Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH:27]([CH3:29])[CH3:28])[C:3]1[C:4]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([CH3:26])=[CH:20]3)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([O:15]C)=[O:14])=[CH:8][CH:7]=2.[OH-].[Na+]>CO.O>[CH3:1][N:2]([CH:27]([CH3:29])[CH3:28])[C:3]1[C:4]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([CH3:26])=[CH:20]3)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([OH:15])=[O:14])=[CH:8][CH:7]=2
Reactant: COC(=O)c1ccc2nc(-c3ccc4[nH]c(C)cc4c3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc2cc(-c3nc4ccc(C(=O)O)cc4nc3N(C)C(C)C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
To a solution of methyl 3-[methyl(propan-2-yl)amino]-2-(2-methyl-1H-indol-5-yl)quinoxaline-6-carboxylate (660 mg, 1.70 mmol) in methanol (40 ml) was added a solution of NaOH (340 mg, 8.50 mmol) in water (5 ml). The resulting solution was stirred overnight at room temperature and then concentrated in vacuo. The residue was dissolved in water (20 ml), adjusted to pH 4 with HCl (3N). The product was precipitated from water and collected by filtration to afford 3-[methyl(propan-2-yl)amino]-2-(2-methyl-1H-indol-5-yl)quinoxaline-6-carboxylic acid as a orange solid (500 mg, 78%).
Reaction SMILES: [CH2:1]([C:13]1[CH:18]=[C:17]([CH2:19][CH3:20])[C:16]([NH2:21])=[C:15]([CH2:22][CH3:23])[CH:14]=1)[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[C:5]([NH2:10])=[C:4]([CH2:11][CH3:12])[CH:3]=1.[CH2:24]([C:26]([CH3:28])=O)[CH3:25]>>[C:24](=[N:21][C:16]1[C:17]([CH2:19][CH3:20])=[CH:18][C:13]([CH2:1][C:2]2[CH:7]=[C:6]([CH2:8][CH3:9])[C:5]([N:10]=[C:1]([CH2:2][CH3:3])[CH3:13])=[C:4]([CH2:11][CH3:12])[CH:3]=2)=[CH:14][C:15]=1[CH2:22][CH3:23])([CH2:26][CH3:28])[CH3:25]
Reactant: CCc1cc(Cc2cc(CC)c(N)c(CC)c2)cc(CC)c1N
Reactant: CCC(C)=O
Product: CCC(C)=Nc1c(CC)cc(Cc2cc(CC)c(N=C(C)CC)c(CC)c2)cc1CC
Temperature: 40 °C
Yield: 94.7 %

Procedure:
A two-liter three neck round bottom flask was equipped with a magnetic stirrer, a heating mantle, a thermocouple, a glass stopper and a Dean Stark trap fitted with a condenser. 4,4′-Methylenebis(2,6-diethylbenzeneamine) (310.5 g, 1.00 mol) and methyl ethyl ketone (450 mL, 350 g, 4.85 mol) were added to the flask. This mixture was stirred at 40° C. to dissolve the 4,4′-methylenebis(2,6-diethylbenzeneamine). Hexanes (300 mL) and Amberlyst-15 (15.54 g) were added to the flask. The mixture was heated to reflux, and water was removed as an azeotrope in the Dean Stark trap. Samples were periodically taken and analyzed by gas chromatography (GC). N,N′-di-sec-butylidene-4,4′-methylenebis(2,6-diethylbenzeneamine) was formed in 94.7% yield. GC results are summarized in Table 1; units for the diamine, monoimine, and diimine are GC area percent.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:15](=N)[CH3:16])=[C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]2=[C:6]([CH:14]=1)[CH2:7][O:8][CH2:9]3.Cl.[O:19]1CCCC1>>[Cl:1][C:2]1[C:3]([C:15](=[O:19])[CH3:16])=[C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]2=[C:6]([CH:14]=1)[CH2:7][O:8][CH2:9]3
Reactant: C1CCOC1
Reactant: CC(=N)c1c(Cl)cc2c3c(cccc13)COC2
Agent: Cl
Product: CC(=O)c1c(Cl)cc2c3c(cccc13)COC2
Temperature: 80 °C

Procedure:
1-(5-Chloro-1H,3H-benzo[de]isochromen-6-yl)-ethylidene-amine (22 g) obtained in Step 1 described above was dissolved in tetrahydrofuran (200 mL), 5 N aqueous hydrochloric acid solution (200 mL) was added, and this was stirred while heating at 80° C. for 48 hours. After cooling the mixture to room temperature, the solvent was removed by using a rotary evaporator. The obtained residue was dissolved in ethyl acetate (400 mL), then washed with water (300 mL) and saturated sodium hydrogen carbonate solution successively, and then dried over sodium sulfate. A residue obtained after filtration and concentration was purified by silica gel column chromatography (developing solvent; n-hexane:dichloromethane:ethyl acetate=10:10:1), and thus, 1-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-ethanone (19.2 g) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][CH:6]([NH:15][C:16](=[O:29])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.Cl.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]Cl)[CH:33]=1>>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][CH:6]([NH:15][C:16](=[O:29])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:38][C:34]2[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=2)=[CH:10][CH:9]=1
Reactant: ClCc1cccnc1
Reactant: COC(=O)CCC(Cc1ccc(O)cc1)NC(=O)CCCCCCc1ccccc1
Agent: Cl
Product: COC(=O)CCC(Cc1ccc(OCc2cccnc2)cc1)NC(=O)CCCCCCc1ccccc1
Yield: 68.8 %

Procedure:
Prepared from (RS)-5-(4-Hydroxy-phenyl)-4-(7-phenyl-heptanoylamino)-pentanoic acid methyl ester 92 (502 mg, 1.22 mmol) and 3-picolylchloride hydrochloride (300 mg, 1.83 mmol) to afford 94 (422 mg, 69%). 13C NMR (CDCl3) δ 174.4, 173.0, 157.3, 149.5, 149.1, 142.8, 135.5, 132.8, 130.6, 128.5, 128.4, 125.8, 123.7, 114.9, 67.7, 51.9, 50.3, 40.6, 37.0, 36.0, 31.4, 31.1, 29.2, 29.1, 29.0, 25.8. ESMS 503 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[C:26]2[CH:31]=[C:30]([O:32][C:33]3[C:38]4[N:39]=[C:40]([NH:42][C:43](=[O:45])[CH3:44])[S:41][C:37]=4[CH:36]=[CH:35][CH:34]=3)[N:29]=[CH:28][N:27]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[CH:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[CH:18][C:17]=2[C:26]2[N:27]=[CH:28][N:29]=[C:30]([O:32][C:33]3[C:38]4[N:39]=[C:40]([NH:42][C:43](=[O:45])[CH3:44])[S:41][C:37]=4[CH:36]=[CH:35][CH:34]=3)[CH:31]=2)[CH2:10][CH2:9]1
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NCC4CCN(C(=O)OC(C)(C)C)CC4)ncn3)cccc2s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NCC4CCNCC4)ncn3)cccc2s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-({2-[6-(2-acetylamino-benzothiazol-4-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenylamino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester, (Example 160), (0.20 g, 0.30 mmol) in CH2Cl2 (10 mL) was added trifluoroacetic acid (30 mL, Aldrich). The reaction mixture was allowed to stir for 3 h at room temperature and then concentrated in vacuum. The residue was dissolved in EtOAc (30 mL), washed with satd NaHCO3 (2×30 mL), dried over Na2SO4, filtered and concentrated in vacuum. Purification by silica gel chromatography (2:1, EtOAc:hexanes) afforded the title compound as yellow film. MS (ESI, pos. ion) m/z: 543 (M+1).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][C:17]2[O:21][N:20]=[C:19]([CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[CH2:25][CH2:24]3)[N:18]=2)[CH:10]=[CH:11][C:12]=1[O:13]C>ClCCl.N>[CH3:33][N:31]([CH3:32])[CH2:30][CH2:29][N:26]1[CH2:25][CH2:24][CH:23]([CH2:22][C:19]2[N:18]=[C:17]([CH:16]=[CH:15][C:9]3[CH:8]=[C:7]([OH:6])[C:12]([OH:13])=[CH:11][CH:10]=3)[O:21][N:20]=2)[CH2:28][CH2:27]1
Reactant: COc1ccc(C=Cc2nc(CC3CCN(CCN(C)C)CC3)no2)cc1OC
Agent: BrB(Br)Br
Agent: N
Solvent: ClCCl
