Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:14]([C:15]([C:22]4[CH:27]=[CH:26][C:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[C:24]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH:23]=4)=[C:16]4[C:21]=2[CH:20]=[CH:19][CH:18]=[CH:17]4)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.[C:40]1([NH:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:47]1([N:46]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:2]2[CH:7]=[CH:6][C:5]([C:8]3[C:9]4[C:14]([C:15]([C:22]5[CH:27]=[CH:26][C:25]([C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=6)=[C:24]([C:34]6[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=6)[CH:23]=5)=[C:16]5[C:21]=3[CH:20]=[CH:19][CH:18]=[CH:17]5)=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:4][CH:3]=2)[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: Clc1ccc(-c2c3ccccc3c(-c3ccc(-c4ccccc4)c(-c4ccccc4)c3)c3ccccc23)cc1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc(-c3c4ccccc4c(-c4ccc(N(c5ccccc5)c5ccccc5)cc4)c4ccccc34)cc2-c2ccccc2)cc1
Yield: 78 %

Procedure:
Under an atmosphere of argon, 9-(4-chlorophenyl)-10-(3,4-diphenylphenyl)anthracene (2.3 g, 4.4 mmole), diphenylamine (0.9 g, 5.3 mmole, 1.2 eq), tris(dibenzylideneacetone)dipalladium(0) (0.1 g, 0.11 mmole, 5% Pd), a toluene solution of tri-t-butylphosphine (66% by weight, 0.05 ml, 0.16 mmole, 0.7 eq to Pd) and sodium t-butoxide (0.6 g, 6.3 mmole, 1.4 eq) were suspended in anhydrous toluene (20 ml). The resultant mixture was refluxed for 8 hours. The reaction mixture was filtered and washed with toluene, water and methanol, and a light yellow solid substance was obtained. The obtained solid substance was suspended in boiling toluene (40 ml). After the suspension was cooled while being left standing, the suspension was filtered, and a light yellow solid substance (2.2 g, the yield: 78%) was obtained. It was confirmed in accordance with 1H-NMR and FDMS that the obtained product was Compound (A11).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:26][CH:27]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]([O:30]CC)=[O:29])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1.[OH-].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:26][CH:27]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]([OH:30])=[O:29])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:17][CH:18]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)c(Br)c1)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCCOc1ccc(CC(Oc2ccccc2)C(=O)O)cc1Br)c1ccc(-c2ccccn2)cc1
Yield: 77.1 %

Procedure:
In a similar manner to that described in Example 2, ethyl 3-[3-bromo-4-[2-(4-pyridine-2-ylbenzoylamino)ethoxy]phenyl]-2-phenoxypropionate (237 mg), which is the product of Example 163, was reacted with aqueous sodium hydroxide solution (1N, 0.80 ml) and the reaction mixture was treated to give the title compound (174 mg) as colorless crystals.
Reaction SMILES: [CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=4[F:32])=[C:20]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:19]=3)[CH:11]=2)[CH2:5][C:6]([O:8]C)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=4[F:32])=[C:20]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[N:19]=3)[CH:11]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: COC(=O)CC(c1cccc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(COc3cccc(C(CC(=O)O)C4CC4)c3)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 3-cyclopropyl-3-(3-((5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)methoxy)phenyl)propanoate (90 mg) in THF (2.0 mL) and methanol (1.0 mL) was added 1N aqueous sodium hydroxide solution (2.0 mL), and the mixture was stirred at room temperature for 4 hr. 1N Hydrochloric acid (2.0 mL) was added to the reaction mixture at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate.
Reaction SMILES: O([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)S(C(F)(F)F)(=O)=O.[CH3:19][N:20]([CH3:26])[CH2:21][CH2:22][O:23][CH:24]=[CH2:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C=O)C>CCCCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:19][N:20]([CH3:26])[CH2:21][CH2:22][O:23][CH:24]=[CH:25][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1
Reactant: O=S(=O)(Oc1ccc2ccccc2c1)C(F)(F)F
Reactant: C=COCCN(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCCCC
Product: CN(C)CCOC=Cc1ccc2ccccc2c1
Yield: 87 %

