Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:24][CH:23]2[CH:21]([CH:22]2[C:25]2[N:29]([CH2:30][CH:31]3[CH2:33][CH2:32]3)[N:28]=[C:27]([C:34]3[CH:35]=[C:36]([O:41][C:42]([F:45])([F:44])[F:43])[C:37]([NH2:40])=[N:38][CH:39]=3)[CH:26]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>O1CCCC1.F.F.F.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>[NH2:40][C:37]1[N:38]=[CH:39][C:34]([C:27]2[CH:26]=[C:25]([CH:22]3[CH:23]4[CH:21]3[CH2:20][CH:19]([OH:18])[CH2:24]4)[N:29]([CH2:30][CH:31]3[CH2:33][CH2:32]3)[N:28]=2)=[CH:35][C:36]=1[O:41][C:42]([F:43])([F:45])[F:44]
Reactant: CC(C)(C)[Si](OC1CC2C(C1)C2c1cc(-c2cnc(N)c(OC(F)(F)F)c2)nn1CC1CC1)(c1ccccc1)c1ccccc1
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ncc(-c2cc(C3C4CC(O)CC43)n(CC3CC3)n2)cc1OC(F)(F)F
Yield: 75.5 %

Procedure:
A solution of 5-(5-(3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)-1-(cyclopropylmethyl)-1H-pyrazol-3-yl)-3-(trifluoromethoxy)pyridin-2-amine (0.30 g, 0.47 mmol) in tetrahydrofuran (2 mL) and triethylamine trihydrofluoride (2 mL) was heated to 60° C. for 16 h. The reaction was diluted with saturated aqueous sodium bicarbonate, and the resulting mixture was extracted with ethyl acetate (2×10 mL). The collected organic was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (50% ethyl acetate in petroleum ether) provided product as a solid (140 mg, 75% yield). LCMS (ESI) [MH]+=394.9.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][C:14]3[N:15]([C:17]([CH2:20][C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[CH:26][CH:25]=[CH:24]5)=[CH:18][N:19]=3)[N:16]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C)C=O.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)[O:46][N:47]1[C:51]2[N:52]=[CH:53][CH:54]=[CH:55][C:50]=2[N:49]=N1.C(N(CC)C(C)C)(C)C.OC(C(F)(F)F)=O.CC1ON=C([C@@H](N)C)N=1>>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][C:14]3[N:15]([C:17]([CH2:20][C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[CH:26][CH:25]=[CH:24]5)=[CH:18][N:19]=3)[N:16]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH:49][C@H:50]([C:51]1[N:52]=[C:53]([CH3:54])[O:46][N:47]=1)[CH3:55])=[O:6]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc(-c2cnc3ncc(Cc4ccc5ncccc5c4)n3n2)cc1Cl
Agent: Cc1nc([C@H](C)N)no1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Cc1nc([C@H](C)NC(=O)c2ccc(-c3cnc4ncc(Cc5ccc6ncccc6c5)n4n3)cc2Cl)no1
Reaction time: 0.25 h

Procedure:
To a solution of 2-chloro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoic acid (50 mg, 0.1 mmol, Example 2, Step 4) in N,N-dimethylformamide (2 mL, 20 mmol) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (68 mg, 0.18 mmol) (Aldrich, Cat #226084) and N,N-diisopropylethylamine (42 μL, 0.24 mmol). After stirring the solution for 15 min, (1S)-1-(5-methyl-1,2,4-oxadiazol-3-yl)ethanamine TFA salt (18 mg, 0.14 mmol, Step 5) was added and stirred overnight. The mixture was purified by RP-HPLC (pH=10) to give the desired product which was further purified by RP-HPLC (pH=2) to afford the desired pure product as the TFA salt. LCMS (M+H)+: m/z=525.0/427.0. 1H-NMR (500 MHz, DMSO-d6): 9.22 (s, 1H), 8.98 (dd, J=5.0, 1.5 Hz, 1H), 9.15 (d, J=8.0 Hz, 1H), 8.56 (d, J=8.5 Hz, 1H), 8.16 (d, J=2.0 Hz, 1H), 8.14 (dd, J=8.0, 1.5 Hz, 1H), 8.06 (s, 1H), 8.04 (d, J=9.0 Hz, 1H), 8.02 (s, 1H), 7.90 (dd, J=9.0, 2.0 Hz, 1H), 7.68 (dd, J=8.5, 5.0 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 5.24 (m, 1H), 4.66 (s, 2H), 2.60 (s, 3H), 1.51 (d, J=7.0 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:5]=[C:6](Br)[CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)[O:18]1.C([O-])(=O)C.[K+].OOS([O-])=O.[K+]>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].CS(C)=O.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:5]=[C:6]([OH:18])[CH:7]=1
Reactant: O=C(c1cccnc1)c1cc(Br)cc(Br)c1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C(c1cccnc1)c1cc(O)cc(Br)c1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 57.4 %

