Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:22]=[C:23]([N:28]2[C:33](=[O:34])[C:32]([O:35][CH2:36][CH2:37][CH2:38][CH3:39])=[C:31](Cl)[CH:30]=[N:29]2)[CH:24]=[CH:25][C:26]=1[F:27].[CH3:41][S:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(C)C>[F:20][C:21]1[CH:22]=[C:23]([N:28]2[C:33](=[O:34])[C:32]([O:35][CH2:36][CH2:37][CH2:38][CH3:39])=[C:31]([C:46]3[CH:47]=[CH:48][C:43]([S:42][CH3:41])=[CH:44][CH:45]=3)[CH:30]=[N:29]2)[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: CCCCOc1c(Cl)cnn(-c2ccc(F)c(F)c2)c1=O
Reactant: CSc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)O
Solvent: O
Product: CCCCOc1c(-c2ccc(SC)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Temperature: 70 °C
Reaction time: 15 h

Procedure:
A slurry of palladium(II) acetate (9.0 mg, 0.04 mmol), triphenylphosphine (21.0 mg, 0.08 mmol) and isopropanol (1 mL) was stirred at room temperature for 10 minutes. To this mixture was added 2-(3,4-Difluorophenyl)-4-(1-butoxy)-5-chloro-3(2H)-pyridazinone (Example 536A, 0.63 g, 2 mmol), 4-(methylthio)benzeneboronic acid (0.403 mg, 2.4 mmol) and isopropanol (4 mL). A solution of K3PO4 (0.66 g, 3 mmol) in water (1 mL) was also added and the resulting reaction mixture was deoxygenated by bubbling nitrogen through it for 2 minutes. The reaction mixture was then stirred under a nitrogen atmosphere for 15 hours at 70° C. The reaction mixture was then cooled to room temperature and water (15 mL) was added to provide a precipitate. The precipitate was collected by filtration and rinsed with water then hexane to give after drying the title compound (0.77 g, 95%).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2=[CH:16][S:17][C:18]([CH3:19])=[C:5]12)=[O:3].[CH2:20]([N:23]([CH2:36][CH2:37][CH3:38])[CH2:24][CH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][NH2:35])[CH2:29][CH2:28]1)[CH2:21][CH3:22].C(OC(C)C)(C)C>>[CH2:36]([N:23]([CH2:20][CH2:21][CH3:22])[CH2:24][CH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][NH:35][C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7](=[O:15])[C:6]3=[CH:16][S:17][C:18]([CH3:19])=[C:5]23)=[O:3])[CH2:29][CH2:28]1)[CH2:37][CH3:38]
Reactant: CCCN(CCC)CCCC1CCN(CCN)CC1
Reactant: Cc1scc2c1N(C(=O)Cl)c1ccccc1NC2=O
Solvent: CC(C)OC(C)C
Product: CCCN(CCC)CCCC1CCN(CCNC(=O)N2c3ccccc3NC(=O)c3csc(C)c32)CC1
Yield: 42 %

Procedure:
Prepared analogously to Example 1 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 2-[4-[3-(dipropylamino)propyl]-piperidin-l-yl]ethanamine in a yield of 42% of theory. Colourless crystals, m.p. 114°-115° C. (diisopropyl ether).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][CH3:16])[C:12]([CH:17]([C:19]2[NH:20][CH:21]=[CH:22][N:23]=2)O)=[C:11]([CH2:24][CH3:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:24][CH3:25])[C:12]([CH2:17][C:19]2[NH:23][CH:22]=[CH:21][N:20]=2)=[C:13]([CH2:15][CH3:16])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(OCc2ccccc2)cc(CC)c1C(O)c1ncc[nH]1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(OCc2ccccc2)cc(CC)c1Cc1ncc[nH]1