Procedure:
Table 1, Entry 7. In the reaction tube were mixed 2-naphthyl triflate (0.276 g, 1.0 mmol), [2-(dimethylamino)ethoxy]ethene (0.23 g, 2.0 mmol), palladium acetate (0.00673 g, 0.030 mmol), triphenylphosphine (0.0173 g, 0.066 mmol) triethylamine (0.202 g, 2.0 mmol) and 0.75 ml DMF.under nitrogen. The contents of the flask were irradiated for 7.00 min with an effect of 35 W. After cooling, the product mixture was diluted with 50 ml pentane, transferred to a separatory funnel and washed with 2×25 ml water. Additional extraction of the aqueous phases was performed with 25 ml pentane. The combined organic portions were then treated 5 times with 20 ml of 0.1 M HCl. The aqueous extracts were combined, poured into a flask containing excess NaOH (1.0 M) and was extracted with 2×50 ml pentane. The combined organic phases were dried (K2CO3) and concentrated by evaporation. The yield was 87% (yellow oil, trans/cis 1/1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:13]([CH2:17][C:18]2[N:19]=[N:20][N:21]([CH3:23])[N:22]=2)[C:14]([OH:16])=O)(=[O:11])=[O:10])=[CH:5][CH:4]=1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.[C:49]([O:53][NH2:54])([CH3:52])([CH3:51])[CH3:50].Cl.CN(CCCN=C=NCC)C>C(Cl)Cl.O>[C:49]([O:53][NH:54][C:14](=[O:16])[CH:13]([N:12]([S:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)(=[O:11])=[O:10])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:17][C:18]1[N:19]=[N:20][N:21]([CH3:23])[N:22]=1)([CH3:52])([CH3:51])[CH3:50]
Reactant: CC(C)(C)ON
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccccc2)[C@H](Cc2nnn(C)n2)C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)C(Cc2nnn(C)n2)C(=O)NOC(C)(C)C)cc1
Reaction time: 8 h