Procedure:
A 50 mL tube was charged with (3,5-dibromo-phenyl)-pyridin-3-yl-methanone (2.55 g, 7.5 mmol), bis(pinacolato)diboron (1.26 g, 5.0 mmol), potassium acetate (1.47 g, 15.0 mmol) and Pd(dppf)Cl2.CH2Cl2 (200 mg). DMSO (15 mL) was added, and the solution was degassed with nitrogen, then the tube was sealed. After heating the tube for 16 h at 80° C., the mixture was diluted with ethyl acetate (10 mL) and extracted with brine (10 mL, three times), and saturated sodium bicarbonate (5 mL), and the organic layer was dried. To a solution of the crude product prepared above in acetone (20 mL) was added an aqueous solution of Oxone (6.15 g in 30 mL water), and the reaction mixture was stirred vigorously for 10 min at room temperature. The reaction was quenched with aqueous sodium hydrogen sulfite. The brown solution was extracted with ethyl acetate, and the organic layer was extracted with brine followed by water, then dried and concentrated. The residue was passed through a short pad of Silica gel column using a gradient of 2% MeOH in methylene chloride to 4% MeOH in methylene chloride as an eluent to give (3-bromo-5-hydroxy-phenyl)-pyridin-3-yl-methanone (800 mg, 2.87 mmol, 57%) as a foam.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F-:11].[K+].C1OCCOCCOCCOCCOCCOC1.[CH2:31]1[S:35](=[O:37])(=[O:36])[CH2:34][CH2:33][CH2:32]1>>[F:11][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:34]1[S:35](=[O:37])(=[O:36])[CH2:31][CH2:32][CH2:33]1
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: O=[N+]([O-])c1ccccc1F
Temperature: 110 °C
Yield: 80 %

Procedure:
1,300 parts of o-chloronitrobenzene, 960 parts of potassium fluoride and 82.5 parts of 18-crown-6 in 1,300 parts of tetramethylenesulfone are stirred under nitrogen for 30 hours at 180° C. The solution is cooled to 110° C. and filtered, the solid residue is rinsed with 500 parts of methylene chloride and the filtrates are combined and distilled. 932 parts (80% of theory) of o-fluoronitrobenzene of boiling point 55°-57° C./1.2 mm Hg and 1,290 parts (99.2% of theory) of tetramethylenesulfone of boiling point 105°-110° C. are obtained. About 70% of the crown ether can be recovered from the distillation residue by repeated extraction by shaking with water.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH2:17][N:18]2[CH2:23][CH2:22][C:21](=[CH:24]OC)[CH2:20][CH2:19]2)=[CH:11][CH:10]=1.Cl.[C:28]1([CH3:36])[CH:33]=[CH:32][C:31]([NH:34]N)=[CH:30][CH:29]=1.C([SiH](CC)CC)C>C(Cl)(Cl)Cl>[CH3:36][C:28]1[CH:33]=[C:32]2[C:21]3([CH2:22][CH2:23][N:18]([CH2:17]/[CH:16]=[CH:15]/[C:12]4[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[CH2:19][CH2:20]3)[CH2:24][NH:34][C:31]2=[CH:30][CH:29]=1
Reactant: COC=C1CCN(C/C=C/c2ccc(Cl)cc2)CC1
Reactant: Cc1ccc(NN)cc1
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c(c1)C1(CCN(C/C=C/c3ccc(Cl)cc3)CC1)CN2
Temperature: 50 °C
Yield: 63 %

