylate (2.2 g, 40%) as an orange oil that solidified upon standing. ESI-MS m/z talc. 318.2, found 319.3 (M+1)+; Retention time: 1.16 minutes (3 min run).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:4]=1.ClC[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[CH2:26]([O:25][C:23]([CH2:22][CH2:21][CH2:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:4]=1)=[O:24])[CH3:27]
Reactant: COc1nc(-c2ccccc2)nc2ccccc12
Reactant: CCOC(=O)CCCCl
Product: CCOC(=O)CCCOc1nc(-c2ccccc2)nc2ccccc12
Yield: 88.6 %

Procedure:
According to the preparation of 69, ethyl 4-chlorobutyrate (1.36 g, 9.00 mmol) was used to yield 72 (1.34 g, 88.6%) as colorless powder.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Cl:18])[C:16]=1Cl.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Cl:18])[C:16]=1[N:7]1[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]1
Reactant: CC(=O)N1CCNCC1
Reactant: Clc1cncc(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(=O)N1CCN(c2c(Cl)cncc2Cl)CC1
Yield: 24.3 %

Procedure:
General procedure C was followed using acetylpiperazine (35 mg, 0.27 mmol), 3,4,5-trichloropyridine (50 mg, 0.27 mmol), triethylamine (0.76 μL, 0.54 mmol) and NMP (1.5 mL). The crude product was purified by flash column chromatography on silica gel (hexane/EtOAc, 1:1) to furnish the title compound as a white solid (18 mg, 24%), m.p. 144-146° C.; umax (CHCl3)/cm−1 3008, 2909, 2856, 1638, 1558, 1470, 1441, 1282, 1240, 1152, 1098; m/z (ESI) C11H14Cl2N3O requires 274.0508, found [M+H]+ 274.0513.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH:14]([NH:28][C:29](=[O:39])[CH2:30][CH:31]2[CH2:36][CH2:35][CH:34]([CH2:37][NH2:38])[CH2:33][CH2:32]2)[B:15]2[O:23][CH:22]3[C:17]([CH3:27])([CH:18]4[CH2:24][CH:20]([CH2:21]3)[C:19]4([CH3:26])[CH3:25])[O:16]2)[C:8]=1[O:40][CH3:41])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:49]([NH:56][CH2:57][CH2:58]Br)([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50].CN(C=O)C>CCOC(C)=O>[C:1]([O:5][C:6](=[O:42])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH:14]([NH:28][C:29](=[O:39])[CH2:30][CH:31]2[CH2:32][CH2:33][CH:34]([CH2:37][NH:38][CH2:58][CH2:57][NH:56][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:35][CH2:36]2)[B:15]2[O:23][CH:22]3[C:17]([CH3:27])([CH:18]4[CH2:24][CH:20]([CH2:21]3)[C:19]4([CH3:25])[CH3:26])[O:16]2)[C:8]=1[O:40][CH3:41])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: COc1c(CC(NC(=O)CC2CCC(CN)CC2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1c(CC(NC(=O)CC2CCC(CNCCNC(=O)OC(C)(C)C)CC2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Temperature: 65 °C
Yield: 47 %

Procedure:
A sealable reaction tube was charged with 3-[2-[2-(4-Aminomethyl-cyclohexyl)-acetylamino]-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-2-methoxy-benzoic acid tert-butyl ester (0.205 g, 0.352 mmol), potassium carbonate (0.057 g, 0.412 mmol), 2-(Boc-amino)ethyl bromide (0.095 g, 0.424 mmol), and DMF (3.0 mL). The tube was sealed and the reaction heated at 65° C. for 24 hr. The reaction was cooled to RT. The reaction was diluted with EtOAc and washed with 5% aqueous LiCl (2×) and brine. The organic layer was dried over Na2SO4, filtered, and concentrated to afford 0.120 g of crude product which was carried to the next step without purification. ESI-MS m/z 726 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([Cu]C(=O)C)(=O)C.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][C:2]1[N:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1c(C)[nH]c2ccccc12
Agent: CC(=O)[Cu]C(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1c(C)n(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 38.7 %