Procedure:
2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-2-[(2-methyl-5-tetrazolyl)methyl]acetic acid (0.96 g, 2.24 mmol), 1-hydroxybenzotriazole (0.30 g, 2.24 mmol), 4-methylmorpholine (0.86 mL, 7.89 mmol), and O-t-butylhydroxylamine hydrochloride (0.30 g, 2.24 mmol) are dissolved in methylene chloride (75.0 mL). N-[dimethylaminopropyl]-N'-ethylcarbodiimide hydrochloride (0.86 g, 4.48 mmol) is added, and the reaction is stirred overnight. The reaction is then diluted with water and extracted with methylene chloride. The combined organic extracts are washed with brine, dried (Na2SO4), and the solvent is evaporated. The crude product is purified by silica gel chromatography (50% ethyl acetate/hexane) to give N-(t-butyloxy)-2-[[4-methoxybenzenesulfonyl](benzyl)amino]-2-[(2-methyl-5-tetrazolyl)methyl]acetamide.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([I:15])=[C:11]([F:16])[CH:10]=2)[CH2:4]1.[F:17][CH:18]([F:22])[C:19](O)=[O:20].C(N(CC)C(C)C)(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[F:17][CH:18]([F:22])[C:19]([NH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([I:15])=[C:11]([F:16])[CH:10]=2)[CH2:4]1)=[O:20]
Reactant: NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Reactant: O=C(O)C(F)F
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1)C(F)F
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
A suspension of (5S)-5-Aminomethyl-3-(3-fluoro-4-iodo-phenyl)-oxazolidin-2-one (1022, 5.0 g, 14.88 mmol) in methylene chloride (CH2Cl2, 50 mL) was treated with difluoroacetic acid (2.14 g, 1.41 mL, 22.32 mmol, 1.5 equiv) and N,N-diisopropylethylamine (DIEA or Hunig's base, 3.85 g, 5.18 mL, 29.76 mmol, 2.0 equiv), and the resulting reaction mixture was cooled down to 0-5° C. before being treated with EDCI (4.30 g, 22.32 mmol, 1.5 equiv) at 0-5° C. The reaction mixture was subsequently stirred at 0-5° C. for 1 h before being gradually warmed up to room temperature for 12 h. When TLC and HPLC/MS showed that the reaction was complete, the reaction mixture was quenched with H2O (50 mL) and CH2Cl2 (50 mL). The two layers were then separated, and the aqueous layer was extracted with CH2Cl2 (2×50 mL). The combined organic extracts were washed H2O (50 mL) and the saturated aqueous NaCl solution (50 mL), dried over MgSO4, and concentrated in vacuo to afford the crude (5S)-2,2-difluoro-N-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide (1026, 5.64 g, 6.16 g theoretical, 91.6%) as off-white powders, which by HPLC/MS and 1H NMR was found to be essentially pure and was directly used in the subsequent reactions without further purification. For 1026: 1H NMR (300 MHz, DMSO-d6) δ 3.54 (t, 2H, J=5.5 Hz), 3.77 (dd, 1H, J=6.3, 9.2 Hz), 4.15 (t, 1H, J=9.2 Hz), 4.77-4.86 (m, 1H), 6.25 (t, 1H, J=53.52 Hz, —CHCF2), 7.18 (dd, 1H, J=2.4, 8.7 Hz), 7.55 (dd, 1H, J=2.4, 8.7 Hz), 7.84 (t, 1H, J=8.5 Hz), 9.19 (t, 1H, J=5.5 Hz, —CONH); C12H10F3IN2O3, LCMS (EI) m/e 415 (M++H), 456 (M++H+CH3CN).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=1.C([Li])CCC.[O:18]1[C:22]2[CH:23]=[CH:24][C:25]([CH:27]=[O:28])=[CH:26][C:21]=2[CH:20]=[CH:19]1.C(O)(C)C>C1COCC1.O>[O:18]1[C:22]2[CH:23]=[CH:24][C:25]([CH:27]([C:2]3[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=3)[OH:28])=[CH:26][C:21]=2[CH:20]=[CH:19]1
Reactant: CCOc1cc(Br)ccc1OC
Reactant: O=Cc1ccc2occc2c1
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CCOc1cc(C(O)c2ccc3occc3c2)ccc1OC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 116.3 %

Procedure:
A stirred mixture of 4-bromo-2-ethoxy-1-methoxy-benzene (1.74 g, 7.5 mmol) and dry THF (15 mL) was cooled to −78° C., evacuated and refilled with nitrogen for 10 cycles. To this clear solution was slowly added n-butyllithium (3.0 mL, 7.5 mmol) and stirred for 20 min. Then a mixture of benzofuran-5-carbaldehyde (1.0 g, 6.8 mmol) in dry THF (10 mL) was added and stirred for 1 hour at −78° C. The mixture was quenched with isopropanol (3.1 mL, 41 mmol) and added water (10 mL). The mixture was extracted with EtOAc (3×50 mL). The combined organic phases were washed with water (2×50 mL), dried over MgSO4 and concentrated to give benzofuran-5-yl-(3-ethoxy-4-methoxy-phenyl)-methanol as an oil (2.36 g, 115% yield). The product was used in the next step without further purification.
Reaction SMILES: CO.C([O:6][C@H:7]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C:9](=[CH:10][C@H:11]([OH:27])[C@@H:12]3[C@@H:21]2[CH2:20][CH2:19][C@@:17]2([CH3:18])[C@H:13]3[CH2:14][CH2:15][C:16]2=[O:26])[CH2:8]1)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>O>[CH3:18][C@:17]12[CH2:19][CH2:20][C@H:21]3[C@@H:12]([C@@H:11]([OH:27])[CH:10]=[C:9]4[C@:22]3([CH3:25])[CH2:23][CH2:24][C@H:7]([OH:6])[CH2:8]4)[C@@H:13]1[CH2:14][CH2:15][C:16]2=[O:26]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=C[C@H](O)[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@]12CC[C@H](O)CC1=C[C@H](O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 67.9 %

