Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:24]=[CH:23][C:6]2[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:8][CH2:9][C:10]3[N:11]([C:12]([CH2:15]Cl)=[N:13][N:14]=3)[C:5]=2[CH:4]=1.[I-].[K+].[CH3:29][CH:30]=[CH:31][CH2:32][NH2:33]>O1CCCC1>[F:1][C:2]([F:26])([F:25])[C:3]1[CH:24]=[CH:23][C:6]2[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:8][CH2:9][C:10]3[N:11]([C:12]([CH2:15][NH:33][CH2:32][CH2:31][CH:30]=[CH2:29])=[N:13][N:14]=3)[C:5]=2[CH:4]=1
Reactant: CC=CCN
Reactant: FC(F)(F)c1ccc2c(c1)-n1c(CCl)nnc1CN=C2c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCCNCc1nnc2n1-c1cc(C(F)(F)F)ccc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Preparation 39, 9-(trifluoromethyl)-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine, potassium iodide and methylallylamine in tetrahydrofuran are reacted to give 9-(trifluoromethyl)-1-[(allylmethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 48 8-Chloro-1-(pyrrolidinomethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Br[CH:35]([CH:37](Br)[CH3:38])[CH3:36]>O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:38][CH2:37][CH2:35][CH2:36]3)=[CH:18][CH:17]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(N)cc2)CC1
Reactant: CC(Br)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(N3CCCC3)cc2)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
To 1-tert-butyloxycarbonyl-4-[(4-aminophenyloxy)methyl]piperidine (0.75 g) obtained in Example 13 were added dimethylformamide (10 ml), potassium carbonate (1.4 g) and dibromobutane (0.54 g) and the mixture was heated to 70° C. and stirred overnight. To the reaction solution was added water which was extracted with ethyl acetate (50 ml×3). The combined extract was dried over sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=5/1 (v/v)) to obtain 1-tert-butyloxycarbonyl-4-[(4-pyrrolidinophenyloxy)methyl]piperidine (0.55 g) as colorless crystals, m.p. 141°-145° C.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:5]=1[O:6][C:7]1[CH:8]=[CH:9][C:10](SC)=[C:11](O)[CH:12]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:31]([CH3:38])[C:32]([O:34][CH2:35][CH2:36][CH3:37])=[O:33].C[S:40]([CH3:42])=O>CCCCCC.C(OCC)(=O)C.O>[N+:1]([C:4]1[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:16][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:9])=[C:42]([CH:8]=1)[S:40][CH:31]([CH3:38])[C:32]([O:34][CH2:35][CH2:36][CH3:37])=[O:33])([O-:3])=[O:2]
Reactant: CCCOC(=O)C(C)Br
Reactant: CSc1ccc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])cc1O
Reactant: CS(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCOC(=O)C(C)Sc1cc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])ccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(2-Nitro-4-trifluoromethylphenoxy)-2-(methylthio)phenol (0.05 mole), potassium carbonate (0.2 mole), propyl 2-bromopropionate (0.08 mole) and dimethylsulfoxide (200 ml) are charged into a 500 ml glass reaction flask equipped with a mechanical stirrer. The reaction mixture is stirred at room temperature for a period of about 8 hours. After this time the mixture is poured into 500 ml of water. The resulting mixture is extracted three times with 100 ml portions of methylene chloride. The extracts are then combined, washed with water and thereafter dried. The dried solution is then stripped of solvent under reduced pressure to leave a residue. The residue is subjected to chromatography using a clay column and hexane/ethyl acetate mixtures as the eluant. The fractions containing the product are combined and stripped of solvent to yield the desired product propyl 2-[5-(2-nitro-4-trifluoromethylphenoxy)-2-methylthiophenoxy]propionate as the residue.
