Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=O)=[C:4]([F:17])[CH:3]=1.[C:18]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C1COCC1.Cl[Ti](Cl)(Cl)Cl.[Zn]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[C:4]([F:17])[CH:3]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Br)cc1F
Reactant: O=C1CCCCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: Oc1ccc(C(=C2CCCCC2)c2ccc(Br)cc2F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
TiCl4 (2.10 mL, 19.0 mmol) was added dropwise to a suspension of zinc powder (2.51 g, 38.4 mmol) in anhydrous THF (60 mL) at RT. After refluxing for 1 h, a mixture of 76 (1.40 g, 4.74 mmol) and cyclohexanone (1.40 g, 14.3 mmol) dissolved in THF (20 mL) was added dropwise. Refluxing was continued for 30 min. The reaction mixture was cooled to RT and filtered through Celite. Water (250 mL) was added and the mixture was extracted with Et2O (3×100 mL). The combined ethereal extracts were washed with water (200 mL), brine (200 mL), and dried over MgSO4. Concentration followed by flash chromatography (20:1 to 5:1 hexanes:EtOAc) afforded 1.23 g (72%) of 77 as a white solid. 1H NMR (400 MHz, CDCl3): δ 1.58 (br s, 6H), 2.05 (m, 2H), 2.25 (m, 2H), 4.68 (br s, 1H), 6.73 (d, J=8.6 Hz, 2H), 6.94-7.00 (m, 3H), 7.19 (d, J=7.9 Hz, 2H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:14][CH:13]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl>C1(C)C(C)=CC=CC=1.[OH-].[Na+].C(=C/C(/C=C/C1C=CC=CC=1)=O)\C1C=CC=CC=1>[N:12]1([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1
Reactant: O=C(O)Cc1ccc(I)cc1
Reactant: c1ccc2[nH]cnc2c1
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1C
Product: O=C(O)Cc1ccc(-n2cnc3ccccc32)cc1
Temperature: 125 °C
Reaction time: 88 h
Yield: 84.5 %

Procedure:
A mixture of 4.4 g of 4-iodophenylacetic acid, 2.98 g of benzoimidazole, 197 mg of trans,trans-dibenzylideneacetone, 3.33 g of 1,10-phenanthroline, 211 mg of copper (I) trifluoromethanesulfonate benzene complex and 6 g of Cs2CO3 in 12 ml of xylene is stirred for 88 hours at 125° C. The mixture obtained is allowed to cool to rt and concentrated in vacuo. The concentration residue obtained is dissolved in 1N NaOH aqueous solution and the mixture obtained is extracted with EtOAc. The pH of the aqueous layer obtained is adjusted to acidic pH by addition of 1N HCl aqueous solution. A precipitate forms and is collected by vacuum filtration (batch 1) is collected by vacuum filtration. The aqueous phase from the filtrate obtained is extracted with CH2Cl2. The organic phase is dried (Na2SO4), filtered and concentrated. The concentration residue obtained (batch 2) is combined with batch 1 and triturated in Et2O. 3.58 g of (4-benzoimidazol-1-yl-phenyl)-acetic acid are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4](I)[C:3]=1[F:10].[F:11][C:12]1[C:17](B(O)O)=[CH:16][CH:15]=[CH:14][N:13]=1.[F-].[K+]>C(#N)C.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:17]2[C:12]([F:11])=[N:13][CH:14]=[CH:15][CH:16]=2)[C:3]=1[F:10]
Reactant: OB(O)c1cccnc1F
Reactant: Nc1cnc(Cl)c(F)c1I
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Nc1cnc(Cl)c(F)c1-c1cccnc1F
Temperature: 90 °C
Yield: 75.2 %

