Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:24]([C:34]([F:37])([F:36])[F:35])[CH:23]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[C:45]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])(=[O:48])[CH:46]=[CH2:47].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO>[C:50]([O:49][C:45](=[O:48])[CH2:46][CH2:47][N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH:28]4[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]4)=[C:24]([C:34]([F:37])([F:35])[F:36])[CH:23]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)([CH3:53])([CH3:52])[CH3:51]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(OCc3ccc(C4CCCCC4)c(C(F)(F)F)c3)nc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)CCN1CCN(c2ccc(OCc3ccc(C4CCCCC4)c(C(F)(F)F)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-[6-(4-Cyclohexyl-3-trifluoromethyl-benzyloxy)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (155 mg, 0.398 mmol) in DCM (2 mL) is added trifluoroacetic acid (TFA) (4 mL). The reaction mixture is stirred at room temperature for 30 minutes and evaporated to dryness. The residue obtained is mixed with tert-butyl acrylate (76 mg, 0.6 mmol) and DIEA (193 mg, 1.49 mmol) in MeOH (4 mL) and the mixture is heated in a microwave oven at 90° C. for 30 minutes. The reaction mixture is poured into saturated aqueous NaHCO3 and extracted with EtOAc. The combined extracts are washed with brine and dried over Na2SO4. After concentration, the residue is purified by silica gel chromatography (150:50:1 hexanes/EtOAc/Et3N) to give 3-{4-[6-(4-Cyclohexyl-3-trifluoromethyl-benzyloxy)-pyridin-3-yl]-piperazin-1-yl}-propionic acid tert-butyl ester. This material is dissolved in DCM/TFA (1:1 v/v, 2 mL), and the solution is stirred at room temperature for 1 hour. After concentration, the crude product is purified by preparative RP LC-MS to give 3-{4-[6-(4-Cyclohexyl-3-trifluoromethyl-benzyloxy)-pyridin-3-yl]-piperazin-1-yl}-propionic acid. 1H NMR (CD3OD): 1.28-1.85 (10H), 2.88 (t, J=6.2 Hz, 2H), 2.90 (m, 1H), 3.15-3.85 (8H), 3.69 (t, J=6.2 Hz, 2H), 5.42 (s, 2H), 7.38 (br, 1H), 7.57 (d, J=7 Hz, 1H), 7.65 (d, J=7 Hz, 1H), 7.71 (s, 1H), 7.91 (s, 1H), 8.05 (br, 1H); ESI-MS m/z 492.2 (MH+).
Reaction SMILES: [CH3:1][C:2]12[CH2:9][CH2:8][N:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]2[C:10](Cl)=[O:11].[NH2:13][C@H:14]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:15]1>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][N:16]2[CH2:17][CH2:18][CH:14]([NH:13][C:10]([C@H:3]3[C:2]4([CH3:1])[CH2:9][CH2:8][N:5]([CH2:6][CH2:7]4)[CH2:4]3)=[O:11])[CH2:15]2)=[CH:22][CH:23]=1
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Reactant: CC12CCN(CC1)CC2C(=O)Cl
Product: CC12CCN(CC1)C[C@H]2C(=O)NC1CCN(CCc2ccc(F)cc2)C1

Procedure:
4-Methylquinuclidine-3-carbonyl chloride and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine were reacted under the same conditions as in Example 53 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-4-methylquinuclidine-3-carboxamide.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10]1)=O)(C)(C)C>C(O)=O>[NH2:8][C@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccc(F)cc2)C1
Solvent: O=CO
Product: N[C@H]1CCN(Cc2ccc(F)cc2)C1
Reaction time: 3 h
Yield: 90.8 %

