Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:19]3[CH2:21][CH2:20]3)[C:10](=[O:18])[N:11]([CH:13]([CH3:17])[C:14](O)=[O:15])[CH:12]=2)=[CH:4][CH:3]=1.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH2:28].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH:19]3[CH2:21][CH2:20]3)[C:10](=[O:18])[N:11]([CH:13]([CH3:17])[C:14]([NH:28][CH2:27][C:26]3[CH:29]=[CH:30][CH:31]=[C:24]([C:23]([F:22])([F:32])[F:33])[CH:25]=3)=[O:15])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)n1cc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Reactant: NCc1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C(=O)NCc1cccc(C(F)(F)F)c1)n1cc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg (0.163 mmol) of 2-(4-[4-chlorophenyl]-3-cyclopropyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-propionic acid from Example 131A, 31.4 mg (0.179 mmol) of 3-trifluoromethylbenzylamine, 40.6 mg (0.212 mmol) of EDC hydrochloride and 26.4 mg (0.196 mmol) of HOBt are dissolved in 1 ml of dry dimethylformamide and stirred overnight at room temperature. The mixture is partitioned between water and dichloromethane, and the separated organic phase is dried over sodium sulphate and concentrated. The crude product that remains is purified by flash chromatography on silica gel (eluent: first dichloromethane, then dichloromethane/methanol 100:1→50:1). 42 mg (56% of theory) of the target compound are thus obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH3:20])[N:8]=[C:9]2[C:18]=1[C:17]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=1[N:11]=[C:10]2[NH2:19].[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.[K].[I-].[Na+].CN(C=O)C>O>[NH2:19][C:10]1[C:9]2=[N:8][N:7]([CH3:20])[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:25]3[C:21](=[O:31])[C:22]4[C:23](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:24]3=[O:26])=[C:18]2[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[N:11]=1
Reactant: Cn1nc2c(N)nc3c(c2c1CCCCCl)CCCC3
Reactant: O=C1NC(=O)c2ccccc21
Agent: [I-]
Agent: [K]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc2c(N)nc3c(c2c1CCCCN1C(=O)c2ccccc2C1=O)CCCC3
Temperature: 90 °C

Procedure:
A mixture of 1-(4-chlorobutyl)-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinoline-4-amine (385 mg, 1.31 mmol), potassium phthalimide (362 mg, 1.96 mmol), sodium iodide (50 mg, 0.327 mmol), and DMF (2 mL) was heated at 90° C. for 4 hours. The reaction mixture was cooled to ambient temperature and then diluted with water (30 mL) while stirring in an ice bath. A precipitate was isolated by filtration to obtain 2-[4-(4-amino-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-1-yl)butyl]-1H-isoindole-1,3(2H)-dione as a yellow solid.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:9][CH:8]([CH3:10])[CH2:7][N:6]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)(=[O:13])=[O:12])[CH2:5][CH:4]1[OH:20].[NH:21]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C@H:22]([C:27](O)=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:33]([O:32][C:30](=[O:31])[NH:21][C@H:22]([C:27](=[O:28])[NH:2][CH:3]1[CH2:9][CH:8]([CH3:10])[CH2:7][N:6]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)(=[O:13])=[O:12])[CH2:5][CH:4]1[OH:20])[CH2:23][CH:24]([CH3:25])[CH3:26])([CH3:34])([CH3:36])[CH3:35]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC1CC(N)C(O)CN(S(=O)(=O)c2ccccn2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1CC(C)CN(S(=O)(=O)c2ccccn2)CC1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
4-Amino-6-methyl-1-(pyridine-2-sulfonyl)-azepan-3-ol HCl salt (0.21 g, 0.59 mmol) was dissolved in 5 ml DMF. To this solution, was added Boc-Leu-OH (0.22 g, 0.88 mmol) and HBTU (0.34 g, 0.90 mmol) and then NMM (0.24 g, 2.4 mmol). The mixture was stirred at RT overnight. DMF was removed under high vacuum. The residue was diluted in EtOAc and washed with H2O, 10% NaHCO3 and brine. Purification by column chromatography gave the title compound (0.2 g, 68% yield). MS (M+H+): 499.1; 1H-NMR (400 Hz, CDCl3): 8.75(d, 1H), 8.0-7.75(m, 2H), 7.5 5(m, 1H) 5.10(m, 1H), 4.15-2.90(m, 10H), 2.10-1.48(m, 14H), 1.00(m, 9H)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[C:14]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:11]=[C:10]([CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:14]([O:22][CH2:23][CH3:24])=[O:21])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1
Reactant: Cc1ccc2nc(Cl)cc(Cl)c2c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1cc(Cl)nc2ccc(C)cc12
Temperature: 70 °C
Reaction time: 3 h
Yield: 39.9 %

