Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([N:9]([CH2:16][CH2:17][O:18][CH3:19])[CH2:10][CH2:11][C:12]([NH:14][CH3:15])=[O:13])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.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]>[Cl:8][C:5]1[N:4]=[C:3]2[C:2]([N:14]([CH3:15])[C:12](=[O:13])[CH2:11][CH2:10][N:9]2[CH2:16][CH2:17][O:18][CH3:19])=[CH:7][N:6]=1
Reactant: CNC(=O)CCN(CCOC)c1nc(Cl)ncc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COCCN1CCC(=O)N(C)c2cnc(Cl)nc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 18.2 %

Procedure:
3-[(5-bromo-2-chloro-pyrimidin-4-yl)-(2-methoxyethyl)amino]-N-methyl-propanamide (Intermediate 110; 1.12 g, 3.185 mmol) was suspended in dioxane (70 mL), Caesium Carbonate (2.08 g, 6.37 mmol) added and the mixture bubbled with nitrogen for 10 minutes. Tris(dibenzylideneacetone)dipalladium(0) (175 mg, 0.151 mmol) and XANTPHOS (166 mg, 0.287 mmol) were added and the mixture heated to 100° C. for 20 hrs. A further 0.06 equivalent of Tris(dibenzylideneacetone)dipalladium(0) and 0.09 equivalent of XANTPHOS were added and heating continued for a further 2 hrs. The reaction mixture was cooled to room temperature filtered and the filter cake washed with DCM. The filtrate was evaporated and dissolved in DCM and purified on silica eluting with a gradient of 40-55% Ethyl Acetate/iso-hexane then 55% Ethyl Acetate/iso-hexane and finally 70% Ethyl Acetate/iso-hexane. Fractions containing product were combined and evaporated to a yellow solid. Which was purified by base modified reverse phase HPLC to yield the title compound as a white solid (157 mg, 18%)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([F:25])[C:14]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]=[CH2:23])=[CH:18][C:17]=2[F:24])=[CH:13][C:8]2=[N:9][CH2:10][N:11]([CH3:12])[C:7]2=[CH:6]1)=[O:4]>O1CCCC1.[Pd]>[CH3:1][O:2][C:3]([C:5]1([F:25])[C:14]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][C:17]=2[F:24])=[CH:13][C:8]2=[N:9][CH2:10][N:11]([CH3:12])[C:7]2=[CH:6]1)=[O:4]
Reactant: C=Cc1ccc(NC2=CC3=NCN(C)C3=CC2(F)C(=O)OC)c(F)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCc1ccc(NC2=CC3=NCN(C)C3=CC2(F)C(=O)OC)c(F)c1

Procedure:
5-Fluoro-6-(2-fluoro-4-vinyl-phenylamino)-3-methyl-3H-benzoimidazole-5-carboxylic acid methyl ester (1.5 g, 4.35 mmol) was combined with 10% palladium/carbon (0.4 g) in tetrahydrofuran (50 mL). The resultant solution was hydrogenated at 4295 psi for 56 min. The reaction mixture was filtered and concentrated in vacuo to afford 0.91 g. Recrystallization from dichlormethane-hexane afforded pure 6-(4-Ethyl-2-fluoro-phenylamino)-5-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid methyl ester, m.p. 238° C.; 1H NMR (400 MHz, CD3OD) δ 8.28 (s, 1 H), 8.24 (br s, 1 H), 8.10 (s, 1 H), 6.93 (dd, J=12.4, 1.5 Hz, 1 H), 6.80 (brd, J=8.3 Hz, 1 H), 6.61 (td, J=8.6,5.4 Hx, 1 H), 3.94 (s,3 H), 3.92 (s, 3 H), 2.55 (q, J=5.6 Hz, 2 H), 1.20 (t, J=5.6 Hz, 3 H). Anal. Calcd/Found for C18H15F2N3O2: C, 62.60/62.11; H, 4.96/4.80; N, 12.15, 11.80.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)=[NH:4].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:21]=[C:20]([C:28](O)=O)[N:19]=2)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[C:22]([C:24]([F:26])([F:25])[F:27])[N:21]=[C:20]([C:28]3[O:1][N:2]=[C:3]([C:5]4[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=4)[N:4]=3)[N:19]=2)=[CH:16][CH:17]=1
Reactant: O=C(O)c1nc(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1
Reactant: N=C(NO)c1cccnc1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-c2nc(-c3cccnc3)no2)n1