Procedure:
A solution of (3S)-3-(tert -butoxycarbonylamino)-1-(4-fluoro-benzyl)-pyrrolidine (400 mg, 1.36 mmol) was stirred in 15 mL of formic acid at room temperature. After 3 h, the clear colorless solution was concentrated to dryness and the residue was taken-up in 20 mL of EtOAc and washed with 10 mL of 5% NH40H, followed by 10 mL of brine. The solution was then dried over MgSO4, filtered and concentrated to give 240 mg (91%) of product, as a yellow oil. 1H-NMR (400 MHz, CDCl3) δ7.28 (m, 2H), 6.99 (m, 2H), 3.56 (d, J =6.2Hz, 2H), 3.47-3.53 (m, 1H), 2.67-2.71 (m, 2H), 2.42-2.48 (m, 1H), 2.28-2.31 (m, 1H), 2.21-2.28 (m, 1H), 1.59 (s, 2H, NH2), 1.43-1.52 (m, 1H).
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[C:6]([C:21]#[N:22])=[C:5]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[N:4]=1.ClC1C=CC=C(C(OO)=O)C=1.CS(C1N=C(N2CCC(C3C=CC=CC=3)CC2)C(C#N)=C(OCC(F)(F)F)N=1)(=O)=O.[N:70]1[CH:75]=[CH:74][CH:73]=[C:72]([CH2:76][NH2:77])[CH:71]=1>O1CCOCC1>[C:15]1([CH:12]2[CH2:13][CH2:14][N:9]([C:7]3[C:6]([C:21]#[N:22])=[C:5]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[N:4]=[C:3]([NH:77][CH2:76][C:72]4[CH:71]=[N:70][CH:75]=[CH:74][CH:73]=4)[N:8]=3)[CH2:10][CH2:11]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CSc1nc(OCC(F)(F)F)c(C#N)c(N2CCC(c3ccccc3)CC2)n1
Reactant: NCc1cccnc1
Agent: CS(=O)(=O)c1nc(OCC(F)(F)F)c(C#N)c(N2CCC(c3ccccc3)CC2)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1COCCO1
Product: N#Cc1c(OCC(F)(F)F)nc(NCc2cccnc2)nc1N1CCC(c2ccccc2)CC1

Procedure:
In analogy to the procedure described in example 57c, the 2-methylsulfanyl-4-(4-phenyl-piperidin-1-yl)-6-(2,2,2-trifluoro-ethoxy)-pyrimidine-5-carbonitrile was oxidized by 3-chloro-perbenzoic acid to the 2-methanesulfonyl-4-(4-phenyl-piperidin-1-yl)-6-(2,2,2-trifluoro-ethoxy)-pyrimidine-5-carbonitrile which was then treated in crude form with 3-picolylamine in dioxane at 40° C. during 18 hours to yield the 4-(4-phenyl-piperidin-1-yl)-2-[(pyridin-3-ylmethyl)-amino]-6-(2,2,2-trifluoro-ethoxy)-pyrimidine-5-carbonitrile as an amorphous, light brown solid; MS: [M+H]+=469.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=O.[C:20]([O:27][CH3:28])(=[O:26])[CH2:21][CH2:22][C:23]([CH3:25])=O.Cl[Si](C)(C)C>CN(C=O)C>[CH3:28][O:27][C:20](=[O:26])[CH2:21][C:22]1[C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:3]2[C:4]3[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:23]=1[CH3:25]
Reactant: Nc1sc2c(c1C(=O)c1ccc(F)cc1)CCCC2
Reactant: COC(=O)CCC(C)=O
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(F)cc1)CCCC3
Yield: 81.7 %

Procedure:
This compound was prepared according to the procedure B from (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(4-fluorophenyl)methanone (0.275 g; 1 mmol), methyl levulinate (0.141 mL; 1.1 mmol), chlorotrimethylsilane (0.511 mL; 4 mmol) in DMF (4 mL) for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-50%) in heptane furnished 0.302 g (82%) of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:11][CH3:12])(=[O:10])[O:6]C(C)C>Cl>[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:11][CH3:12])(=[O:6])[OH:10]
Reactant: CCP(=O)(CCCN)OC(C)C
Agent: Cl
Product: CCP(=O)(O)CCCN
Reaction time: 14 h

