Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:10]1[C:11]([Cl:17])=[N:12][C:13]([Cl:16])=[CH:14][CH:15]=1)[OH:9]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[C:11]([Cl:17])=[N:12][C:13]([Cl:16])=[CH:14][CH:15]=1)=[O:9]
Reactant: OC(c1ccccc1Cl)c1ccc(Cl)nc1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1Cl)c1ccc(Cl)nc1Cl
Yield: 115.9 %

Procedure:
(2-Chloro-phenyl)-(2,6-dichloro-pyridin-3-yl)-methanol (12.2 g, 42.3 mmol) was dissolved in 200 mL of dry toluene, and 87 g of manganese dioxide was added. The reaction mixture was refluxed for 2.5 hours, and was then hot filtered through Celite. The Celite plug was washed with 80 mL of hot EtOAc (in several portions), and the organic solvents were combined. Removal of solvent under reduced pressure yielded 14.05 g of (2-chloro-phenyl)-(2,6-dichloro-pyridin-3-yl)-methanone as a viscous yellow oil. Mass Spec. M+H=288.
Reaction SMILES: [O:1]=[C:2]1[C:11]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]([O:20][CH3:21])=[O:19])[CH:8]=2)[NH:3]1.N1C=CC=CC=1.[O:28](S(C(F)(F)F)(=O)=O)[S:29]([C:32]([F:35])([F:34])[F:33])(=O)=[O:30]>ClCCl>[N:12]1([C:11]2[C:2]([O:1][S:29]([C:32]([F:35])([F:34])[F:33])(=[O:30])=[O:28])=[N:3][C:4]3[C:9]([N:10]=2)=[CH:8][C:7]([C:18]([O:20][CH3:21])=[O:19])=[CH:6][CH:5]=3)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCCCC3)nc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCCC3)nc2c1
Temperature: 0 °C

Procedure:
To a solution of methyl 2-oxo-3-(piperidin-1-yl)-1,2-dihydroquinoxaline-6-carboxylate (200 mg, 0.70 mmol) in dichloromethane (30 mL) was added pyridine (220 mg, 2.8 mmol) and then Tf2O (393 mg, 1.4 mmol) was added dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature and then quenched by the addition of water (50 mL), extracted with dichloromethane (3×10 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford methyl 3-(piperidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red solid (280 mg, crude).
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:13])=[CH:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=O)=[O:2].Cl.[NH:15]1[CH2:18][CH:17]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[CH2:16]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CCOC(C)=O>[CH:1]([C:3]1[C:4]([CH3:13])=[CH:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8]([N:15]1[CH2:18][CH:17]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[CH2:16]1)=[O:10])=[O:2]
Reactant: Cc1cc(C)c(C(=O)O)cc1C=O
Reactant: N#Cc1ccc(C2CNC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.8 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 5-formyl-2,4-dimethylbenzoic acid (compound 151.3, 500 mg, 2.81 mmol) in DCM (10 mL) 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2, 545 mg, 2.80 mmol), DIEA (1.4 mL, 8.41 mmol) and HBTU (1.60 g, 4.22 mmol) were added. The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was diluted with 150 mL of EtOAc, then washed with 2×50 mL of NH4Cl (sat.) and 1×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1/1) as eluent to furnish 480 mg (54%) of the title compound as a white solid.
Reaction SMILES: [H-].[Na+].CCOP(OCC)([CH2:8][C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])=O.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[C:26]=2[CH:37]=O)=[CH:21][CH:20]=1.O>C1COCC1>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:35])[CH3:36])[C:26]=2/[CH:37]=[CH:8]/[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])=[CH:21][CH:20]=1
Reactant: CCOP(=O)(CC(=O)N(C)OC)OCC
Reactant: CC(C)n1c(C=O)c(-c2ccc(F)cc2)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CON(C)C(=O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Reaction time: 8 h