Procedure:
The title compound was prepared from available N-hydroxy-3-pyridinecarboxamidine [CAS-No. 1594-58-7] (0.103 g, 0.75 mmol) and 4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.1) (0.15 g, 0.5 mmol) according to the general procedure V. Obtained as a yellow solid (0.092 g, 46%). MS (ISP) 404.4 [(M+H)+]; mp 168.5° C.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@@H:25]1[CH2:29]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C>[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@@H:25]1[CH2:29][S:14][C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: Sc1ccc(Oc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CSc1ccc(Oc2ccccc2)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 71.4 %

Procedure:
To a solution of 4-phenoxy benzenethiol (200 mg, 0.988 mmol) in DMF (3 mL) at 0-5° C. was added 60% NaH (73 mg, 1.83 mmol) at 0-5° C. The reaction mixture was stirred at rt for 15 min at 0-5° C. A solution of (R)-2-(Toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (357 mg, 1 mmol) in DMF (2 mL) was added to the above mixture at 0-5° C. The reaction mixture was warmed to it and then heated at 90° C. for 15 h. The mixture was concentrated, diluted with saturated aq NaHCO3 and extracted with ethyl acetate. The aqueous layer was re-extracted with ethylacetate. The combined organic layers were dried over anhy. MgSO4 and the solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography to obtain the title product (272 mg, 71%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:4]=2[N:5]=[C:6]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[N:7]=1.[CH:27]1([NH:30][C:31](=[O:49])[C:32]2[CH:37]=[C:36](B3OC(C)(C)C(C)(C)O3)[C:35]([CH3:47])=[C:34]([F:48])[CH:33]=2)[CH2:29][CH2:28]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[CH:27]1([NH:30][C:31](=[O:49])[C:32]2[CH:33]=[C:34]([F:48])[C:35]([CH3:47])=[C:36]([C:2]3[C:3]4[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]5[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=5[F:26])[C:4]=4[N:5]=[C:6]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[N:7]=3)[CH:37]=2)[CH2:28][CH2:29]1
Reactant: O=c1ccc2c(Cl)nc(NC(CO)CO)nc2n1-c1c(F)cccc1F
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1nc(NC(CO)CO)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 100 °C
Yield: 9.8 %

Procedure:
4-Chloro-8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]-amino}pyrido[2,3-d]pyrimidin-7(8H)-one (0.056 g, 0.17 mmol), N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.065 g, 0.17 mmol), K2CO3 (0.07 g, 0.51 mmol) and tetrakis triphenyl phosphine palladium (10 mg, 0.05 eq) are dissolved in dioxane/water (3:1, 10 mL) and heated to about 100° C. for about 3 h. The mixture is concentrated and purified via reverse phase HPLC to afford the title compound (9 mg, yellow powder, mp 214.2-217.5): LC-MS m/z 540 (M+H)+, 1.69 min (ret time). HPLC indicates 96% pure.
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[CH:5][S:4][C:3]=1[N+:8]([O-:10])=[O:9].C([Sn](CCCC)(CCCC)[C:16]1[O:17][CH:18]=[CH:19][N:20]=1)CCC>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:7][C:6]1[C:2]([C:16]2[O:17][CH:18]=[CH:19][N:20]=2)=[C:3]([N+:8]([O-:10])=[O:9])[S:4][CH:5]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Reactant: O=[N+]([O-])c1scc(Br)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1scc(Br)c1-c1ncco1
Temperature: 90 °C
Yield: 66.9 %

Procedure:
A mixture of 3,4-dibromo-2-nitrothiophene (0.166 mg, 0.581 mmol), Pd(PPh3)4 (67 mg, 0.0581 mmol) and 2-(tributylstannyl)oxazole (250 mg, 0.698 mmol) in DMF (1.1 mL) was evacuated and purged with nitrogen three times. The reaction mixture was heated to 90° C. for 18 h and the resulting solution was cooled to room temperature and diluted with Et2O. The solution was washed with brine and the organic phase was separated, dried (Na2SO4), filtered, concentrated under vacuum and purified on a silica gel column (eluant hexane/ethyl acetate, 20/1 to 1/1, v/v) to give 2-(4-bromo-2-nitrothiophen-3-yl)oxazole (107 mg, 67%). Retention time (min)=1.948, method [1], MS (ESI) 274.9 (M+H).
Reaction SMILES: [OH-].[Na+].C(O)C.[S:6]1[CH:10]=[CH:9][C:8]2[C:11]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][O:24][C:25]4[N:29]([CH3:30])[N:28]=[C:27]([C:31]([O:33]C)=[O:32])[CH:26]=4)[CH2:17][CH2:16]3)=[CH:12][CH:13]=[CH:14][C:7]1=2.Cl>ClCCl>[S:6]1[CH:10]=[CH:9][C:8]2[C:11]([N:15]3[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][CH2:23][O:24][C:25]4[N:29]([CH3:30])[N:28]=[C:27]([C:31]([OH:33])=[O:32])[CH:26]=4)[CH2:19][CH2:20]3)=[CH:12][CH:13]=[CH:14][C:7]1=2
Reactant: COC(=O)c1cc(OCCCN2CCN(c3cccc4sccc34)CC2)n(C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: Cn1nc(C(=O)O)cc1OCCCN1CCN(c2cccc3sccc23)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 98 %