Procedure:
A mixture of 7.73 g of isopropyl 3-aminopropyl(ethyl)-phosphinate and 40 ml of 20% hydrochloric acid is refluxed with stirring for 14 hours. The clear solution is evaporated to dryness and the residue is recrystallized from methanol/propylenoxide to give 3-aminopropyl(ethyl)phosphinic acid as a white solid, m.p. 233°-239°; 1H-NMR (D2O): 0.4-1.8 (m, 9H, PCH2CH2 and PCH2CH3); 2.7 (t, 2H,NCH2); 4.55 (s, 3H, OH, NH2).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[C:27]([O:31][C:32](=[O:35])[CH2:33]Br)([CH3:30])([CH3:29])[CH3:28]>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:33][C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:35])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 90 °C
Yield: 54.6 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (80 mg, 0.30 mmol), potassium carbonate (84 mg, 0.61 mmol) and tert-butylbromoacetate (67 μL, 0.46 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 90° C. for 1 hour. The reaction was cooled, diluted with dichloromethane, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography using hexanes:ethyl acetate:dichloromethane 3.5:0.5:4 afforded 62 mg (62%) 3-(2-pyridyl)-5-(3-cyano-5-(2-tert-butoxy-2-oxoethoxy)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.86 (d, 1H), 8.23 (d, 1H), 8.21 (s, 1H), 7.98 (s, 1H), 7.91 (t, 1H), 7.50 (t, 1H), 7.28 (s, 1H), 5.30 (s, 2H), 1.52 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:6]=[CH:5][C:4]=1[C:14]1[NH:15][C:16]2[C:17]([N:22]=1)=[N:18][CH:19]=[CH:20][CH:21]=2.[OH:23]O>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:6]=[CH:5][C:4]=1[C:14]1[NH:15][C:16]2[C:17]([N:22]=1)=[N+:18]([O-:23])[CH:19]=[CH:20][CH:21]=2
Reactant: OO
Reactant: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ncccc2[nH]1
Product: COc1cc(OS(C)(=O)=O)ccc1-c1nc2c(ccc[n+]2[O-])[nH]1

Procedure:
3.19 g of 2-(2-methoxy-4-methanesulfonyloxy-phenyl)imidazo[4,5-b]pyridine were dissolved in 25 ml of and then 5 ml of 30% hydrogen peroxide were added dropwise thereto. The mixture was refluxed for one hour and concentrated to about one-tenth of its volume. The residue was poured onto ice and digested until it had crystallized throughout. Yield: 2.1 g (63% of theory). Melting point: 110°-125° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[H-].[Na+].I[CH3:14]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:14])[CH:8]=[CH:7]2
Reactant: Clc1cccc2cc[nH]c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1ccc2cccc(Cl)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-chloroindole (610 mg, 4 mmol) in anhydrous DMF (6 mL) was added NaH (170 mg, 60% dispersion in mineral oil, 4.3 mmol) at 0° C. under argon. The mixture was stirred at room temperature for 30 min before adding iodomethane (240 mg, 4 mmol). The resulting mixture was stirred overnight. The reaction mixture was diluted with EtOAc (200 mL), washed with saturated NaCl (10 mL×3), dried over anhydrous MgSO4, filtered, and concentrated to give 7-chloro-1-methylindole. The residue was used directly for the next step without further purification. NMR (500 MHz, CDCl3): 4.14 (s, 3H), 6.46 (d, 1H, J=2.5), 6.95-6.98 (m, 2H), 7.12-7.14 (m, 1H), 7.48 (1H, dd, J=1.5, 7.5).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10](C(O)=O)[C:11](=[O:14])[NH:12][CH:13]=2)=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c[nH]c1=O
Solvent: c1ccc2ncccc2c1
Product: O=c1ccc(-c2ccc(Cl)cc2)c[nH]1

Procedure:
A mixture of 40.0 g. of 5-(4-chlorophenyl)-1,2-dihydro-2-oxo-3-pyridinecarboxylic acid (prepared as described in Example 12) and 120 ml. of quinoline is heated at reflux temperature for 4 hours. The mixture is cooled and filtered. The solid is washed with ether and then is dissolved in chloroform. The chloroform solution is treated with activated charcoal and is filtered. The filtrate is concentrated and diluted with hexane yielding 22.0 g. of the product of the Example as a tan solid. The solid is recrystallized from chloroform-hexane to give tan crystals, m.p. 183°-185.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[CH2:24]([O:26][C:27]([CH:29]1[CH:33]([C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)[CH2:32][N:31]([C:41](=[O:48])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:30]1)=[O:28])[CH3:25].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>O1CCCC1.CN(C)C=O>[CH2:24]([O:26][C:27]([CH:29]1[CH:33]([C:34]2[CH:39]=[CH:38][C:37]([NH:40][C:21](=[O:23])[CH2:20][C:5]3[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:36][CH:35]=2)[CH2:32][N:31]([C:41](=[O:48])[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:30]1)=[O:28])[CH3:25]
Reactant: CCOC(=O)C1CN(C(=O)c2ccccc2)CC1c1ccc(N)cc1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)C1CN(C(=O)c2ccccc2)CC1c1ccc(NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Reaction time: 1 h
Yield: 93.4 %