Procedure:
2-(4-Benzyloxy-2,6-diethyl-benzyl)-1H-imidazole was prepared from rac-(4-benzyloxy-2,6-diethyl-phenyl)-(1H-imidazol-2-yl)-methanol, triethylsilane and trifluoroacetic acid in analogy to Example 191e): white crystals; MS (ISP): 321.1 ([M+H]+, 100%).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17]C(=O)OC(C)(C)C)=[CH:13][CH:12]=1)[C:2]#[CH:3].Cl.O1CCOCC1>C(Cl)Cl>[CH2:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[C:2]#[CH:3]
Reactant: C#CCOCCOCCOc1ccc(NC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C#CCOCCOCCOc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl 4-(2-(2-(prop-2-ynyloxy)ethoxy)ethoxy)phenylcarbamate (I-7a: 1.91 g, 5.69 mmol) in CH2Cl2 (14.24 mL) was added 4N HCl in dioxane (14.24 mL, 56.9 mmol). The mixture was stirred at room temperature for 2 hours, concentrated in vacuo, followed by the addition of aqueous saturated sodium bicarbonate. The mixture was then extracted twice with ethyl acetate, dried over MgSO4, filtered, and concentrated in vacuo. 4-(2-(2-(prop-2-ynyloxy)ethoxy)ethoxy)aniline (I-7b) was used as is for next step. LC-MS (M+1) 236.1, t=0.87 minute.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[NH2:11][CH2:12][C:13]1[N:17]([C:18]2[S:19][C:20]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:21][C:22]=2[C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:16]([CH3:37])=[N:15][N:14]=1>>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:23]([C:22]1[CH:21]=[C:20]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[S:19][C:18]=1[N:17]1[C:16]([CH3:37])=[N:15][N:14]=[C:13]1[CH2:12][NH:11][C:9]([NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[O:10])=[O:31]
Reactant: O=C=Nc1ccccc1Cl
Reactant: COC(=O)Cc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Product: COC(=O)Cc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)Nc2ccccc2Cl)s1

Procedure:
2-Chlorophenyl isocyanate and methyl (2-(3-aminomethyl-5-methyl[1,2,4]triazol-4-yl)-3-(2-chlorobenzoyl)thiophen-5-yl)acetate are reacted to give methyl (3-(2-chlorobenzoyl)-2-(3-(3-(2-chlorophenyl)ureidomethyl)-5-methyl[1,2,4]triazol-4-yl)thiophen-5-yl)acetate.
Reaction SMILES: [C:1](=[N:4][OH:5])([NH2:3])[CH3:2].[CH:6]1([C:9](=[O:15])[CH2:10][C:11](OC)=O)[CH2:8][CH2:7]1>C1(C)C=CC=CC=1>[CH:6]1([C:9](=[O:15])[CH2:10][C:11]2[O:5][N:4]=[C:1]([CH3:2])[N:3]=2)[CH2:8][CH2:7]1
Reactant: COC(=O)CC(=O)C1CC1
Reactant: CC(N)=NO
Solvent: Cc1ccccc1
Product: Cc1noc(CC(=O)C2CC2)n1
Temperature: 130 °C

Procedure:
Under an inert atmosphere, acetamidoxime (1.56 g) is added to a solution of methyl 3-cyclopropyl-3-oxopropanoate (3.0 g) in 50 ml of toluene; the stirred mixture is heated to 130° C. while distilling off the solvent and methanol formed in the reaction.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]=[N:15][CH:16]=[C:11]2[C:10]([CH:25]=[O:26])=[C:9]1[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([N:8]1[C:12]2=[C:13]([NH:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:14]=[N:15][CH:16]=[C:11]2[C:10]([CH2:25][OH:26])=[C:9]1[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C=O)c2cnnc(NCc3ccccc3)c2n1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(CO)c2cnnc(NCc3ccccc3)c2n1Cc1ccccc1
Yield: 80 %