Procedure:
0.465 g (10.65 mmol) of sodium hydride (55%) are introduced into a 100 ml three-necked, round-bottomed flask, equipped with a magnetic stirrer, thermometer, dropping funnel and nitrogen delivery line, and washed twice with 5 ml of pentane. The pentane is removed using a pipette and the sodium hydride is blown dry with nitrogen. 10 ml of THF, rendered absolute using sodium, are added, and 1.84 g (7.46 mmol) of diethyl (N-methoxy-N-methylcarbamoyl-methyl)phosphonate dissolved in 5 ml of THF are slowly added dropwise so that the temperature does not exceed 30° C. 1 g (3.55 mmol) of 3-(4-fluorophenyl)-1-isopropyl-1H-indole-2-carbaldehyde dissolved in 10 ml of THF is then added dropwise and the clear, slightly yellow solution is stirred overnight. The reaction mixture is poured into 100 ml of water and extracted 3 times with 50 ml of ethyl acetate. The combined organic phases are washed twice with 50 ml of saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated by evaporation. Flash chromatography (hexane/ethyl acetate=2:1) and crystallisation from 94% ethanol yields slightly yellow crystals having a melting point of from 123 to 124° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[NH:30]([CH2:34][CH2:35][OH:36])[CH2:31][CH2:32][OH:33]>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:30]([CH2:34][CH2:35][OH:36])[CH2:31][CH2:32][OH:33])[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: OCCNCCO
Reactant: ClCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: OCCN(CCO)CCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 18 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and diethanolamine to give the title compound in 18% yield; NMR Spectrum: 2.66 (t, 4H), 2.98 (t, 2H), 3.44-3.48 (m, 4H), 4.35 (t, 2H), 4.43 (t, 2H), 5.28 (s, 2H), 7.23 (d, 1H), 7.37 (t, 1H), 7.57-7.60 (m, 2H), 7.87 (t, 1H), 7.94 (d, 1H), 8.29 (s, 1H), 8.44 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 500 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:10][C:11]1[CH:24]=[CH:23][C:14]([O:15][CH:16]([C:20](=O)[CH3:21])[C:17](=O)[CH3:18])=[CH:13][CH:12]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:8][C:7]1[C:2]2[N:1]=[C:20]([CH3:21])[C:16]([O:15][C:14]3[CH:13]=[CH:12][C:11]([Cl:10])=[CH:24][CH:23]=3)=[C:17]([CH3:18])[C:3]=2[C:4]([OH:9])=[CH:5][CH:6]=1
Reactant: Nc1cc(O)ccc1Cl
Reactant: CC(=O)C(Oc1ccc(Cl)cc1)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Cc1nc2c(Cl)ccc(O)c2c(C)c1Oc1ccc(Cl)cc1
Temperature: 125 °C

Procedure:
A mixture of 3-amino-4-chlorophenol (0.36 g), 3-(4-chlorophenoxy)pentane-2,4-dione (0.57 g) and p-toluenesulfonic acid monohydrate (0.020 g) was heated at 125° C. for 3 hours. The mixture was cooled to room temperature and purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1:0 to 0:1 by volume) to afford title compound as a brown oil, 0.16 g.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Cl[C:11]1[CH:12]=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[C:15]([CH:17]=1)[NH2:16]>>[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([C:11]2[CH:12]=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[C:15]([CH:17]=2)[NH2:16])[CH2:6][CH2:5]1
Reactant: CN1CCNCC1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Yield: 99 %

Procedure:
The mother liquor of the reaction was recycled by the addition of NaOH pellets (34.9 g, 869 mmol, 1 equiv) to the mother liquor, followed by stirring until the NaOH was dissolved. 1-Methylpiperazine (96.5 mL, 869 mmol, 1 equiv) and 5-chloro-2-nitroaniline (150 g, 869 mmol) were charged to the vessel. Purging, followed by heating to completion, cooling, filtration, and washing with heptane was repeated as above to yield 5-(4-methyl-piperazin-1-yl)-2-nitroaniline (203.2 g, 98.9% yield). Residual N-methylpiperazine was not detected by 1H NMR.
Reaction SMILES: C1(CO[NH:9][C:10]2([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:19][CH2:18][CH2:17][C:16]3[N:15]=[C:14]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:13]=[CH:12][C:11]2=3)C=CC=CC=1.B.O1CCCC1.O>O1CCCC1>[C:22]1([CH2:21][O:20][C:14]2[CH:13]=[CH:12][C:11]3[C:10]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([NH2:9])[CH2:19][CH2:18][CH2:17][C:16]=3[N:15]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(CONC2(Cc3ccccc3)CCCc3nc(OCc4ccccc4)ccc32)cc1
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: NC1(Cc2ccccc2)CCCc2nc(OCc3ccccc3)ccc21
Temperature: 0 °C
Yield: 62.5 %