Procedure:
A degassed mixture of 6-chloro-5-fluoro-4-iodopyridin-3-ylamine (98.7 g, 362 mmol), 2-fluoropyridine 3-boronic acid (68.3 g, 485 mmol), bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (7.7 g, 10.9 mmol) and potassium fluoride (63 g, 1.09 mol) in a mixture of acetonitrile (900 mL) and water (275 mL) was heated at 90° C. for 2 hours. The reaction mixture was allowed to cool to ambient temperature and filtered through Celite© and washed through with ethyl acetate. The filtrate was diluted with ethyl acetate and the organic layer collected, dried (Na2SO4), filtered and concentrated in-vacuo to afford a residue. The resultant residue was triturated with diethyl ether to afford the title compound as a grey solid (65.8 g, 75%). The trituration liquors were concentrated and purified by flash chromatography (silica: dichloromethane to 20% ethyl acetate/dichloromethane) to afford, after trituration with ether, an additional batch of the title compound as a grey solid (9.7 g, 11%). Total yield=75.5 g, 86%. 1H NMR (400 MHz, CDCl3): 8.39 (ddd, J=4.9, 2.0, 1.1 Hz, 1H), 7.86-7.84 (m, 2H), 7.39 (ddd, J=7.4, 4.9, 1.9 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH2:20]=O>C(O)(=O)C.S(=O)(=O)(O)O.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:8][CH:9]([C:10]([O:12][CH3:13])=[O:11])[N:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:20]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)NC(Cc1ccc(Cl)cc1)C(=O)OC
Reactant: C=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)N1Cc2cc(Cl)ccc2CC1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
A mixture of methyl 3-(4-chlorophenyl)-2-(ethoxycarbonylamino)propanoate (3.55 g, 12.4 mmol) in acetic acid (12 mL) and sulfuric acid (4 mL) was treated with paraformaldehyde (0.392 g, 13.0 mmol). After stirring at room temperature overnight, the mixture was added to ice (50-60 g), diluted with water (30 mL) and extracted with ethyl acetate (3×˜50 mL). The combined organic phase was washed with saturated aqueous sodium chloride (25 mL), dried over MgSO4 and concentrated. Purification by silica gel chromatography (90 g column, 25-50% ethyl acetate in hexanes) gave 2-ethyl 3-methyl 7-chloro-3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate (2.19 g, 59%) as a clear, viscous oil. 1H NMR (CDCl3, 400 MHz) δ 7.12 (m, 3 H), 5.20 (m, ˜0.6 H), 4.98 (m, ˜0.4 H), 4.76 (m, 1 H), 4.53 (m, 1H), 4.25 (m, 2 H), 3.65 (s, 3 H), 3.20 (m, 2 H), 1.35 (t, J=7 Hz, ˜1.8 H), 1.28 (t, J=7 Hz, ˜1.2 H) (mixture of rotamers). ESI+ MS found for C14H16ClNO4 m/z 298.0 (M+H, weak).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]([CH3:18])[CH3:17])=[CH:13][CH:14]=3)[C:9]([S:19][CH2:20][CH:21]3[CH2:23][CH2:22]3)=[C:8]2[CH2:24][C:25]([CH3:30])([CH3:29])[C:26](O)=[O:27])=[CH:4][CH:3]=1.[Al]([NH2:36])(C)C>C(Cl)Cl.CCCCCC.C(Cl)Cl>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]([CH3:18])[CH3:17])=[CH:13][CH:14]=3)[C:9]([S:19][CH2:20][CH:21]3[CH2:23][CH2:22]3)=[C:8]2[CH2:24][C:25]([CH3:30])([CH3:29])[C:26]([NH2:36])=[O:27])=[CH:4][CH:3]=1
Reactant: C[Al](C)N
Reactant: CC(C)c1ccc2c(c1)c(SCC1CC1)c(CC(C)(C)C(=O)O)n2Cc1ccc(Cl)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)c1ccc2c(c1)c(SCC1CC1)c(CC(C)(C)C(N)=O)n2Cc1ccc(Cl)cc1

Procedure:
To a solution of 110 mg of methyl 1-(p-chlorobenzyl) α,α- dimethyl-5-isopropyl-3-cyclopropylmethylthioindole-2-propanoate (from Example 108) in 1 ml CH2Cl2 was added 1 ml of aminodimethylalane (Me2AlNH2) in hexane/CH2Cl2 (1.0M) and the reaction heated at 65° for 16h. The reaction was quenched with 2N HCl at 0° C., 0.5M NaK tartrate was added and the solution extracted with ether. The product from ether was purified by chromatography on silica gel (Toluene/Acetone/Acetic acid) 85:15:1 to yield the title compound, m.p. 137°-138°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18](I)[CH3:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(O)ccc1OCc1ccccc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(OCc2ccccc2)c(C=O)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 92.2 %