Product: CN(C)CCN1CCC(Cc2noc(C=Cc3ccc(O)c(O)c3)n2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Boron tribromide (0.14 mL, 1.49 mmol) was added dropwise to a cooled solution of [2-(4-{5-[2-(3,4-dimethoxy-phenyl)-vinyl]-[1,2,4]oxadiazol-3-ylmethyl}-piperidin-1-yl)-ethyl]-dimethyl-amine (compound of Example 23; 0.10 g, 0.25 mmol) in dichloromethane (5 mL) at −78° C. The reaction mixture was warmed to room temperature and stirred for 6 h. The reaction mass was quenched with methanol (2 mL) and the organic solvent was evaporated. The residue obtained was dissolved in 8% methanolic ammonia (5 mL) and the inorganic solid obtained was removed by filtration. The filtrate was concentrated and purified by column chromatography (silica gel, 3% methanol in chloroform) to afford the title compound.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[O:19][CH:18]=[CH:17][C:16]=12)=[O:10].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33](O)=[O:34])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[S:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[O:19][CH:18]=[CH:17][C:16]=23)=[O:10])=[O:34])=[CH:25][CH:26]=1
Reactant: O=C(NC[C@H]1NC[C@@H]2C[C@@H]21)c1cccc2occc12
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3occc23)c(-c2ccc(F)cc2)s1

Procedure:
prepared by reaction of benzofuran-4-carboxylic acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=0.90 min; [M+H]+=476.1.
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[C:4]([CH:11]=[O:12])[CH:3]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[C:4]([CH2:11][OH:12])[CH:3]=1
Reactant: O=Cc1cc(F)c2c(c1)OCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cc(F)c2c(c1)OCO2
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 7-fluoro-benzo[1,3]dioxole-5-carbaldehyde (0.80 g, 4.7 mmol) in MeOH (50 mL) was added NaBH4 (0.36 g, 9.4 mmol) in portions at 0° C. The mixture was stirred at this temperature for 30 min and was then concentrated to dryness. The residue was dissolved in EtOAc. The EtOAc layer was washed with water, dried over Na2SO4 and concentrated to dryness to afford (7-fluoro-benzo[1,3]dioxol-5-yl)-methanol (0.80 g, 98%), which was directly used in the next step.
Reaction SMILES: CN[C@@H]1CCCC[C@H]1NC.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[N:19]1[NH:20][CH:21]=[C:22]2[CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][C:23]=12.[CH2:34]([N:37]1[C:45]2[C:40](=[N:41][C:42](I)=[C:43]([Cl:46])[CH:44]=2)[N:39]=[C:38]1[O:48][C@@H:49]1[CH2:53][O:52][C@@H:51]2[C@H:54]([O:57][Si:58]([C:61]([CH3:64])([CH3:63])[CH3:62])([CH3:60])[CH3:59])[CH2:55][O:56][C@H:50]12)[CH:35]=[CH2:36].[C:65]([OH:71])([C:67]([F:70])([F:69])[F:68])=[O:66]>O1CCOCC1.[Cu]I.C1C=CC=CC=1.C(O)C.C(Cl)Cl>[F:68][C:67]([F:70])([F:69])[C:65]([OH:71])=[O:66].[CH2:34]([N:37]1[C:45]2[C:40](=[N:41][C:42]([N:20]3[CH:21]=[C:22]4[CH2:26][NH:25][CH2:24][C:23]4=[N:19]3)=[C:43]([Cl:46])[CH:44]=2)[N:39]=[C:38]1[O:48][C@@H:49]1[CH2:53][O:52][C@@H:51]2[C@H:54]([O:57][Si:58]([C:61]([CH3:64])([CH3:63])[CH3:62])([CH3:59])[CH3:60])[CH2:55][O:56][C@H:50]12)[CH:35]=[CH2:36]
Reactant: C=CCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O[Si](C)(C)C(C)(C)C)nc2nc(I)c(Cl)cc21
Reactant: CC(C)(C)OC(=O)N1Cc2c[nH]nc2C1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: c1ccccc1
Solvent: ClCCl
Product: C=CCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O[Si](C)(C)C(C)(C)C)nc2nc(-n3cc4c(n3)CNC4)c(Cl)cc21
