Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[S:8])=[CH:4][CH:3]=1.O.[OH-].[Na+:25]>CC(C)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]([NH:9][C@H:10]([C:18]([O-:20])=[O:19])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[S:8])=[CH:21][CH:22]=1.[Na+:25]
Reactant: Cc1ccc(CC(=S)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(CC(=S)N[C@@H](Cc2ccccc2)C(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
3.6 G (0.011 mol) of N-(4-methylbenzylthiocarbonyl)-L-phenylalanine was dissolved in 10 ml of acetone. To the mixture were added 30 ml of water and 10 ml of 1N-sodium hydroxide and then the mixture was stirred at room temperature for 1 to 2 minutes to obtain a transparent solution. After the solution was washed with 30 ml of ether twice, the water layer was evaporated under reduced pressure. To remove the remaining amounts of water from the residue, a small quantity of ethanol was added to the residue and then evaporated under reduced pressure. This operation was repeated three times. Thus, the residue was completely dried to obtain 3.4 g of white powder of the desired sodium salt.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@@H:8]([C:20](=[O:43])[N:21]([CH3:42])[C@@H:22]([C:30](=[O:41])[N:31]([CH3:40])[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:42][N:21]([C@@H:22]([C:30](=[O:41])[N:31]([CH3:40])[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:20](=[O:43])[C@H:8]([NH:7][CH3:6])[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1
Reactant: CN(CCc1ccccn1)C(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)N(C)CCc1ccccn1
Reaction time: 0.67 h
Yield: 95.5 %

Procedure:
N-Methyl-N-[(1R)1-(N-methyl-N-{(1R)-1-[N-methyl-N-(2-(pyridinyl)ethyl)carbamoyl]-2-phenylethyl}carbamoyl)-2-(2-naphthyl)ethyl]carbamic acid tert-butyl ester (14.9 g, 24.5 mmol) was dissolved in dichloromethane (75 mL). Trifluoroacetic acid (75 mL, 0.978 mol) was added to the stirred solution. The reaction mixture was stirred for 40 min. The solvent was removed in vacuo. The product was dissolved in dichloromethane (50 mL) and sat. aqueous sodium hydrogen carbonate solution (40 mL). The mixture was neutralised with solid sodium hydrogen carbonate. Dichloromethane (100 mL) was added and the aqueous phase was extracted with dichloromethane (2×150 mL). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo, to give 11.9 g of (2R)-N-Methyl-2-(methylamino)-N-{(1R)-1-[N-methyl-N-(2-(pyridin-2-yl)ethyl)carbamoyl]-2-phenylethyl}-3-(2-naphthyl)propionamide.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[CH2:6][N:7]1[CH2:11][C@H:10]2[C@@H:12]([NH:15][C:16](=[O:23])[C@H:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[NH2:18])[CH2:13][CH2:14][C@H:9]2[CH2:8]1.C(N(CC)CC)C.[CH:36]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37]1>ClCCl>[CH:36]1([S:39]([NH:18][C@H:17]([C:16]([NH:15][C@@H:12]2[C@H:10]3[C@H:9]([CH2:8][N:7]([CH2:6][C:5]4[CH:24]=[CH:25][CH:26]=[C:3]([C:2]([F:27])([F:1])[F:28])[CH:4]=4)[CH2:11]3)[CH2:14][CH2:13]2)=[O:23])[CH2:19][CH:20]([CH3:21])[CH3:22])(=[O:41])=[O:40])[CH2:38][CH2:37]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(C)C[C@H](N)C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NS(=O)(=O)C1CC1)C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N1-{(3aS,4S,6aR)-2-[3-(trifluoromethyl)benzyl]octahydrocyclopenta[c]pyrrol-4-yl}-L-leucinamide from Step A (80 mg, 0.184 mmol) in dichloromethane (0.5 mL) was added triethylamine (0.064 mL, 0.461 mmol) followed by cyclopropanesulfonyl chloride (38.9 mg, 0.277 mmol) in a solution of 300 μL dichloromethane and the reaction mixture was stirred at room temperature overnight. The