Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:6]=[CH:7][C:8]([C:11]([NH:13][C:14]2[CH:15]=[C:16]([C:21]3[CH:22]=[C:23]([NH:28][CH:29]4[CH2:34][CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30]4)[C:24](=[O:27])[NH:25][N:26]=3)[CH:17]=[CH:18][C:19]=2[F:20])=[O:12])=[N:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl>CO.O1CCOCC1>[C:1]([C:5]1[N:6]=[CH:7][C:8]([C:11]([NH:13][C:14]2[CH:15]=[C:16]([C:21]3[CH:22]=[C:23]([NH:28][CH:29]4[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]4)[C:24](=[O:27])[NH:25][N:26]=3)[CH:17]=[CH:18][C:19]=2[F:20])=[O:12])=[N:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2cc(-c3ccc(F)c(NC(=O)c4cnc(C(C)(C)C)cn4)c3)n[nH]c2=O)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(C)c1cnc(C(=O)Nc2cc(-c3cc(NC4CCCNC4)c(=O)[nH]n3)ccc2F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
In a 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer 10d (300 mg, 0.530 mmol) was dissolved in methanol (3.0 mL). To this solution 4M hydrogen chloride in dioxane (3 mL) was added, and this mixture was stirred at room temperature for 2 h under nitrogen. The reaction mixture was then concentrated under reduced pressure, and the resulting residue was partitioned between ethyl acetate (20 mL) and water (20 mL). The mixture was neutralized with saturated potassium carbonate to pH 6.5 (pH meter). The aqueous layer was separated and extracted with ethyl acetate (2×50 mL), The combined organic layers were washed with brine (100 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was evaporated under reduced pressure. The resulting residue was purified on a silica gel column eluting the desired product with 16% methanol in methylene chloride to afford a 65% yield (161 mg) of 10e as a off-white solid: mp 140-141° C.; 1H NMR (500 MHz, DMSO d6) δ 12.79 (s, 1H), 10.37 (s, 1H), 9.23 (s, 1H), 8.92 (s, 1H), 8.48 (d, 1H, J=7.5 Hz), 7.75 (m, 1H), 7.40 (m, 1H), 6.91 (s, 1H), 4.19 (d, 1H, J=9.5 Hz), 4.03 (d, 1H, J=13.0 Hz), 2.99-2.82 (m, 4H), 1.93 (m, 1H), 1.75 (m, 1H), 1.58 (m, 1H), 1.42 (s, 9H), 1.29 (m, 1H); MS (APCI−) m/z 464.6 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7](=[O:9])[CH3:8])[S:5][CH:6]=1.CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:7](=[O:9])[CH:8]=[CH:12][N:13]([CH3:15])[CH3:14])[S:5][CH:6]=1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cc(Cl)cs1
Product: CN(C)C=CC(=O)c1cc(Cl)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
A mixture of 1-(4-chloro-2-thienyl)ethanone (32.1 mmol) and N,N-dimethylformamide dimethyl acetal (112.2 mmol) was refluxed for 3 h and then allowed to cool to room temperature whereupon crystallization occurred. The reaction mixture was stored in a freezer at −18° C. for 2 h. The supernatant liquid was decanted, the crystals were dried in vacuum to afford 5.3 g (77% yield) of 1-(4-chloro-2-thienyl)-3-(dimethylamino)prop-2-en-1-one which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]([Cl:12])[C:5](Cl)=[C:6]([N+:8]([O-])=O)[CH:7]=1.ClC1C([N+]([O-])=O)=C(Cl)C(Cl)=C(Cl)C=1Cl.C1(O)C=CC=CC=1.I.[H][H]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Cl:12])[CH:3]=1)[NH2:8]
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1Cl
Reactant: [H][H]
Agent: I
Agent: O=[N+]([O-])c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Solvent: Oc1ccccc1
Product: Nc1cc(Cl)cc(Cl)c1
Yield: 92 %

Procedure:
150 parts of a mixture of tetrachloronitrobenzene and pentachloronitrobenzene, the composition of which corresponds to that of the polychloroaniline mixture of Example 3, 200 parts of phenol and 10 parts of aqueous hydroiodic acid (57% strength) are reacted with hydrogen in the presence of 20 parts of ruthenium-on-charcoal catalyst (5% strength), starting at approximately 60° C. to a maximum of 165° C. under a pressure of 20 bars, at the beginning, to a maximum of 50 bars, during the course of 10 hours. After working up, 84.5 parts of 3,5-dichloroaniline are obtained. Yield 92% of theory.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[CH3:16][O:17][CH2:18][O:19][N:20]1[C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([C:29]([O:31][CH3:32])=[O:30])[C:23]=2[CH:22]=[CH:21]1.CN(C)[CH:35]=[O:36]>O1CCCC1>[CH:35]([C:21]1[N:20]([O:19][CH2:18][O:17][CH3:16])[C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([C:29]([O:31][CH3:32])=[O:30])[C:23]=2[CH:22]=1)=[O:36]
Reactant: CN(C)C=O
Reactant: COCOn1ccc2c(C(=O)OC)cccc21
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOn1c(C=O)cc2c(C(=O)OC)cccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (1.97 g) in tetrahydrofuran (24.0 ml) was added dropwise n-butyllithium (6.8 ml, 1.64M solution in n-hexane) at −40° C. and the mixture was stirred at 0° C. for 30 minutes. A solution of methyl 1-methoxymethoxyindole-4-carboxylate (1.64 g) in tetrahydrofuran (12.0 ml) was added t the above solution at −60° C. and the solution was stirred at the same temperature for 30 minutes. A solution of N,N-dimethylformamide (662 mg) in tetrahydrofuran (9.0 ml) was added to the reaction mixture at −60° C. and the solution was stirred at the same temperature for 2 hours. The temperature was raised to −320° C. and the reaction was quenched with saturated ammonium chloride aqueous solution. The aqueous solution was extracted with ethyl acetate (80 ml) and the organic layer was washed with brine. Drying, filtering and removal of solvents afforded a crude product. The crude product was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=9:1) to give methyl 2-formyl-1-methoxymethoxyindole-4-carboxylate (1.15 g).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:10][C:11]=2Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.CC([O-])(C)C.[K+].[Cl-].[Li+]>C1COCC1>[C:1]1([C:7]2[O:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:10][C:11]=2[N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCNCC1
Reactant: Clc1cc(-c2ccccc2)oc1-c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: c1ccc(-c2cc(N3CCCCC3)c(-c3ccccc3)o2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 84 %

Procedure:
30 mmol of 2,5-diphenyl-3-chlorofuran (7.64 g), 32 mmol of freshly distilled piperidine (3.0 g), 32 mmol of KOtBu (3.6 g), 2 mmol of lithium chloride (42.5 mg) and 44 mg of trans-di-μ-acetatobis[2-[bis(1,1-dimethylethyl)phosphino]-2-methylpropyl-C,P]dipalladium(II) (0.2 mol %) are suspended in 50 ml of THF and placed in a pressure tube under protective gas. After 12 hours at 110° C., the tube is cooled to room temperature, the salts are filtered off and washed with petroleum ether. The solvents are removed from the filtrate on a rotary evaporator. Crystallization from 96% strength ethanol gives 2,5-diphenyl-3-piperidinofuran as a colorless solid; yield: 84%; melting point: 103° C.
Reaction SMILES: [Li+].[Br-].[CH3:3][Mg]Cl.Cl[C:7]([CH2:9][C@H:10]1[C:14](=[O:15])[O:13][CH2:12][N:11]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:8].[NH4+].[Cl-]>C1COCC1.O.CCCCCCC>[O:15]=[C:14]1[O:13][CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C@H:10]1[CH2:9][C:7](=[O:8])[CH3:3]
Reactant: O=C(Cl)C[C@H]1C(=O)OCN1C(=O)OCc1ccccc1
Reactant: C[Mg]Cl
Agent: [Br-]
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CC(=O)C[C@H]1C(=O)OCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