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH3:24])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:25][C:26]1[O:30][C:29]([CH:31]=O)=[CH:28][CH:27]=1.O>C1(C)C=CC=CC=1>[Br:25][C:26]1[O:30][C:29]([CH:31]=[CH:20][C:21]([O:23][CH3:24])=[O:22])=[CH:28][CH:27]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Br)o1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C=Cc1ccc(Br)o1
Temperature: 80 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
4.58 g (13.7 mmol, 1.2 eq) of methyl triphenylphosphoranylideneacetate are added to a solution of 2.0 g (11.4 mmol, 1.0 eq) of 5-bromofuran-2-carbaldehyde in 15 mL of toluene. The reaction mixture is stirred for 1 hour at 80° C. The reaction is stopped by adding 20 ml of water and is then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (80/20 heptane/ethyl acetate). 2.0 g of methyl 3-(5-bromofuran-2-yl)acrylate are obtained. Yield=77%.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][C@@:13]1([O:46][C:47](=[O:54])[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@H:26]([O:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@H:25]([CH2:36][O:37][C:38](=[O:45])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:24][C@H:14]1OC(=O)C1C=CC=CC=1.C1CCN2C(=NCCC2)CC1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>CC#N.CCOC(C)=O>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([C@@H:14]3[O:24][C@H:25]([CH2:36][O:37][C:38](=[O:45])[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C@@H:26]([O:27][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C@@:13]3([CH3:12])[O:46][C:47](=[O:54])[C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2[nH]cc(I)c12
Reactant: C[C@]1(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@@]1(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1cc(I)c2c(Cl)ncnc21
Temperature: 70 °C
Reaction time: 22.5 h
Yield: 48.1 %

Procedure:
To a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine 8 (903 mg, 3.23 mmol), 2-C-methyl-1,2,3,5-tetra-O-benzoyl-β-D-ribofuranose 9 (1.7 g, 2.93 mmol) and DBU (1.3 ml, 8.69 mmol) in MeCN (20 ml) was dropwise added TMSOTf (2.1 ml, 11.62 mmol) at 0° C. and the mixture was then stirred at 70° C. for 22.5 h. After cooling, the mixture was diluted with AcOEt (100 ml), washed with aq NaHCO3 (sat., 25 ml), water (25 ml) and brine (25 ml). The organic layer was dried over MgSO4 and evaporated. The residue was chromatographed on silica (hexanes/toluene, 1:1; then hexanes/toluene/MeCN, 49:49:2→3:3:4) affording title compound 10 as a white foam (1.04 g, 48%). Compound was recrystallized from EtOH. Mp 95° C. [α]20D −69.3 (c 0.280, CHCl3). 1H NMR (500 MHz, CDCl3): 1.59 (s, 3H, CH3); 4.72 (td, 1H, J4′,3′=J4′,5′b=5.8, J4′,5′a=3.4, H-4′); 4.85 (dd, 1H, Jgem=12.2, J5′b,4′=5.8, H-5′b); 4.95 (dd, 1H, Jgem=12.2, J5′a,4′=3.4, H-5′a); 6.03 (d, 1H, J3′,4′=5.8, H-3′); 6.95 (s, 1H, H-1′); 7.34, 7.46 and 7.47 (3×m, 3×2H, H-m-Bz); 7.54, 7.59 and 7.61 (3×m, 3×1H, H-p-Bz); 7.69 (s, 1H, H-6); 7.96, 8.10 and 8.11 (3×m, 3×2H, H-o-Bz); 8.75 (s, 1H, H-2). 13C NMR (125.7 MHz, CDCl3): 17.92 (CH3); 52.68 (C-5); 63.33 (CH2-5′); 75.55 (CH-3′); 80.04 (CH-4′); 84.93 (C-2′); 88.95 (CH-1′); 117.71 (C-4a); 128.49, 128.54 and 128.63 (CH-m-Bz); 128.65, 129.50 and 129.61 (C-i-Bz); 129.78, 129.83 and 129.92 (CH-o-Bz); 132.66 (CH-6); 133.38, 133.66, 133.72 (CH-p-Bz); 150.68 (C-7a); 151.17 (CH-2); 153.15 (C-4); 165.09, 165.33 and 166.32 (CO). IR (CHCl3): 3092, 3066, 3034, 1727, 1602, 1587, 1577, 1538, 1504, 1493, 1451, 1444, 1339, 1316, 1269, 1248, 1178, 1162, 1141, 1116, 1070, 1027, 1002, 952, 943, 843, 822, 725, 712, 686, 617, 600. MS (FAB): m/z 738 (M+H). HRMS (FAB) for C33H26ClIN3O7 [M+H] calcd: 738.0504. found: 738.0491. Anal. Calcd for C33H25ClIN3O7: C, 53.71; H, 3.41; N, 5.69. Found: C, 53.91; H, 3.29; N, 5.38.