Procedure:
0.2 g (0.56 mmol) of 1-benzyl-7-benzylamino-3-formyl-2-methylpyrrolo[2,3-d]pyridazine and 23 mg (0.62 mmol) of sodium borohydride are reacted in 20 ml of methanol as described for Example 1a. Yield: 80%, m.p.: 238°-240° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:12](Cl)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]1([O:25][C:26]2[CH:27]=[C:28]([C:34](=[O:44])[CH2:35][C:36]3[C:41]([Cl:42])=[CH:40][N:39]=[CH:38][C:37]=3[Cl:43])[CH:29]=[CH:30][C:31]=2[O:32][CH3:33])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([O:25][C:26]2[CH:27]=[C:28](/[C:34](/[O:44][C:12](=[O:13])[C:11]3[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:10]=3)=[CH:35]/[C:36]3[C:41]([Cl:42])=[CH:40][N:39]=[CH:38][C:37]=3[Cl:43])[CH:29]=[CH:30][C:31]=2[O:32][CH3:33])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COc1ccc(C(=O)Cl)cc1OCc1ccccc1
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)cc1OC1CCCC1
Product: COc1ccc(C(=O)O/C(=C\c2c(Cl)cncc2Cl)c2ccc(OC)c(OC3CCCC3)c2)cc1OCc1ccccc1

Procedure:
The compound was obtained starting from 3-benzyloxy-4-methoxy-benzoyl chloride and 1-(3-cyclopentyloxy-4-methoxy-phenyl)-2-(3,5-dichloro -pyridin-4-yl)-ethanone, following the procedure of Example 7.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH2:14])=O)[NH:3]1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]#[N:14])[N:3]=1
Reactant: NC(=O)c1nc2ccccc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1nc(Cl)c2ccccc2n1
Yield: 62 %

Procedure:
4-Oxo-3,4-dihydroquinazoline-2-carboxamide (40b, 0.51 g, 2.69 mmol) was heated to 100° C. in POCl3 (7.0 mL) for three hours. The solvent was removed under reduced pressure. Ice-cold water was carefully added to the flask, and the insoluble product was filtered off. The filtrate was extracted three times with chloroform. The combined organics were dried (MgSO4) and evaporated to give 4-Chloroquinazoline-2-carbonitrile (40c, 0.21 g). 95% pure by HPLC and used without further purification. The insoluble product was purified by flash silica gel chromatography eluting with 3-30% EtOAc/hexane to give an additional 0.22 g of 40c as a white solid for an overall yield of 62%. Rf=0.53 (30% EtOAc/hexane). 1H NMR (400 MHz, DMSO-d6): δ 8.07-8.11 (m, 1H), 8.24-8.31 (m, 2H), 8.41 (d, J=8.4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]([CH2:18][OH:19])[N:15]=[N:14]1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[CH:17]=[C:16]([CH:18]=[O:19])[N:15]=[N:14]1
Reactant: OCc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nn1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of this alcohol (1.7 g) and manganese dioxide (6.9 g) in chloroform (40 ml) was stirred at room temperature for 24 hours. This mixture was then filtered through Kieselguhr and the solvent evaporated to give crude material, which was purified by flash column chromatography (silica) to give 1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-1,2,3-triazole-4-carboxaldehyde, m.p 143°-144.5°. The aldehyde (2.32 g) and diaminomaleonitrile (0.85 g) were heated under reflux in methanol (40 ml) for 6 hours and then left to stand for 60 hours at room temperature. The solvent was evaporated and the residue was purified by column chromatography and recrystallisation from ethyl acetate/light petroleum (bp 60°-80°) to give 1-(2,6-dichloro-4-trifluoromethylphenyl)-4-[(2-amino-1,2-dicyanoethenylimino)methyl]-1H-1,2,3-triazole, m.p.184°-186°(dec.).
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C@H:31]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([NH2:40])[CH:35]=2)[C@H:30]([OH:41])[CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C@H:31]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([NH:40][C:2]3[N:20]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)[CH:35]=2)[C@H:30]([OH:41])[CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2cccc(N)c2)[C@H](O)C1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CC(C)(C)OC(=O)N1CC[C@H](c2cccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)c2)[C@H](O)C1