Procedure:
A 6N aqueous sodium hydroxide solution (2 ml) was added to an ethanol solution (10 ml) of methyl 5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1-methyl-1H-pyrazole-3-carboxylate (1.62 g, 3.9 mmol) and the mixture was stirred at room temperature for 4 days. Then, 6N hydrochloric acid (2 ml) was added to the reaction solution under ice cooling and the solution mixture was stirred. Dichloromethane was added to the reaction solution and the precipitate was obtained by filtration. The filtrate was separated and the organic phase was concentrated under reduced pressure. The filter cake and the residue were combined, washed with water and dried to obtain 5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1-methyl-1H-pyrazole-3-carboxylic acid (1.53 g) as white powder.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[S:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.[Br:10][C:11]1[CH:12]=[CH:13][C:14]([F:19])=[C:15]([CH:18]=1)[CH:16]=O>>[S:9]1[C:8]([CH2:16][C:15]2[CH:18]=[C:11]([Br:10])[CH:12]=[CH:13][C:14]=2[F:19])=[CH:7][C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]1=2
Reactant: c1ccc2sccc2c1
Reactant: O=Cc1cc(Br)ccc1F
Product: Fc1ccc(Br)cc1Cc1cc2ccccc2s1

Procedure:
Thianaphthene and 5-bromo-2-fluorobenzaldehyde were treated in a manner similar to Reference Example 7 to give the target compound.
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)(=O)[C:2]([CH3:5])([CH3:4])C.C([Li])(CC)C.C1CCCCC1.CN(C)C=O.C(=O)CC.C[Si](C)(C)[N-][Si](C)(C)C.[K+].C1(C)C=CC=CC=1>O1CCCC1>[CH3:15][O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]2[C:9]=1[CH:5]=[C:2]([CH3:4])[CH:1]=[N:7]2
Reactant: COc1cccc(NC(=O)C(C)(C)C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Agent: [Li]C(C)CC
Solvent: Cc1ccccc1
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: COc1cccc2ncc(C)cc12
Temperature: 2.5 °C
Reaction time: 0.2 h
Yield: 4.6 %