reaction was reduced in volume and loaded onto a silica gel cartridge (Analogix®, Burlington, Wis., RS-12). The title compound was eluted with a gradient of 20% to 100% ethyl acetate/hexanes over 20 minutes to give N2-(cyclopropylsulfonyl)-N1-{(3aS,4S,6aR)-2-[3-(trifluoromethyl)benzyl]octahydrocyclopenta[c]pyrrol-4-yl}-L-leucinamide: 1H NMR (500 MHz, pyridine-d5) δ ppm 9.34 (d, J=9.0, 1H), 8.84 (d, J=6.8, 1H), 7.73 (s, 1H), 7.64 (d, J=7.5, 1H), 7.59 (d, J=12.3, 1H), 7.43 (dd, J=6.6, 14.3, 1H), 4.53-4.42 (m, 2H), 3.76 (d, J=13.2, 1H), 3.41 (d, J=13.2, 1H), 2.99 (qd, J=4.2, 8.0, 1H), 2.90 (dd, J=3.6, 9.5, 1H), 2.82-2.74 (m, 1H), 2.57-2.48 (m, 1H), 2.40 (dd, J=8.5, 19.8, 2H), 2.30 (dd, J=3.4, 9.2, 1H), 2.02 (td, J=6.5, 13.7, 1H), 1.94-1.85 (m, 2H), 1.85-1.78 (m, 1H), 1.71 (td, J=6.2, 11.6, 1H), 1.67-1.58 (m, 1H), 1.40-1.28 (m, 2H), 1.22 (dt, J=4.7, 10.8, 1H), 0.93 (ddd, J=6.6, 12.3, 14.0, 2H), 0.87 (d, J=6.5, 3H), 0.84 (d, J=6.7, 3H); MS (ESI+) m/z 502 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][C@H:12]1[CH2:17][NH:16][CH2:15][CH2:14][NH:13]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[CH3:11][C@@H:12]1[NH:13][CH2:14][CH2:15][N:16]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:17]1
Reactant: C[C@H]1CNCCN1
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@H]1CN(c2ccccc2[N+](=O)[O-])CCN1
Yield: 479.1 %

Procedure:
To a solution of 2-bromo-nitrobenzene (0.6 g, 3.0 mmol) in 1,4-dioxane (15 mL) was added (S)-(+)-2-methylpiperazine (0.5 g, 0.5 mmol) and powdered K2CO3 (15.0 mmol, 1.5 g) and the resulting suspension was heated at reflux for 10 h. After the suspension was cooled, it was filtered through a sintered glass funnel and the solvent was evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel (1:1 hexane/EtOAc followed by 4:1 EtOAc/MeOH) to yield (S)-(+)-3-methyl-1-(2-nitrophenyl)-piperazine as an orange oil (0.53 g, 80%). It was converted into (S)-(+)-3-methyl-1-(2-nitrophenyl)-4-(3-aminopropyl)-piperazine by the usual procedure.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.Cl.[F:17][C:18]1[CH:19]=[C:20]([CH:24]([NH:28][C:29]2[CH:34]=[C:33]([F:35])[C:32]([F:36])=[C:31]([F:37])[CH:30]=2)[C:25]([OH:27])=[O:26])[CH:21]=[CH:22][CH:23]=1.C1C=CC2N(O)N=NC=2C=1.[N:48]12[CH2:55][CH2:54][CH:51]([CH2:52][CH2:53]1)[C@@H:50](O)[CH2:49]2>O1CCCC1>[F:17][C:18]1[CH:19]=[C:20]([CH:24]([NH:28][C:29]2[CH:34]=[C:33]([F:35])[C:32]([F:36])=[C:31]([F:37])[CH:30]=2)[C:25]([O:27][C@@H:50]2[CH:51]3[CH2:54][CH2:55][N:48]([CH2:53][CH2:52]3)[CH2:49]2)=[O:26])[CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)C(Nc1cc(F)c(F)c(F)c1)c1cccc(F)c1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1cc(F)c(F)c(F)c1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
Polymer-Supported DiCyclohexylCarbodiimide (PS-DCC) (972 mg, 1.29 mmol, loading: 1.33 mmol/g) was suspended in dry tetrahydrofuran (10 ml). 2-(3-fluorophenyl)-2-(3,4,5-trifluorophenylamino)acetic acid hydrochloride (I42) (217 mg, 0.65 mmol), HOBT (198 mg, 1.29 mmol), and (R)-quinuclidin-3-ol (247 mg, 1.94 mmol) were added, and the mixture was shaken at r.t. for 16 hours. PS-DCC was filtered off, the filtrate was evaporated and the residue was dissolved in EtOAc and washed with NaHCO3, water and brine. The organic layer was dried over Na2SO4, filtered and evaporated. The resulting crude compound was purified by filtration through a pad of silica-gel eluting with DCM/MeOH=93/7. The resulting white foam was dissolved in DCM and passed through an Isolute PE-AX cartridge (5 g, 0.6 mmol/g, DCM/MeOH=9/1) to obtain (R)-quinuclidin-3-yl 2-(3-fluorophenyl)-2-(3,4,5-trifluorophenylamino)acetate (264 mg, 32% yield).