Procedure:
A mixture of 2-benzyloxy-5-hydroxybenzaldehyde (8.93 g), ethyl iodide (7.31 g), anhydrous potassium carbonate (5.40 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give 2-benzyloxy-5-ethoxybenzaldehyde as a colorless oil (9.25 g, 92%) from a fraction eluted with ethyl acetate-hexane (1:9, v/v).
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]1[C:13]2[CH:14]=[CH:15][C:16]([N:18]3[CH2:23][CH2:22][S:21][CH2:20][CH2:19]3)=[CH:17][C:12]=2[CH2:11][CH2:10][O:9]1)(=O)=O.[C:24]([C:26]1[CH:41]=[CH:40][C:29]2[C:30]([N:33]3[CH2:38][CH2:37][NH:36][C@H:35]([CH3:39])[CH2:34]3)=[CH:31][S:32][C:28]=2[CH:27]=1)#[N:25]>>[CH3:39][C@H:35]1[N:36]([CH2:6][CH2:7][C@H:8]2[C:13]3[CH:14]=[CH:15][C:16]([N:18]4[CH2:19][CH2:20][S:21][CH2:22][CH2:23]4)=[CH:17][C:12]=3[CH2:11][CH2:10][O:9]2)[CH2:37][CH2:38][N:33]([C:30]2[C:29]3[CH:40]=[CH:41][C:26]([C:24]#[N:25])=[CH:27][C:28]=3[S:32][CH:31]=2)[CH2:34]1
Reactant: CS(=O)(=O)OCC[C@@H]1OCCc2cc(N3CCSCC3)ccc21
Reactant: C[C@@H]1CN(c2csc3cc(C#N)ccc23)CCN1
Product: C[C@@H]1CN(c2csc3cc(C#N)ccc23)CCN1CC[C@@H]1OCCc2cc(N3CCSCC3)ccc21

Procedure:
Prepared by condensation of 2-[(1S)-6-(4-thiomorpholinyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl methanesulfonate with (3R)-1-(6-cyano-1-benzothien-3-yl)-3-methylpiperazine, as described for Example 1b). M+H=519.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[N:14]=[N:13][C:12]([C:15]2[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=2)[C:18]([O:20]CC)=[O:19])=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].Cl>C1COCC1>[CH2:1]([O:8][CH2:9][N:10]1[N:14]=[N:13][C:12]([C:15]2[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=2)[C:18]([OH:20])=[O:19])=[N:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc(-c2nnn(COCc3ccccc3)n2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-c2nnn(COCc3ccccc3)n2)c1
Reaction time: 16 h

Procedure:
A solution of ethyl 3-(2-(benzyloxymethyl)-2H-tetrazol-5-yl)benzoate (653 mg, 1.93 mmol) in THF (10 mL) was treated with a 0.5 M aqueous lithium hydroxide solution (5.8 mL, 2.9 mmol), and the reaction mixture was stirred for about 16 h. Analysis by LC/MS indicated that the reaction had not gone to completion, so the mixture was treated with a 0.5 M aqueous lithium hydroxide solution (1 mL, 0.5 mmol), and the reaction mixture was stirred for an additional 6 hours. The THF was removed under reduced pressure, and the aqueous solution was treated with 1 N HCl (3.5 mL, 3.5 mmol). The resulting mixture was extracted 3× with ethyl acetate, and the combined organic phases were dried over sodium sulfate and concentrated in vacuo to yield the title compound as a colorless powder which was used as-is in the next step.
Reaction SMILES: O.FC(F)(F)C(O)=[O:5].[NH2:9][C:10]([NH:12][C:13]1[NH:14][C:15]2[C:20]([C:21]=1[C:22]([NH2:24])=[O:23])=[CH:19][CH:18]=[C:17]([C:25]#[CH:26])[CH:16]=2)=[O:11].[OH-].[Na+]>O1CCOCC1>[C:25]([C:17]1[CH:16]=[C:15]2[C:20]([C:21]([C:22]([NH2:24])=[O:23])=[C:13]([NH:12][C:10]([NH2:9])=[O:11])[NH:14]2)=[CH:19][CH:18]=1)(=[O:5])[CH3:26]
Reactant: O=C(O)C(F)(F)F
Reactant: C#Cc1ccc2c(C(N)=O)c(NC(N)=O)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)c1ccc2c(C(N)=O)c(NC(N)=O)[nH]c2c1
Temperature: 95 °C
Reaction time: 5 h
Yield: 55.6 %