Procedure:
To a stirred solution of N-pivaloyl-3-methoxyaniline (4.14 g, 20 mmol) in dry tetrahydrofuran (80 mL) at 0° C. under argon was added a solution of sec-butyllithium in cyclohexane (1.4 M, 35.7 mL, 50 mmol), dropwise over 0.2 h (T≦0° C.) and the resulting mixture was stirred at 0-5° C. for 2 h. The mixture was cooled to −5° C. then dry N,N-dimethylformamide (2.3 mL, 30 mmol) was added dropwise, and the resulting solution stirred at 0° C. for 1 h then at 20° C. for 20 h. The mixture was cooled to 0° C. and propionaldehyde (1.17 g, 20.2 mmol) was added dropwise followed by a solution of potassium hexamethyldisilazide in toluene (0.5 M, 80 mL, 40 mmol) dropwise over 0.2 h. The mixture was stirred at 0° C. for 0.25 h, then at 20° C. for 2 h and at 30° C. for 1 h. The resulting mixture was partitioned between saturated aqueous NH4Cl (200 mL) and ether (3×50 mL), and the combined organic extracts dried (Na2SO4) and evaporated in vacuo. Chromatography of the residue on silica with 20-100% ether in hexane gradient elution gave 5-methoxy-3-methylquinoline (0.16 g, 5%) as an oil. A mixture of 5-methoxy-3-methylquinoline (0.16 g, 0.92 mmol) and pyridine hydrochloride (0.064 g, 5.5 mmol) was heated under argon at 200° C. with stirring for 2.5 h, then cooled and partitioned between saturated aqueous NaHCO3 (30 mL) and dichloromethane (5×30 mL). Combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give a solid which was purified by chromatography on silica eluting with ethyl acetate to give the title compound (0.089 g, 60%) as a solid.
Reaction SMILES: [CH3:1][C:2]([CH:4]=[CH2:5])=[O:3].C([O-])(=O)C.[Na+].C(O)(=O)C.O.[C:16]1([CH3:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OCC)(=O)C>[CH:5]1[C:16]2([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:22][CH2:1][C:2](=[O:3])[CH:4]=1
Reactant: C=CC(C)=O
Reactant: Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1C=CC2(CCCCC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the above product (1) (22.6 g) in toluene (100 ml) was added methylvinyl ketone (9.6 g), and the mixture was stirred at room temperature. After 3 hours, to the reaction mixture were added sodium acetate (10 g), acetic acid (40 ml) and water (40 ml), and the mixture was heated under reflux. After 4 hours, the reaction mixture was cooled to room temperature and then ethyl acetate (100 ml) was added thereto. The mixture was washed with water (100 ml), 2 mol/l hydrochloric acid (50 ml) and then brine (100 ml), and the organic layer was dried over sodium sulfate, and the solvent was removed in vacuo. The residue was distilled under reduced pressure (95° C., 1 mmHg) to give 4.3 g of spiro[5.5]undecen-3-one.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([NH:20][S:21]([C:24]1[CH:33]=[C:32]([NH:34][NH2:35])[CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27])(=[O:23])=[O:22])([CH3:19])([CH3:18])[CH3:17].[C:36]1([CH2:42][C:43](O)=[O:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:16]([NH:20][S:21]([C:24]1[CH:33]=[C:32]([NH:34][NH:35][C:43](=[O:44])[CH2:42][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27])(=[O:23])=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)c1ccc(NN)cc1S(=O)(=O)NC(C)(C)C
Reactant: O=C(O)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(NNC(=O)Cc2ccccc2)cc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1.5 g (7.3 mmol) of dicyclohexylcarbodiimide (DCC) are added to a solution of 2.0 g (6.6 mmol) of methyl 2-(N-tert-butylsulfamoyl)-4-hydrazinobenzoate, 0.9 g (6.6 mmol) of phenylacetic acid and 0.03 g of 4-dimethylaminopyridine (DMAP) in 20 ml of CH2Cl2 at 0° C. The mixture is stirred at 25° C. for 15 hours, the solid is filtered off with suction and the organic phase is washed successively with water, 1N HCl and NaHCO3 solution, dried and evaporated. This gives 1.6 g (58% of theory) of methyl 2-(N-tert-butylsulfamoyl)-4-(2-phenylacetyl-hydrazino)benzoate with the following nuclear magnetic resonance data:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:51]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.[C:52](Cl)(=[O:54])[CH3:53]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[C:52]([N:48]1[CH2:47][CH2:46][CH:45]([NH:44][C:36]2[CH:37]=[CH:38][C:39]3[NH:40][C:41]4[N:42]=[C:26]([NH:27][C:28]5[CH:29]=[N:30][CH:31]=[C:32]([CH:51]=5)[CH2:33][CH2:34][C:35]=2[CH:43]=3)[N:25]=[CH:24][C:23]=4[Cl:22])[CH2:50][CH2:49]1)(=[O:54])[CH3:53]
Reactant: Clc1cnc2nc1Nc1ccc(NC3CCNCC3)c(c1)CCc1cncc(c1)N2
Reactant: CC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCC(Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 57 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 6-chloro-N-piperidin-4-yl-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tris(trifluoroacetate) and acetyl chloride as the starting materials in 57% yield. LCMS for C24H27ClN7O (M+H)+: m/z=464.2.
Reaction SMILES: [O:1]=[C:2]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)[CH:3]([C:9]1[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=1)C(OCC)=O.Cl>O>[C:11]1([CH3:15])[CH:12]=[CH:13][CH:14]=[C:9]([CH2:3][C:2]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)=[O:1])[CH:10]=1
Reactant: CCOC(=O)C(C(=O)c1ccc(C)cc1)c1cccc(C)c1
Agent: Cl
Solvent: O
Product: Cc1ccc(C(=O)Cc2cccc(C)c2)cc1
Temperature: 25 °C
Yield: 70.1 %

