Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]1[CH2:19]OC[CH2:16]1.C([Mg]Cl)(C)C>[NH4+].[Cl-]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:14])[CH:15]([CH3:19])[CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C=O)C1
Reactant: C1CCOC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C

Procedure:
(S)-3-Formylpyrrolidine-1-carboxylic acid t-butyl ester (10.0 g, 50.2 mmol) and THF (100 mL, 1000 mmol) were combined under nitrogen, and the resulting solution was cooled to −78° C. 2.0M isopropylmagnesium chloride in THF (30.1 mL, 60.2 mmol) was then added dropwise over 10 minutes. The mixture was allowed to warm to room temperature slowly overnight. Then saturated aqueous NH4Cl (100 mL) was added dropwise to quench the reaction. The THF was removed under vacuum and the resulting mixture was extracted with EtOAc (2×100 mL), and the combined organic layers were washed with saturated aqueous NaCl (1×100 mL), then dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by normal phase chromatography (300 g SiO2, 12 g crude, 50-60% diethyl ether in hexanes) to yield the following as clear oils:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.C(O)C.[NH2:18][C:19]1[CH:24]=[C:23]([CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:22]=[CH:21][C:20]=1[S:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1>>[O:26]([CH2:25][C:23]1[CH:22]=[CH:21][C:20]([S:33][C:34]2[CH:35]=[CH:36][C:37]([OH:40])=[CH:38][CH:39]=2)=[C:19]([NH:18][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:24]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Nc1cc(COc2ccccc2)ccc1Sc1ccc(O)cc1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Solvent: CCO
Product: CCCc1ccc2c(Nc3cc(COc4ccccc4)ccc3Sc3ccc(O)cc3)ccnc2n1
Temperature: 80 °C

Procedure:
The product from Example 2g as a 4.1M solution in ethanol (0.050 mL, 0.205 mmol) was reacted with the product from Example 221d (0.066 g, 0.205 mmol) for 16.5 h following the procedure from Example 1g. Consumption of starting material required a second addition of the product from Example 2g (0.025 mL, 0.102 mmol) and continued heating at 80° C. (12 h). The crude title compound was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (0.0269 g, 21.5%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J=7.54 Hz, 3H) 1.76-1.99 (m, 2H) 3.00 (t, J=7.35 Hz, 2H) 5.12 (s, 2H) 6.31 (d, J=6.99 Hz, 1H) 6.79 (d, J=8.82 Hz, 2H) 6.91-7.07 (m, 4H) 7.17-7.37 (m, 4H) 7.43-7.55 (m, 2H) 7.84 (d, J=8.82 Hz, 1H) 8.47 (d, J=7.35 Hz, 1H) 9.04 (d, J=8.46 Hz, 1H) 9.97 (s, 1H); MS (ESI+) m/z 494.2 (M+H)+; (ESI−) m/z 492.2 (M−H)−.
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[NH:8][C:7](=[O:17])[CH2:6]1)C.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH2:27][C:28]([NH2:30])=[NH:29])=[CH:19]1>>[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH2:27][C:28]2[N:30]=[CH:4][C:5]3[CH2:6][C:7](=[O:17])[NH:8][C:9]4[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=4[C:11]=3[N:29]=2)=[CH:19]1
Reactant: CN(C)C=C1CC(=O)Nc2ccccc2C1=O
Reactant: N=C(N)Cc1c[nH]c2ccccc12
Product: O=C1Cc2cnc(Cc3c[nH]c4ccccc34)nc2-c2ccccc2N1
Yield: 80 %

Procedure:
Analogous to Scheme 1, from 4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepine-2,5-dione and 2-(1H-indol-3-yl)-acetamidine. Yield: 80%.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[CH:8]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:7]2.[C:19]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Na+].[Na+].C(O)CO>O>[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[C:9](=[O:11])[CH:8]([CH2:12][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:7]3)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: O=C1c2c(Cl)cccc2CC1CC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: OCCO
Product: CC(C)(C)c1ccc(-c2cccc3c2C(=O)C(CC2CCCCC2)C3)cc1
Temperature: 125 °C