Procedure:
5,6,7,8-Tetrahydro-N,2-bis(phenylmethoxy)-5-(phenylmethyl)-5-quinolinamine (40.0 g) in tetrahydrofuran (90 ml) was treated dropwise with borane-tetrahydrofuran complex (1M in tetrahydrofuran, 267 ml) at 0° C. The solution was heated under reflux for 3 hrs, cooled to 0° C. and water (30 ml) was added. The reaction mixture was concentrated in vacuo, 20% potassium hydroxide solution (60 ml) was added, and the mixture was heated under reflux for 8 hrs. The mixture was cooled, acidified with conc hydrochloric acid, and washed with diethyl ether. The aqueous phase was basified with 20% potassium hydroxide solution and extracted with dichloromethane. The combined organic layers were washed with brine, dried over potassium carbonate, filtered, and the filtrate was concentrated to afford 19.1 g (37.0%) of product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:23])=[C:20]([CH:22]=2)[NH2:21])[CH:5]=[CH:4][N:3]=1.[F:24][C:25]1[CH:26]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:23])=[C:20]([NH:21][S:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([F:24])[CH:26]=3)(=[O:33])=[O:32])[CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)c1nc(-c2ccc(F)c(N)c2)c(-c2ccnc(Cl)n2)s1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Product: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3cccc(F)c3)c2)c(-c2ccnc(Cl)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluoroaniline (12 g, 34.5 mmol) and 3-fluorobenzenesulfonyl chloride (8.72 g, 44.8 mmol) the title compound of Step A was obtained (9.3 g, 53.4%). 1H NMR (400 MHz, CDCl3) δ ppm 8.35 (d, J=5.3 Hz, 1H), 7.65-7.73 (m, 1H), 7.52-7.60 (m, 1H), 7.41-7.50 (m, 2H), 7.20-7.37 (m, 1H), 7.04-7.12 (m, 1H), 6.83-7.00 (m, 2H), 3.30-3.40 (m, 1H), 1.46 (d, J=6.8 Hz, 6H). MS (ES+): 507 [M+H]+.
Reaction SMILES: [CH3:1]I.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12](=[S:20])[O:13][C:14]=2[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:6][CH:5]=1.[OH-].[Na+].Cl>O.CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([S:20][CH3:1])[O:13][C:14]=2[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:6][CH:5]=1
Reactant: CI
Reactant: O=C(O)CCc1oc(=S)[nH]c1-c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc(-c2ccc(Cl)cc2)c(CCC(=O)O)o1
Reaction time: 0.5 h
Yield: 97 %