Reaction SMILES: C(C1C=NC(C2C=CC(O[CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]([O:30][C:31]([F:48])([F:47])[C:32]([F:46])([F:45])[O:33][C:34]([F:44])([F:43])[C:35]([F:42])([F:41])[O:36][C:37]([F:40])([F:39])[F:38])([F:29])[F:28])=CC=2)=NC=1)CCCCCCC.[CH2:49]([O:55][C:56]1[CH:57]=[N:58][C:59]([C:62]2[CH:67]=[CH:66][C:65]([OH:68])=[CH:64][CH:63]=2)=[N:60][CH:61]=1)[CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]>O>[CH2:49]([O:55][C:56]1[CH:61]=[N:60][C:59]([C:62]2[CH:63]=[CH:64][C:65]([O:68][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]([O:30][C:31]([F:47])([F:48])[C:32]([F:45])([F:46])[O:33][C:34]([F:43])([F:44])[C:35]([F:41])([F:42])[O:36][C:37]([F:40])([F:39])[F:38])([F:29])[F:28])=[CH:66][CH:67]=2)=[N:58][CH:57]=1)[CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: CCCCCCCCc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1
Reactant: CCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Solvent: O
Product: CCCCCCOc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 3-(2-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-1-chloropropane (5.42 g, 11.4 mmol, Example 24) with 5-hexyloxy-2-(4-hydroxyphenyl)pyrimidine (3 g, 10.0 mmol). Product was isolated by addition of water (100 mL) to the resulting mixture, followed by filtration and recrystallization from ethanol. The recrystallized precipitate was dried at about 130° C., and the resulting product was further purified by Kugelrohr distillation (b.p. 170°-180° C. at 2.0 torr; yield of 5.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[NH2:50][CH2:51][CH2:52][CH2:53][N:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1>>[CH3:47][O:46][C:43]1[CH:44]=[CH:45][C:40]([CH2:39][N:8]([CH2:7][C:6]2[CH:48]=[CH:49][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([NH:50][CH2:51][CH2:52][CH2:53][N:54]6[CH2:59][CH2:58][O:57][CH2:56][CH2:55]6)=[O:35])=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:41][CH:42]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Reactant: NCCCN1CCOCC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)NCCCN4CCOCC4)cc3)cn2)cc1
Yield: 75.2 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid (50.0 mg, 0.0758 mmol) obtained in Step A in Example 1-D-19 and N-(3-aminopropyl)morpholine (22.1 μl, 0.152 mmol) instead of 3-(aminomethyl)pyridine, amidation was conducted in the same manner as Step B in Example 1-D-19, to obtain a crude product of 4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-N-(3-morpholin-4-yl-propyl)-benzamide as a yellow solid (44.8 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-93) as a yellow powder (29.3 mg, 71%).