Procedure:
186 d) (±)-(cis)-3-Hydroxy-4-{3-[8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (270.0 mg, 0.8773 mmol) and (±)-(cis)-4-(3-amino-phenyl)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (286.0 mg, 0.9782 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (77.0 mg, 0.141 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow solid (0.313 g, 63%). MP=166-170° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.51 (d, J=6.6 Hz, 1H), 8.23 (d, J=7.8 Hz, 2H), 8.09 (d, J=7.8 Hz, 2H), 7.66 (d, J=7.5 Hz, 1H), 7.53 (s, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.33 (t, J=7.5 Hz, 1H), 7.03 (t, J=6.8 Hz, 1H), 6.96-6.90 (m, 2H), 4.35 (br s, 2H), 4.02 (br s, 1H), 3.11 (s, 3H), 3.08-3.00 (m, 1H), 2.90-2.80 (m, 2H), 2.36-2.24 (m, 1H), 1.72-1.60 (m, 2H), 1.50 (s, 9H). MS=586 (M+Na)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:16]([CH2:39][C:40](O)=[O:41])[C:17](=[O:38])[C:18]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[C:23]([F:29])[CH:22]=3)[N:20]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].C[N:46](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[N:16]([CH2:39][C:40](=[O:41])[NH2:46])[C:17](=[O:38])[C:18]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[C:23]([F:29])[CH:22]=3)[N:20]=2)[CH2:13][CH2:14]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1ccc(-c2c(-c3ccc(C#N)c(F)c3)nc(N3CCC(NC(=O)OC(C)(C)C)CC3)n(CC(=O)O)c2=O)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2c(-c3ccc(C#N)c(F)c3)nc(N3CCC(NC(=O)OC(C)(C)C)CC3)n(CC(N)=O)c2=O)cc1
Yield: 43.4 %

Procedure:
To a solution of [2-(4-tert-butoxycarbonylamino-piperidin-1-yl)-4-(4-cyano-3-fluoro-phenyl)-5-(4-methoxy-phenyl)-6-oxo-6H-pyrimidin-1-yl]-acetic acid (120 mg, 0.2 mmol) in DMF (5 mL) was added NH4Cl (17 mg, 0.3 mmol), HATU (95 mg, 0.25 mmol) and DIEA (25 mg, 0.4 mmol). After completion of the reaction, the solution was diluted with H2O and extracted with DCM for (3×). The combined organics were dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC to give 50 mg of the title product as a yellow solid (43%). [M+H] Calc'd for C30H33FN6O5, 577. Found, 577.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][N:3]=1.[OH-].[K+].[C:11]([N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([CH2:24]Br)[CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].O>CS(C)=O>[Br:8][C:6]1[CH:5]=[CH:4][N:3]([CH2:24][CH:20]2[CH2:21][CH2:22][CH2:23][N:18]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:19]2)[C:2](=[O:1])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(CBr)C1
Reactant: Oc1cc(Br)ccn1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(Cn2ccc(Br)cc2=O)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.9 %

Procedure:
To a solution of 2-hydroxy-4-bromopyridine (0.10 g, 0.57 mmol) in DMSO (1.50 mL) was added KOH (0.095 g, 1.70 mmol) and the resulting reaction mixture was stirred for 10 min at room temperature followed by addition of 1-Boc-3-bromomethylpiperidine (0.16 g, 0.57 mmol). The reaction mixture was then stirred at 45° C. for 16 h. After the completion of reaction (TLC monitoring), water was added to the reaction and extracted with EtOAc (3×25 mL). The combined organics was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified over silica gel (100-200 M, 1% MeOH-DCM) to obtain the desired product (0.15 g, 95%). MS: 371.10 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:18])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7]2.[F:19][C:20]([F:32])([F:31])[C:21]1[CH:22]=[C:23]([Sn](C)(C)C)[CH:24]=[CH:25][CH:26]=1.C(OCC)(=O)C.O>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].CCCCCC.C(OCC)(=O)C>[CH3:18][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([C:20]([F:32])([F:31])[F:19])[CH:26]=3)[CH:3]=1)[N:10]=[C:9]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7]2
Reactant: C[Sn](C)(C)c1cccc(C(F)(F)F)c1
Reactant: Cc1cc(Br)c2nc(OCC(F)(F)F)ccc2c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c2nc(OCC(F)(F)F)ccc2c1
Reaction time: 3 h
Yield: 29.3 %