Procedure:
To a solution of 2,4-dichloro-6-methylquinoline (2.11 g, 10 mmol) and 1,3-diethyl propanedioate (2.64 g, 20 mmol) in N,N-dimethylformamide (40 mL) was added anhydrous potassium carbonate (2.8 g, 20 mmol). The mixture was stirred at 70° C. for 3 hours, then poured into ice/water (100 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (150 mL×2), dried over sodium sulfate. The residue was purified by flash column chromatography on silica gel (eluting with 20-30% ethyl acetate in petroleum ether) to afford 1.34 g of the desired product (yield was 40%). MS obsd. (ESI+) [(M+H)+] 336.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:26]=[CH:25][C:13]([CH2:14][NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1.FC(F)(F)S(O[C:33]1[C:42]([N+:43]([O-:45])=[O:44])=[C:41]([NH:46][CH2:47][CH2:48][CH2:49][NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=1)(=O)=O>C1(C)C=CC=CC=1>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:15]([CH2:14][C:13]2[CH:12]=[CH:11][C:10]([O:9][CH3:8])=[CH:26][CH:25]=2)[C:33]2[C:42]([N+:43]([O-:45])=[O:44])=[C:41]([NH:46][CH2:47][CH2:48][CH2:49][NH:50][C:51](=[O:52])[O:53][C:54]([CH3:56])([CH3:55])[CH3:57])[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Reactant: CC(C)(C)OC(=O)NCCCNc1c([N+](=O)[O-])c(OS(=O)(=O)C(F)(F)F)nc2ccccc12
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc3ccccc3c(NCCCNC(=O)OC(C)(C)C)c2[N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
Triethylamine (56.8 mL, 408 mmol) and N,N-bis(4-methoxybenzyl)amine (93.5 g, 0.340 mol) were sequentially added to a solution of 4-({3-[(tert-butoxycarbonyl)amino]propyl} amino)-3-nitroquinolin-2-yl trifluoromethanesulfonate (168 g, 0.340 mol) in toluene (200 mL) at ambient temperature. The solution was stirred at ambient temperature for a few minutes, heated at 65° C. overnight, allowed to cool to ambient temperature, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (>200 mL), and the resulting solution was washed three times with water, dried over magnesium sulfate, filtered through a layer of CELITE filter agent, concentrated under reduced pressure, and further dried under high vacuum to provide tert-butyl 3-({2-[bis(4-methoxybenzyl)amino]-3-nitroquinolin-4-yl} amino)propylcarbamate as a red oil, which was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:18][CH2:17][NH:16][CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:19][N:20]([CH3:24])[C:21](Cl)=[O:22]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:18][CH2:17][N:16]([C:21]([N:20]([CH3:24])[CH3:19])=[O:22])[CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)Cl
Reactant: Clc1cccc(C#CC2=NOC3(CCNC3)C2)c1
Solvent: ClCCl
Product: CN(C)C(=O)N1CCC2(CC(C#Cc3cccc(Cl)c3)=NO2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.8 %