Procedure:
Water (6 μl L, 0.25 mmol) and trifluoroacetic acid (150 μL, 2.0 mmol) were added to a solution of 2-aminocarbonylamino-6-ethynylindole-3-carboxamide (Compound 10-1, 20 mg, 0.083 mmol) in 1,4-dioxane (2 mL), the mixture was stirred at 95° C. for 5 hours. 1 N Sodium hydroxide aqueous solution (2 mL) was added to the reaction mixture under ice-cooling, and the whole was extracted with ethyl acetate (20 mL). The organic layer was washed with brine (10 mL), and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the resultant solid was washed with diethyl ether (2 mL) and dried under reduced pressure to give the title compound (12 mg) as a colorless solid (yield 57%).
Reaction SMILES: [SH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.Cl[CH2:13][C:14]1[O:15][CH:16]=[CH:17][CH:18]=1>>[O:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[CH2:13][S:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: ClCc1ccco1
Reactant: Sc1ncnc2ccccc12
Product: c1coc(CSc2ncnc3ccccc23)c1
Yield: 49.4 %

Procedure:
The title compound(3.69 g) was prepared from 4-mercaptoquinazoline(5.0 g) and 2-chloromethylfuran(5.4 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:21]([NH:23][CH2:24][C:25]3[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=3[CH3:31])=[O:22])[C:12]3[CH:17]=[N:16][N:15]([CH:18]([CH3:20])[CH3:19])[C:13]=3[N:14]=2)=[CH:5][CH:4]=1.[CH3:34][N:35]([CH3:41])[CH2:36][CH2:37][CH2:38][NH:39][CH3:40]>CN(C=O)C>[CH3:31][C:30]1[CH:29]=[C:28]([CH3:32])[NH:27][C:26](=[O:33])[C:25]=1[CH2:24][NH:23][C:21]([C:11]1[C:12]2[CH:17]=[N:16][N:15]([CH:18]([CH3:20])[CH3:19])[C:13]=2[N:14]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][N:39]([CH2:38][CH2:37][CH2:36][N:35]([CH3:41])[CH3:34])[CH3:40])=[CH:8][CH:7]=2)[CH:10]=1)=[O:22]
Reactant: CNCCCN(C)C
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CBr)cc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN(C)CCCN(C)C)cc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
6-(4-(Bromomethyl)phenyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.) was suspended in DMF and N1,N1,N3-trimethylpropane-1,3-diamine (5 equiv.) was added to it. The reaction mixture was stirred at room temperature for overnight. On completion of reaction, solvent was removed under reduced pressure and residue was purified by prep. HPLC chromatography to provide the desired compound (30% yield). LCMS: 544.25 (M+1)+; HPLC: 99.96% (@ 254 nm) (Rt; 4.732); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (bs, 1H), 10.14-9.80 (m, 1H), 8.95 (bs, 1H), 8.40-8.35 (m, 3H), 8.22-8.19 (m, 1H), 7.75-7.69 (m, 2H), 5.91 (s, 1H), 5.35-5.32 (m, 1H), 4.42 (d, 2H, J=3.6 Hz), 3.08-2.98 (m, 6H), 2.80-2.62 (m, 8H), 2.23 (s, 3H), 2.13 (s, 3H), 2.07 (m, 2H). 1.55 (d, 6H, J=6.4 Hz).
Reaction SMILES: [CH2:1]([C:3]([C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[C:30]([CH3:43])[CH:29]=1)([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]([O:23][CH2:24][O:25][CH3:26])([C:19]([F:22])([F:21])[F:20])[C:15]([F:18])([F:17])[F:16])=[C:8]([CH3:27])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[CH3:44][O:45][C:46](=[O:55])[CH2:47][C:48]1[CH:49]=[N:50][CH:51]=[C:52](Br)[CH:53]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[CH3:44][O:45][C:46](=[O:55])[CH2:47][C:48]1[CH:49]=[N:50][CH:51]=[C:52]([C:31]2[CH:32]=[CH:33][C:28]([C:3]([CH2:4][CH3:5])([C:6]3[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]([O:23][CH2:24][O:25][CH3:26])([C:19]([F:21])([F:22])[F:20])[C:15]([F:17])([F:18])[F:16])=[C:8]([CH3:27])[CH:7]=3)[CH2:1][CH3:2])=[CH:29][C:30]=2[CH3:43])[CH:53]=1
Reactant: CCC(CC)(c1ccc(C#CC(OCOC)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: COC(=O)Cc1cncc(Br)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(C#CC(OCOC)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Temperature: 140 °C
Yield: 56.6 %