Procedure:
A mixture of 1.5 g (6.2 mmol) of 8-bromo-6-methyl-2-(2,2,2-trifluoroethoxy)quinoline, 2.3 g of crude 3-(trifluoromethyl)phenyltrimethylstannane (Example 1), and 0.2 g of tetrakis(triphenylphosphine)palladium(O) was heated in 30 ml of toluene atreflux with stirring for 3 hours. Ethyl acetate (200 ml) and excess water was added. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo to give an oil. Silica gel column chromatography (20:1 followed by 10:1 hexane/ethyl acetate) afforded 0.7 g of product, isolated as an oil. NMR(CDCl3): ppm 2.55 (s, 3H), 4.71 (q, 2H), 7.15 (d, 1H), 7.5-8.15 (m, 7H).
Reaction SMILES: [C:1](/[C:3](=[CH:19]\[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)/[C:4]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]COC)=[CH:11][CH:10]=1)=[O:5])#[N:2].[ClH:26]>CO.C(O)C>[ClH:26].[C:1](/[C:3](=[CH:19]\[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)/[C:4]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)=[O:5])#[N:2]
Reactant: COCOc1ccc(CCNC(=O)/C(C#N)=C/c2cccnc2)cc1
Agent: Cl
Solvent: CCO
Solvent: CO
Product: N#C/C(=C\c1cccnc1)C(=O)NCCc1ccc(O)cc1
Reaction time: 72 h
Yield: 72 %

Procedure:
(E)-2-cyano-N-(4-methoxymethoxyphenethyl)-3-(3-pyridyl)-2-propenoic acid amide (0.81 g, 2.4 mmol) obtained in Example 1 was dissolved in a mixed solution of methanol (10 ml) and ethanol (10 ml) and concentrated hydrochloric acid (0.3 ml) was added and stirred for 3 days. The precipitated crystal was filtered and washed with ether to yield the titled compound (0.57 g, 72%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:32]2[CH2:36][CH2:35][O:34][CH2:33]2)=[CH:27][N:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:32]2[CH2:36][CH2:35][O:34][CH2:33]2)=[CH:27][N:26]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Brc1ccc(OC2CCOC2)cn1
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OC2CCOC2)cn1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and rac-2-bromo-5-(tetrahydro-furan-3-yloxy)-pyridine (Intermediate 21) in analogy to Example 1a): MS (ISN): 465.0 and 467.0 (M−H)−.
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[C@@H:9]([CH3:27])[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:23](=[O:24])[C:22]2[N:21]([CH3:25])[CH:20]=[N:19][C:18]=2[N:17]([CH3:26])[C:15]1=[O:16])(=O)=O.O>CS(C)=O>[C:1]([C@H:9]([CH3:27])[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:23](=[O:24])[C:22]2[N:21]([CH3:25])[CH:20]=[N:19][C:18]=2[N:17]([CH3:26])[C:15]1=[O:16])#[N:2]
Reactant: [C-]#N
Reactant: C[C@@H](CCCCn1c(=O)c2c(ncn2C)n(C)c1=O)OS(C)(=O)=O
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@@H](C#N)CCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: 50 °C
Yield: 45 %