Procedure:
Trifluoroacetic acid (0.75 ml) was added to a stirred solution of 1-[trans-3-(4-chlorophenyl)allyl]-4-methoxymethylenepiperidine- and 4-tolylhydrazine hydrochloride (28 mg) in chloroform (5 ml) and the reaction was heated to 50° C. for 5 h. Triethylsilane (2 ml) was added and the reaction was heated at 50° C. for a further 5 h. The mixture was allowed to cool and was quenched in concentrated ammonia solution/ice chips (20 ml). The aqueous phase was extracted twice with chloroform and the combined organics were dried over anhydrous magnesium sulphate and concentrated in vacuo to yield 0.04 g (63%) of the desired indoline. 1H NMR (400 MHz, CDCl3) 1.75 (d, J=9 Hz, 2H), 1.96 (td, J=8 & 2, 2H), 2.13 (t, J=9 Hz, 2H), 2.25 (s, 3H), 2.95 (d, J=10 Hz, 2H), 3.19 (d, J=5 Hz, 2H), 3.42 (s, 2H), 6.30 (dt, J=11 & 5 Hz, 1H), 6.48 (d, J=11 Hz, 1H), 6.58 (d, J=7 Hz, 1H), 6.85 (d, J=7 Hz, 1H), 6.9 (s, 1H), 7.30 (m, 4H). MS (ES+) 353/355 (M+H+), 203 (M-4-chlorocinnamyl+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:63][C:64]([C@H:66]1[CH2:70][CH2:69][CH2:68][NH:67]1)=[O:65]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:67]1[CH2:68][CH2:69][CH2:70][C@@H:66]1[C:64]([NH2:63])=[O:65])=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: NC(=O)[C@H]1CCCN1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCC[C@@H]3C(N)=O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and (2R)-2-(aminocarbonyl)-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[OH-].[Na+].[I-:14].[Na+].Cl[O-].[Na+].Cl>CO.[Cl-].[Na+].O>[I:14][C:7]1[CH:6]=[CH:5][C:4]([OH:9])=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:8]=1
Reactant: [I-]
Reactant: Oc1ccccc1C(F)(F)F
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Oc1ccc(I)cc1C(F)(F)F

Procedure:
A solution of 2-trifluoromethylphenol (10 g, 61.7 mmol) in methanol (125 mL) at room temperature was treated with sodium hydroxide (13.87 g, 93 mmol) and stirred until homogeneous. The mixture was cooled in an ice bath and sodium iodide (2.96 g, 74 mmol) was added portionwise followed by the addition of 10% sodium hypochlorite (84 mL, 136 mmol) dropwise, dividing these reagents into 3 portions and adding them sequentially over 30 minutes. The solution was then adjusted to pH 1 by dropwise addition of concentrated hydrochloric acid and poured into brine. The product was extracted into ethyl acetate, concentrated in vacuo and purified by silica gel flash chromatography eluting with ethyl acetate/hexane (0% to 5%) to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)(=[O:5])=[O:4].[Li]CCCC.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>C1COCC1.O>[CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])(=[O:4])=[O:5]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN(C)S(=O)(=O)n1ccnc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1ccnc1[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 24 h

Procedure:
Imidazole (Intermediate L1, available from Aldrich, 20.0 g, 0.29 mol), triethylamine (41.0 mL, 0.29 mol) and N,N-dimethylsulfamoyl chloride (31.6 mL, 0.29 mol) were added to benzene (320 mL). The reaction was stirred for 48 h at rt and then filtered. The filtrate was collected and concentrated under reduced pressure. Vacuum distillation of the crude product (˜0.5 mmHg, 115-118° C.) afforded dimethylsulfamoyl) imidazole (Intermediate L2) 38.7 g (76%) as a clear and colorless oil. Upon cooling the product solidifies to give white crystals. 1-(Dimethylsulfamoyl) imidazole (Intermediate L2) (18.8 g, 0.11 mol) was added to THF (430 mL). The solution was cooled to −78° C. A solution of n-BuLi (70.9 mL, 1.6 M in hexane) was added dropwise to the reaction mixture. Upon completion, the solution was stirred for 1 h at −78° C. t-Butyldimethylsilylchloride (TBSCl) (17.8 g, 0.12 mol) in THF (50 mL) was added via cannula to the mixture. After the addition was completed the reaction mixture was warmed slowly to rt and stirred for 24 h. The mixture was diluted with water and the organic layer separated. The organic phase was washed with brine and then dried over Na2SO4. The mixture was filtered and the filtrate concentrated under reduced pressure. Column chromatography on SiO2 with 20% ethyl acetate/hexane afforded 1-dimethylsulfamoyl-2-t-butyldimethylsilyl imidazole (Formula 13) as a light yellow solid. Recrystallization from pentane gave 30 g (94%) of white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH2:17])[CH:13]=2)[N:8]=1.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>C(#N)C.C(=O)(O)[O-].[Na+].O>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:17][C:25]([CH:22]3[CH2:24][CH2:23]3)=[O:26])[CH:13]=2)[N:8]=1
Reactant: COc1ccccc1CNc1ccc2cc(N)ccc2n1
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccccc1CNc1ccc2cc(NC(=O)C3CC3)ccc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N2-(2-Methoxy-benzyl)-quinoline-2,6-diamine (example 10, step B, 150 mg, 0.537 mmol) was dissolved in 6 mL acetonitrile and 6 mL saturated sodium bicarbonate solution. Cyclopropane carbonyl chloride (63 mg, 0.60 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with 50 mL water and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with water (30 ml), dried with sodium sulfate and evaporated. The crude product was recrystallized from diisopropyl ether. The title compound was obtained as a white solid (123 mg, 66%), MS: m/e=348.3 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][O:22][CH3:23].[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26]([C:34](O)=[O:35])[CH:25]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][O:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:34]([C:26]3[CH:25]=[N:24][C:33]4[C:28]([CH:27]=3)=[CH:29][CH:30]=[CH:31][CH:32]=4)=[O:35])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=C(O)c1cnc2ccccc2c1
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)c1cnc2ccccc2c1
Yield: 28.5 %