Procedure:
60 g (228 mmole) 7-Chloro-2-cyclohexylmethyl-indan-1-one, 49 g (1.2 eq.) 4-tert-butyl-benzene boronic acid, 53 g sodium carbonate, 750 ml ethylene glycol and 150 ml water were placed in a 2 l-roundbottom flask equipped with a mechanical stirrer and a reflux condenser. The mixture was degassed three times by slight evacuation and recharging with argon. A premixed catalyst solution consisting of 103 mg (0.2 mole %) palladium acetate, 3 ml NaTPPTS (2.6 M in water, 0.8 mole %) and 2 ml of water was added and the mixture was refluxed at 125° C. until complete conversion (approx. 4 h). 300 ml of water were added and the mixture was extracted three times with 150 ml of toluene each. The combined organic layers were washed twice with 100 ml water and once with 100 ml of a saturated sodium chloride solution. Drying over magnesium sulphate and evaporation of the solvent in vacuo yielded 87.2 g (quant.) of the desired product as a yellow sticky oil. 1H-NMR (400 MHz, CDCl3): δ=7.54 (t, 1H, aromatic), 7.43, 7.38 (2×d, 4H, aromatic), 7.24 (m, 2H, aromatic), 3.30 (m, 1H, COCH), 2.80-2.67 (3×m, 2H, benzylic), 1.85-1.47 (m, 7H, aliphatic), 1.35 (s, 9H, C(CH3)3), 1.27-0.87 (m, 6H, aliphatic) ppm.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li:18])CCC.CCCCCC>C1COCC1>[C:1]1([Li:18])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: [Li]CCCC
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Solvent: C1CCOC1
Solvent: CCCCCC
Product: [Li]c1cccc2c1Cc1ccccc1-2

Procedure:
To a solution of 10.38 g (62.5 mmol) of fluorene in 250 ml of THF at 0° C. was added dropwise a 1.6 molar solution of butyllithium in hexane (39.05 ml, 62.5 mmol) in order to produce fluorenyllithium. The solution was stirred for 3 h at room temperature and then added dropwise over a period of 2 h via a cannula to 125 ml (1.45 mol) of 1,2-dibromoethane. The solution was stirred overnight at room temperature. After hydrolysis with 125 ml aqueous NH4Cl, the organic layer was separated. The aqueous layer was extracted twice with ether. The combined organic layers were dried on MgSO4, filtered and the solvents were removed. The excess 1,2-dibromoethane was recovered by trap to trap distillation at 0.5 mm Hg with gentle heating by a warm water bath. A chilled receiving flask was used. The resulting yellow residue was dissolved in pentane, filtered, concentrated and cooled to -20° C. to give 1-(9-fluorenyl)-2-bromoethane (10.25 g, 60%) as a yellow solid; melting point: 48-49° C. 1H NMR data was consistent with that reported in literature.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].[C:11]([O:14][CH:15](OC(=O)C)[C:16]([CH3:18])=[CH2:17])(=[O:13])[CH3:12]>>[C:11]([O:14][CH:15]=[C:16]([CH3:18])[CH2:17][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([O:9][CH3:10])[CH:5]=1)(=[O:13])[CH3:12]
Reactant: COc1ccccc1OC
Reactant: C=C(C)C(OC(C)=O)OC(C)=O
Product: COc1ccc(CC(C)=COC(C)=O)cc1OC
Temperature: 22.5 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
In an argon gas atmosphere, a three necked flask having a capacity of 25 ml was charged with 13.82 g (100 m moles) of 1,2-dimethoxybenzene and 1.87 g (10 m moles) of 3,3-diacetoxy-2-methylpropene having a purity degree of 92.0% by mass. Then, the resultant mixture was mixed with 0.142 g (1 m mole) of boron trifluoride-ether complex at an internal temperature of 18 to 19° C. The mixture was stirred at an internal temperature of 22 to 23° C. for 2 hours. After the reaction was completed, the resultant reaction liquid was subjected to a quantitative analysis using a high performance liquid chromatography. In the result, the target 1-acetoxy-2-methyl-3-(3,4-dimethoxyphenyl)propene was obtained in a yield of 94.4% (amount: 2.36 g).
Reaction SMILES: O=[C:2]1[CH2:7][O:6][C@H:5]([C:8]2[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=2[F:16])[C@@H:4]([NH:17]C(=O)OCCCC)[CH2:3]1.[F:25][C:26]([F:38])([F:37])[C:27]1[N:28]=[CH:29][C:30]2[CH2:36][CH2:35][NH:34][CH2:33][C:31]=2[N:32]=1.[B][B][B][B][B][B][B][B][B][B].[ClH:49]>CO>[ClH:49].[ClH:49].[F:38][C:26]([F:25])([F:37])[C:27]1[N:28]=[CH:29][C:30]2[CH2:36][CH2:35][N:34]([C@H:2]3[CH2:7][O:6][C@H:5]([C:8]4[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=4[F:16])[C@@H:4]([NH2:17])[CH2:3]3)[CH2:33][C:31]=2[N:32]=1
Reactant: FC(F)(F)c1ncc2c(n1)CNCC2
Reactant: CCCCOC(=O)N[C@H]1CC(=O)CO[C@@H]1c1cc(F)c(F)cc1F
Agent: Cl
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: N[C@H]1C[C@@H](N2CCc3cnc(C(F)(F)F)nc3C2)CO[C@@H]1c1cc(F)c(F)cc1F
Reaction time: 8 h

