Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:27][C:28]([N:30]1[CH2:36][C@@H:35]([OH:37])[C@H:34]([N:38]=[N+]=[N-])[CH2:33][CH2:32][C@H:31]1[CH3:41])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.O.C1(C)C=CC=CC=1>[CH2:20]([O:27][C:28]([N:30]1[CH2:36][C@@H:35]([OH:37])[C@H:34]([NH2:38])[CH2:33][CH2:32][C@H:31]1[CH3:41])=[O:29])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: C[C@@H]1CC[C@@H](N=[N+]=[N-])[C@H](O)CN1C(=O)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C[C@@H]1CC[C@@H](N)[C@H](O)CN1C(=O)OCc1ccccc1
Temperature: 45 °C

Procedure:
Triphenylphosphine (2.13 g, 8.14 mmol) was added to a solution (2R,5R,6R)-5-Azido-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester (1.65 g, 5.43 mmol) in THF (200 ml) and H2O (0.8 ml), then was heated to 45 degrees C. overnight. The reaction mixture was then diluted with toluene (100 ml×2) and was azeotroped in vacuo by rotary evaporation twice. The resulting oil was dissolved in MeOH and HCl in Et2O and the resulting salt was collected following filtration and was used in the next reaction without further purification (1.7 g, quantitative).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][C:13](O)=O)[CH:7]=1)[CH3:2].Cl.[NH2:18][C:19]1[C:24]([Cl:25])=[C:23]([Cl:26])[CH:22]=[CH:21][C:20]=1[SH:27]>>[Cl:25][C:24]1[C:19]2[N:18]=[C:13]([CH2:12][C:8]3[CH:7]=[C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:16])[CH:11]=[CH:10][CH:9]=3)[S:27][C:20]=2[CH:21]=[CH:22][C:23]=1[Cl:26]
Reactant: CCOC(=O)Cc1cccc(CC(=O)O)c1
Reactant: Nc1c(S)ccc(Cl)c1Cl
Agent: Cl
Product: CCOC(=O)Cc1cccc(Cc2nc3c(Cl)c(Cl)ccc3s2)c1
Yield: 56.3 %

Procedure:
The procedure of Example 16-i) was repeated using 1,3-phenylene diacetic acid monoethyl ester (847 mg, 3.3 mmol) and 2-amino-3,4-dichlorothiophenol hydrochloride (831 mg, 4.3 mmol) to obtain ethyl 3-[(4,5-dichlorobenzothiazol-2-yl)methyl]phenylacetate (706 mg, 56%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.CO.Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1>[OH-].[Na+].O.[O-]S([O-])(=O)=O.[Cu+2]>[NH2:1][C@@H:2]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:8][CH:9]=1)[C:11]([OH:13])=[O:12]
Reactant: Cc1ccc(CBr)cc1
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccc(COc2ccc(C[C@H](N)C(=O)O)cc2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A mixture of tyrosine (1.83 g, 10 mmol) and CuSO4 (0.81 g, 5 mmol) in 10 mL of 2N NaOH and 5 mL H2O was heated to 60° C. and cooled to room temperature. The reaction mixture was treated with MeOH (35 mL) and 2N NaOH (1.5 mL) followed by α-bromo-p-xylene. The resulting mixture was stirred at 25° C. for 2 hours and filtered. The solid obtained was washed with a 17.5:5 H2O/MeOH solution followed by MeOH. The solid was triturated with 1N HCl (3×10 mL), H2O (2×5 mL), 1.5N NH4OH solution (3×10 mL), and H2O (2×5 mL). The solid obtained was dried overnight under vacuum to give the title compound as a solid (1.99 g, 70%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([N+:22]([O-])=O)[CH:20]=3)[N:15]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][O:11][CH3:12]>CO.C1(C)C=CC=CC=1.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH2:22])[CH:20]=3)[N:15]([C:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][O:11][CH3:12]
Reactant: COCCOc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc([N+](=O)[O-])cc23)cc1F
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CO
Product: COCCOc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(N)cc23)cc1F
Reaction time: 6 h
Yield: 98 %