Procedure:
To a solution of Compound 27d (0.12 g, 0.46 mmol) in 10 mL of dichloromethane was added TEA (0.02 mL, 1.38 mmol) followed by N,N-dimethylchloroformamide (0.051 mL, 0.59 mmol). The reaction mixture was stirred at r.t. for 4 h. Afterwards, it was evaporated to dryness and purified by means of automated flash chromatography (SP01®TM-Biotage; gradient Petroleum Ether-EtOAc from 3:7 to 0:1) to give the title compound as a pale yellow solid. Yield: 68.8%.
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C>[CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
Ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (270 mg, 0.80 mmol)) was dissolved in ethanol (2 mL) and 1M aqueous NaOH solution was added. The solution was stirred one hour at room temperature, then neutralized by addition of 1M aqueous HCl. The resulting solid was collected, washed with water, and dried under vacuum overnight to give the title compound (208 mg, 84%). LC/MS m/z 312 (M+H+)
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[C:11]([Cl:13])[N:10]=[C:9](Cl)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].CN1C(=O)CCC1.[CH2:23]([Mg]Cl)[CH:24]([CH3:26])[CH3:25]>C1COCC1>[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:8]=[C:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[N:10]=[C:11]([Cl:13])[CH:12]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)nc(Cl)c1
Reactant: CC(C)C[Mg]Cl
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CC(C)Cc1cc(C(=O)OC(C)(C)C)cc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of 2,6-dichloro-isonicotinic acid tert.-butyl ester (1.74 g, 7.0 mmol), Fe(acac)3 (706 mg, 2.0 mmol) and NMP (1.0 g, 10 mmol) in THF (250 mL), a solution of isobutylmagnesium chloride (1.15 g, 9.8 mmol) in THF is slowly added at −77° C. The brown solution turns turbid and black. Stirring is continued for 1 h at −72° C. before it is warmed to rt. The mixture is again cooled to −40° C. and then stirred for 16 h. The reaction is carefully quenched with 0.5 N aq. HCl (100 mL) and diluted with ether. The org. layer is separated and the aq. phase is extracted five more times with ether. The combined org. extracts are dried over MgSO4, filtered and evaporated. The crude product is purified by MPLC on silica gel to give 2-chloro-6-isobutylisonicotinic acid tert.-butyl ester as a pale yellow oil (1.70 g) which contains 2,6-di-isobutylisonicotinic acid tert.-butyl ester as an impurity; LC-MS: tR=1.12 min, [M+1]+=270.07.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:32])=[C:4]([CH:29]=[CH:30][CH:31]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:26])[CH2:24]Cl)[CH2:19][CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[I-].[Na+].[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[Cl:1][C:2]1[C:3]([F:32])=[C:4]([CH:29]=[CH:30][CH:31]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:26])[CH2:24][N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)[CH2:19][CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)CCl)CC1
Reactant: C1CCNC1
Agent: [I-]
Agent: [Na+]
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)CN2CCCC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 4-(3-chloro-2-fluoroanilino)-6-[1-(chloroacetyl)piperidin-4-yloxy]-7-methoxyquinazoline (0.15 g) (starting material used in Example 17) and sodium iodide (0.02 g) in pyrrolidine (5 ml) was stirred at ambient temperature for 16 hours. The mixture was evaporated under vacuum and the residue dissolved in methylene chloride/methanol. This was adsorbed onto silica and purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 92/8). The fractions containing the title product were combined and evaporated under vacuum and the residue triturated with diethyl ether, filtered and dried under vacuum to give the title product as a white crystalline solid. (0.085 g); 1H NMR Spectrum: (DMSO d6) 1.57-1.77 (m, 6H), 1.92-2.09 (m, 2H), 3.20-3.48 (m, 8H), 3.80-3.90 (m, 2H), 3.94 (s, 3H), 4.75 (m, 1H), 7.2-7.31 (m, 2H), 7.45-7.55 (m, 2H), 7.86 (s, 1H), 8.37 (s, 1H), 9.53 (s, 1H); Mass Spectrum: (M−H)+ 514.
Reaction SMILES: ClC1SC2[NH:6][C:7]([C:9]([NH:11][CH:12]3[CH2:21][C:20]4[C:15](=CC=CC=4)[N:14](CC4NN=NN=4)[C:13]3=O)=[O:10])=[CH:8]C=2C=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:6][CH:7]1[CH2:8][C:21]2[C:12](=[CH:13][N:14]=[CH:15][CH:20]=2)[NH:11][C:9]1=[O:10]
Reactant: O=C(NC1Cc2ccccc2N(Cc2nnn[nH]2)C1=O)c1cc2cc(Cl)sc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1Cc2ccncc2NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 319.5 %

Procedure:
tert-Butyl (2-oxo-1,2,3,4-tetrahydro-1,7-naphthyridine-3-yl)carbamate (Method 29, 284 mg) was dissolved in DCM (10 mL) and treated with trifluoroacetic acid (5 mL). After stirring at ambient temperature for 1 hour the reaction mixture was evaporated under reduced pressure and the residue triturated with ether (20 mL), to give a light brown solid which was collected by filtration, washed with ether and dried to give the title compound (346 mg, 82%) as a bis trifluoracetate salt.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1C(OC(C)(C)C)=O.Cl.CCOCC>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][NH:10]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1cc(F)ccc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Fc1ccc(F)c([C@H]2CCCN2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To (R)-tert-butyl 2-(2,5-difluorophenyl)pyrrolidine-1-carboxylate (23.9 g, 84.4 mmol) was added 4N HCl in dioxane (56.2 mL). After stirring at ambient temperature for 2 hours, ether (200 mL) was added and the mixture was stirred for 10 minutes. The resulting slurry was filtered, yielding the title compound hydrochloride salt as a white solid (17.2 g). To obtain the free base, the HCl salt product was dispersed in a mixture of EtOAc (200 mL) and NaOH solution (100 mL, 2 N aq.) The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were filtered and concentrated to give the desired product as a liquid (13.2 g, 85% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]1([CH2:14][CH2:13][CH2:12]1)[C:7](=[O:15])[C:6]([C:16](OCC)=[O:17])=[C:5]2[OH:21].Cl.[C:23]([O:27][C:28](=[O:31])[CH2:29][NH2:30])([CH3:26])([CH3:25])[CH3:24].CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]1([CH2:14][CH2:13][CH2:12]1)[C:7](=[O:15])[C:6]([C:16]([NH:30][CH2:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:31])=[O:17])=[C:5]2[OH:21]
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCC2)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCC2)C1=O
Temperature: 75 °C
Reaction time: 3.5 h
Yield: 76.3 %

