Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[C:5](I)=[C:4]([CH3:13])[N:3]=1.[CH2:14]([N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29])[CH2:15][CH2:16][C:17]#[CH:18].C(N(CC)CC)C.[Cl-].[NH4+]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([CH3:13])[C:5]([C:18]#[C:17][CH2:16][CH2:15][CH2:14][N:19]2[C:20](=[O:29])[C:21]3[C:22](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:24])=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:7]=1
Reactant: CCCNc1nc(Cl)nc(C)c1I
Reactant: C#CCCCN1C(=O)c2ccccc2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCNc1nc(Cl)nc(C)c1C#CCCCN1C(=O)c2ccccc2C1=O
Temperature: 45 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
To a solution of 2-chloro-5-iodo-6-methyl-N-propylpyrimidin-4-amine (T2, 150 mg) in N,N-dimethylformamide (3 mL), N-(4-pentynyl)phthalimide (133 mg), bis(triphenylphosphine)palladium(II) dichloride (34 mg), copper(I) iodide (18 mg) and triethylamine (334 μL) were added at room temperature, and the mixture was stirred at 45° C. for 1 hour under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and then saturated aqueous ammonium chloride and ethyl acetate were added to the reaction mixture. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 90 to 70% hexane in ethyl acetate) to obtain 2-(5-(2-chloro-4-methyl-6-(propylamino)pyrimidin-5-yl)-4-pentyn-1-yl)isoindoline-1,3-dione (T3, 131 mg).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)=[O:8])[CH2:2]1.C1(C)C=CC(S(O[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:37]([C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH2:29][N:1]2[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]34[CH2:18][CH:13]5[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]5)[CH2:10]3)[CH2:16]4)=[O:8])[CH2:2]2)=[CH:32][CH:33]=1)#[N:38]
Reactant: O=C(N[C@H]1CCNC1)C12CC3CC(CC(C3)C1)C2
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C#N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(CCN2CC[C@H](NC(=O)C34CC5CC(CC(C5)C3)C4)C2)cc1
Temperature: 70 °C
Yield: 73.2 %

Procedure:
(S)-N-(Pyrrolidin-3-yl)-1-adamantanecarboxamide (1.0 g) and 2-(4-cyanophenyl)ethyl p-toluenesulfonate (1.2 g) were dissolved in acetonitrile, and potassium carbonate was added thereto. The mixture was stirred under heating at 70° C. for 5 hours. After the completion of the reaction, the solvent was evaporated under reduced pressure. Ethyl acetate was added to the obtained residue and the mixture was washed with saturated brine. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (chloroform:methanol=30:1). The obtained eluate was concentrated and IPE was added to the obtained residue. The precipitated crystals were collected by filtration to give (S)-N-(1-(2-(4-cyanophenyl)ethyl)pyrrolidin-3-yl)-1-adamantanecarboxamide (1.1 g), melting point 104-105° C.
Reaction SMILES: C[O-].[Na+].C1(C)C=CC=CC=1.[CH:11](OCC)=[O:12].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:19]=[C:20]([CH2:24][C:25]#[N:26])[CH:21]=[CH:22][CH:23]=1>O>[CH:11]([CH:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:27])([F:28])[F:16])[CH:19]=1)[C:25]#[N:26])=[O:12]
Reactant: CCOC=O
Reactant: N#CCc1cccc(C(F)(F)F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#CC(C=O)c1cccc(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
To a slurry of 30.0 g. of sodium methoxide in 1200 ml. of toluene and 43.4 g. of ethyl formate is added dropwise with stirring 98.75 g. of 3-(trifluoromethyl)benzeneacetonitrile in 75 ml. of toluene over a 10 minute period. The temperature of the mixture rises to 35° C. and the mixture thickens. Stirring is continued for 2 hours and then one liter of water is added. The aqueous layer is acidified and a precipitate is formed by scratching to give 85.0 g. of the product of the Example as a white solid, m.p. 103°-106.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.[I:23]I>CO.S([O-])([O-])(=O)=O.[Ag+2]>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([I:23])=[CH:4][C:3]=1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: II
Reactant: COc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COc1cc(F)c(C2CCN(C(=O)OC(C)(C)C)CC2)cc1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred mixture of tert-butyl 4-(2-fluoro-4-methoxyphenyl)piperidine-1-carboxylate (Step A; 255 mg; 0.825 mmol) in MeOH. (15 mL) was treated with iodine (345 mg; 1.107 mmol) and silver sulfate (281 mg; 1.107 mmol). The reaction was stirred at room temperature for 2 h. The reaction was filtered through Celite and the filtrate was concentrated in vacuo. The residue was redissolved in ether (50 mL) and washed with H2O (50 mL). The aqueous layer was extracted with ether (3×50 mL) and the combined extracts were washed with brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-10% EtOAc/hexanes gradient) to afford tert-butyl 4-(2-fluoro-5-iodo-4-methoxyphenyl)piperidine-1-carboxylate as a colorless glass. The aqueous layer was then re-extracted with EtOAc (3×100 mL) and the combined extracts were dried (MgSO4), filtered, and the solvent was removed under reduced pressure until a precipitate formed. This solid was collected by filtration and dried in a vacuum oven to afford 4-(2-fluoro-5-iodo-4-methoxyphenyl)piperidine as a off-white solid.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13][C@H:14]1[CH2:19][O:18][C:17]([CH3:21])([CH3:20])[O:16][C@H:15]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:12].[OH-].[Li+]>C1COCC1>[CH3:20][C:17]1([CH3:21])[O:16][C@@H:15]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@@H:14]([NH:13][C:11](=[O:12])[NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:28])=[O:2])[CH2:19][O:18]1
Reactant: COC(=O)c1ccccc1NC(=O)N[C@H]1COC(C)(C)O[C@H]1c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)OC[C@H](NC(=O)Nc2ccccc2C(=O)O)[C@H](c2ccccc2)O1