Procedure:
A solution of 2-(4-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-1-butynyl)-phenyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Example 25-(4); 47.7 mg, 0.1 mmol), (5-bromo-pyridin-3-yl)acetic acid methyl ester (Example 24-(2); 26.8 mg, 0.11 mmol), tetrakistriphenylphosphine palladium (12.5 mg, 0.0108 mmol) and potassium phosphate (24.7 mg, 0.11 mmol) in N,N-dimethylformamide (0.25 mL) was stirred with microwave heating at 140° C. for 10 minutes. The reaction mixture was filtered through cotton plug, and the mixture was purified by silica gel chromatography (40% ethyl acetate/hexane) to give the title compound (36.0 mg, 72%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18](=O)[CH2:17][CH:16]([C:20](O)=[O:21])[CH2:15]2)=[CH:10][CH:9]=1.C(OCC)(=O)C.[OH-].[Na+]>C1COCC1>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][CH:16]([CH2:20][OH:21])[CH2:15]2)=[CH:10][CH:9]=1
Reactant: O=C(O)C1CC(=O)N(c2ccc(Cl)cc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCC1CCN(c2ccc(Cl)cc2)C1
Yield: 97.8 %

Procedure:
Lithium aluminum hydride (2.93 g) is suspended in THF (90 ml) under ice-cooling and thereto is added 1-(4-chlorophenyl)-5-oxo-3-pyrrolidinecarboxylic acid (4.63 g) in portions. The mixture is stirred under refluxing for 20 hours. Ethyl acetate and a small amount of 1N aqueous sodium hydroxide solution are added to the reaction mixture to decompose the excess reducing agent. The mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is subjected to silica gel column chromatography and eluted with a mixed solvent of chloroform/methanol [40:1 (v/v)]to give the desired product (4.00 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[CH:35]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>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].CCCCCC.C1(C)C=CC=CC=1>[CH3:40][C:36]1[CH:35]=[C:34]([NH:33][C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:14]4[C:9]3=[CH:10][CH:11]=[CH:12][CH:13]=4)=[CH:4][CH:3]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: Cc1cccc(N)c1
Reactant: Brc1ccc(C2(c3ccccc3)c3ccccc3-c3ccccc32)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1cccc(Nc2ccc(C3(c4ccccc4)c4ccccc4-c4ccccc43)cc2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
In a 200 mL three-neck flask were put 4.7 g (11.8 mmol) of 9-(4-bromophenyl)-9-phenylfluorene and 3.4 g (35.4 mmol) of sodium tert-butoxide. The air in the flask was replaced with nitrogen. To this mixture were added 60.0 mL of toluene, 1.3 mL (12.0 mmol) of m-toluidine, and 0.2 mL of a 10% hexane solution of tri(tert-butyl)phosphine. The temperature of this mixture was set to 60° C., and 36.7 mg (0.1 mmol) of bis(dibenzylideneacetone)palladium(0) was added to the mixture. The temperature of this mixture was raised to 80° C., followed by stirring for 2.0 hours. After the stirring, the mixture was suction-filtered through Florisil, Celite, and alumina to give a filtrate. The filtrate was concentrated to give a solid, which was then purified by silica gel column chromatography (the developing solvent has a 1:1 ratio of hexane to toluene). Accordingly, 4.7 g of a white solid was obtained in 93% yield, which was the substance to be produced. The synthesis scheme of this Step 1 is shown in the following (E8-1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:19])N(OC)C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([Mg]Br)=[CH:24][C:23]=1[CH3:30].[NH4+].[Cl-]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:19])[C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[C:23]([CH3:30])[CH:24]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc([Mg]Br)cc1C
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51 %