CuBr (24.54 g, 168 mmol, 1.2 eq.) and LiBr (29.18 g, 336 mmol, 2.4 eq.) were initially charged in a baked-out flask under argon, then dissolved in 600 ml of absolute THF and stirred at RT for 20 min. This gave a clear yellow-orange solution. The mixture was then cooled to −78° C., and MeMgCl solution (55.46 ml, 168 mmol, 1.2 eq.) was added dropwise thereto. This led to a yellow suspension which was difficult to stir, so that a further 75 ml of THF were added dropwise; the mixture was subsequently stirred at −60° C. for 15 min. The carbonyl chloride from example 12 dissolved in about 150 ml of THF (41.67 g, 140 mmol) was initially stirred at −60° C. and then slowly added dropwise. The reaction mixture thus formed was stirred at this temperature for 1 h. The workup was effected by adding about 100 ml of saturated NH4Cl solution; the mixture was stirred vigorously at −60° C. for 10 min, then 200 ml of heptane and 60 ml of water were added and the mixture was stirred at RT for a further 15 min. The phases were separated, and the aqueous phase was admixed with 50 ml of 1 M HCl (green solution) and extracted twice with about 100 ml of ethyl acetate. The combined organic phases were washed with 2 M HCl solution, saturated NaHCO3 and saturated NaCl solution, dried over sodium sulfate and concentrated under reduced pressure. Subsequently, purification was effected by means of silica gel flash chromatography (5:1-2:1 heptane/ethyl acetate); production fractions were combined and freed of solvent residues under reduced pressure. Yield: 21.6 g, 56% of theory
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:7]([NH:8][C:9]([C:11]2[NH:12][C:13]([CH2:17][CH3:18])=[C:14]([Cl:16])[N:15]=2)=[O:10])[CH2:6][CH2:5][N:4]([C:19]2[S:20][C:21]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:3]1.[CH3:33][CH:34]([CH3:37])[CH:35]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:16][C:14]1[N:15]=[C:11]([C:9]([NH:8][C@H:7]2[CH2:6][CH2:5][N:4]([C:19]3[S:20][C:21]4[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)[CH2:3][C@H:2]2[NH:1][CH2:33][CH:34]([CH3:37])[CH3:35])=[O:10])[NH:12][C:13]=1[CH2:17][CH3:18]
Reactant: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](N)C3)sc12
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](NCC(C)C)C3)sc12
Yield: 88 %

Procedure:
The same operation as in Example (77d) was performed using ethyl cis(±)-2-(3-amino-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-benzothiazole-7-carboxylate obtained by the method described in Example (81e) (30 mg, 0.063 mmol), 2-methylpropanal (7 μL, 0.077 mmol) and sodium (triacetoxy)borohydride (60 mg, 0.28 mmol), to obtain 29.6 mg of the title compound as a white solid (88%).
Reaction SMILES: COC1C=CC(C[N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[C:17]2[C:18]([O:23][C:24]3[C:33]([CH3:34])=[CH:32][CH:31]=[C:30]4[C:25]=3[CH:26]=[CH:27][N:28]=[C:29]4[NH:35][C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=3)=[N:19][CH:20]=[CH:21][CH:22]=2)=CC=1>C(O)(C(F)(F)F)=O>[N:12]1[C:13]([C:17]2[C:18]([O:23][C:24]3[C:33]([CH3:34])=[CH:32][CH:31]=[C:30]4[C:25]=3[CH:26]=[CH:27][N:28]=[C:29]4[NH:35][C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=3)=[N:19][CH:20]=[CH:21][CH:22]=2)=[C:14]2[C:9]([NH:8][CH:16]=[N:15]2)=[N:10][CH:11]=1
Reactant: COc1ccc(Cn2cnc3c(-c4cccnc4Oc4c(C)ccc5c(Nc6ccc(Cl)cc6)nccc45)ncnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(Nc3ccc(Cl)cc3)nccc2c1Oc1ncccc1-c1ncnc2[nH]cnc12

Procedure:
A solution of 5-(3-(9-(4-methoxybenzyl)-9H-purin-6-yl)pyridin-2-yloxy)-N-(4-chlorophenyl)-6-methylisoquinolin-1-amine (0.22 g, 0.37 mmol) in TFA (5 mL) was stirred in a 65° C. oil bath for 3.5 h. The TFA was removed in vacuo and the residue was dissolved in MeOH (50 mL) and 2 M NH3 in MeOH (50 mL) and adsorbed onto a pad of silica gel. The crude product was chromatographed through a Redi-Sep® pre-packed silica gel column (12 g), eluting with a gradient of 1% to 8% 1 M NH3.MeOH in CH2Cl2 (over 20 min), to give 5-(3-(9H-purin-6-yl)pyridin-2-yloxy)-N-(4-chlorophenyl)-6-methylisoquinolin-1-amine as a white solid. 1H NMR (400 MHz, DMSO-d6) □ ppm 2.23 (s, 3H), 7.24-7.33 (m, 2H), 7.35 (d, J=8.53 Hz, 2H), 7.53 (d, J=8.53 Hz, 1H), 7.88-7.97 (m, 3H), 8.13 (d, J=5.02 Hz, 1H), 8.24 (d, J=7.53 Hz, 1H), 8.34 (d, J=8.53 Hz, 1H), 8.68 (s, 1H), 9.07 (s, 1H), 9.27 (s, 1H), 13.64 (s, 1H); MS (ESI, pos. ion) m/z: 480.1 [M+H]+
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[C:22]([C:24](OC)=[O:25])[CH:21]=[C:20]([N+:28]([O-:30])=[O:29])[CH:19]=2)=[O:16])[CH:7]=[C:8]([C:10](OC)=[O:11])[CH:9]=1)([O-:3])=[O:2].[NH2:31][CH:32]([CH2:35][OH:36])[CH2:33][OH:34]>>[N+:28]([C:20]1[CH:19]=[C:18]([NH:17][C:15]([NH:14][C:6]2[CH:7]=[C:8]([C:10]([NH:31][CH:32]([CH2:35][OH:36])[CH2:33][OH:34])=[O:11])[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:16])[CH:23]=[C:22]([C:24]([NH:31][CH:32]([CH2:35][OH:36])[CH2:33][OH:34])=[O:25])[CH:21]=1)([O-:30])=[O:29]
Reactant: COC(=O)c1cc(NC(=O)Nc2cc(C(=O)OC)cc([N+](=O)[O-])c2)cc([N+](=O)[O-])c1
Reactant: NC(CO)CO
Product: O=C(Nc1cc(C(=O)NC(CO)CO)cc([N+](=O)[O-])c1)Nc1cc(C(=O)NC(CO)CO)cc([N+](=O)[O-])c1
Yield: 95 %

Procedure:
The reaction was performed analogous to the synthesis described above for Example 10c starting from N,N'-bis(3-nitro-5-methoxycarbonylphenyl)urea (12.0 g, 28.7 mmol) and serinol (6.83 g, 75 mmol). The crude reaction product was purified by trituration with acetonitrile (2×50 ml), with water (200 ml) and with acetonitrile (3×50 ml) to give 95% pure product. Yield: 12.0 g (78%).
Reaction SMILES: C[N:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[C:3]1CN(C)CC#C.[Br:18][CH2:19][CH2:20]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:18][CH2:19][CH2:20][O:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:2][CH:3]=[CH:4]2
Reactant: C#CCN(C)Cc1cc2cc(O)ccc2n1C
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: BrCCOc1ccc2[nH]ccc2c1
Yield: 37 %

Procedure:
A solution of 1-methyl-2-{[methyl(prop-2-yn-1-yl)amino]methyl}-1H-indol-5-ol (8) (Cruces, M. A.; Elorriaga, C.; Fernández-Álvarez, E. Eur. J. Med. Chem. 1991, 26, 33-41) (0.215 g, 0.942 mmol), 1,2-dibromoethane (1.77 g, 9.42 mmol), and potassium carbonate (0.65 g, 4.71 mmol) in 2-butanone (8 mL) was heated at 85° C. for 6 h. The mixture was evaporated under vacuum and the residue was extracted with dichloromethane (10 mL) and water (10 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by column chromatography, eluting with a 4% methanol mixture in dichloromethane to give compound 9 (117.3 mg, 37%). Rf=0.76 (CH2Cl2/AcOEt, 10/1); pf 75-77° C.; RMN of 1H (300 MHz, CDCl3) δ 2.31 (t, J=2.4 Hz, 1H, ≡CH), 2.36 (s, 3H, N—CH3), 3.32 (d, J=2.4 Hz, 2H, N—CH2—C≡), 3.66 (t, J=6.4 Hz, 2H, —CH2—Br), 3.69 (s, 2H, N—CH2), 3.75 (s, 3H, N—CH3), 4.33 (t, J=6.4 Hz, 2H, —CH2—O—), 6.36 (s, 1H, CH3), 6.9 (dd, J=8.8, 2.5 Hz, 1H, CH6), 7.07 (d, J=2.4 Hz, 1H, CH4), 7.2 (d, J=8.8 Hz, 1H, CH7); RMN of 13C (75 MHz, CDCl3) δ 29.6 (CH2—Br), 29.9 (N—CH3), 41.5 (N—CH3), 44.7 (—CH2—C≡), 51.7 (CH2—N), 69.1 (CH2—O), 73.5 (≡CH), 78.3 (—C≡), 102.15 (CH3ind), 104.42 (CH4ind), 109.7 (CH7ind), 112.2 (CH6ind), 127.4 (C3aind), 133.8 (C7aind), 137.3 (C2ind), 152.2 (C5ind); EM (IE) m/z (%): 131 (48), 160 (66) [M-((Br(CH2)2)—NCH3CH2C≡CH)]+, 267 (100) [M-NCH3CH2C≡CH)]+, 334 (25)[M]+
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:15](O)=[O:16])[CH:12]=2)[C:7]([CH3:18])=[N:6]1.[C:24]([O:28][C:29](=[O:32])[NH:30][NH2:31])([CH3:27])([CH3:26])[CH3:25].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:15]([NH:31][NH:30][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:32])=[O:16])[CH:12]=2)[C:7]([CH3:18])=[N:6]1