Procedure:
A mixture of ethyl 6′-chloro-4′-hydroxy-2′-oxo-spiro[cyclobutane-1,1′-naphthalen]-3′-carboxylate (155 mg, 505 μmol) and glycine tert-butyl ester hydrochloride (102 mg, 606 μmol) were mixed in dioxane (4 mL). DIPEA (106 μL, 606 μmol) was added, and the reaction mixture was stirred at 75° C. for 3.5 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting yellow solid was purified by silica flash chromatography (0-50% DCM/hexane) to give the desired compound as a white solid (151 mg). MS (m/e)=336.1 (M+H-tBu)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:6][CH:5]=[CH:4][N:3]=1.S(O[CH:22]([CH2:26][C:27]#[CH:28])[C:23](=O)[CH3:24])(C)(=O)=O>C(O)C>[CH3:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][C:7]1[C:2]2[N:3]([C:22]([CH2:26][C:27]#[CH:28])=[C:23]([CH3:24])[N:1]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: C#CCC(OS(C)(=O)=O)C(C)=O
Reactant: Cc1ccccc1CNc1cccnc1N
Solvent: CCO
Product: C#CCc1c(C)nc2c(NCc3ccccc3C)cccn12
Yield: 30.3 %

Procedure:
A solution of 2-amino-3-(2-methylbenzylamino)pyridine (2 g) and 3-mesyloxy-5-hexyn-2-one (1.78 g) in ethanol (40 ml) was refluxed for 31.5 hours and then evaporated in vacuo. The residue was treated with aqueous sodium bicarbonate solution and extracted with methylene chloride. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (40 g) with a mixtutre of methylene chloride and ethyl acetate (50:1 to 10:1) as an eluent to give 8-(2-methylbenzylamino)-3-(2-propynyl)-2-methylimidazo[1,2-a]pyridine (0.82 g).
Reaction SMILES: [CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([F:24])[CH:18]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[F:25][C@H:26]([CH2:30][CH2:31][CH3:32])[CH2:27][CH2:28]O>>[CH2:1]([C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:28][CH2:27][C@H:26]([F:25])[CH2:30][CH2:31][CH3:32])=[C:19]([F:24])[CH:18]=2)=[N:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCC[C@@H](F)CCO
Reactant: CCCCCCCCCCc1cnc(-c2ccc(O)c(F)c2)nc1
Product: CCCCCCCCCCc1cnc(-c2ccc(OCC[C@H](F)CCC)c(F)c2)nc1
Yield: 28.9 %

Procedure:
The titled compound was synthesized from 5-decyl-2-(3-fluoro-4-hydroxyphenyl)pyrimidine and (R)-3-fluorohexanol.
Reaction SMILES: C(N(CC)CC)C.[SH:8][C:9]1[O:13][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:15]=2)=[N:11][N:10]=1.[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br>>[C:23]([O:22][C:21](=[O:27])[NH:20][C:16]1[CH:15]=[C:14]([C:12]2[O:13][C:9]([S:8][CH2:32][C:31]3[CH:34]=[CH:35][CH:36]=[C:29]([F:28])[CH:30]=3)=[N:10][N:11]=2)[CH:19]=[CH:18][N:17]=1)([CH3:24])([CH3:26])[CH3:25]
Reactant: Fc1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(-c2nnc(S)o2)ccn1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cc(-c2nnc(SCc3cccc(F)c3)o2)ccn1
Yield: 93 %

Procedure:
In the same manner as in Example 1 and using tert-butyl [4-(5-mercapto-1,3,4-oxadiazol-2-yl)-2-pyridyl]carbamate triethylamine salt instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 3-fluorobenzyl bromide instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 93%) was obtained as colorless crystals.
Reaction SMILES: C([N:3]([CH2:14][CH3:15])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[CH3:12])C.[Li]CCCC.C(C1[CH:39]=[CH:38][C:26]([C:27]([N:29]([CH3:37])[CH:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[O:28])=[CH:25][CH:24]=1)#N.O>C1COCC1>[CH3:37][N:29]([CH:30]1[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]1)[C:27](=[O:28])[C:26]1[CH:38]=[CH:39][C:15]([C:14]2[NH:3][C:4](=[O:13])[C:5]3[C:6]([CH:12]=2)=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=3)=[CH:24][CH:25]=1
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Reactant: CN1CCC(N(C)C(=O)c2ccc(C#N)cc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc2c(=O)[nH]c(-c3ccc(C(=O)N(C)C4CCN(C)CC4)cc3)cc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 44.3 %