Procedure:
A stirred solution of [3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetic acid (5.1 g) in anhydrous tetrahydrofuran (140 ml), at 23° C. and under an atmosphere of argon, was treated with benzotriazol-lyloxytris(dimethylamino)phosphonium hexafluorophosphate (8.61 g). After stirring for 1 hour the mixture was treated with 1-benzoyl-4-(4-amino-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester (5.48 g, Reference Example 8) then with triethylamine (9.1 ml), dimethylaminopyridine (0.2 g) and dimethylformamide (5 ml). The resulting mixture was stirred at 23° C. for 2 days then evaporated (40° C. and 2.7 kPa). The residue was treated with ethyl acetate (300 ml) and the resulting solution was washed twice with water (200 ml), twice with hydrochloric acid (200 ml, 1N), then twice with aqueous sodium bicarbonate solution (200 ml, 10%), then with brine (100 ml), then with water (100 ml), then dried over magnesium sulphate and then evaporated (40° C. and 2.7 kPa). The resulting white meringue was triturated with diethyl ether (50 ml) for 20 hours affording the title compound (9.6 g) as a white powder, m.p. 130° C. 1H-NMR [500 MHz, (CD3)2SO at 383° K.]: δ 1.15 (t, J=7 Hz, 3H); 2.30 (s, 3H); 3.33 (m, 1H); 3.50 to 3.70 (m, 2H); 3.62 (s, 2H); 3.77 (m, 1H); 3.85 to 4.00 (m, 2H); 3.91 (s, 3H); 4.10 (q, J=7 Hz, 2H); 6.89 (bd, J=8 Hz, 1H); 6.95 to 7.05 (m, 1H); 7.04 (d, J=2 Hz, 1H); 7.15 (t, J=8 Hz, 1H); 7.20 (d, J=7.5 Hz, 1H); 7.25 (d, J=8 Hz, 2H); 7.45 (m, 3H); 7.54 (m, 4H); 7.69 (d, J=8 Hz, 1H); 8.01 (d, J=8 Hz, 1H); 8.16 (s, 1H); 8.22 (s, 1H); 9.56 (s, 1H). MS [DCI (reactant gas, ammonia)]: 635[M+H]+.
Reaction SMILES: [OH-].[Na+:2].C([O:5][C:6](=[O:22])[CH2:7][C:8]1[NH:9][C:10](=[O:21])[C:11]([F:20])=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:13]=1)C>C1COCC1>[F:20][C:11]1[C:10](=[O:21])[NH:9][C:8]([CH2:7][C:6]([O-:22])=[O:5])=[N:13][C:12]=1[N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1.[Na+:2]
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)c(F)c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C([O-])Cc1nc(N2CCOCC2)c(F)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.9 ml of 2N sodium hydroxide are added to a solution of 800 mg of (5-fluoro-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetic acid ethyl ester in 10 ml of THF. The reaction medium is stirred at ambient temperature for 24 hours. The reaction medium is concentrated under reduced pressure. The residue obtained is oven-dried under vacuum in the presence of P2O5, so as to give 780 mg of sodium (5-fluoro-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate, the characteristics of which are the following:
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]2[NH:16][C:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][N:13]=2)[C:9]([OH:25])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C:15]2[NH:16][C:12]([C:10]3[C:9]([OH:25])=[C:8]4[C:3]([CH:4]=[CH:5][CH:6]=[N:7]4)=[C:2]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[N:11]=3)=[N:13][N:14]=2)=[CH:19][CH:20]=1
Reactant: Oc1c(-c2nnc(Cc3ccc(F)cc3)[nH]2)nc(Br)c2cccnc12
Reactant: C1COCCN1
Product: Oc1c(-c2nnc(Cc3ccc(F)cc3)[nH]2)nc(N2CCOCC2)c2cccnc12
Yield: 55 %