Procedure:
Methyl iodide (0.34 ml) was dropwise added to a mixture of 3-[4-(4-chlorophenyl)-2-thioxo-4-oxazolin-5-yl]propionic acid (1.42 g), an aqueous solution of 2N sodium hydroxide (5.5 ml) and N,N-dimethylformamide (15 ml), with cooling with ice. After the reaction mixture was stirred for 30 minutes, water was added to the resulting reaction mixture, which was then acidified with 2 N hydrochloric acid. The crystals thus precipitated were collected by filtration to obtain 4-(4-chlorophenyl)-2-methylthio-5-oxazolepropionic acid (1.45 g, 97%). This was recrystallized from ethanol to give colorless needles. mp 183-184° C.
Reaction SMILES: [CH:1]1([N:7]([C@H:18]2[CH2:23][CH2:22][C@H:21]([CH3:24])[CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=[O:17])=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].O>CO>[CH:1]1([N:7]([C@H:18]2[CH2:19][CH2:20][C@H:21]([CH3:24])[CH2:22][CH2:23]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH2:16][OH:17])=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(C=O)s2)C2CCCCC2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(CO)s2)C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-cyclohexyl-3-(5-formyl-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-urea (175 mg, 0.5 mmol) in MeOH (5 mL) was added sodium borohydride (38 mg, 1 mmol). The mixture was stirred at rt for 10 min and the solution was poured into water (25 mL). The aqueous layer was extracted with ethyl acetate (2×20 mL). The organic layer was washed with water (2×20 mL), brine (1×20 mL), dried (anhydrous Na2SO4) and concentrated to get trans-1-cyclohexyl-3-(5-hydroxymethyl-thiazol-2-yl)-1-(4-methyl-cyclohexyl)-urea in (90%, 158 mg) yield.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([CH2:19]O)[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:45]I>C(Cl)Cl>[CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([CH2:19][I:45])[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC[C@H](CO)NC(=O)OC(C)(C)C
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC[C@H](CI)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a solution of crude 1,1-dimethylethyl (4R)-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-hydroxypentanoate (23.8 g, 82.4 mmol), triphenylphosphine (32.42 g, 123.6 mmol) and imidazole (8.41 g, 123.6 mmol) in 515 mL anhydrous CH2Cl2 under N2 at 0° C. was added iodine over 15 min portionwise. The ice bath was removed and the reaction was allowed to warm to room temperature and stirred over 30 minutes. The reaction was quenched with 200 mL H2O. The aqueous layer was extracted with diethyl ether (2×150 mL). The combined organic layers were washed with sat. aq. Na2SO3 solution (2×25 mL) and brine (25 mL), dried over MgSO4, and concentrated in vacuo. Purification of the residue by silica gel chromatography (Analogix IF280, 5%-50% EtOAc/Hex) afforded the title compound as a white solid (25.34 g, 77%). ESMS [M+H]+=400.4.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[C:35]([F:37])[CH:36]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:30][C:31]1[CH:32]=[C:33]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]4)=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:29])[CH2:3][CH2:4]2)=[O:9])[CH:34]=[C:35]([F:37])[CH:36]=1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cc(F)cc(F)c2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1, 100 mg, 1.0 eq.), anhydrous copper(II) acetate (90 mg, 2.0 eq.), 3,5-difluorophenylboronic acid (123 mg, 3 eq.) and pyridine (80 uL, 4 eq.) in dichloromethane (2.5 mL) was stirred at room temperature for 2 days, evaporated to dryness and purified on silica gel, eluting with a 98:2 to 95:5 gradient of dichloromethane/methanol, to yield 79 mg (61%) from the desired product as light yellow foam. MS (m/e): 518.4 (MH+, 100%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][C:7]#[N:8])=[O:4].C(N(CC)CC)C.[C:24](Cl)(=[O:29])[CH2:25][CH2:26][CH:27]=[CH2:28]>ClCCl>[I:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][C@H:2]([NH:1][C:24](=[O:29])[CH2:25][CH2:26][CH:27]=[CH2:28])[C:3]([O:5][CH2:6][C:7]#[N:8])=[O:4])=[CH:15][CH:14]=1
Reactant: N#CCOC(=O)[C@@H](N)Cc1ccc(I)cc1
Reactant: C=CCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCCC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 77.7 %