Procedure:
The title compound was prepared upon treatment of the product of Example 40 with lithium hydroxide in aqueous THF.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH2:7]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](Cl)=[N:16][N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:25][C@@H:26]1[CH2:31][NH:30][CH2:29][CH2:28][NH:27]1>O1CCOCC1>[CH2:7]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([N:30]2[CH2:29][CH2:28][NH:27][C@H:26]([CH3:25])[CH2:31]2)=[N:16][N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1nnc(Cc2ccccc2)c2ccccc12
Reactant: C[C@@H]1CNCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@@H]1CN(c2nnc(Cc3ccccc3)c3ccccc23)CCN1
Yield: 57.7 %

Procedure:
Solid Na2CO3 (200 mg, 1.9 mmol, 1.9 eq) is added to a solution of 1-benzyl-4-chlorophthalazine (250 mg, 0.98 mmol, 1 eq) and (R)-2-methyl-piperazine (400 mg, 4.0 mmol, 4.0 eq) in dioxane (5 mL) in a microwave vial. The vial is sealed and irradiated in the microwave at 150° C. (high absorption setting) for 30 minutes. The reaction mixture is filtered and concentrated, then diluted with EtOAc (50 mL) and water (15 mL). The organic fraction washed with water and then brine, then is dried over sodium sulfate. The solvent is evaporated under reduced pressure to afford the title compound as a white solid (180 mg, 58% yield).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]2[CH:6]=[C:7]([C:9](OCC)=[O:10])[N:8]=[C:2]12.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.Cl>ClCCl.O>[S:1]1[CH2:5][CH2:4][N:3]2[CH:6]=[C:7]([CH:9]=[O:10])[N:8]=[C:2]12
Reactant: CCOC(=O)c1cn2c(n1)SCC2
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=Cc1cn2c(n1)SCC2
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 42.8 %