Procedure:
A suspension of 3-[3-fluoro-4-(2-methoxy-ethoxy)-phenyl]-1-trityl-5-nitro-1H-indazole 4 (2.8 g, 4.88 mmol) and catalytic amount of Pd on carbon (5 wt %, 0.5 g) in 120 mL of methanol/toluene (1:1) was stirred under a hydrogen atmosphere for 6 h and filtered through Celite. The filtrate was concentrated to provide 3-[3-fluoro-4-(2-methoxy-ethoxy)-phenyl]-1-trityl-1H-indazol-5-ylamine 5 (2.6 g) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([CH2:16][CH2:17][O:18][C:19]3[NH:20][CH:21]=[C:22]([CH2:26][C:27]4[CH:28]=[N:29][CH:30]=[N:31][CH:32]=4)[C:23](=[O:25])[N:24]=3)=[CH:11][C:10]=2[F:33])=[CH:4][C:3]=1[C:34]([F:37])([F:36])[F:35].[CH3:38]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([CH2:16][CH2:17][O:18][C:19]3[N:20]([CH3:38])[CH:21]=[C:22]([CH2:26][C:27]4[CH:32]=[N:31][CH:30]=[N:29][CH:28]=4)[C:23](=[O:25])[N:24]=3)=[CH:11][C:10]=2[F:33])=[CH:4][C:3]=1[C:34]([F:35])([F:36])[F:37]
Reactant: O=c1nc(OCCc2cc(F)c(Oc3ccc(Cl)c(C(F)(F)F)c3)c(F)c2)[nH]cc1Cc1cncnc1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CI
Product: Cn1cc(Cc2cncnc2)c(=O)nc1OCCc1cc(F)c(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 6108108 %

Procedure:
To the solution of 2-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-3,5-difluorophenyl)ethyl]oxy}-5-(5-pyrimidinylmethyl)-4(1H)-pyrimidinone (80 mg, 0.148 mmol) and DIPEA (0.078 mL, 0.445 mmol) in DCM (3.0 mL) was added MeI (0.019 mL, 0.297 mmol) dropwise. The reaction mixture was stirred at room 25° C. for 3 h. Purification via MDAP then afforded the title compound (5 mg, 9.04 mol, 6.0% yield). LCMS: rt=3.46 min, [M+H]=553
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][CH:10]=[CH:11][N:12]=1.C(N(CC)CC)C.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26]([N:12]2[CH:11]=[CH:10][N:9]=[C:8]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Brc1ccccc1-c1ncc[nH]1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2ccnc2-c2ccccc2Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2.50 g (11.6 mmol ) of 2-(2-bromophenyl)imidazole in 10 mL of methylene chloride was treated with 1.9 mL of triethylamine (13.8 mmol), 2.64 g (13.8 mmol) of p-toluenesulfonyl chloride and 100 mg of 4-dimethylaminopyridine. The reaction mixture was stirred at room temperature for 15 minutes then transferred to a separatory funnel and washed with water, 5% aqueous citric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic layer was removed, dried over magnesium sulfate, filtered and solvents removed under vacuum. The crude product was chromatographed on silica, eluting with hexane/ethyl acetate (1:1), to give 4.16 g (11.0 mmol 95%) of the product which was recrystallized from hexane. FAB-MS: calculated for C16H13BrN2O2S 376,378; found 377,379 (M+H, 50%). 1H NMR (200 MHz, CDCl3): 2.32 (s, 3H), 7.09 (d, 2 Hz, 1H), 7.12 (d, 8 Hz, 2H), 7.28 (m, 5H), 7.46 (m, 1H), 7.57 (d, 2 Hz, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][CH:9]=O)[CH:2]=1.[NH2:11][C:12]1[S:13][C:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19][C:20]=2[N:21]=1.C([BH3-])#N.[Na+]>>[NH2:11][C:12]1[S:13][C:14]2[CH2:15][CH2:16][N:17]([CH2:9][CH:8]=[CH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:18][CH2:19][C:20]=2[N:21]=1
Reactant: O=CC=Cc1cccnc1
Reactant: Nc1nc2c(s1)CCNCC2
Agent: [BH3-]C#N
Agent: [Na+]
Product: Nc1nc2c(s1)CCN(CC=Cc1cccnc1)CC2
Yield: 40 %

Procedure:
Prepared from 3-(3-pyridyl)acrolein and 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine by reductive amination with sodium cyanoborohydride. Yield: 40% of theory, Melting point: 162°-165° C.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH:11][C:12]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[CH:16][CH:15]=3)=O)=[C:9]([C:24]#[N:25])[C:8]([CH2:26][CH3:27])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:28].[K+].O.OO>C(O)(=O)C>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:14]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[N:17]=[CH:16][CH:15]=4)=[N:25][C:24](=[O:28])[C:9]3=[C:8]([CH2:26][CH3:27])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1nn(C2CCCC2)c(NC(=O)c2ccnc3ccccc23)c1C#N
Reactant: [OH-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccnc4ccccc34)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 24 h
Yield: 28.5 %