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1.[CH3:14][CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][C:19]([CH3:24])=[CH:20][CH:21]=2)[C:16]1=O>O>[CH3:14][C:15]1([CH2:1][OH:4])[CH2:16][C:17]2[C:22](=[CH:21][CH:20]=[C:19]([CH3:24])[CH:18]=2)[CH2:23]1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc2c(c1)C(=O)C(C)C2
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc2c(c1)CC(C)(CO)C2
Reaction time: 2 h
Yield: 215.1 %

Procedure:
147.53 g of K2CO3, 875 g of toluene and 350 g of 2,6-dimethyl indanone were introduced, under nitrogen, into a Schmizo-type 1.5 l vessel provided with a condenser and a mechanical stirrer. The mixture was heated to 51°. 122.45 g of Formcel® 55% (origin: Hoechst) were then added over a period of 1 h. The mixture was stirred continuously at 51° for 2 h. The reaction medium was then cooled to 24° and 350 g of water were added. After being stirred for 10 mins, the mixture was decanted, then washed 3 times with water. Concentration in vacuo produced 404.71 g of raw product pure to 97.6% (GC).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][CH:17]3[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26](F)[CH:25]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:42][NH2:43]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][CH:17]3[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:25]=[C:26]3[C:27]([C:30]([NH2:31])=[N:42][NH:43]3)=[CH:28][CH:29]=2)[N:3]=1
Reactant: NN
Reactant: CC1CCC(NC(=O)[C@H]2CCCN(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC1CCC(NC(=O)[C@H]2CCCN(c3cc(-c4ccc5c(N)n[nH]c5c4)nc(N)n3)C2)CC1
Temperature: 150 °C
Yield: 64.1 %

Procedure:
Into a microwave tube, (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-(4-methylcyclohexyl)-3-piperidinecarboxamide (190 mg, 0.435 mmol), 3 mL of EtOH, Hunig's base (0.30 mL, 1.74 mmol), and hydrazine anhydrous (0.082 mL, 2.61 mmol) were added, and the yellow mixture was heated at 150° C. for 180 minutes under microwave conditions. The solution turned black. LCMS showed mainly product. The black solids were filtered and the yellow filtrate was evaporated. The yellow residue was sonicated in EtOAc at 50° C., and the solid was filtered. This material was then sonicated in water at 50° C., and the solid was filtered and washed with water to afford the title compound (125 mg) as a light yellow solid. LC-MS (ES) m/z=449 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.87 (m, 3H), 0.89-1.94 (m, 13H), 2.18-2.44 (m, 1H), 2.78-3.05 (m, 2H), 3.76 (m, 1H), 4.39 (m, 2H), 5.38 (s, 2H), 6.12 (s, 2H), 6.62 (s, 1H), 7.54-7.79 (m, 3H), 7.90-7.99 (m, 1H), 11.51 (s, 1H).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([CH2:23][CH2:24][C:25](O)=[S:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][SH:34])=[CH:31][CH:30]=1>C(Cl)Cl>[CH2:16]([CH2:23][CH2:24][C:25](=[S:26])[S:34][CH2:33][C:32]1[CH:35]=[CH:36][C:29]([F:28])=[CH:30][CH:31]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OC(=S)CCCc1ccccc1
Reactant: Fc1ccc(CS)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: Fc1ccc(CSC(=S)CCCc2ccccc2)cc1
Reaction time: 8 h

Procedure:
6.18 g (30 mmoles) of dicyclohexylcarbodiimide in 20 ml of methylene chloride were added to a solution, which had been cooled to 0° C., of 5.9 g (30 mmoles) of 3-benzylthiopropionic acid and 4.26 g (30 mmoles) of 4-fluorobenzylmercaptan in 25 ml of methylene chloride, and the mixture was kept overnight at room temperature. After filtering off the dicyclohexylurea and stripping off the solvent, the crude product was purified, first by chromatography, on silica gel, from 1:2 methylene chloride/petroleum ether and then by distillation in a bulb tube.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[C:11]([CH2:13][C:14]([NH:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:18][CH2:19][CH3:20])=[O:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([O:1][C:2]1[CH:12]=[C:11]([CH2:13][C:14]([NH:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:18][CH2:19][CH3:20])=[O:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCc1ccccc1
Reactant: CCCC(NC(=O)Cc1ccc(C(=O)OCC)c(O)c1)c1ccccc1N1CCCCC1
Product: CCCC(NC(=O)Cc1ccc(C(=O)OCC)c(OCc2ccccc2)c1)c1ccccc1N1CCCCC1

Procedure:
Prepared from ethyl 2-hydroxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate, using benzyl bromide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[CH2:11]([N:14]1[C:18]2[N:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[CH2:23]Cl)[CH2:12][CH3:13]>C(#N)C>[CH2:11]([N:14]1[C:18]2[N:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[CH2:23][NH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:12][CH3:13]
Reactant: COc1ccc(CN)cc1
Reactant: CCCn1c(CCl)nc2cccnc21
Solvent: CC#N
Product: CCCn1c(CNCc2ccc(OC)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 10 h
Yield: 60.9 %

Procedure:
4-Methoxybenzylamine (3.8 g, 27 mmol) is dissolved in 20 mL dry acetonitrile. 1-propyl-2-chloromethyl-7-azabenzimidazole (173)(940 mg, 4.5 mmol) dissolved in 4.5 mL acetonitrile is added dropwise. The mixture is stirred 10 hours at room temperature. The solvent is removed in vacuo and the residue dissolved in 20 mL ethyl acetate. This solution is washed once with 20 mL 1 N NaOH, once with 20 mL water, once with 20 mL 5% HOAc in water, then once with 5 N NaOH. The organic phase was dried over MgSO4, filtered, then concentrated in vacuo. The product mixture is purified by flash chromatography eluting with ethyl acetate followed by 95/5/1 ethyl acetate/methanol/triethylamine to afford 850 mg of the 1-propyl-2-(4-methoxybenzylamino)methyl-7-azabenzimidazole (184).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](N2CCC(C3N(C)C=C(C4C=CC(F)=C(C(F)(F)F)C=4)N=3)CC2)[N:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O.[N:40]1([CH2:44][CH2:45][N:46]2[CH:50]=[C:49]([C:51]3[CH:56]=[CH:55][C:54]([O:57][CH:58]([F:60])[F:59])=[CH:53][CH:52]=3)[N:48]=[C:47]2[CH:61]2[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]2)[CH2:43][CH2:42][CH2:41]1>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:64]2[CH2:63][CH2:62][CH:61]([C:47]3[N:46]([CH2:45][CH2:44][N:40]4[CH2:43][CH2:42][CH2:41]4)[CH:50]=[C:49]([C:51]4[CH:52]=[CH:53][C:54]([O:57][CH:58]([F:60])[F:59])=[CH:55][CH:56]=4)[N:48]=3)[CH2:66][CH2:65]2)[N:5]=[CH:4][N:3]=1
Reactant: FC(F)Oc1ccc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)cc1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(OC(F)F)cc3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile using 4-[1-(2-Azetidin-1-yl-ethyl)-4-(4-difluoromethoxy-phenyl)-1H-imidazol-2-yl]-piperidine trifluoroacetate instead of 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine. LC-MS: (M+1=495, obsd.=495).