Procedure:
(S)-Cyanomethyl 2-amino-3-(4-iodophenyl)propanoate (0.65 g, 1.78 mmol) was dissolved in dichloromethane (25.0 ml) under a nitrogen atmosphere, and triethylamine (0.45 g, 4.45 mmol) was added dropwise under ice-cooling. A solution of pent-4-enoyl chloride (0.25 g, 2.14 mmol) in dichloromethane (25.0 ml) was then added dropwise under ice-cooling, and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (petroleum ether:ethyl acetate=50:50-33:67) to afford (S)-cyanomethyl 3-(4-iodophenyl)-2-(pent-4-enamido)propanoate (Compound 92) (0.57 g, 78%).
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].FC(F)(F)C(O)=O.[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:53]=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[O:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[C:54]1([N:60]=[C:61]=[O:62])[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>>[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].[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:53]=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[O:44][CH2:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:61]([NH:60][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[O:62])[CH2:51][CH2:52]1
Reactant: O=C=Nc1ccccc1
Reactant: Clc1cnc2nc1Nc1ccc(OCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccccc1)N1CCC(CCOc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 50 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-(2-piperidin-4-ylethoxy)-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-nonaene tris(trifluoroacetate) and phenyl isocyanate as the starting materials in 50% yield. LCMS for C31H33ClN7O2 (M+H)+: m/z=570.1.
Reaction SMILES: F[C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[C:24]1[NH:28][C:27]([CH3:29])=[N:26][CH:25]=1.CC1NC(C2C=C(C=CC=2F)C([N:42]2[CH2:47][CH2:46][CH:45](C3C=CC(C#N)=CC=3)CC2)=O)=C(C)N=1>>[N:42]1([C:2]2[CH:23]=[CH:22][C:5]([C:6]([N:8]3[CH2:13][CH2:12][CH:11]([C:14]4[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=4)[CH2:10][CH2:9]3)=[O:7])=[CH:4][C:3]=2[C:24]2[NH:28][C:27]([CH3:29])=[N:26][CH:25]=2)[CH2:45][CH2:46][CH2:47]1
Reactant: Cc1nc(C)c(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)ccc2F)[nH]1
Reactant: Cc1ncc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)ccc2F)[nH]1
Product: Cc1ncc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)ccc2N2CCC2)[nH]1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 25, except 4-(1-(4-fluoro-3-(2-methyl-1H-imidazol-5-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 132.3) was used in place of 4-(1-(3-(2,4-dimethyl-1H-imidazol-5-yl)-4-fluorobenzoyl)piperidin-4-yl)benzonitrile (compound 25.1). m/z (ES+) 426 (M+H)+.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)([CH3:20])[CH3:19])[CH3:16])=[CH:11][CH:10]=1>CC(C)=O>[CH3:16][C:15]([C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:1](=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5])=[CH:14][CH:13]=1)=[CH:17][C:18]([CH3:20])([CH3:19])[C:21]1[CH:22]=[CH:23][C:24]([NH:27][C:1](=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5])=[CH:25][CH:26]=1
Reactant: O=C1C=CC(=O)O1
Reactant: CC(=CC(C)(C)c1ccc(N)cc1)c1ccc(N)cc1
Solvent: CC(C)=O
Product: CC(=CC(C)(C)c1ccc(NC(=O)/C=C\C(=O)O)cc1)c1ccc(NC(=O)/C=C\C(=O)O)cc1

Procedure:
Maleic anhydride (43 g) was dissolved in 250 ml of acetone. While this solution was being kept at 18° C., 53 g of 2,4-di(p-amino-phenyl)-4-methyl-2-pentene was slowly added thereto with stirring. The resulting reaction mixture was stirred at 18° C. for 21/2 hours to form N,N'-(1-methyl-3,3-dimethyl-1-propenylenedi-p-phenylene)-bismaleamic acid having the formula ##STR20## At this time, the reaction mixture was a yellow slurry. Then, 0.5 g of cobalt acetate tetrahydrate, 10 g of triethylamine, and 50 g of acetic anhydride were added, with stirring, to the above slurry. After completion of the addition, the slurry was heated to 61° C. and stirred at that temperature for 8 hours, so that it became a clear brown solution. This solution was cooled to room temperature and, thereafter, worked up in the same manner as described in Example 1. However, the amount of methyl alcohol added to the solution was 80 ml and the amount of water into which the solution was poured was 7,000 ml. As a result, there was obtained 80 g of product melting at 99°-110° C. Its yield was 94% based on the amount of diamine used as the starting material. It was confirmed by infrared absorption spectroscopy, nuclear magnetic resonance spectroscopy, and elemental analysis that the product was N,N'-(1-methyl-3,3-dimethyl-1-propenylenedi-p-phenylene)-bismaleimide having the formula ##STR21##
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1.Cl[C:22]1[CH:23]=[C:24]2[N:31]([CH3:32])[C:30]([CH3:34])([CH3:33])[CH2:29][N:25]2[C:26](=[O:28])[N:27]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=1)[CH2:19][O:20][C:22]1[CH:23]=[C:24]2[N:31]([CH3:32])[C:30]([CH3:34])([CH3:33])[CH2:29][N:25]2[C:26](=[O:28])[N:27]=1
Reactant: OCc1ccc(Oc2ccc(C(F)(F)F)nc2)c(F)c1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CN1c2cc(OCc3ccc(Oc4ccc(C(F)(F)F)nc4)c(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from (3-fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol and 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.