Procedure:
To a mixture of 1-cyclopentyl-3-ethyl-4-cyano-5-(4-quinolinecarboxamido)-1H-pyrazole (4.6 g, 12.7 mmol), potassium hydroxide (1.7 g, 25.4 mmol) and water (250 ml) at room temperature was added 30% hydrogen peroxide (7.8 ml, 76.0 mmol). The reaction mixture was heated to reflux and stirred for 24 hours. One equivalent of potassium hydroxide and 2 equivalents of 30% hydrogen peroxide were added and the mixture was refluxed for another 24 hours. One equivalent of potassium hydroxide and 2 equivalents of 30% hydrogen peroxide were again added and the mixture was heated at reflux for 3 days. The reaction mixture was cooled to room temperature, treated with acetic acid until a pH of 6.5 was obtained and the resulting precipitate was collected by filtration. The product was purified by column chromatography on silica eluting with ethyl acetate to afford 1.3 g (35%) of 1-cyclopentyl-3-ethyl-6-(4-quinolinyl)-pyrazolo[3,4-d]pyrimidin-4-one as a white solid, m.p. 205°-206° C., when recrystallized from ethyl acetate and dried at 110° C. for 16 hours in high vacuum.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][C@@H:11]2[CH3:16])[N:3]=1.O.[O:18]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:41])[NH:25][C:26]2[CH:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)=[N:19]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.COCCOC.C(O)C>[OH:9][CH2:8][C:6]1[CH:5]=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][C@@H:11]2[CH3:16])[N:3]=[C:2]([C:29]2[CH:28]=[CH:27][C:26]([NH:25][C:24]([NH:23][C:20]3[CH:21]=[CH:22][O:18][N:19]=3)=[O:41])=[CH:31][CH:30]=2)[N:7]=1
Reactant: CC1(C)OB(c2ccc(NC(=O)Nc3ccon3)cc2)OC1(C)C
Reactant: C[C@H]1COCCN1c1cc(CO)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]1COCCN1c1cc(CO)nc(-c2ccc(NC(=O)Nc3ccon3)cc2)n1
Temperature: 90 °C
Yield: 37.8 %

Procedure:
[2-Chloro-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-4-yl]methanol (500 mg) was dissolved in an 18% DMF in a mixture of 7:3:2 DME:water:ethanol (10 mL). 3-(1,2-Oxazol-3-yl)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea (811 mg) and 2M aqueous sodium carbonate solution (4 mL) were then added to the solution and the resultant mixture degassed for 5 min. Dichlorobis(triphenylphosphine) palladium catalyst (73 mg) was added and the solution refluxed at 90° C. for 7 h under nitrogen atmosphere. The reaction was allowed to cool then neutralised with concentrated hydrochloric acid and loaded directly onto a SCX-2 column (50 g), the column was washed with methanol and the product eluted with 7N ammonia in methanol. The material was further purified by chromatography on silica, eluting with 5% methanol in DCM, to give the desired material (318 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:6](B2OC(C)(C)C(C)(C)O2)=[C:5]([CH3:16])[O:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:23][C:24]1[C:28]([C:29]2[CH:30]=[C:31](C3C(C)=CC=C4C=3C=CC=N4)[C:32]3[NH:36][C:35](=[O:37])[NH:34][C:33]=3[CH:38]=2)=[C:27]([CH3:50])[O:26][N:25]=1>>[CH3:23][C:24]1[C:28]([C:29]2[C:38]3[NH:36][C:35](=[O:37])[NH:34][C:33]=3[CH:32]=[C:31]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:16])[CH:30]=2)=[C:27]([CH3:50])[O:26][N:25]=1
Reactant: Cc1ccc2ncccc2c1-c1cc(-c2c(C)noc2C)cc2[nH]c(=O)[nH]c12
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1noc(C)c1-c1cc(-c2c(C)noc2C)c2[nH]c(=O)[nH]c2c1

Procedure:
4,6-bis(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one was synthesized using 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole and Cs2CO3 in a similar fashion as 6-(3,5-dimethylisoxazol-4-yl)-4-(6-methylquinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-one (Example 2).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9](\[C:11]2[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=2)[C:14]([NH:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[O:15])/O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[N:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]3=[N:36][C:9]=2[C:11]2[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=2)[C:14]([NH:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[O:15])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(/C(O)=C\c2ccnc(Cl)n2)c1
Reactant: Nc1ccccn1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Temperature: 60 °C
Yield: 77 %