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A mixture of (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (25 uL, 0.158 mmol), copper (I) iodide (4.0 mg, 0.021 mmol), potassium phosphate tribasic (69.7 mg, 0.328 mmol), tert-butyl 4,6-dihydro-2H-pyrrolo[3,4-c]pyrazole-5-carboxylate (42.7 mg, 0.204 mmol) and [(3R,3aR,6R,6aS)-3-(1-allyl-6-chloro-5-iodo-imidazo[4,5-b]pyridin-2-yl)oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy-tert-butyl-dimethyl-silane (84 mg, 0.145 mmol) in dioxane (1.0 ml) was degassed (3×) and placed under nitrogen before being heated to 100° C. After 6 hours, the reaction mixture was diluted with EtOAc (30 ml), washed with water (20 ml), brine (10 mL), dried over MgSO4, filtered, and evaporated under reduced pressure to give an oil. The oil was purified on preparative silica plates (1×1000 u developed with 1:1 EtOAc/hexanes). The resulting solid (86.4 mg, 0.131 mmol) was dissolved in TFA (1.0 mL) and DCM (1.0 mL) and was stirred at room temperature. After 1 hour, the reaction mixture was evaporated to give an oil, and which was lyophilized from ethanol and benzene to give the title compound as a solid. LC-MS: calculated for C26H35ClN6O4Si 558.22 observed m/e: 559.27 (M+H)+ (Rt 1.15/2 min).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([NH:6][S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[N+:19]([O-])([OH:21])=[O:20].O>C(O)(=O)C>[F:1][C:2]1[CH:18]=[CH:17][C:5]([NH:6][S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[C:4]([N+:19]([O-:21])=[O:20])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(F)cc2)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(F)cc2[N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 97 %

Procedure:
To a suspension of 4′-fluoro-p-toluenesulfonanilide (486.6 g (1.80 mol) in acetic acid (955 ml), 97% fuming nitric acid (128.6 g (1.98 mol) was added dropwise, keeping the inner temperature at 45° C., over a period of 40 minutes. After completion of the addition, the reaction mixture was stirred at 50° C. for 2 hours and left to cool to room temperature. Water (2000 ml) was then added and the mixture was stirred for 30 minutes. The crystals separated were filtered and washed with water to give 543.5 g (97%) of 4′-fluoro-2′-nitro-p-toluenesulfonanilide as yellow crystals.
Reaction SMILES: [C:1](O)(=O)/[C:2](=[C:4](\[CH:6]=[O:7])/[Cl:5])/[Cl:3].[F:10][C:11]([F:25])([F:24])[C:12]1[CH:13]=[C:14]([NH:22][NH2:23])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1>C(O)C>[Cl:3][C:2]1[CH:1]=[N:23][N:22]([C:14]2[CH:15]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:17]=[C:12]([C:11]([F:10])([F:24])[F:25])[CH:13]=2)[C:6](=[O:7])[C:4]=1[Cl:5]
Reactant: NNc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C/C(Cl)=C(/Cl)C(=O)O
Solvent: CCO
Product: O=c1c(Cl)c(Cl)cnn1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 90.8 %

Procedure:
To a solution of 28.1 grams (0.166 mol.) of mucochloric acid dissolved in 120 milliliters of ethanol were added 37 grams (0.151 mol.) of 3,5-bis-(trifluoromethyl)phenylhydrazine. The mixture was stirred for about one hour, and then the ethanol was removed from the solution by evaporation under reduced pressure. Eighty milliliters of glacial acetic acid and 80 milliliters of acetic anhydride were added to the residue in one portion. The mixture was heated to reflux for four hours, and then cooled and the solvent was removed by evaporation under reduced pressure. Recrystallization of the residue from ethanol produced 51.7 grams of 4,5-dichloro-1-[3,5-bis(trifluoromethyl)-phenyl]-1,6-dihydro-6-oxopyridazine.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](Cl)=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Si](N1N=[CH:21][CH:20]=[N:19]1)(C)(C)C>S1(CCCC1)(=O)=O>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][CH:21]=[CH:20][N:19]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)n1nccn1