Procedure:
A 500 L reactor was charged 230 kg methanol, 33 kg (wet) 3β-acetoxy-7β-hydroxy-5-androsten-17-one, 108 kg water and 15 kg Na2CO3. The mixture was heated to reflux for 3 hours. Methanol was removed under vacuum whereupon 250 kg of water was added to the residue. The mixture was put in refrigerator overnight to give a precipitate. The solids were collected by filtration, then washed with water and dried at 40-50° C. to yield 9.5-10.5 kg (67.9-75.0%) of the title compound as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[NH:12][C:11]3=[CH:13][C:14]([C:16]4[CH:21]=[N:20][CH:19]=[CH:18][N:17]=4)=[N:15][C:10]3=[CH:9][N:8]=2)[CH2:3][CH2:2]1.CC[O:24]C(C)=O.[ClH:28]>CO>[OH2:24].[ClH:28].[NH:1]1[CH2:2][CH2:3][CH:4]([C:7]2[NH:12][C:11]3=[CH:13][C:14]([C:16]4[CH:21]=[N:20][CH:19]=[CH:18][N:17]=4)=[N:15][C:10]3=[CH:9][N:8]=2)[CH2:5][CH2:6]1
Reactant: CCOC(C)=O
Agent: Cl
Agent: c1cnc(-c2cc3[nH]c(C4CCNCC4)ncc-3n2)cn1
Solvent: CO
Product: O

Procedure:
Using the method described in Example 30 by employing 2-(1-pyrrolidinylvinyl)pyrazine (freshly prepared before use) (2.39 g, 13.7 mmol), 4,6-dichloro-5-nitropyrimidine (Aldrich Chemical Company) (2.60 g, 13.7 mmol), N,N-diisopropylethyl amine (Aldrich Chemical Company) (2.4 mL, 13.7 mmol), piperidine (Aldrich Chemical Company) (2.2 mL, 21.9 mmol), NEt3 (Aldrich Chemical Company) (2.0 mL) and SnCl2 (41 mL of a 2M solution in DMF). The residue was purified by flash chromatography on silica gel with 95:5 CHCl3:MeOH as elutant to give 143 mg (4%) of the free base as a beige colored solid. 1H NMR (DMSO-d6; 400 MHz): δ 1.67 (br s, 6), 3.77 (s, 4), 7.28 (s, 1), 8.28 (s, 1), 8.63 (s, 1), 8.74 (s, 1), 9.36 (s, 1), 11.48 (s, 1). MS m/z: 281 (M+1). To a hot solution of 4-piperidyl-6-pyrazin-2-ylpyrrolo[3,2-d]pyrimidine (0.14 g, 0.51 mmol) in 10:1 EtOAc:MeOH (40 mL) was added 1M etheral HCl (Aldrich Chemical Company) (0.51 mL, 0.51 mmol). Cyrstallization occurred as the mixture cooled and the precipitate was collected by filtration. The crystals were washed with Et2O (3×10 mL) and dried under vacuum to give 128 mg (80%) of the title compound as a beige colored solid. Mp:>280° C. 1H NMR (DMSO-d6; 400 MHz): δ 1.73 (s, 6), 4.10 (s, 4), 7.37 (s, 1), 8.66 (s, 1), 8.75 (d, 1, J=2.5), 8.83 (t, 1, J=1.5), 9.49 (d, 1, J=1.2), 12.53 (s, 1), 14.56 (s, 1). MS m/z: 281 (M+1). Anal. Calcd for C15H16N6.HCl.0.25H2O: C, 56.00; H, 5.49; N, 26.13; Cl, 11.10. Found C, 56.00; H, 5.49; N, 26.11; Cl, 11.09.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[CH3:9][O:10][C:11](=[O:28])[C:12]1[CH:17]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:15]=[C:14]([Br:27])[CH:13]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:9][O:10][C:11](=[O:28])[C:12]1[CH:17]=[C:16]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=2)[CH:15]=[C:14]([Br:27])[CH:13]=1
Reactant: Cc1ccc(Br)nc1
Reactant: COC(=O)c1cc(Br)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(Br)cc(-c2ccc(C)cn2)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
A mixture of 2-bromo-5-methyl-pyridine (10.27 g, 59.68 mmol) and palladium tetrakis(triphenylphosphine) (1.88 g, 1.65 mmol) in 300 mL DME was stirred at 60° C. under nitrogen for 30 minutes. To this mixture was added 3-bromo-5-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-benzoic acid methyl ester (18.5 g, 54.25 mmol), followed by K3PO4 23.03 g, 108.5 mmol) in 40 mL water. The mixture was refluxed for eight hours, then cooled to room temperature and partitioned between water and EtOAc. The combined organic layers were washed with water, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography (5:1 EtOAc/hexanes) to give 8.5 g of 3-bromo-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester, MS (M+H)=306.
Reaction SMILES: C(OC(=O)[N:10]([CH2:21][CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:32]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[O:33])[CH:30]=2)[NH:25][C:24]=1[C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[C:42]([CH3:47])[CH:41]=1)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)C1C=CC=CC=1.[H][H].[NH4+].[OH-]>[OH-].[OH-].[Pd+2].COCCO>[CH3:47][C:42]1[CH:41]=[C:40]([C:24]2[NH:25][C:26]3[C:31]([C:23]=2[CH2:22][CH2:21][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:30][C:29]([C:32]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[O:33])=[CH:28][CH:27]=3)[CH:45]=[C:44]([CH3:46])[CH:43]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)N4CCOCC4)cc3c2CCN(CCCCc2ccncc2)C(=O)OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [NH4+]
Agent: [OH-]
Solvent: COCCO
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)N4CCOCC4)cc3c2CCNCCCCc2ccncc2)c1