Reaction SMILES: C[O-].[Na+].[CH2:4]([O:6][CH:7]([O:10][CH2:11][CH3:12])[C:8]#[N:9])[CH3:5].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][NH2:18]>CO>[CH2:4]([O:6][CH:7]([O:10][CH2:11][CH3:12])[C:8](=[NH:9])[NH:18][CH2:17][C:16]1[CH:19]=[CH:20][CH:21]=[C:14]([F:13])[CH:15]=1)[CH3:5]
Reactant: NCc1cccc(F)c1
Reactant: CCOC(C#N)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(OCC)C(=N)NCc1cccc(F)c1
Temperature: 25 °C
Yield: 108.1 %

Procedure:
A solution of sodium methoxide (23%, 4.1 mL, 16 mmol) in MeOH was added to a solution of diethoxyacetonitrile (22 g, 86 mmol) in MeOH (400 mL) with stirring. The solution was stirred at room temperature overnight. The solvent was distilled off under reduced pressure. The residue was dissolved in diethyl ethyl (200 mL) and washed with washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The crude material was dissolved in MeOH (100 mL), and m-fluorobenzylamine (10 g, 80 mmol) was added. Then this solution was heated under reflux overnight. After cooled to room temperature, the solvent was distilled off under reduced pressure to give the crude title compound (22 g).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(CC)CC)C.[Br:12][C:13]1[C:18]([O:19][CH2:20][CH3:21])=[CH:17][C:16]([OH:22])=[C:15]([CH2:23][CH3:24])[CH:14]=1>C(Cl)Cl>[Br:12][C:13]1[C:18]([O:19][CH2:20][CH3:21])=[CH:17][C:16]([O:22][C:1](=[O:3])[CH3:2])=[C:15]([CH2:23][CH3:24])[CH:14]=1
Reactant: CC(=O)Cl
Reactant: CCOc1cc(O)c(CC)cc1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc(OC(C)=O)c(CC)cc1Br
Reaction time: 0.75 h
Yield: 53.4 %

Procedure:
Acetyl chloride (0.91 mL, 12.8 mmol) followed by triethylamine (1.8 mL, 12.8 mmol) were added to a stirred solution of 4-bromo-5-ethoxy-2-ethyl-phenol (2.6 g, 10.7 mmol) dissolved in CH2Cl2 (20 mL). The reaction was stirred for 45 mins and then partitioned between 1N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine dried over Na2SO4 and concentrated. Purification by flash column chromatography (0% to 20% EtOAc in hexanes) gave the product as a clear oil (1.64 g, 53%). 1H NMR (400 MHz, CDCl3): δ 1.16 (t, J=7.6 Hz, 3 H), 1.45 (t, J=7.1 Hz, 3 H), 2.31 (s, 3 H), 2.45 (q, J=7.6 Hz, 2 H), 4.05 (q, J=7.1 Hz, 2 H), 6.58 (s, 1 H), 7.41 (s, 1 H).
Reaction SMILES: [CH2:1]([N:3]([CH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)[C:4]1[C:5]([CH3:37])=[C:6]([CH:22]=[C:23]([C:25]2[CH:26]=[N:27][C:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[CH:29][CH:30]=2)[CH:24]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:21])[NH:13][C:14]([CH3:20])=[CH:15][C:16]=1[CH2:17][CH2:18][CH3:19])=[O:8])[CH3:2].[CH3:44][N:45]1[CH2:50][CH2:49][C:48](=O)[CH2:47][CH2:46]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH2:1]([N:3]([CH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)[C:4]1[C:5]([CH3:37])=[C:6]([CH:22]=[C:23]([C:25]2[CH:26]=[N:27][C:28]([N:31]3[CH2:36][CH2:35][N:34]([CH:48]4[CH2:49][CH2:50][N:45]([CH3:44])[CH2:46][CH2:47]4)[CH2:33][CH2:32]3)=[CH:29][CH:30]=2)[CH:24]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:21])[NH:13][C:14]([CH3:20])=[CH:15][C:16]=1[CH2:17][CH2:18][CH3:19])=[O:8])[CH3:2]
Reactant: CN1CCC(=O)CC1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N3CCNCC3)nc2)cc(N(CC)C2CCOCC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N3CCN(C4CCN(C)CC4)CC3)nc2)cc(N(CC)C2CCOCC2)c1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 41.4 %

Procedure:
To a stirred solution of 3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-N-((6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl)-5-(6-(piperazin-1-yl)pyridin-3-yl)benzamide (0.45 g, 0.76 mmol) and 1-methylpiperidin-4-one (0.173 g, 1.53 mmol) in dichloroethane (10 mL), acetic acid (0.276 g, 4.6 mmol) was added and reaction stirred at room temperature for 20 minutes. Then sodium triacetoxyborohydride (0.488 g, 2.3 mmol) was added at 0° C. and reaction stirred at room temperature for 2 h. On completion, reaction was quenched with aqueous sodium bicarbonate, organic phase was separated and aqueous phase was extracted with dichloromethane. Combined organic layers were dried over sodium sulphate and concentrated under reduced pressure to give crude material was purified by column chromatography to afford the title compound (0.215 g, 41%).