Procedure:
Ethyl 2,3-dihydroimidazo[2,1-b]thiazole-6-carboxylate (4.2 g; 21.21 mmol) was dissolved in dry dichloromethane (150 ml) and cooled to -70° C. under a stream of dry argon. This solution was treated with a solution of diisobutylaluminium hydride in toluene (1.5M, 26.9 ml, 2 equivalents) over 40 minutes at -70° C. The reaction mixture was stirred at -70° C. for a further 0.5 h. Water (10 ml) was added and the mixture stirred at ambient temperature for 0.5 hr. The mixture was acidified with 5M HCl, filtered through a celite pad and the pad further washed with dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulphate and evaporated to dryness. Chromatography on silica gel, eluting with ethyl acetate, gave the title compound (1.4 g, 43%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7](/[CH:26]=[CH:27]/[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:8][C:9]=2[C:11]([NH:13][CH2:14][C:15]2[C:16](=[O:25])[NH:17][C:18]([CH3:24])=[CH:19][C:20]=2[CH2:21][CH2:22][CH3:23])=[O:12])[N:4]([CH:33]([CH3:35])[CH3:34])[CH:3]=1>C(O)C>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:8][C:9]=2[C:11]([NH:13][CH2:14][C:15]2[C:16](=[O:25])[NH:17][C:18]([CH3:24])=[CH:19][C:20]=2[CH2:21][CH2:22][CH3:23])=[O:12])[N:4]([CH:33]([CH3:35])[CH3:34])[CH:3]=1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(/C=C/C(=O)OCC)cc2c1c(C)cn2C(C)C
Solvent: CCO
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(CCC(=O)OCC)cc2c1c(C)cn2C(C)C
Reaction time: 12 h
Yield: 58.2 %

Procedure:
In a 50 ml flask was added ethyl (2E)-3-[3-methyl-1-(1-methylethyl)-4-({[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]amino}carbonyl)-1H-indol-6-yl]-2-propenoate (120 mg, 0.251 mmol), and Ethanol (10 mL). PdOH2 (70.6 mg, 0.503 mmol) was added and the reaction was degassed with N2 for 15 min then H2 was bubbled in (via balloon) and the reaction stirred for 12 hr. The reaction was purged with N2 for 30 min and then filtered through an acro disc and evaporated. The residue was suspended in MeOH/Water (2 mL/4 mL) and filtered and washed with water to give a white solid. ethyl 3-[3-methyl-1-(1-methylethyl)-4-({[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]amino}carbonyl)-1H-indol-6-yl]propanoate (70 mg, 0.146 mmol, 58.1% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.49 (br. s., 1H) 7.90 (br. s., 1H) 7.34 (s, 1H) 7.21 (s, 1H) 6.82 (s, 1H) 5.90 (s, 1H) 4.63-4.73 (m, 1H) 4.34 (d, J=4.55 Hz, 2H) 4.04 (q, J=7.07 Hz, 2H) 2.92 (t, J=7.33 Hz, 2H) 2.64 (t, J=7.45 Hz, 2H) 2.55-2.62 (m, 2H) 2.12 (s, 6H) 1.52-1.62 (m, 2H) 1.40 (d, J=6.32 Hz, 6H) 1.16 (t, J=7.07 Hz, 3H) 0.94 (t, J=7.20 Hz, 3H). MS(ES) [M+H]+ 479.8.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([Cl:18])[CH:12]=3)[CH:7]=1.[F:24][C:25]1[CH:26]=[C:27]([N:32]=[C:33]=[O:34])[CH:28]=[C:29]([F:31])[CH:30]=1>C1COCC1>[Cl:22][C:5]1[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([Cl:18])[CH:12]=3)=[CH:7][C:2]([NH:1][C:33]([NH:32][C:27]2[CH:28]=[C:29]([F:31])[CH:30]=[C:25]([F:24])[CH:26]=2)=[O:34])=[C:3]([F:23])[CH:4]=1
Reactant: O=C=Nc1cc(F)cc(F)c1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(Cl)cc21
Solvent: C1CCOC1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3cc(F)cc(F)c3)c(F)cc2Cl)cc2cnc(Cl)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
A solution of Example A3 (0.20 g, 0.568 mmol) in THF (6 mL) was treated with TEA (0.098 mL, 0.710 mmol) followed by 3,5-difluorophenyl isocyanate (0.092 g, 0.596 mmol) and stirred at RT for 2 h. Additional 3,5-difluorophenyl isocyanate (0.14 g, 0.903 mmol) was added and the mixture stirred at RT overnight. More 3,5-difluorophenyl isocyanate (0.25 g, 1.61 mmol) was added and the mixture stirred at RT for 24 h. The mixture was cooled to 0° C. and the solids collected via filtration and dried. The filtrate was concentrated to dryness and purified via silica gel chromatography (THF/Hex) and combined with the isolated solid to afford 1-(4-chloro-5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3,5-difluorophenyl)urea (177 mg, 61% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.27 (br s, 2H), 8.79 (s, 1H), 8.15 (d, J=8.5 Hz, 1H), 8.08 (s, 1H), 7.74 (s, 1H), 7.57 (d, J=10.9 Hz, 1H), 7.16 (m, 2H), 6.77 (m, 1H), 4.27 (q, J=7.0 Hz, 2H), 1.20 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 507.1 [M+H]+.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.C([O-])([O-])=O.[K+].[K+].[Cl:18][CH2:19][CH2:20]Cl>CN(C=O)C>[Cl:18][CH2:19][CH2:20][O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: ClCCCl
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCCCl
Temperature: 67.5 °C
Reaction time: 16 h
Yield: 85.4 %