Procedure:
A tautomeric mixture of 3-[(2-chloro-4-pyrimidinyl)acetyl]-N-(2,6-fluorophenyl)benzamide and 3-[(E)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]-N-(2,6-difluorophenyl)benzamide (5.73 g, 14.8 mmol) was dissolved in 150 mL of DCM with stirring. NBS (2.63 g, 14.8 mmol) was added in a single portion, and the reaction was stirred for 15 minutes. The reaction was concentrated in vacuo. Dioxane (100 mL) was added to dissolve the residue with stirring. 2-Aminopyridine (4.18 g, 44.4 mmol) was added, and the reaction was heated to 60° C. for 16 hours. The reaction was cooled to rt and poured into half-saturated NaHCO3 solution and EtOAc. The layers were separated, and the organic layer was washed with brine. The combined aqueous layers were extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The mixture was purified by flash chromatography to afford 5.26 g (77%) of the desired product. 1H NMR (400 MHz, DMSO-d6): δ 10.20 (s, 1H), 9.40 (d, J=7.0 Hz, 1H), 8.56 (d, J=5.3 Hz, 1H), 8.33 (s, 1H), 8.08 (d, J=7.9 Hz, 1H), 7.85 (d, J=7.9 Hz, 1H), 7.81 (d, J=9.0 Hz, 1H), 7.66-7.54 (m, 2H), 7.89 (m, 1H), 7.27-7.15 (m, 4H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[N:4]=1.[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1>C(O)C.O>[N:18]1([CH2:2][C:3]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:6]3[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=3[N:4]=2)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: ClCc1nc2ccccc2n1-c1ccccc1
Reactant: c1c[nH]cn1
Solvent: O
Solvent: CCO
Product: c1ccc(-n2c(Cn3ccnc3)nc3ccccc32)cc1
Yield: 69 %

Procedure:
A solution of 2-chloromethyl-1-phenyl-1H-benzimidazole (3.4 g) and imidazole (4.8 g) in ethanol (25 ml) was stirred at 60° C for 7 hours. The reaction mixture was concentrated under reduced pressure to give an oil, which was diluted with water and extracted three times with dichloromethane. The combined extract was washed twice with water and once with brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (100 g) with a mixture of methanol and dichloromethane (3:97) as an eluent to afford an oil, which was crystallized from a mixture of ethyl acetate and hexane to give 2-(imidazol-1-yl)methyl-1-phenyl-1H-benzimidazole (2.65 g).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:12][O:11][CH2:10]1)C1C=CC=CC=1>CO.FC(F)(F)C(O)=O.[OH-].[OH-].[Pd+2]>[NH2:8][C:9]1([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:17])([F:18])[F:19])[CH2:12][O:11][CH2:10]1
Reactant: O=C(NCC1(N(Cc2ccccc2)Cc2ccccc2)COC1)C(F)(F)F
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: NC1(CNC(=O)C(F)(F)F)COC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-{[3-(dibenzylamino)oxetan-3-yl]methyl}-2,2,2-trifluoroacetamide (4.0 g, 10.57 mmol) in methanol (80 mL) was added 20% palladium hydroxide on carbon (0.8 g) and trifluoroacetic acid (one drop). The mixture was stirred at room temperature under hydrogen overnight and then filtered. The filtrate was concentrated in vacuo to afford the crude product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24]Cl)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C>O>[N:22]1([C:19]2[CH:20]=[CH:21][C:2]([Cl:1])=[C:3]([CH:18]=2)[C:4]([NH:6][CH2:7][C:8]23[CH2:17][CH:12]4[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]4)[CH2:9]2)[CH2:15]3)=[O:5])[CH2:23][CH2:24]1
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(NCCCl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(N2CC2)ccc1Cl
Temperature: 100 °C
Yield: 17 %

Procedure:
2-Chloro-5-(2-chloroethyl)amino-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.15 g), cesium carbonate (0.192 g) and acetonitrile (3 ml) were combined and heated in a sealed tube at 100° C. for 24 hours. The cooled reaction mixture was poured into water (50 ml) and the product extracted into ethyl acetate, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by NPHPLC eluting with 0-5% ethanol in dichloromethane to give the title compound as a white solid (0.023 g).
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[CH:21]=[C:20]([C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)[NH:19][N:18]=1.[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(#N)C>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:9]1[C:17]1[CH:21]=[C:20]([C:22]2[CH:28]=[CH:27][C:25]([NH:26][C:36]([NH:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:37])=[CH:24][CH:23]=2)[NH:19][N:18]=1
Reactant: Nc1ccc(-c2cc(-c3nc4ccccc4[nH]3)n[nH]2)cc1
Reactant: O=C=Nc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)Nc1ccc(-c2cc(-c3nc4ccccc4[nH]3)n[nH]2)cc1
Yield: 35.7 %