Reaction SMILES: CN(C(/N=N/C(N(C)C)=O)=O)C.C(OC([N:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:27]([O:32]CCO)=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:22][CH2:21]1)=O)(C)(C)C.[C:36]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:37]=1.[F:55][C:56]1[C:61]([F:62])=[C:60]([F:63])[CH:59]=[CH:58][C:57]=1[OH:64]>C1COCC1>[N:23]1([C:26]2[C:27](=[O:32])[N:28]([CH2:36][CH2:37][O:64][C:57]3[CH:58]=[CH:59][C:60]([F:63])=[C:61]([F:62])[C:56]=3[F:55])[CH:29]=[CH:30][N:31]=2)[CH2:22][CH2:21][NH:20][CH2:25][CH2:24]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Reactant: Oc1ccc(F)c(F)c1F
Agent: CN(C)C(=O)/N=N/C(=O)N(C)C
Solvent: C1CCOC1
Product: O=c1c(N2CCNCC2)nccn1CCOc1ccc(F)c(F)c1F
Reaction time: 2 h
Yield: 17.5 %

Procedure:
TMAD (0.207 g, 1.20 mmol) was added to a solution of 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-pyrazinyloxy]ethanol (0.324 g, 1.00 mmol), triphenylphosphine (0.315 g, 1.20 mmol) and 2,3,4-trifluorophenol (0.296 g, 2.00 mmol) in THF (1 mL) at room temperature. After being stirred for 2 h, the mixture was concentrated in vacuo and put through a silica column using toluene/EtOAc (7:3) as eluent. Solvents were removed in vacuo and the resulting N-t-BOC derivative was treated with dichloromethane/TFA/H2O (50:45:5; 5 mL) for 15 min with stirring. The mixture was concentrated and the residue purified by chromatography on silica gel using EtOAc/HOAc/MeOH/H2O (20:3:3:2) as eluent. The product-containing fractions were concentrated, washed between dichloromethane/5% aqueous NaOH, and put through a silica column using dichloromethane/MeOH (8:2) as eluent to give 62 mg (17%) of the title compound. HRMS m/z calcd for C16H17F3N4O2 (M)+ 354.1304, found 354.1321.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[S:29](Cl)([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30]>C(OCC)(=O)C>[C:35]1([CH3:36])[CH:37]=[CH:38][C:32]([S:29]([O:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:14]2[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:12][CH2:13]2)(=[O:31])=[O:30])=[CH:33][CH:34]=1
Reactant: O=C(OCc1ccccc1)N1CCC(CCCCCO)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCCCCCC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 0 °C
Yield: 66.5 %

Procedure:
A mixture of 18 g of 5-(1-benzyloxycarbonyl-4-piperidy)pentanol and 150 ml of pyridine is stirred under ice-cooling, and 14.6 g of tosyl chloride is added portionwise to the mixture over the period of 30 minutes. After stirring for another 1 hour under ice-cooling, 2 ml of ice-cold water is added dropwise. Ethyl acetate (500 ml) is added to the reaction solution, which is then washed with 500 ml of 2 N-hydrochloric acid and 500 ml of 1 N hydrochloric acid successively, further with dilute aqueous sodium hydrogen-carbonate solution and water successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily material is purified by silica-gel column chromatography to give 18 g of 5-(1-benzyloxycarbonyl-4-piperidyl)pentyl p-toluenesulfonate as an oily material.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[S:16]1(=[O:23])[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[N:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:4][C:3]3[C:13](=[O:14])[NH:15][C:19]4([CH2:20][CH2:21][S:16](=[O:23])[CH2:17][CH2:18]4)[NH:1][C:2]=3[CH:6]=2)=[CH:12][CH:11]=1
Reactant: O=C1CCS(=O)CC1
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: O=C1NC2(CCS(=O)CC2)Nc2cc(-c3ccncc3)sc21
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 16.6 %