Procedure:
A stirred solution of 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (3.0 g, 11.02 mmol) in 30 mL THF was cooled to 0° C., then (4-methoxy-3-methylphenyl)magnesium bromide (6.21 g, 27.5 mmol) was added dropwise via a syringe under N2 and the reaction mixture was stirred at the same temperature for 1.5 h, then gradually warmed up to room temperature over 1 h when the reaction was judged complete by LCMS. To the reaction mixture was slowly added 40 mL of saturated aqueous NH4Cl then the aqueous solution was extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with brine, dried over Na2SO4 and the solvent was removed to yield the crude product. Purification by flash chromatography gave the title compound as a white solid (1.97 g, 5.62 mmol, 51% yield). MS (ESI) m/z 334.4 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) retention time=1.57 min. 1H NMR (400 MHz, CDCL3) 8 ppm 1.48 (s, 9H) 1.62-1.91 (m, 4H) 2.27 (s, 3H) 2.78-3.02 (m, 2H) 3.27-3.46 (m, 1H) 3.91 (s, 3H) 4.12-4.27 (m, 2H) 6.87 (d, J=8.59 Hz, 1H) 7.77 (t, J=8.10 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:11]=2)[CH2:6][CH2:7][CH2:8]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Brc1ccc2c(c1)NCCC2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)N(Cc1ccccc1)CCC2
Temperature: 60 °C
Yield: 71.2 %

Procedure:
To a stirred solution of 7-bromo-1,2,3,4-tetrahydroquinoline (7.0 g, 33.0 mmol) in DMF (50 mL) was added potassium carbonate (13.6 g, 99.0 mmol), and benzyl bromide (4.33 mL, 36.3 mmol), and the mixture was heated to 60° C. for 12 h, then cooled to room temperature and quenched by the addition of ice-cold water (150 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL), and the organic layers were combined and washed with water (50 mL) and brine (50 mL), then dried over sodium sulfate, concentrated and purified by silica gel column chromatography to furnish 1-benzyl-7-bromo-1,2,3,4-tetrahydro-quinoline (7.1 g).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-])=O)[N:4]([CH2:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])[N:3]=1.[NH4+].[Cl-]>CO.[Zn]>[NH2:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:2]=[N:3][N:4]2[CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]#[N:19]
Reactant: N#Cc1cccc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: N#Cc1cccc(Cn2ncc3c(N)cccc32)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
A slurry of 3-((3-iodo-4-nitro-1H-indazol-1-yl)methyl)benzonitrile (0.200 g, 0.495 mmol) and MeOH (10.0 mL) was cooled to 0° C., then Zn dust (0.162 g, 2.47 mmol) was added followed by saturated aqueous NH4Cl (10 mL). The mixture was stirred at 0° C. for 1 hour, then warmed to ambient temperature and stirred overnight. The mixture was diluted with MeOH and filtered. The solid was washed with CH2Cl2 and MeOH. To the filtrate was added saturated aqueous NH4OAc and the mixture was concentrated to remove bulk MeOH. The mixture was then extracted with EtOAc, and the combined organic extracts were washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (25 to 100% EtOAc/hexane) to afford 0.090 g (73%) of the desired product as an orange oil.