Procedure:
A mixture of vanillin (10.00 g, 65.7 mmol), K2CO3 (45.4 g, 329 mmol), 1,2-dichloroethane (104 mL, 1.31 mol), and DMF (300 mL) was stirred at 65-70° C. for 16 h. The dichloroethane was evaporated and the remaining slurry was poured onto ice. The oil that separated was extracted with Et2O (×4) and EtOAc (×3). The combined extracts were washed with water (×3), dried (Na2SO4 /MgSO4), and evaporated to give a clear oil that solidified upon trituration with hexanes. Crystallization from Et20 gave 4-(2-chloroethoxy)-3-methoxybenzaldehyde (12.04 g, 85%) as white needles, mp 60-61° C. 1H NMR (CDCl3) δ 9.87 (s, 1 H, CHO), 7.46 (dd, J=8.0, 2.0 Hz, 1 H, H-6), 7.43 (d, J=2.0 Hz, 1 H, H-5), 6.99 (d, J=8.0 Hz, 1 H, H-2), 4.36 (t, J=6.1 Hz, 2 H, OCH2), 3.94 (s, 3 H, OCH3), 3.89 (t, J=6.1 Hz, 2 H, CH2Cl); 13C NMR δ 190.8 (CHO), 153.9 (C-4), 150.0 (C-3), 130.8 (C-1), 126.3 (C-6), 112.3 (C-2), 109.8 (C-5), 68.9 (OCH2), 56.0 (OCH3), 41.2 (CH2Cl).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][N:18]4[C:26](=[O:27])[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[C:19]4=[O:28])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:34]1[CH:39]=[N:38][CH:37]=[CH:36][N:35]=1)CCC>>[N:35]1[CH:36]=[CH:37][N:38]=[CH:39][C:34]=1[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][N:18]4[C:19](=[O:28])[C:20]5[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:26]4=[O:27])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc2c(c1)ncn2-c1cccc(Br)c1
Product: O=C1c2ccccc2C(=O)N1Cc1ccc2c(c1)ncn2-c1cccc(-c2cnccn2)c1

Procedure:
This was prepared analogously from 2-[1-(3-bromo phenyl)-1H-benzimidazole-5-yl methyl]-isoindole-1,3-dione and 2-tri butylstannylpyrazine.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+:15]>CO.O.[Pd]>[C:1]([N:5]1[CH2:10][CH2:9][CH:8]([NH2:15])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1CCC(=O)CC1
Reactant: [NH4+]
Agent: [Pd]
Agent: O=C[O-]
Solvent: CO
Solvent: O
Product: CC(C)(C)N1CCC(N)CC1
Reaction time: 8 h