Procedure:
To ethyl 3-oxo-2-m-tolyl-3-p-tolylpropanoate (2.213 g, 7.47 mmol) was added aqueous HCl solution (8.96 mL, 112 mmol). The reaction was heated to reflux overnight. The reaction was cooled to room temperature, the mixture was diluted with water and extracted with EtOAc three times. The combined extracts were washed with brine, dried (MgSO4) and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a white solid (1.174 g). 1H NMR (400 M Hz, CDCl3) δ ppm 2.31-2.32 (m, 3H), 2.40 (s, 3H), 4.21 (s, 2H), 7.00-7.09 (m, 3H), 7.20 (t, J=7.45 Hz, 1H), 7.22-7.27 (m, 2H), 7.91 (d, J=8.34 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:16]2[C:20](=[O:21])[C:19]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]3[C:17]2=[O:26])[CH2:13][CH2:14][OH:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[H-].[Na+].Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.[NH4+].[Cl-]>[CH2:27]([O:15][CH2:14][CH2:13][CH:12]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: CCOc1cc(C(CCO)N2C(=O)c3ccccc3C2=O)ccc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOc1cc(C(CCOCc2ccccc2)N2C(=O)c3ccccc3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 60 %

Procedure:
To a stirred solution of 3-(3'-ethoxy-4'-methoxyphenyl)-3-phthalimido-1-propanol (680 mg, 1.92 mmol), benzyl bromide (0.46 mL, 3.86 mmol), and tetrabutyl ammonium iodide (80 mg, 0.21 mmol) in THF (20 mL) at room temperature, was added NaH (240 mg, 60%, 6.0 mmol). The mixture was stirred at room temperature for 15 h. To the mixture was added a few drops of NH4Cl, then HCl (1N, 25 mL). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine (25 mL), and dried over magnesium sulfate. Removal of solvent and chromatography (silica gel 100 grams, 1:5 EtOAc:hexane) gave 1-benzyloxy-3-(3'-ethoxy-4'-methoxyphenyl)-3-phthalimidopropane as an oil, (510 mg, 60% yield): 1H NMR (CDCl3)δ1.46 (t, J=6.9 Hz, 3H, CH3), 2.51-2.59 (m, 1H, CHH), 2.86-2.96 (m, 1H, CHH), 3.51 (t, J=5.5 Hz, CH2), 3.85 (s, 3H, CH3), 4.10 (q, J=7 Hz, CH2), 4.43 (s, 2H, PhCH2), 5.54 (dd, J=6.5, 9.5 Hz, 1H, NCH), 6.80 (d, J=8 Hz, 1H, Ar), 7.09-7.27 (m, 7H, Ar), 7.65-7.79 (m, 4H, Ar); 13C NMR (CDCl3)δ14.73, 31.37, 52.12, 55.88, 64.29, 67.31, 73.10, 111.11, 112.95, 120.59, 123.09, 127.42, 127.62, 128.22, 131.92, 132.09, 133.77, 138.09, 148.12, 148.84, 168.42; Anal Calcd for C27H27 NO5 : C, 72.79; H, 6.11; N, 3.14. Found: C, 72.66; H, 6.32; N, 3.16.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13](Cl)(=[O:15])=[O:14].[NH2:18][C@H:19]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=2)[CH2:24][CH2:23]1>>[CH3:1][N:2]([CH3:17])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13]([NH:18][C@H:19]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=2)[CH2:24][CH2:23]1)(=[O:15])=[O:14]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NS(=O)(=O)c3cccc4c(N(C)C)cccc34)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using 5-(dimethylamino)-1-naphthalenesulfonyl chloride and N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 613.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9](COCC[Si](C)(C)C)[CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[C:7]=2[C:6]([C:27]#[N:28])=[CH:5][N:4]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[C:8]2[NH:9][CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[C:7]=2[C:6]([C:27]#[N:28])=[CH:5][N:4]=1
Reactant: COc1ncc(C#N)c2c(-c3ccccc3C)cn(COCC[Si](C)(C)C)c12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(C#N)c2c(-c3ccccc3C)c[nH]c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 149.5 %

Procedure:
To a solution of 7-methoxy-3-(2-methylphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-c]pyridine-4-carbonitrile (1.20 g) in trifluoroacetic acid (15.25 mL) was added triethylsilane (1.46 mL) at room temperature, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate/hexane), and crystallized from ethyl acetate and hexane to give the title compound (1.20 g).
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([C:19](O)=[O:20])[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][N:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH2:24]>>[CH:1]1([C:7]2[CH:8]=[C:9]([C:19]([NH:24][N:23]([CH3:22])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:20])[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:17])([F:16])[F:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(N)c1ccccc1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Product: CN(NC(=O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1)c1ccccc1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-3-pyridinecarboxylic acid (example 12c) and 1-methyl-1-phenyl-hydrazine (CAN 618-40-6) as starting materials; MS (EI) 408.4 (M+H)+.