Procedure:
A solution of 5-bromo-7-[5-(4-fluorobenzyl)-4H-1,2,4-triazol-3-yl]-1,6-naphthyridin-8-ol (34 mg, 0.09 mmol) in neat morpholine was heated in a sealed tube at 150° C. for 16 hours. The excess amine was removed in vacuo and the residue purified by preparative HPLC to provide the title compound (19 mg, 55%) as a white solid. 1H NMR (CDCl3): δ 9.14 (dd, J=4.4, 1.6 Hz, 1 H), 8.45 (dd, J=8.4, 1.6 Hz, 1 H), 7.57 (dd, J=8.4, 4.4 Hz, 1 H), 7.36 (dd, J=8.4, 5.2 Hz, 2 H), 7.01 (t, J=8.4 Hz, 2 H), 4.19 (s, 2 H), 3.98 (t, J=4.4 Hz, 4 H), 3.33 (t, J=4.4 Hz, 4 H); 13C NMR (CDCl3): δ 168.49, 161.79 (d, JCR=243.6 Hz), 154.85, 153.95, 153.40, 146.07, 144.75, 133.88, 132.99 (d, JCF=3.0 Hz), 130.40 (d, JCF=130.4 Hz), 122.67, 120.81, 119.70, 115.37 (d, JCF=21.2 Hz), 66.88, 52.06, 33.71; MS m/z 407 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[S:13][C:12]([NH2:14])=[N:11][C:10]=1[C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)=[O:8].[C:20](N1C=CN=C1)(N1C=CN=C1)=[O:21].CCCCCC>ClCCl>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:10]1[N:11]=[C:12]([N:14]=[C:20]=[O:21])[S:13][C:9]=1[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:8]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1nc(-c2ccco2)c(C(=O)c2ccccn2)s1
Solvent: ClCCl
Solvent: CCCCCC
Product: O=C=Nc1nc(-c2ccco2)c(C(=O)c2ccccn2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
Compound 186 (200 mg, 0.737 mmol) was suspended in dichloromethane (15 mL), and carbonyldiimidazole (179 mg, 1.11 mmol) was added thereto at room temperature, followed by stirring at room temperature for 2 hours. Hexane (7.5 mL) was added to the reaction mixture, and the precipitated solid was collected by filtration to afford the entitled Compound y (133 mg, 61%) as a brown solid.
Reaction SMILES: Cl(O)(=O)(=O)=O.[NH2:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16](=O)[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:13]=2)[CH2:8]1.[H][H]>C(O)(=O)C.[Pd]>[NH2:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:13]=2)[CH2:8]1
Reactant: [H][H]
Reactant: COC(=O)CCC(=O)c1ccc2c(c1)CC(N)C2
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: COC(=O)CCCc1ccc2c(c1)CC(N)C2

Procedure:
3 ml of perchloric acid and 3 g of 10% palladium-on-charcoal are added to 15 g (52.8 mmol) of methyl 4-(2-amino-indan-5-yl)-4-oxobutyrate in 200 ml of glacial acetic acid and the mixture is hydrogenated at 50° C. and a hydrogen pressure of 5 bar. When the calculated amount of hydrogen has been absorbed, the catalyst is filtered off, the filtrate is evaporated, sodium hydroxide is added to the residue and the reaction product is extracted with ether. After drying and evaporation. The desired product is obtained in the form of an oil.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:26][C:11]2[N:12](C(OC(C)(C)C)=O)[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][C:10]=2[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1CC2NC(C(OC)=O)=CC=2C1=O)C1C=CC=CC=1.N1C=CC=C1>>[CH2:1]([CH:8]1[CH2:26][C:11]2[NH:12][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc2c(n1C(=O)OC(C)(C)C)CC(Cc1ccccc1)C2=O
Agent: COC(=O)c1cc2c([nH]1)CC(Cc1ccccc1)C2=O
Solvent: c1cc[nH]c1
Product: COC(=O)c1cc2c([nH]1)CC(Cc1ccccc1)C2
Yield: 7 %