Procedure:
To a solution of 1-tert-butylpiperidin-4-one (5.0 g) in methanol (100 mL) and water (10 mL) was added ammonium formate (20.3 g) and 0.5 g of Pd/C (10%). The mixture was stirred overnight. The mixture was filtered and the filtrate was concentrated under vacuum and the residue was diluted with ethyl acetate (500 mL) and washed with water and brine. After drying over Na2SO4 and filtration, the solvent was evaporated under vacuum to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH2:20]O)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:22]=1.[CH3:23][C:24]1[NH:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH2:20][N:25]4[C:26]5[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=5[N:28]=[C:24]4[CH3:23])=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:22]=1
Reactant: COC(=O)c1nc2n(c1CO)C1CC(C1)c1ccc(Br)cc1-2
Reactant: Cc1nc2ccccc2[nH]1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1nc2n(c1Cn1c(C)nc3ccccc31)C1CC(C1)c1ccc(Br)cc1-2
Temperature: 0 °C
Yield: 43 %

Procedure:
10-bromo-3-formyl-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was subjected to General Procedure 0 (ketone/aldehyde reduction) to afford crude methyl 10-bromo-3-(hydroxymethyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate. To a reaction flask was placed a solution of methyl 10-bromo-3-(hydroxymethyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate (1 eq), 2-methylbenzimidazole (1.05 eq) and triphenylphosphine (1.20 equiv) in tetrahydrofuran. This was followed by the addition of di-tert-butylazodicarboxylate (1.1 eq) in Tetrahydrofuran (1.0 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 3 hours at room temperature. The resulting mixture was extracted with dichloromethane and saturated ammonium chloride. The residue was purified by flash column chromotography to afford 114 mg (43%) of methyl 10-bromo-3-((2-methyl-1H-benzo[d]imidazol-1-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate as a light yellow oil. 10-bromo-3((2-methyl-1H-benzo[d]imidazol-1-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was subjected to General Procedure L to afford 89 mg (81%) of 10-bromo-3((2-methyl-1H-benzo[d]imidazol-1-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide as a white solid. 10-bromo-3((2-methyl-1H-benzo[d]imidazol-1-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford 6.8 mg (15.1%) of 10-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-3-[(2-methylbenzimidazol-1-yl)methyl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][N:4]=[C:5]([NH2:19])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][CH2:15][CH2:16][C:17]#[N:18])[N:8]=1.C(=O)([O-])[O-:23].[Na+].[Na+]>S(=O)(=O)(O)O>[F:21][C:2]([F:1])([F:20])[CH2:3][N:4]=[C:5]([NH2:19])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][CH2:15][CH2:16][C:17]([NH2:18])=[O:23])[N:8]=1
Reactant: N#CCCSCc1nccc(NC(N)=NCC(F)(F)F)n1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)CCSCc1nccc(NC(N)=NCC(F)(F)F)n1

Procedure:
A solution of 3-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylmethylthio]propionitrile (850 mg.) in concentrated sulphuric acid (4 ml.) was kept at 20° for 16 hours then added dropwise to saturated aqueous sodium carbonate. The mixture was extracted with EtOAc (3×20 ml.) and the extract dried (MgSO4) and evaporated in vacuo to give 3-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-ylmethylthio]propionamide as an oil. The maleic acid salt was prepared in acetone (yield 720 mg; 60%), m.p. 168°-169° (decomp.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[CH2:7][CH2:8][C@H:9]([NH:26]C(OCC1C=CC=CC=1)=O)[C:10]([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:20])[CH2:14][CH2:13]1)=[O:11])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([O:5][C:6](=[O:37])[CH2:7][CH2:8][C@H:9]([NH2:26])[C:10]([N:12]1[CH2:13][CH2:14][CH:15]([NH:18][C:19]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:20])[CH2:16][CH2:17]1)=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCOC(=O)NC1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCCCOC(=O)NC1CCN(C(=O)[C@@H](N)CCC(=O)OC(C)(C)C)CC1
Reaction time: 12 h