Procedure:
To a solution of 45 mg (0.13 mmol) of tent-butyl [(2R,3S)-5-oxo-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl]carbamate and 27 mg (0.13 mmol) of 2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine in 2.0 mL of dry methanol was added 5.0 mg (0.039 mmol) of decaborane. The reaction mixture was stirred overnight and concentrated in vacuo, then purified by preparative thin layer chromatography using an Analtech® 1000 micron plate (5% methanol/methylene chloride, 1% concentrated ammonium hydroxide) to give the product which was stirred with hydrochloric acid in methanol (1.3M, 4 mL) for 1 h to give the title product. LC/MS 432.93 (M+1).
Reaction SMILES: [OH-].[Na+].[C:3]1([CH2:9][SH:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:11][CH2:12][CH2:13][N:14]([CH2:38][CH2:39][Cl:40])[P:15]([N:31]([CH2:35][CH2:36][Cl:37])[CH2:32][CH2:33][Cl:34])(=[O:30])[O:16][CH2:17][CH2:18]OS(C1C=CC(Br)=CC=1)(=O)=O.C1(C)C=CC=CC=1>CO>[Cl:37][CH2:36][CH2:35][N:31]([P:15]([N:14]([CH2:13][CH2:12][Cl:11])[CH2:38][CH2:39][Cl:40])([O:16][CH2:17][CH2:18][S:10][CH2:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:30])[CH2:32][CH2:33][Cl:34]
Reactant: O=P(OCCOS(=O)(=O)c1ccc(Br)cc1)(N(CCCl)CCCl)N(CCCl)CCCl
Reactant: SCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=P(OCCSCc1ccccc1)(N(CCCl)CCCl)N(CCCl)CCCl
Reaction time: 0.08 h