Procedure:
A mixture of methyl 2-methyl-1H-indole-3-carboxylate (500 mg, 2.65 mmol), phenylboronic acid (384 mg, 3.17 mmol), diacetylcopper (453 mg, 3.98 mmol), triethylamine (0.44 ml, 3.98 mmol), N,N-dimethylpyridin-4-amine (486 ml, 3.98 mmol) and 4A molecular sieve (1.02 g) in dichloromethane (15 mL) was stirred at room temperature for 12 hours. After filtration, the mixture was concentrated and purified by chromatography (silica gel, petroleum: ethyl acetate=10:1) to afford methyl 2-methyl-1-phenyl-1H-indole-3-carboxylate as white solid (272 mg, 39%). 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J=8.0 Hz, 1H), 7.66-7.51 (m, 3H), 7.36 (dd, J=5.3, 3.2 Hz, 2H), 7.30 (s, 1H), 7.21-7.14 (m, 1H), 7.04 (d, J=8.2 Hz, 1H), 4.00 (s, 3H), 2.62 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]([NH:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[CH:28]=[N:27][CH:26]=[CH:25]3)=[O:20])[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:5][CH:4]=1.[CH3:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36].C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[CH3:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35]([O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH2:10][NH:11][C:12]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:18])[C:19]([NH:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[CH:28]=[N:27][CH:26]=[CH:25]3)=[O:20])=[CH:7][CH:8]=1)=[O:36]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(CO)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1ccccc1C(=O)OCc1ccc(C(CNC(=O)OC(C)(C)C)C(=O)Nc2ccc3cnccc3c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl 2-(4-(hydroxymethyl)phenyl)-3-(isoquinolin-6-ylamino)-3-oxopropylcarbamate (E139) in pyridine was added 2-methylbenzoyl chloride and the solution was stirred for 2 h at room temperature. The mixture was poured into NaHCO3 and extracted with EtOAc. The organics were dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 5% MeOH/CH2Cl2) gave pure 4-(3-(tert-butoxycarbonylamino)-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2-methylbenzoate (E140).
Reaction SMILES: [CH:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][N:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][O:18][C:19]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[C:20]=1[C:21]([N:23]=[C:24]=[O:25])=[O:22].CN(C=O)C>O>[CH3:31][O:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:19]([O:18][CH3:17])[C:20]=1[C:21]([NH:23][C:24]([NH:16][C:13]1[CH:12]=[N:11][C:10]([S:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)(=[O:8])=[O:9])=[CH:15][CH:14]=1)=[O:25])=[O:22]
Reactant: Nc1ccc(S(=O)(=O)C2CCCCC2)nc1
Reactant: COc1cccc(OC)c1C(=O)N=C=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(OC)c1C(=O)NC(=O)Nc1ccc(S(=O)(=O)C2CCCCC2)nc1

Procedure:
2-Cyclohexylsulfonyl-5-aminopyridine (1.0 gram) and 2,6-dimethoxybenzoyl isocyanate (0.9 gram) were mixed in 50 ml. of DMF and stirred at room temperature overnight (about 18 hours). The reaction mixture was then poured into water and filtered to separate the product. It was crystallized from ethyl acetate-hexanes, yield 0.5 gram, m.p., 123°-125° C.
Reaction SMILES: [CH2:1]([S:3]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:20])[C:15]([O:17]CC)=[O:16])=[CH:10][C:9]=1[F:21])(=[O:5])=[O:4])[CH3:2].C(O)(C(F)(F)F)=O>CN(C=O)C.[Mn]>[CH2:1]([S:3]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:20])[C:15]([OH:17])=[O:16])=[CH:10][C:9]=1[F:21])(=[O:5])=[O:4])[CH3:2]
Reactant: CCOC(=O)C(C)c1ccc(CNS(=O)(=O)CC)c(F)c1
Agent: [Mn]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCS(=O)(=O)NCc1ccc(C(C)C(=O)O)cc1F
Temperature: 65 °C
Reaction time: 24 h