Procedure:
To a solution of N,N-diethyl-2,3-dimethyl-benzamide (578 mg, 2.82 mmol) in anhydrous THF (3 mL) under N2 at −78° C. was added dropwise n-BuLi (2.5M in n-hexanes, 2.4 mL, 5.92 mmol) to give a deep red solution. The reaction mixture was stirred at −78° C. for 30 minutes. The reaction mixture was transferred dropwise, via syringe, to a reaction vessel containing 4-cyano-N-methyl-N-(1-methyl-piperidin-4-yl)-benzamide (725 mg, 2.82 mmol) in anhydrous THF (5 mL) at −78° C. and under N2. The reaction mixture was stirred at −78° C. for 3.5 h. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (10 mL) and CH2Cl2 (10 mL). The combined organic layers concentrated in vacuo and the resultant solid was triturated with 2:1 isohexane/EtOAc, filtered and dried in vacuo. The crude material was purified by silica gel column chromatography, eluting with CH2Cl2 and increasing the polarity to 15% MeOH/CH2Cl2 to afford N-methyl-4-(5-methyl-1-oxo-1,2-dihydro-isoquinolin-3-yl)-N-(1-methyl-piperidin-4-yl)-benzamide as a white solid (487 mg, 44%).
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][N:17]=[C:18]([Cl:19])[C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>C(#N)C>[Cl:19][C:18]1[C:12]2[O:11][CH2:10][CH2:9][NH:8][CH2:14][C:13]=2[CH:15]=[CH:16][N:17]=1
Reactant: Clc1nccc2c1OCCN(Cc1ccccc1)C2
Agent: CC(Cl)OC(=O)Cl
Solvent: CC#N
Product: Clc1nccc2c1OCCNC2
Temperature: 90 °C
Reaction time: 2 h
Yield: 42.2 %

Procedure:
To a solution of the compound (0.30 g) obtained in Example 8 in acetonitrile (10 mL) was added 1-chloroethyl chloroformate (0.13 mL) at room temperature, and the mixture was stirred at 90° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and then the obtained residue was dissolved in MeOH (10 mL), and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in ethyl acetate and water, and made basic with aqueous sodium hydroxide solution. The resultant product was extracted with ethyl acetate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient; 50% ethyl acetate/hexane→0.1% aqueous ammonia/ethyl acetate) to give the title compound (0.085 g, 42%) as a white powder.
Reaction SMILES: Cl.[OH:2][C:3]1[C:4]([CH2:9][OH:10])=[N:5][CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH:17]1(Br)[CH2:20][CH2:19][CH2:18]1.Cl>CN(C)C=O.O>[CH:17]1([O:2][C:3]2[C:4]([CH2:9][OH:10])=[N:5][CH:6]=[CH:7][CH:8]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: BrC1CCC1
Reactant: OCc1ncccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCc1ncccc1OC1CCC1
Yield: 27.3 %

Procedure:
3-Hydroxy-2-(hydroxymethyl)pyridine hydrochloride (1.57 g, 0.009 mol), potassium carbonate (8.09 g, 0.058 mol) and cyclobutyl bromide (5.0 g, 0.037 mol) were stirred together under nitrogen in N,N-dimethylformamide (20 ml) at 50° C. overnight. Water (40 ml) was added, and the resultant solution was acidified to pH 1 with hydrochloric acid (5 N). The solution was washed with dichloromethane (3×100 ml), basified to pH 14 with sodium hydroxide solution (4 N), and extracted with dichloromethane (3×100 ml). The organic layers from the extraction were combined, washed with water (1×100 ml), dried over magnesium sulfate and concentrated in uacuo to give a dark brown solid which was recrystallised from hexane to give the title compound (0.44 g). 1H NMR (250 MHz, CDCl3) δ 1.61-1.81 (1H, m), 1.86-1.91 (1H, m), 2.09-2.22 (2H, m), 2.39-2.51 (2H, m), 4.31 (1H, br s), 4.66 (1H, m), 4.74 (1H, s), 6.97 (1H, m), 7.07-7.17 (1H, m), 8.13 (1H, m); MS (ES+) m/e 180 [MH]+.