Procedure:
Sodium hydroxide, 6.4 g (161 mmol), was dissolved in 100 mL methanol under nitrogen at room temperature, and α-toluenethiol, 9.52 mL (10 g, 80.5 mmol), was added. After the resulting mixture was stirred for 5 minutes, 2-(4-bromobenzenesulfonyloxy)ethyl tetrakis(2-chloroethyl)phosphorodiamidate, 80.5 mL of 1 M solution in toluene (80.5 mmol), was added with stirring. A precipitate formed within 1 minute of the addition, and stirring was continued. Analysis of the reaction after 2 hours showed that the reaction was nearly complete, and stirring was continued overnight at room temperature. Analysis then showed that the reaction was complete, and stirring was stopped and the reaction mixture allowed to stand and then filtered to remove the precipitated sodium 4-bromobenzenesulfonate. The methanol was removed from the filtrate by evaporation and the residue was dissolved in 250 mL isopropyl acetate. The isopropyl acetate solution was washed with aqueous sodium hydroxide (100 mL of 1 M), water (100 mL), and brine (100 mL), and was then dried over anhydrous sodium sulfate and filtered. The isopropyl acetate was removed by vacuum evaporation to give an oil, which was dried under vacuum at 40° C. overnight, giving 40.4 g of α-[[2-[[bis[bis(2-chloroethyl)amino]phosphinyl]oxy]ethyl]thio]toluene as an orange oil containing residual toluene. HPLC analysis of the product showed a purity of 96.8%. 1H NMR: δ 7.16-7.33 (m, 5H), 4.04-4.06 (m, 2H), 3.74 (s, 2H), 3.60-3.65 (m, 8H), 3.36-3.43 (m, 8H), 2.69 (t, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].I[C:15]1[CH:23]=[CH:22][C:18]2[N:19]=[CH:20][S:21][C:17]=2[CH:16]=1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[S:21]1[C:17]2[CH:16]=[C:15]([N:10]3[CH2:11][CH2:12][N:8]([C:3]4[CH:4]=[N:5][CH:6]=[CH:7][C:2]=4[CH3:1])[C:9]3=[O:13])[CH:23]=[CH:22][C:18]=2[N:19]=[CH:20]1
Reactant: Ic1ccc2ncsc2c1
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc3ncsc3c2)C1=O
Yield: 49.5 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.847 mmol) was reacted with 6-iodo-benzothiazole (200.93 mg, 0.847 mmol), 1,4-dioxane (20 mL), copper iodide (16.135 mg, 0.0847 mmol), trans-1,2-diamino cyclohexane (0.03 mL, 0.254 mmol) and potassium carbonate (233.97 mg, 1.694 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% MeOH in chloroform) afforded 130 mg of the product (49.6% yield).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH2:7][C:6]1=[O:15].C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[CH:24](=[C:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH2:25][CH2:26][CH3:27]>C(Cl)Cl.CO>[CH:24](=[C:28]1[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][N:5]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:8][CH2:7][C:6]2=[O:15])[CH2:30][CH2:29]1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCC=C1CCNCC1
Reactant: O=C1CSc2ccccc2N1CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: CCCC=C1CCN(CCCN2C(=O)CSc3ccccc32)CC1
Yield: 35.2 %

Procedure:
4-(3-Chloropropyl)-4H-benzo[1,4]thiazin-3-one (81MF07) (0.073 g, 0.30 mmol), K2CO3 (0.12 g, 0.90 mmol), NaI (0.090 g, 0.6 mmol) and 4-butylidenepiperidine (0.050 g, 0.28 mmol) were mixed according to GP12. Prep TLC (SiO2; CH2Cl2/MeOH 10:1) gave the title compound (81MF26) (0.034 g, 33%). 1H NMR (CDCl3) δ7.34-7.31 (m, 1H), 7.23-7.20 (m, 1H), 7.00-6.95 (m, 1H), 5.10 (t, J=7.2 Hz, 1H), 4.04 (t, J=7.2 Hz, 2H), 3.34 (s, 2H), 2.37-2.32 (m, 6H), 2.23-2.14 (m, 2H), 1.96-1.90 (m, 2H), 1.86-1.78 (m, 2H), 1.37-1.27 (m, 2H), 0.86 (t, J=7.2 Hz, 3H); 13C NMR (CDCl3) δ 165.1, 139.6, 136.0, 128.5, 127.2, 124.1, 123.4, 122.7, 118.1, 55.6, 55.4, 54.8, 43.2, 36.1, 31.7, 29.2, 28.3, 25.2, 23.2, 13.8.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]3[C:17]([CH3:24])=[C:18]([NH2:23])[C:19]([CH3:22])=[C:20]([CH3:21])[C:15]=3[O:14][C:13]2([CH3:26])[CH3:25])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[C:27]([CH2:31][C:32](Cl)=[O:33])([CH3:30])([CH3:29])[CH3:28].C(N(CC)CC)C.O>ClCCl>[C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]3[C:17]([CH3:24])=[C:18]([NH:23][C:32](=[O:33])[CH2:31][C:27]([CH3:30])([CH3:29])[CH3:28])[C:19]([CH3:22])=[C:20]([CH3:21])[C:15]=3[O:14][C:13]2([CH3:26])[CH3:25])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)(C)C)cc1)C(C)(C)O2
Reactant: CC(C)(C)CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)(C)C)cc1)C(C)(C)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
To a solution of 3-(4-tert-butylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine hydrochloride obtained in Reference Example 76 (400 mg, 1.16 mmol) and tert-butylacetyl chloride (0.17 mL, 1.22 mmol) in dichloromethane (10 mL) was added triethylamine (0.35 mL, 2.50 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with 1 N hydrochloric acid and an aqueous saturated sodium hydrogen carbonate solution, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane ethyl acetate=8:1) to obtain 110 mg (yield: 41%) of the title compound. Amorphous substance.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:37])[C@H:19]([CH2:33][CH2:34][CH2:35][NH2:36])[N:20]([C:29](=[O:32])[CH2:30][NH2:31])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:38](=[NH:43])(OCC)[CH3:39]>C(O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:37])[C@H:19]([CH2:33][CH2:34][CH2:35][NH2:36])[N:20]([C:29](=[O:32])[CH2:30][NH:31][C:38](=[NH:43])[CH3:39])[CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NCCC[C@@H](C(=O)NCCCc1ccccc1)N(CCc1ccccc1)C(=O)CN
Reactant: CCOC(C)=N
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(=N)NCC(=O)N(CCc1ccccc1)[C@@H](CCCN)C(=O)NCCCc1ccccc1