Reactant: Cc1nn(Cc2c(Cl)cccc2Cl)c2cc(CC(=O)O)ccc12
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1nn(Cc2c(Cl)cccc2Cl)c2cc(CC(=O)NNC(=O)OC(C)(C)C)ccc12
Reaction time: 18 h
Yield: 86.5 %

Procedure:
To a solution of the compound [97] (73.2 mg) in chloroform (1.1 mL) were added tert-butylcarbazate (222.0 mg), 1-hydroxybenzotriazole monohydrate (113.5 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (161.0 mg) at room temperature, and then the reaction mixture was stirred for 18 hours. The reaction mixture was quenched with water, and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (84.0 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([Cl:18])[N:3]=1.[F:19][CH:20]([F:28])[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([NH2:27])[CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[Cl:18][C:4]1[N:3]=[C:2]([NH:27][C:23]2[CH:22]=[C:21]([CH:20]([F:28])[F:19])[CH:26]=[CH:25][N:24]=2)[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:5]=1
Reactant: Nc1cc(C(F)F)ccn1
Reactant: Clc1cc(C2CCN(C3COC3)CC2)cc(Cl)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: FC(F)c1ccnc(Nc2cc(C3CCN(C4COC4)CC3)cc(Cl)n2)c1
Temperature: 80 °C
Reaction time: 22 h
Yield: 77.1 %

Procedure:
A round-bottomed flask was charged with 2,6-dichloro-4-[1-(oxetan-3-yl)-4-piperidyl]pyridine (1.00 g, 3.48 mmol), 4-(difluoromethyl)pyridin-2-amine (502 mg, 3.48 mmol), tris(dibenzylideneacetone)dipalladium(0) (82.2 mg, 2.5 mol %), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (125 mg, 6 mol %) and cesium carbonate (1.59 g, 4.87 mmol). The flask was sealed with a septum and purged with nitrogen gas before injecting anhydrous 1,4-dioxane (14 mL, 0.25 M). The reaction mixture was stirred at 80° C. for 22 hr before cooling to rt and filtering through Celite, rinsing with CH2Cl2. After concentration, flash column chromatography (100:0-95:5 CH2Cl2/MeOH) afforded 6-chloro-N-(4-(difluoromethyl)pyridin-2-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-2-amine as a colorless solid (1.06 g, 77%); 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J=5.1 Hz, 1H), 7.53 (s, 1H), 7.46 (s, 1H), 7.34 (br s, 1H), 7.00 (d, J=5.1 Hz, 1H), 6.80 (s, 1H), 6.61 (t, J=55.8 Hz, 1H), 4.72-4.60 (m, 4H), 3.57-3.46 (m, 1H), 2.94-2.81 (m, 2H), 2.58-2.41 (m, 1H), 2.00-1.75 (m, 6H); ESI-LRMS m/z [M+1]+=395.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].CN(C)CCN(C)CCN(C)C.C([Li])CCC.C[O:28]B(OC)OC.C(O)(=O)C.OO>O.O1CCCC1>[F:1][C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][C:7]=1[OH:28]
Reactant: COc1ccccc1F
Reactant: COB(OC)OC
Agent: CN(C)CCN(C)CCN(C)C
Agent: OO
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc(O)c1F
Temperature: -78 °C
Yield: 73.2 %

Procedure:
A mixture of 2-fluoroanisole (1.8 ml, 15.85 mmol), pentamethyldiethyenetriamine (3.6 mL, 17.45 mmol) and tetrahydrofuran (10 mL) is stirred at −78° C. A 2.5 M solution of n-butyllithium in hexanes (7 ml, 17.45 mmol) is added dropwise and the resulting solution is stirred at −78° C. 2 hr. Trimethylborate (2 mL, 17.45 mmol) is added and the reaction is warmed to room temperature and stirred 1 hr. Acetic acid (1.4 ml, 23.8 mmol) is added followed by an aqueous 30% solution of hydrogen peroxide (1.8 mL, 17.45 mmol) and the resulting mixture is stirred rapidly 18 hr at room temperature. The reaction mixture is diluted with water and extracted with ethyl acetate (3×50 mL). The combined extracts are dried over magnesium sulfate, filtered and concentrated to about 10 mL volume. The resulting mixture is purified via silica chromatography eluting with hexanes to 8:1 hexanes:ethyl acetate to give the title compound (1.65 g, 73%) as a colorless oil. MS ES 141 M−1.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([F:24])[CH:3]=1.[O:25]1[CH2:29][CH:28]=[N:27][C:26]1=[O:30]>>[F:24][C:4]1[CH:3]=[C:2]([N:27]2[CH2:28][CH2:29][O:25][C:26]2=[O:30])[CH:7]=[C:6]([F:8])[C:5]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10]