Procedure:
Triethylamine (35 μL, 0.25 mmol) was added to a suspension of 4-[3-(1H-benzimidazol-2-yl)-1H-pyrazol-5-yl]aniline (20 mg, 0.064 mmol) and phenyl isocyanate (7.6 mg, 0.064 mmol) in anhydrous acetonitrile (1.0 mL) at room temperature. After twelve hours the reaction was concentrated in vacuo and purified on reverse phase HPLC using water-acetonitrile gradient (0.1% TFA) to provide the title compound (9 mg, 36% yield) as a white solid: 1H NMR (400 MHz, DMSO-d6): δ 9.08 (s, 1H), 8.92 (s, 1H), 7.78 (m, 4H), 7.63 (m, 2H), 7.48 (m, 4H), 7.40 (s, 1H), 7.30 (m, 2H), 7.00 (m, 1H); MS (EI) for C23H18N6O: 395.2 (MH+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3](B(O)O)[CH:2]=1.Cl[C:15]1[N:20]=[C:19]([C:21]2[NH:29][C:28]3[C:27]4([CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30]4)[CH2:26][NH:25][C:24](=[O:41])[C:23]=3[CH:22]=2)[CH:18]=[CH:17][N:16]=1.C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1>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.CCO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:15]2[N:20]=[C:19]([C:21]3[NH:29][C:28]4[C:27]5([CH2:33][CH2:32][NH:31][CH2:30]5)[CH2:26][NH:25][C:24](=[O:41])[C:23]=4[CH:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CNC(=O)c3cc(-c4ccnc(Cl)n4)[nH]c32)C1
Reactant: OB(O)c1cnc2ccccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C1NCC2(CCNC2)c2[nH]c(-c3ccnc(-c4cnc5ccccc5c4)n3)cc21
Temperature: 140 °C
Reaction time: 0.25 h
Yield: 47.9 %

Procedure:
A mixture of quinolin-3-ylboronic acid (53.2 μmol, 9.2 mg), D7 (53.2 μmol, 21.5 mg), 2 N aqueous K2CO3 (106 μL), toluene (837 μL) and EtOH (209 μL) was purged with nitrogen. Then tetrakis(triphenylphosphine)palladium(0) (2.7 μmol; 3.1 mg) was added. The reaction mixture was stirred for 15 minutes at 140° C. in the microwave. The mixture was washed with water (1 mL). Brine (1 mL) was added to the aqueous phase, followed by an extraction with EtOAc (2×2 mL). The combined organic phase was concentrated. The residue was treated with 4N HCl in dioxane (2 mL) at room temperature for 30 minutes. The mixture was centrifuged and decanted. Subsequently, the residue was suspended in diethyl ether, centrifuged and decanted for another 2 times. The residue was dried in vacuo and purified by semi-preparative HPLC (method A), which obtained 10.1 mg of the desired product as a TFA salt (37%). 1H NMR (400 MHz, DMSO-D6, 300K): δ=2.21 (1H, m), 2.55 (1H, m), 3.50 (6H, m), 7.50 (1H, d, J=2.2 Hz), 7.56 (1H, br s), 7.73 (1H, m), 7.90 (1H, m), 7.91 (1H, d, J=5.4 Hz); 8.14 (1H, br d, J=8.6 Hz), 8.23 (1H, br d, J=8.2 Hz), 8.90 (1H, d, J=5.4 Hz), 9.10 (1H, br s), 9.25 (1H, br s), 9.49 (1H, d, J=2.1 Hz), 10.08 (1H, d, 2.1 Hz), 12.02 (1H, br s); MS (ES) C23H20N6O requires: 396. found: 397.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:12][NH2:13]>CO>[NH:12]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[NH2:13]
Reactant: NN
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: O
Solvent: CO
Product: NNc1ncccc1[N+](=O)[O-]

Procedure:
2-Chloro-3-nitropyridine (100 g, 0.63 mol), hydrazine monohydrate (70.4 mL, 72.6 g, 1.45 mol) and methanol (1.3 L) were mixed and heated to reflux with stirring. After 30 min the reaction mixture was cooled and filtered collecting the insoluble materials. The filtrate was concentrated by evaporation under reduced pressure and the residue obtained as well as the insoluble materials from the filtration were diluted with water. The insoluble solids present were collected by filtration, washed with water, and dried to obtain 95.2 g (98 percent of theory) of the title compound as a bright yellow powder melting at 168°-169° C.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:19]=1>>[N:23]1[CH:24]=[CH:25][C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[CH:28]=[C:27]([C:29]([F:31])([F:30])[F:32])[S:26][C:16]=3[N:17]=2)=[CH:21][CH:22]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3ccncc3)nc2s1
Product: FC(F)(F)c1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-4-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-methylenedioxyphenethylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.