Procedure:
Glycyl-Nα-(phenethyl)omithine 3-phenylpropylamide trifluoroacetate was treated with ethyl acetimidate in ethanol at pH9 and the product was purified by HPLC: 1H NMR (400 MHz, D2O) δ 1.6-2.0 (m, 6 H), 2.3 (s, 3 H), 2.7 (t, J=6.4 Hz, 2 H), 2.9-3.1 (m, 4 H), 3.2-3.4 (m, 2 H), 3.5-3.7 (m, 2 H), 4.1-4.3 (m, 2 H), 4.7-4.8 (m, 1 H), and 7.2-7.5 (m, 10 H); mass spectrum, m/e 453 (M+), 354, 300, 247, and 219.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:24][C:25]([O:27]C)=[O:26])[CH:7]=[CH:8][C:9]=1[NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=2)[CH:16]=[CH:15][N:14]=1)=[O:12].Cl>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH2:24][C:25]([OH:27])=[O:26])[CH:7]=[CH:8][C:9]=1[NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=2)[CH:16]=[CH:15][N:14]=1)=[O:12]
Reactant: COC(=O)Cc1ccc(NC(=O)c2nccc3ccc(F)cc23)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(NC(=O)c2nccc3ccc(F)cc23)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.4 %

Procedure:
In THF (5 ml), 0.25N NaOH (4 ml, 4.82 mmol) was added to methyl (3-chloro-4-((7-fluoro-1-isoquinolinylcarbonyl)amino)phenyl)acetate (100 mg, 0.27 mmol) and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into 1N HCl (2.0 ml). The crystals thus precipitated were collected by filtration under reduced pressure, washed with water, and dried under reduced pressure to give (3-chloro-4-((7-fluoro-1-isoquinolinylcarbonyl)amino)phenyl)acetic acid (75 mg, 78%) as a colorless solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.NCC([N:55]1[CH2:60][CH2:59][CH:58]([NH:61][C:62]2[CH:67]=[C:66]([Br:68])[CH:65]=[CH:64][C:63]=2[O:69][CH3:70])[CH2:57][CH2:56]1)=O>CN(C=O)C.O>[Br:68][C:66]1[CH:65]=[CH:64][C:63]([O:69][CH3:70])=[C:62]([NH:61][CH:58]2[CH2:57][CH2:56][N:55]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:18]3[CH:17]=[C:16]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:20][N:19]=3)=[O:22])[CH2:60][CH2:59]2)[CH:67]=1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: COc1ccc(Br)cc1NC1CCN(C(=O)CN)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Br)cc1NC1CCN(C(=O)CNC(=O)c2cc(-c3ccccc3)[nH]n2)CC1
Reaction time: 0.03 h
Yield: 35 %