Procedure:
To a stirred solution of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.050 g, 0.23 mmol) in acetic acid (3 mL) were added tetrahydro-4H-thiopyran-4-one 1-oxide (0.061 g, 0.46 mmol) and p-toluenesulfonic acid (0.0040 g, 0.023 mmol). The mixture was heated at 80° C. overnight. Then, the solvent was removed and the obtained residue was taken up in methanol (20 mL). Solid NaHCO3 (1.5 g) was added, and the mixture was stirred for 10 min. The mixture was filtered, and the filtrate was chromatographed (Combiflash, silica gel, dichloromethane to 80:20 dichloromethane/methanol) to give the title compound (0.0127 g, 16%) as a yellow solid:
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8](I)=[CH:9][CH:10]=3)[C@@:5]3([CH2:20][O:19][C:18]([NH2:21])=[N:17]3)[C:4]=2[CH:3]=1.[N:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[N:24][CH:23]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>O.C(OCC)(=O)C.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>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:26]4[CH:27]=[N:22][CH:23]=[N:24][CH:25]=4)=[CH:9][CH:10]=3)[C@@:5]3([CH2:20][O:19][C:18]([NH2:21])=[N:17]3)[C:4]=2[CH:3]=1
Reactant: OB(O)c1cncnc1
Reactant: NC1=N[C@]2(CO1)c1cc(Br)ccc1Oc1ccc(I)cc12
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: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: NC1=N[C@]2(CO1)c1cc(Br)ccc1Oc1ccc(-c3cncnc3)cc12
Temperature: 70 °C

Procedure:
A 100 ml RBF was charged with (R)-2′-bromo-7′-iodo-5H-spiro[oxazole-4,9′-xanthen]-2-amine (3.3 g, 7.22 mmol), pyrimidin-5-ylboronic acid (1.163 g, 9.39 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.834 g, 0.722 mmol). To this were added DME (51.6 mL) followed by sodium carbonate (10.83 mL, 21.66 mmol) (2M solution) and the mixture was heated at 70° C. for 24 hrs. The mixture was diluted with water and ethyl acetate, filtered and organic layer was separated and concentrated. The crude material was purified by FC on 80 g RediSep column using 5-70% gradient of DCM/MeOH/NH4OH in DCM to give (S)-2′-bromo-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]([NH2:17])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:18]([NH:25][C@H:26]([C:31](O)=[O:32])[C@H:27]([CH2:29][CH3:30])[CH3:28])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[C:18]([NH:25][CH:26]([CH:27]([CH3:28])[CH2:29][CH3:30])[C:31]([NH:17][CH:12]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:11][CH2:10][CH2:9]1)[CH2:13][CH:14]([CH3:15])[CH3:16])=[O:32])([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)CC(N)C1(c2ccc(Cl)cc2)CCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CCC(C)C(NC(=O)OC(C)(C)C)C(=O)NC(CC(C)C)C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
250 mg of 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine (II) and 210 mg of Boc-isoleucine (R in Formula is Boc) was dissolved in anhydrous THF (5 mL). 220 mg DCC was dissolved in 25 mL anhydrous THF. The solution of DCC in THF was added dropwisely into the reaction solution, and then stirred overnight at room temperature to give white precipitate. The solid was filtered off and washed for at least three times with anhydrous ethyl ether. The filtrate and washed ethyl ether were collected, evaporated and purified by column chromatography to give title compound 2-(Boc-amino)-N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-3-methylvaleramide (Formula I, wherein R is Boc).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]([F:30])([F:29])[F:28])=[N:4][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C:13]3[N:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[N:18]=[CH:19][C:12]2=3)=[O:10])[C:6]=1[CH3:7].[H-].[Na+].[CH2:33]=O.CN([CH:38]=[O:39])C>>[Cl:1][C:2]1[C:3]([C:27]([F:30])([F:29])[F:28])=[N:4][N:5]([CH:8]([CH2:33][O:39][CH3:38])[C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C:13]3[N:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[N:18]=[CH:19][C:12]2=3)=[O:10])[C:6]=1[CH3:7]