Procedure:
Potassium cyanide (280 mg, 4.30 mmol) was added to a solution of (5)-1-(5-methanesulfonyloxyhexyl)-3,7-dimethylxanthine (prepared as described for CT11558) (770 mg, 2.15 mmol) in dimethylsulfoxide (10 ml). After heating at 50° C. for 24 hours, the mixture was poured into water (50 ml) and extracted with ethyl acetate (3x 50 ml). The combined extracts were washed with water (40 ml), saturated aqueous sodium chloride solution (40 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate to provide (R)-1-(5-cyanohexyl)-3,7-dimethylxanthine (CT16575) (280 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH2:8]Cl)=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]=2[N:22]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][N:18]([CH2:8][CH:7]=[CH:6][C:5]3[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:19][CH2:20][C:21]=2[N:22]=1
Reactant: ClCC=Cc1ccc(Cl)cc1
Reactant: Nc1nc2c(s1)CCNCC2
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: Nc1nc2c(s1)CCN(CC=Cc1ccc(Cl)cc1)CC2
Yield: 26 %

Procedure:
Prepared from 4-chloro-cinnamyl chloride and 1 equivalent of 2-amino-4,5,7,8-tetrahydro-6H- thiazolo[5,4-d]azepine in chloroform. Yield: 26% of theory, Melting point: 148°-153° C. (ether).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[O:10][N:9]=2)[CH:5]=[N:6][CH:7]=1.B1([C:25]2[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=2)OCCCO1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]1[O:10][N:9]=[C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[CH:3]=2)[N:12]=1
Reactant: c1cncc(B2OCCCO2)c1
Reactant: Brc1cncc(-c2noc(-c3ccccn3)n2)c1
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: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: c1ccc(-c2nc(-c3cncc(-c4cccnc4)c3)no2)nc1
Yield: 43.1 %

Procedure:
A mixture of 3-(5-bromo-pyrid-3-yl)-5-(2-pyridyl)-1,2,4-oxadiazole 30.3 mg, 0.1 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (32.5 mg, 0.2 mmol), and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, 15 mg, 0.013 mmol), in a solution of ethylene glycol dimethyl ether (1 mL) and 2M sodium carbonate (1 mL) was heated in a sealed vial at 100° C. for 1 hour. The reaction was cooled, diluted with dichloromethane, washed with water and saturated brine, filtered, and concentrated. Silica gel chromatography using 50% ethyl acetate in hexane and 100% ethyl acetate afforded 13 mg (43.2%) 5-(2-pyridyl)-3-[5-(3-pyridyl)-pyrid-3-yl]-1,2,4-oxadiazole. 1H-NMR (CDCl3), δ (ppm): 9.49 (d, 1H), 9.01 (d, 1H), 8.93 (dd, 2H), 8.72 (t, 2H), 8.35 (d, 2H), 8.00 (dt, 1H), 7.59 (m, 1H), 7.47 (dd, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH3:18])[CH:12]=2)=[C:4]([CH3:20])[CH:3]=1.Cl.[NH2:22][C:23]([NH2:25])=[O:24]>CCO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:25][C:23](=[O:24])[N:22]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH3:18])[CH:12]=3)[CH:9]=2)=[C:4]([CH3:20])[CH:3]=1
Reactant: Cc1cc(/C=C/C(=O)c2ccc(N)cc2C)ccc1O
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: Cc1cc(-c2cc(-c3ccc(N)cc3C)[nH]c(=O)n2)ccc1O
Temperature: 110 °C
Yield: 63.9 %

Procedure:
To a sealed pressure vessel was added (E)-1-(4-amino-2-methylphenyl)-3-(4-hydroxy-3-methylphenyl)prop-2-en-1-one (2) (1.5 g, 5.6 mmol), EtOH (10 mL), 4N HCl in dioxanes (20 mL, 80 mmol), and urea (1.74 g, 29.1 mmol). The pressure vessel was sealed and heated to 110° C. overnight. Another 1 g of urea was added and heated for another 5 h. The reaction was then cooled to rt, concentrated via rotary evaporation and columned purified on silica gel (10:90 to 20:80 MeOH:EtOAc) to give 6-(4-amino-2-methylphenyl)-4-(4-hydroxy-3-methylphenyl)pyrimidin-2(1H)-one (3) (1.1 g, 64% yield).