Procedure:
The title compound was synthesized from a mixture of 1-tert-butyl 2-methyl 5-benzyl-4-oxo-5,6-dihydrocyclopenta[b]pyrrole-1,2(4H)-dicarboxylate and methyl 5-benzyl-4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.267 g, 0.99 mmol, using the formula weight of the free pyrrole) according to General Procedure 5.1. Purification by column chromatography (0-30% EtOAc/heptane) yielded methyl 5-benzyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate as an off-white solid (0.017 g, 7% yield). Rf (1:1 EtOAc:heptane)=0.66; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.30-2.52 (m, 2H), 2.72-2.90 (m, 4H), 3.10-3.25 (m, 1H), 3.82 (s, 3H), 6.64 (s, 1H), 7.21-7.33 (m, 5H).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:31])([CH3:30])[CH:14]([O:20]CC1C=CC(OC)=CC=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2]>[Pd].C(O)C>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:30])([CH3:31])[CH:14]([OH:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:9])=[O:10])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(OCc1ccc(OC)cc1)C(C)(C)COS(=O)(=O)CCCNC(C)=O
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(O)C(C)(C)COS(=O)(=O)CCCNC(C)=O
Reaction time: 8 h
Yield: 68.4 %

Procedure:
Following the general procedure for the hydrogenolysis of benzyl ethers of Description 18, a mixture of ethyl (2R/S)-4-{[3-(acetylamino)propyl]sulfonyloxy}-2-[(4-methoxyphenyl)methoxy]-3,3-dimethylbutanoate (23c) (0.26 g, 0.56 mmol) and 140 mg of 10 wt.-% of palladium on activated carbon in 20 mL of ethanol (EtOH) was stirred overnight under a hydrogen atmosphere. After purification by mass-guided preparative HPLC and lyophilization of the solvents, 130 mg (68% yield) of the title compound (23) was obtained as a colorless, viscous oil. 1H NMR (400 MHz, CDCl3): δ=0.97 (s, 3H), 1.14 (s, 3H), 1.35 (t, J=6.8 Hz, 3H), 2.01 (s, 3H), 2.06-2.13 (m, 2H), 3.13-2.26 (m, 2H), 3.33-3.46 (m, 2H), 3.97 (d, J=8.8 Hz, 1H), 4.04 (s, 1H), 4.17 (d, J=9.2 Hz, 1H), 4.26-4.35 (m, 2H), 5.92 (br. m, 1H) ppm. MS (ESI) m/z: 340.04 (M+H)+, 338.01 (M−H)−. The analytical data was consistent with the proposed structure and the data for the enantiopure compound (22).
Reaction SMILES: [F:1][CH:2]([F:39])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([CH:20]3[CH2:25][CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:5]=2[N:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:39][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([CH:20]3[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(C2CCCN(C(=O)OC(C)(C)C)C2)nc(N2CCOCC2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(C2CCCNC2)nc(N2CCOCC2)n1

Procedure:
Reaction of tert-butyl 3-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperidinecarboxylate (0.22 g, 0.40 mmol) with TFA (0.5 mL) in CH2Cl2 (8 mL) gave 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(3-piperidinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole, which was dissolved in a mixture of CH2Cl2 (4 mL) and NEt3 (0.29 mL, 2.1 mmol) and cooled to 0° C. Methanesulfonyl chloride (0.05 mL, 0.65 mmol) was added, and the resulting mixture was allowed to warm to room temperature over 2 hrs. The reaction mixture was then diluted with water, extracted with CH2Cl2, and dried. Chromatography on silica eluting first with hexanes/EtOAc (4:1), followed by hexanes/EtOAc (1:1), and then CH2Cl2/MeOH (99:1), gave 0.19 g (91% yield) of 2-(difluoromethyl)-4-methoxy-1-[4-[1-(methylsulfonyl)-3-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole: mp 237-239° C.; 1H NMR (CDCl3) δ 7.98 (dd, J=8.4, 0.7 Hz, 1H), 7.54 (t, JHF=53.5 Hz, 1H), 7.40 (t, J=8.3 Hz, 1H), 6.85 (d, J=8.1 Hz, 1H), 4.08-3.92 (m, 8H), 3.86-3.72 (m, 5H), 3.14 (dd, J=11.5, 10.2 Hz, 1H), 3.07-2.99 (m, 1H), 2.86-2.77 (m, 4H), 2.30-2.22 (m, 1H), 2.00-1.71 (m, 3H); Anal. Calcd. for C22H27F2N7O4S.0.5; H2O: C, 49.6; H, 5.3; N, 18.4. Found: C, 49.7; H, 5.2; N, 18.3%.