Procedure:
Using the general method of Example 181 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (2.0 g, 6.37 mmol) was reacted with quinoline-3-carboxylic acid (1.33 g, 7.66 mmol) to provide 850 mg of N-{4-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}quinoline-3-carboxamide as a yellow solid, m.p. 114-116° C. Analysis: Calculated for C27H28N6O2·0.2H2O: % C, 68.68 ; % H, 6.06; % N, 17.80; Found: % C, 68.68; % H, 5.85; % N, 17.76.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][C:6]3=[CH:5][C:4]=2[CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Cl[C:46]1[C:55]([CH2:56][CH3:57])=[CH:54][C:49]([C:50]([O:52][CH3:53])=[O:51])=[C:48]([O:58][CH3:59])[N:47]=1.C([O-])([O-])=O.[K+].[K+]>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]>[C:18]([O:17][C:15]([N:13]1[CH2:12][CH2:11][N:7]2[C:8]3[CH:9]=[CH:10][C:2]([C:46]4[C:55]([CH2:56][CH3:57])=[CH:54][C:49]([C:50]([O:52][CH3:53])=[O:51])=[C:48]([O:58][CH3:59])[N:47]=4)=[CH:3][C:4]=3[CH:5]=[C:6]2[CH2:14]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCn2c(cc3cc(Br)ccc32)C1
Reactant: CCc1cc(C(=O)OC)c(OC)nc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Product: CCc1cc(C(=O)OC)c(OC)nc1-c1ccc2c(c1)cc1n2CCN(C(=O)OC(C)(C)C)C1
Temperature: 120 °C
Yield: 28.6 %

Procedure:
To a vial was added tert-butyl 8-bromo-3,4-dihydropyrazino[1,2-a]indole-2(1H)-carboxylate (0.318 g, 0.9 mmol), bis(pinacolato)diboron (0.3 g, 1.2 mmol), potassium acetate (0.27 g, 2.7 mmol), and Pd(dppf)Cl2 (26 mg, 4 mol %). The vial was evacuated and back filled with argon. Dioxane (3 mL) was added, the vial was sealed under argon and heated to 120° C. for 18 h. The reaction mixture was then cooled to room temperature and methyl 6-chloro-5-ethyl-2-methoxynicotinate (0.23 g, 1.0 mmol) was added along with K2CO3 (0.38 g, 2.7 mmol) and H2O (300 μL). The vial was sealed again under argon and heated to 120° C. for a further 12 h. The reaction mixture was then cooled to room temperature and diluted with H2O (20 mL). The aqueous layer was extracted with CH2Cl2 (3×50 mL). The combined organics were dried over Na2SO4, filtered, and concentrated. The crude residue was purified on silica gel (1:1 hexanes/EtOAc) to afford the title compound as a clear oil (0.12 g, 30%).
Reaction SMILES: [N:1]1([C:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:48][C:49]1[CH:60]=[CH:59][C:52]2[NH:53][C:54]([CH:56]([NH2:58])[CH3:57])=[N:55][C:51]=2[CH:50]=1.ClCl>O1CCCC1.C(Cl)Cl.C(O)C>[Cl:48][C:49]1[CH:60]=[CH:59][C:52]2[NH:53][C:54]([CH:56]([NH:58][C:12](=[O:14])[C:11]3[CH:10]=[CH:9][C:8]([C:6]([N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[O:7])=[CH:16][CH:15]=3)[CH3:57])=[N:55][C:51]=2[CH:50]=1
Reactant: O=C(O)c1ccc(C(=O)N2CCCC2)cc1
Reactant: CC(N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCO
Product: CC(NC(=O)c1ccc(C(=O)N2CCCC2)cc1)c1nc2cc(Cl)ccc2[nH]1
Yield: 98 %