Procedure:
A mixture of 113 mg (0.175 mmol) of [2-[2-(3,5-dimethylphenyl)-5-(morpholine-4-carbonyl)-1H-indol-3-yl]ethyl]-(4-pyridin-4-ylbutyl)carbamic acid benzyl ester, 50 mg of 20% palladium hydroxide on carbon, and 10 mL of 2-methoxyethanol was shaken with hydrogen (approx. 50 psig) in a pressure vessel for 2.5 hours. The catalyst was removed by filtration through Celite, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (gradient elution from 99:1:0.1 to 94:6:0.6 CH2Cl2-MeOH-concd. NH4OH) yielded 53.2 mg (60%) of a white, stiff foam; homogeneous by TLC in 95:5:0.5 CH2Cl2-MeOH-concd. NH4OH. 500 MHz 1H NMR (CDCl3) was consistent with the assigned structure. Mass spectrum (ESI): m/e=511.5 (M+H).
Reaction SMILES: C[Si](Cl)(C)C.Br[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH3:15][C:16]1[CH:23]=[C:22]([O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH:21]=[C:20]([B:31]2[O:35]C(C)(C)[C:33](C)(C)[O:32]2)[C:17]=1C=O>C1COCC1.[Zn]>[OH:35][B:31]1[C:20]2[CH:21]=[C:22]([O:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)[CH:23]=[C:16]([CH3:15])[C:17]=2[CH:33]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[O:32]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1cc(OC2CCCCO2)cc(B2OC(C)(C)C(C)(C)O2)c1C=O
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: Cc1cc(OC2CCCCO2)cc2c1C(CC(=O)OC(C)(C)C)OB2O
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 70.1 %