Procedure:
To a solution of ethyl 2-(4-(ethylsulfonamidomethyl)-3-fluorophenyl)propanoate (305 mg, 1.03 mmol) in DMF, manganese (113 mg, 2.06 mmol), NiBr2bipy (27 mg, 0.07 mmol), ethyl-2-chloro propionate (0.17 mL, 1.34 mmol) was added, followed by addition of TFA (0.002 mL, 0.028 mmol). The mixture was stirred for 1 day at 65° C. The reaction mixture was quenched by conc. HCl (7-drops) and then extracted with diethyl ether, dried (MgSO4) and the solvent was evaporated in vacuo. The residue was purified by CC (EtOAc/n-hexane). 2-(4-(ethyl-sulfonamidomethyl)-3-fluorophenyl)propanoic acid in pure form (65 mg, 20%) was obtained.
Reaction SMILES: O1B([C@@H](NC(=O)[C@@H](NC(C2C=NC=CN=2)=O)CC2C=CC=CC=2)CC(C)C)[O:5][B:4]([C@@H:32]([NH:37][C:38](=[O:56])[C@@H:39]([NH:47][C:48]([C:50]2[CH:55]=[N:54][CH:53]=[CH:52][N:51]=2)=[O:49])[CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:33][CH:34]([CH3:36])[CH3:35])[O:3]B1[C@@H](NC(=O)[C@@H](NC(C1C=NC=CN=1)=O)CC1C=CC=CC=1)CC(C)C.[C:82](O)(=[O:90])[C@H:83]([C@@H:85]([C:87]([OH:89])=[O:88])[OH:86])O.CCCCCCC>CC(C)=O>[OH:86][C@@H:85]([C@H:83]1[C:82](=[O:90])[O:3][B:4]([C@@H:32]([NH:37][C:38](=[O:56])[C@@H:39]([NH:47][C:48]([C:50]2[CH:55]=[N:54][CH:53]=[CH:52][N:51]=2)=[O:49])[CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:33][CH:34]([CH3:35])[CH3:36])[O:5]1)[C:87]([OH:89])=[O:88]
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1)B1OB([C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)c2cnccn2)OB([C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)c2cnccn2)O1
Solvent: CC(C)=O
Solvent: CCCCCCC
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1)B1OC(=O)[C@H]([C@H](O)C(=O)O)O1
Yield: 547 %

Procedure:
A mixture of N,N′,N″-(boroxin-2,4,6-triyltris{[(1R)-3-methylbutane-1,1-diyl]imino[(2S)-1-oxo-3-phenylpropane-1,2-diyl]})tripyrazine-2-carboxamide (0.180 g, 0.164 mmol) and D-tartaric acid (147.5 mg, 0.33 mmol) were mixed in acetone (4 mL). The mixture was heated to form a solution. The solution was cooled uncontrolled until the internal temperature was about 25° C. Heptane (8 mL) was added. The mixture was evaporated to yield (S)-2-hydroxy-2-((S)-2-((R)-3-methyl-1-((S)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido)butyl)-5-oxo-1,3,2-dioxaborolan-4-yl)acetic acid (0.447 g) which also contained a dimeric species. MS (m/z) in CH3CN: [M+H] calculated for C23H28BN4O8, 499.2000. found, 499.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:26]([F:29])([F:28])[F:27])[O:14][N:13]=[C:12]([C:15]3[S:19][C:18]([C:20]([OH:22])=O)=[C:17]4[CH2:23][CH2:24][CH2:25][C:16]=34)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].C(N(CC)C(C)C)(C)C.Cl.[NH2:40][CH2:41][C:42]([NH:44][CH2:45][C:46]([F:49])([F:48])[F:47])=[O:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:26]([F:28])([F:29])[F:27])[O:14][N:13]=[C:12]([C:15]3[S:19][C:18]([C:20]([NH:40][CH2:41][C:42](=[O:43])[NH:44][CH2:45][C:46]([F:49])([F:48])[F:47])=[O:22])=[C:17]4[CH2:23][CH2:24][CH2:25][C:16]=34)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: NCC(=O)NCC(F)(F)F
Reactant: O=C(O)c1sc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2c1CCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CNC(=O)c1sc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2c1CCC2)NCC(F)(F)F
Yield: 84.8 %

Procedure:
Stir a mixture of 3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic acid (1.0 g, 2.14 mmol), N,N-diisopropylethylamine (827 mg, 6.41 mmol), 2-amino-N-(2,2,2-trifluoroethyl) acetamide hydrochloride (658 mg, 2.56 mmol) and HATU (1.2 g, 3.2 mmol) in CH2Cl2 (10 mL) at room temperature for 2 hours. The reaction mixture is diluted with CH2Cl2 (50 mL) and is washed with water (10 mL×3) and brine. Then the organic layer is dried over anhydrous Na2SO4 and is concentrated under vacuum. Purify the residue by preparative HPLC to afford 3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxamide as a white solid (1.1 g, 84.6%). MS (m/z): 606.0 (M+1).