Reactant: Cc1ccc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)nc1
Reactant: O=C1N=CCO1
Product: Cc1ccc(N2CCN(C(=O)c3c(F)cc(N4CCOC4=O)cc3F)CC2)nc1
Yield: 63.7 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using (4-bromo-2,6-difluorophenyl)[4-(5-methylpyridin-2-yl)piperazin-1-yl]methanone (396 mg) described in Preparation Example 185 and oxazolin-2-one (104 mg), the title compound (256 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH2:9].C1(P(C2C=CC=CC=2)C2(P(C3C=CC=CC=3)C3C=CC=CC=3)CC=C3C(C=CC=C3)=C2C2C3C(=CC=CC=3)C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:63]1[C:72]2[C:71](=[O:73])[NH:70][N:69]=[C:68]([CH3:74])[C:67]=2[N:66]([CH3:75])[C:65](=[O:76])[C:64]=1[CH3:77]>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:63]1[C:72]2[C:71](=[O:73])[NH:70][N:69]=[C:68]([CH3:74])[C:67]=2[N:66]([CH3:75])[C:65](=[O:76])[C:64]=1[CH3:77]
Reactant: Cc1c(Cl)c2c(=O)[nH]nc(C)c2n(C)c1=O
Reactant: Cc1ccc(N)c(F)c1
Agent: [Pd+2]
Agent: C1=c2ccccc2=C(c2cccc3ccccc23)C(P(c2ccccc2)c2ccccc2)(P(c2ccccc2)c2ccccc2)C1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(Nc2c(C)c(=O)n(C)c3c(C)n[nH]c(=O)c23)c(F)c1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
2-Fluoro-4-methylphenylamine (1.10 equivalents), palladium (II) acetate (0.10 equivalents), rac-2,2-bis(diphenylphosphino)-1,1′-binaphthyl (0.15 equivalents), and cesium carbonate (1.50 equivalents) are added to a solution of 4-chloro-1,3,8-trimethyl-1H,6H-pyrido[2,3-d]pyridazine-2,5-dione (1.00 equivalent) in toluene in a sealed vial. After stirring 10 minutes, the mixture is heated to 80° C. After 24 hours, the reaction mixture is cooled to room temperature and diluted with EtOAc. The resulting precipitate is filtered and washed with EtOAc. The filtrate is diluted with EtOAc and washed with water. The aqueous layer is reextracted with EtOAc. The combined organic layers are washed with brine, dried (Na2SO4) and concentrated. Purification by flash column chromatography gives the desired product.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]([OH:19])=O.[CH3:20][C:21]1([CH3:35])[C:25]([CH3:27])([CH3:26])[O:24][B:23]([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)[O:22]1.C(N(C(C)C)CC)(C)C>CN(C)C=O.ClCCl>[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]([NH:32][C:31]1[CH:30]=[CH:29][C:28]([B:23]2[O:24][C:25]([CH3:27])([CH3:26])[C:21]([CH3:35])([CH3:20])[O:22]2)=[CH:34][CH:33]=1)=[O:19]
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: Cn1c(C(=O)O)cc2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(C(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc2ccccc21
Yield: 70.2 %

Procedure:
A mixture of oxalyl chloride (0.35 mL) and dimethylformamide (1 drop) was added to a solution of 1-methyl-1H-2-indolecarboxylic acid (440 mg, 2.51 mmol) in dichloromethane (10 mL). After one hour the mixture was evaporated, dissolved in dichloromethane (10 mL), and added to a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (500 mg, 2.28 mmol) and diisopropylethylamine (0.35 mL) in dichloromethane (10 mL). After 16 hours the mixture was washed with water (10 mL), dried (MgSO4), filtered, concentrated, and purified by flash column chromatography to provide the desired product (600 mg, 1.60 mmol) after lyophilization: MS m/e 377.4 (M+H)+.