Procedure:
To a suspension of zinc powder (2.81 g, 43.35 mmol) in dry THF was added TMSCl (0.94 g, 8.67 mmol) at 40° C. The mixture was stirred at 55° C. for 15 min. The mixture was allowed to cooled to 30° C. and tert-butyl 2-bromoacetate (6.76 g, 34.68 mmol) was added slowly to the reaction mixture between 37-40° C. After completion of addition, the resulting mixture was stirred at room temperature for an additional 30 min. To a solution of 2-methyl-4-(tetrahydro-2H-pyran-2-yloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (3 g, 8.67 mmol) in 20 mL dry THF at −78° C. was added dropwise the above prepared reaction mixture. The reaction mixture was stirred at room temperature for 1 h and quenched by ice-water at 0° C. The mixture was extracted with EtOAc (3×15 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column (EA:PE=1:10) to give 2.2 g of desired product as a light yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:23][CH2:24][CH2:25][Cl:26].C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:23][CH2:24][CH2:25][Cl:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCCBr
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccc(F)c(Cl)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC[C@H](N(CCCCl)c2ccc(F)c(Cl)c2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 26.9 %

Procedure:
3(S)-[(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (3 g, 9.5 mmol), 1-bromo-3-chloropropane (4.7 ml, 48 mmol) and potassium carbonate (1.97 g, 14.3 mmol) were suspended in N-methylpyrrolidone (NMP, 15 ml), followed by stirring at 100° C. for 8 hours. After cooling to room temperature, water was added to the reaction solution, and extraction with ethyl acetate was conducted. After drying the organic layer over sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), and the purified product was concentrated under reduced pressure to thereby obtain 1.0 g of oily colorless 3(S)-[(3-chloro-4-fluorophenyl)-(3-chloropropyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9](=[O:16])[NH:10][O:11][CH2:12][C:13]([OH:15])=O)=[CH:3][CH:2]=1.[NH2:17][C@@H:18]([CH3:41])[C:19]([N:21]([CH2:31][C:32]1[C:33]2[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=2[S:35][CH:36]=1)[C@@H:22]([CH3:30])[CH:23]([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])=[O:20]>>[S:35]1[CH:36]=[C:32]([CH2:31][N:21]([C@@H:22]([CH3:30])[CH:23]([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[C:19](=[O:20])[C@@H:18]([NH:17][C:13](=[O:15])[CH2:12][O:11][NH:10][C:9]([NH:8][CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[O:16])[CH3:41])[C:33]2[CH:40]=[CH:39][CH:38]=[CH:37][C:34]1=2
Reactant: O=C(O)CONC(=O)NCc1ccncc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](C)N
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](C)NC(=O)CONC(=O)NCc1ccncc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-(pyridin-4-ylmethyl)ureidooxy)acetic acid (Compound VI-10) 93 mg (0.41 mmol) was coupled with (S)-2-amino-N-(benzo[b]thiophen-3-ylmethyl)-N—((S)-1,1-diethoxypropan-2-yl)-propanamide (Compound IV-12) 100 mg (0.27 mmol) to obtain the title compound.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:5]1[C:13]2[CH:12]=[CH:11][C:10]([F:14])=[CH:9][C:8]=2[C:7]2[C:15]([C:26](OC)=[O:27])=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18](=[O:19])[C:6]1=2)[CH3:4]>O1CCCC1.CO>[CH2:3]([N:5]1[C:13]2[CH:12]=[CH:11][C:10]([F:14])=[CH:9][C:8]=2[C:7]2[C:15]([CH2:26][OH:27])=[N:16][N:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:18](=[O:19])[C:6]1=2)[CH3:4]
Reactant: CCn1c2ccc(F)cc2c2c(C(=O)OC)nn(-c3ccccc3)c(=O)c21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCn1c2ccc(F)cc2c2c(CO)nn(-c3ccccc3)c(=O)c21
Temperature: 0 °C
Reaction time: 4 h
Yield: 78.4 %

Procedure:
5.1 g (135 mmol) of sodium borohydride are added, in several portions and at room temperature, to a solution of 10 g (27.3 mmol) of methyl 5-ethyl-8-fluoro-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxylate in 200 ml of tetrahydrofuran and 5.8 ml of methanol and the mixture is stirred for 4 h at reflux. The mixture is poured onto an ice-cold 0.1N hydrochloric acid solution, an insoluble material is separated by filtration, the insoluble material being washed with water and with diethyl ether, on sintered glass, and then it is dried. 7.2 g (21.4 mmol) of compound are isolated in the form of a white solid which is used as is in the following stage.