Procedure:
To a solution of 0.91 g (S)-4-Benzyloxycarbonylamino-5-(4-butoxycarbonylamino-piperidin-1-yl)-5-oxo-pentanoic acid tert-butyl ester in 10 ml EtOH were added 0.2 g Pd/C (10%) and the suspension stirred under an atmosphere of hydrogen (3 bar) for 12 h. The reaction mixture was filtrated over Celite and washed with EtOH. The title compound was used without further purification after evaporation of the solvent. Yield: 0.67 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14]([C:17]4[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=4)=[CH:15][N:16]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1.Br[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1.Cl.CC([O-])(C)C.[Na+].N#N>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]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14]([C:17]4[CH:18]=[C:19]([NH:23][C:25]5[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=5)[CH:20]=[CH:21][CH:22]=4)=[CH:15][N:16]=[C:10]3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2cnc3cc(-c4ccc(F)cc4)ccn23)c1
Reactant: Brc1ccncc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: Fc1ccc(-c2ccn3c(-c4cccc(Nc5ccncc5)c4)cnc3c2)cc1
Temperature: 100 °C

Procedure:
A mixture 3-[7-(4-fluoro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-phenylamine (200 mg, 0.65 mmol), 4-bromopyridine.HCl (130 mg, 0.67 mmol), (±)-Binap (63 mg, 0.1 mmol) and NaOtBu (250 mg, 2.6 mmol) in dry dioxane (3 ml) was deoxygenated by evacuation/refill with N2 (×3). Pd2(dba)3 (30 mg, 0.03 mmol) was added and the mixture was deoxygenated again (×3). The reaction was stirred and heated at 100° C. for 18 hours under N2. The mixture was partitioned between CH2Cl2/H2O, then filtered. The layers were separated and the solid was combined with the organic layer, which was then evaporated. The residue was purified by chromatography on silica followed by preparative HPLC to give the title compound (40 mg, solid). 1H NMR (400 MHz, Me-d3-OD): 8.63 (1H, d), 8.44 (1H, s), 8.22 (2H, d), 7.87-7.79 (4H, m), 7.70 (1H, t), 7.63-7.59 (2H, m), 7.48-7.43 (1H, m), 7.37 (1H, dd), 7.31-7.24 (2H, m), 7.17 (2H, d).
Reaction SMILES: F[C:2](F)(F)[C:3]([NH:5][CH2:6][CH2:7][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[CH3:2][C:3]1[C:12]2[CH:11]=[CH:10][S:9][C:8]=2[CH2:7][CH2:6][N:5]=1
Reactant: O=C(NCCc1cccs1)C(F)(F)F
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1=NCCc2sccc21
Yield: 25 %

Procedure:
In close analogy to the procedure described above, 2,2,2-Trifluoro-N-(2-thiophen-2-yl-ethyl)-acetamide is reacted with phosphorus pentoxide to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][C:12]([C:18](O)=[O:19])=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:21])=[CH:4][CH:3]=1.[N:24]1([CH2:30][CH2:31][NH2:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([CH2:30][CH2:31][NH:32][C:18]([C:12]2[CH:11]=[C:10]3[C:15]([C:16](=[O:17])[N:7]([CH2:6][C:5]4[CH:22]=[CH:23][C:2]([Cl:1])=[CH:3][CH:4]=4)[C:8](=[O:21])[NH:9]3)=[CH:14][CH:13]=2)=[O:19])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)c1ccc2c(=O)n(Cc3ccc(Cl)cc3)c(=O)[nH]c2c1
Reactant: NCCN1CCCCC1
Product: O=C(NCCN1CCCCC1)c1ccc2c(=O)n(Cc3ccc(Cl)cc3)c(=O)[nH]c2c1

Procedure:
65 mg (55%) of the target compound was obtained using 3-(4-chloro-benzyl)-2,4-dioxoquinazoline-7-carboxylic acid (90 mg, 0.272 mol) obtained in Example 1 and 2-piperidine-1-yl-ethylamine (85 mL, 0.598 mmol).