Procedure:
Prepared analogously to Example 1g from 4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and 1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in tetrahydrofuran. Yield: 98%; Rf value: 0.50 (silica gel; methylene chloride/ethanol=9:1); C21H21ClN4O2 (396.88); mass spectrum: (M+H)+=397/399 (chlorine isotope).
Reaction SMILES: C(OC([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])[CH2:14][CH2:13]1)=O)C1C=CC=CC=1.O.C(O)(C(F)(F)F)=O>O1CCCC1.CO.[C].[Pd]>[NH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])[CH2:14][CH2:13]1
Reactant: COC(=O)c1cccc(N2CCC(NC(=O)OCc3ccccc3)CC2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COC(=O)c1cccc(N2CCC(N)CC2)c1
Reaction time: 3 h

Procedure:
10% palladium-carbon (wet, 200 mg) was added to a mixed solution of methyl 3-(4-benzyloxycarbonylaminopiperidin-1-yl)benzoate obtained in Example (192c) (120 mg, 0.345 mmol) in tetrahydrofuran/methanol=1/1 (10 mL), and the mixture was catalytically hydrogenated at room temperature for three hours. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to obtain methyl 3-(4-aminopiperidin-1-yl)benzoate as a colorless oily substance. The resulting amine was dissolved in a mixed solution of N,N-dimethylacetamide/dichloromethane=1/1 (8 mL). 4-Chloro-5-ethyl-1H-imidazole-2-carboxylic acid (described in Example 1d, 190 mg, 1.1 mmol), 1-hydroxybenzotriazole (220 mg, 1.63 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (312 mg, 1.63 mmol) and triethylamine (227 μL, 1.63 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with brine, and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=1/1) to obtain 88 mg of the title compound as a colorless solid (41%).
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[O:13]1[CH2:17][CH2:16][NH:15][C:14]1=[O:18].C(=O)([O-])[O-].[K+].[K+].CNCCNC>[Cu]I.O.C1(C)C=CC=CC=1>[O:18]=[C:14]1[N:15]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:16][CH2:17][O:13]1
Reactant: O=C1NCCO1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(N2CCOC2=O)cc1

Procedure:
To a mixture of ethyl 4-iodobenzoate (1.5 mL), oxazolidin-2-one (940 mg), potassium carbonate (2.5 g) and copper (I) iodide (171 mg) were added toluene (9 mL) and N,N′-dimethylethylenediamine (195 μL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give the title compound (1.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[OH:11].Cl.CCCCCCC>C(O)C.[Fe]>[NH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[OH:11]
Reactant: O=[N+]([O-])c1cccc(Cl)c1O
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: CCCCCCC
Product: Nc1cccc(Cl)c1O
Temperature: 25 °C
Yield: 57.6 %

Procedure:
A solution of 2-chloro-6-nitrophenol (1.210 g, 6.972 mmol) in ethanol (50 mL) was treated with iron powder (1.947 g, 34.86 mmol) and concentrated HCl (3 mL). The yellow mixture was heated to reflux for 18 h and then cooled to room temperature. The reaction mixture was filtered through a pad of Celite, and the filtrate was neutralized with satd aq NaHCO3 solution. The resulting gray suspension was filtered through a pad of Celite, and the filtrate was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to give a black solid. Trituration with heptane afforded 2-amino-6-chlorophenol (0.577 g, 58%) as a dark brown solid. RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 100 Å, 5 μm, 250×4.6 mm column) tr=7.30 min., 91%; m/z 143 (MH+).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[CH:15]=2)[CH:10]=[N:9][CH:8]=1)(=O)=O.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[CH:15]=3)[CH:10]=[N:9][CH:8]=2)=[CH:31][CH:30]=1
Reactant: C[Si](C)(C)CCOC(=O)c1ccc2cncc(OS(=O)(=O)C(F)(F)F)c2c1
Reactant: OB(O)c1ccc(Cl)cc1
Product: C[Si](C)(C)CCOC(=O)c1ccc2cncc(-c3ccc(Cl)cc3)c2c1
Yield: 71.5 %

Procedure:
From 2-(trimethylsilyl)ethyl 4-{[(trifluoromethyl)sulfonyl]oxy}isoquinoline-6-carboxylate (6.00 g, 14.2 mmol) and 4-chlorophenylboronic acid (3.30 g, 30.0 mmol), 2-(trimethylsilyl)ethyl 4-(4-chlorophenyl)isoquinoline-6-carboxylate (3.90 g, yield 71%) was obtained by the same method as in Example 8 (8a). Further, using this compound (3.90 g, 9.9 mmol), the desired title compound (1.96 g, yield 70%) was obtained by the same method as in Example 4 (4b).