Procedure:
DIPEA (45 mg, 0.35 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (26 mg, 0.1 mmol) in DMF (1 mL) followed by HOBt (20 mg, 0.15 mmol) and EDCI.HCl (28 mg, 0.15 mmol). After 2 minutes of stirring, 2-amino-1-[4-(5-bromo-2-methoxy-phenylamino)-piperidin-1-yl]-ethanone hydrochloride (prepared according to Step 2 and 5 of the General Scheme) (0.03 g, 0.0001 mmol) was added and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure Purification by column chromatography (using neutral alumina and 5% MeOH in CHCl3 as eluent) to afford 60 mg (35% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(5-bromo-2-methoxy-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 512.4, 91%, 1H NMR (300 MHz, DMSO-d6): δ10.2 (m, 1H), 7.9 (m, 1H), 7.7 (m, 7H), 7.4 (m, 2H), 7.2 (m, 1H), 3.6 (m, 5H), 2.0 (m, 2H), 1.8 (m, 2H).
Reaction SMILES: Br[C:2]1[C:3](=[O:15])[C:4]([CH3:14])([CH3:13])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[CH3:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)=[N:21][CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:13][C:4]1([CH3:14])[C:3](=[O:15])[C:2]([C:28]2[CH:27]=[CH:26][C:25]([O:24][CH2:23][C:20]3[CH:19]=[CH:18][C:17]([CH3:16])=[CH:22][N:21]=3)=[CH:30][CH:29]=2)=[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[O:5]1
Reactant: Cc1ccc(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)nc1
Reactant: CC1(C)OC(c2ccncc2)=C(Br)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(COc2ccc(C3=C(c4ccncc4)OC(C)(C)C3=O)cc2)nc1
Yield: 53.3 %

Procedure:
A mixture of 4-bromo-2,2-dimethyl-5-(pyridin-4-yl) furan-3(2H)-one (0.11 g, 0.34 mmol), 5-methyl-2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy)methyl)pyridine (0.1 g, 0.37 mmol), and Cs2CO3 (0.55 g, 1.86 mmol) in toluene (7 mL) and water (3 mL) was degassed, Pd(dppf)Cl2 (0.058 g, 0.07 mmol) was added under an inert atmosphere and the mixture was degassed again. Then the reaction was refluxed for 2 h and was filtered through a pad of Celite®. The filtrate was diluted with EtOAc (50 mL), washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 2,2-dimethyl-4-(4-((5-methylpyridin-2-yl)methoxy)phenyl)-5-(pyridin-4-yl)furan-3(2H)-one (70 mg, 48%) as a solid. 1H NMR (500 MHz, d6-DMSO): δ 8.72 (d, J=8.5 Hz, 2H), 8.42 (t, J=7.9 Hz, 1H), 7.70 (d, J=8.2 Hz, 2H), 7.63 (t, J=8.2 Hz, 1H), 7.52-7.43 (m, 3H), 7.18 (d, J=7.4 Hz, 2H), 7.11 (d, J=7.5 Hz, 2H), 5.18 (s, 2H), 2.35 (s, 3H), 1.54 (s, 6H). MS: [M+H]: m/z=387.0. HPLC: 91.4% (RT-1.73 min), Column: Acquity BEH-C-18, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), ACN (B), Flow rate: 0.5 ml/min (Gradient).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:22])[C:8]4[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:42][C:43]1([CH3:50])[O:47][C@@H:46]([CH2:48]O)[CH2:45][O:44]1.C(OC(N=NC(OC(C)C)=O)=O)(C)C>C(OCC)(=O)C.C1COCC1>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:22])[C:8]4[CH:20]=[C:19]([O:21][CH2:48][C@H:46]5[CH2:45][O:44][C:43]([CH3:50])([CH3:42])[O:47]5)[CH:18]=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: CC1(C)OC[C@H](CO)O1
Reactant: CC1(C)c2ccc(O)cc2C(=O)c2c1[nH]c1cc(Br)ccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)OC[C@H](COc2ccc3c(c2)C(=O)c2c([nH]c4cc(Br)ccc24)C3(C)C)O1
Temperature: 50 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
Under nitrogen atmosphere, 3-bromo-9-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound JJ2, 356 mg, 1.00 mmol) and triphenylphosphine (317 mg, 1.2 eq.) were added with THF (3 ml), followed by dropwise addition of ((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (148 μl, 1.2 eq.) and diisopropyl azodicarboxylic acid (252 μl, 1.3 eq.). The mixture was then stirred at 50° C. for 2 hr. After cooling, the reaction solution was added with ethyl acetate, washed with brine and dried over magnesium sulfate. After filtration and the concentration under reduced pressure, the resulting residues were purified by silica gel column chromatography (ethyl acetate/dichloromethane) to yield the solid, which was then washed with dichloromethane to obtain the title compound (white powder, 241.6 mg, 51%).