Reactant: C=O
Reactant: CN(C)C=O
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCCc2c1cnn2-c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Product: COCC(C(=O)N1CCCc2c1cnn2-c1ccc(F)cc1)n1nc(C(F)(F)F)c(Cl)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12 %

Procedure:
To a mixture of 2-[4-chloro-5-methyl-3-(trifluoromethyl)pyrazol-1-yl]-1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]ethanone (0.045 g, 0.10 mmol) and NaH (0.030 g, 0.75 mmol, 60% in mineral oil) in DMF (0.8 mL) was added dry paraformaldehyde (0.015 g, 0.50 mmol). The mixture was stirred at rt for 30 min. It was then quenched with water. The mixture was partitioned between EtOAc (50 mL) and brine (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo, and purified by reverse phase HPLC to afford the desired product (0.006 g, 12%). 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.44 (dd, J=8.8, 4.6 Hz, 2H), 7.16 (dd, J=8.4, 8.4 Hz, 2H), 5.51 (dd, J=8.0, 7.2 Hz, 1H), 4.18 (m, 1H), 4.08 (m, 1H), 3.75 (m, 1H), 3.37 (s, 3H), 3.35 (m, 1H), 2.78 (m, 2H), 2.33 (s, 3H), 2.09 (m, 2H); MS: (ES) m/z calculated for C21H20ClF4N5O2 [M+H]+ 486.1, found 486.1.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[N:18]=[CH:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:50][C:51]1[CH:58]=[CH:57][C:54]([C:55]#[N:56])=[CH:53][C:52]=1[O:59][CH:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1>CN(C=O)C.O>[C:55]([C:54]1[CH:57]=[CH:58][C:51]([CH3:50])=[C:52]([CH:53]=1)[O:59][CH:60]1[CH2:61][CH2:62][N:63]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:19]2[N:18]=[CH:17][N:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:20]=2)=[O:22])[CH2:64][CH2:65]1)#[N:56]
Reactant: Cc1ccc(C#N)cc1OC1CCNCC1
Reactant: O=C(O)CNC(=O)c1cn(-c2ccccc2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C#N)cc1OC1CCN(C(=O)CNC(=O)c2cn(-c3ccccc3)cn2)CC1
Reaction time: 0.03 h
Yield: 82.7 %

Procedure:
DIPEA (236 mg, 1.826 mmol) was added to a stirred solution of [(1-phenyl-1H-imidazole-4-carbonyl)-amino]-acetic acid (prepared from Intermediate 68 by means of Step 3 of the General Scheme) (100 mg, 0.4 mmol) in DMF (5 mL) followed by HOBt (60.5 mg, 0.4 mmol) and EDCI (195 mg, 1.02 mmol). After 2 minutes of stirring, 4-methyl-3-(piperidin-4-yloxy)-benzonitrile hydrochloride (113 mg, 0.45 mmol) (prepared by the method used for the synthesis of Intermediate 15) was added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with cold water, the precipitate was collected and purified by recrystallisation from a mixture of diethyl ether (15 mL) and MeOH (0.1 mL) to afford 149 mg (82.7% Yield) of 1-phenyl-1H-imidazole-4-carboxylic acid {2-[4-(5-cyano-2-methyl-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 443, 98.73%. 1H NMR (300 MHz, DMSO-d6): δ 8.4 (s, 1H), 8.3 (s, 1H), 8.08 (t, 1H), 7.8 (d, 2H), 7.6 (t, 3H), 7.4-7.18 (m, 3H), 4.85 (m, 1H), 4.2 (d, 2H), 3.85-3.6 (d, 2H), 3.5 (bs, 2H), 2.3 (s, 3H), 2.1 (d, 2H), 1.8 (d, 2H).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)=[N:7][CH:8]=1.[C:23]([CH:28]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:25][CH2:26][CH3:27])=[O:24]>O1CCOCC1.[O-2].[Mn+4].[O-2]>[CH2:26]([O:25][C:23](=[O:24])/[CH:28]=[CH:2]/[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)=[N:7][CH:8]=1)[CH3:27]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ccc(CO)cn2)C1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/c1ccc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)nc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 89.3 %

Procedure:
To a solution of tert-butyl (3R)-3-{[5-(hydroxymethyl)-2-pyridinyl]amino}-1-piperidinecarboxylate (3.65 g, 11.9 mmol) in dioxane (50 mL) was added manganese(IV) oxide (7.7 g, 89 mmol) and (carbethoxymethylene)triphenylphosphorane (6.2 g, 17.8 mmol). After stirring for 18 hrs at 60° C., a resulting precipitate was filtered and the filtrate was evaporated in vacuo and the residue was partitioned between water and EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (CHCl3/methanol=95/5)to give tert-butyl (3R)-3-({5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-piperidinecarboxylate (3.99 g, 89%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:24])=[C:14]([C:20](OC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1.[CH3:29][O:30][CH2:31][CH2:32][NH2:33]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:24])=[C:14]([C:20]([NH:33][CH2:32][CH2:31][O:30][CH3:29])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[C:4]([C:25]([F:28])([F:26])[F:27])[CH:3]=1
Reactant: COC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3C(F)(F)F)cc2[nH]c1=O
Reactant: COCCN
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3C(F)(F)F)cc2[nH]c1=O

Procedure:
This compound was prepared from methyl 7-{[4-fluoro-2-(trifluoromethyl)phenyl]methyl}-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-methoxyethylamine employing methods similar to those those described in Example 9 and was purified by recrystallization from DMSO and MeOH. The product was obtained as a white solid: 1H NMR (d6-DMSO) δ 11.72 (1H, s), 10.28 (1H, brt, J=5 Hz), 8.47 (1H, s), 7.67 (1H, dd, J=9.3, 2.5 Hz), 7.59-7.51 (2H, m), 7.30 (1H, s), 4.29 (2H, s), 3.52-3.46 (4H, m), 3.26 (3H, s); HRMS calcd for C20H17F4N3O4+H+: 440.1233. Found: 440.1224.
Reaction SMILES: CO[C:3]([CH:5]1[CH2:9][C:8](=O)[CH2:7][N:6]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4].[F:18][C:19]([F:34])([F:33])[C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:23][NH:24][CH3:25].[CH3:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>>[CH2:11]([N:6]1[CH2:7][C@@H:8]([N:24]([CH2:23][C:22]2[CH:21]=[C:20]([C:19]([F:33])([F:34])[F:18])[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=2)[CH3:25])[CH2:9][C@H:5]1[C:3]([N:46]1[CH2:45][CH2:44][N:43]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[O:36][CH3:35])[CH2:48][CH2:47]1)=[O:4])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)C1CC(=O)CN1Cc1ccccc1
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(C(=O)[C@@H]2C[C@H](N(C)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CN2Cc2ccccc2)CC1
Yield: 12.2 %

Procedure:
As described for Example 56b and 56d, 1-benzyl-4-oxo-pyrrolidine-2-carboxylic acid methyl ester (100 mg, 0.428 mmol) was converted, using (3,5-bis-trifluoromethyl-benzyl)-methyl-amine instead of 3,5-bis-trifluoromethyl-benzylamine, and using 1-(2-methoxy-phenyl)-piperazine instead of 1-(3-trifluoromethyl-phenyl)-piperazine, to the title compound (11.3 mg, 12.2%) as light yellow oil. MS m/e=635.5 [M+H]+.