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Solvent: O=S1(=O)CCCC1
Product: CC(=O)Oc1ccc(-c2ncco2)cc1
Temperature: 150 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-(chlorocarbonyl)phenyl acetate (45.6 g, 0.23 mol) in sulfolane (200 mL) was added 2-TMS-1,2,3-triazole (1.1 eq., 34 mL) over one minute. After stirring for 5 minutes under nitrogen, the reaction was exothermic and the temperature was increased to between 35° C. and 40° C. The reaction mixture was placed under vacuum for 10 minutes to remove the chlorotrimethylsilane (b.p.=57° C.). The reaction mixture was heated at 150° C. for 2.5 hours. After 10 minutes, gas evolution was observed. After cooling, the reaction mixture was poured into water (1.2 L) and extracted with ether (3×). The combined organic layers were washed with water (3×) and brine, dried and concentrated to give 4-(2-oxazolyl)phenyl acetate (44.8 g, 96% th.; 98% pract) as a solid; 1H NMR (CDCl3) δ 8.05 (d, 2H), 7.70 (s, 1H), 7.20 (m, 3H), 2.35 (s, 3H) ppm.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][OH:8].CC(C)([O-])C.[Na+].[C:15]([C:19]1[O:23]/[C:22](=[N:24]\[C:25](=[O:37])[C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=2F)/[N:21]([CH2:38][C@H:39]2[CH2:43][CH2:42][CH2:41][O:40]2)[CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[C:15]([C:19]1[O:23]/[C:22](=[N:24]\[C:25](=[O:37])[C:26]2[CH:31]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:29]=[CH:28][C:27]=2[O:8][CH2:7][C@@H:3]2[CH2:4][CH2:5][CH2:6][N:2]2[CH3:1])/[N:21]([CH2:38][C@H:39]2[CH2:43][CH2:42][CH2:41][O:40]2)[CH:20]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CN1CCC[C@H]1CO
Reactant: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)o1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC[C@H]1COc1ccc(C(F)(F)F)cc1C(=O)/N=c1\oc(C(C)(C)C)cn1C[C@H]1CCCO1
Temperature: 22 °C
Reaction time: 0.33 h

Procedure:
To a solution of (S)-(1-methylpyrrolidin-2-yl)methanol (Aldrich) (0.860 mL, 7.24 mmol) in 15 mL of THF was added sodium tert-butoxide (0.696 g, 7.24 mmol). The reaction was stirred at 22° C. for 20 min. The reaction was cooled to 5° C. and a solution of Example 32C (1.5 g, 3.62 mmol) in 5 mL of THF was added. The reaction was stirred at 5° C. for 2 h, then at 22° C. for 1 h. The solvent was evaporated under reduced pressure. The residue was dissolved with methylene chloride, washed with NaHCO3, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography on SiO2 using an Analogix® Intelliflash280™ (solvent A=CH2Cl2; solvent B=3 N NH3/MeOH:CH2Cl2 (1:9); eluting with A:B (100:0) changing to A:B (0:100) over the run time of approximately 30 minutes) to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.17 (s, 9H), 1.53-1.98 (m, 8H), 1.97-2.15 (m, 2H), 2.19-2.35 (m, 1H), 2.46 (s, 3H), 2.62-2.81 (m, 1H), 3.07 (t, J=8.1 Hz, 1H), 3.62 (dd, J=14.1, 7.6 Hz, 1H), 3.72-3.94 (m, 2H), 4.01-4.21 (m, 2H), 6.53 (s, 1H), 6.96 (d, J=8.8 Hz, 1H), 7.55 (dd, J=9.0, 2.9 Hz, 1H), 7.93 (d, J=2.0 Hz, 1H); MS (ESI) m/z 511 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]2[N:15]([CH2:16][C:17]([N:19]3[CH2:24][CH:23]([CH3:25])[CH2:22][CH:21]([CH3:26])[CH2:20]3)=[O:18])[CH:14]=[C:13]([CH2:27][S:28][CH3:29])[N:8]2[C:9](=[O:12])[C:10]=1[OH:11])=O.[Cl:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=1[Cl:39])[CH2:34][NH2:35]>>[Cl:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=1[Cl:39])[CH2:34][NH:35][C:3]([C:5]1[N:6]=[C:7]2[N:15]([CH2:16][C:17]([N:19]3[CH2:20][CH:21]([CH3:26])[CH2:22][CH:23]([CH3:25])[CH2:24]3)=[O:18])[CH:14]=[C:13]([CH2:27][S:28][CH3:29])[N:8]2[C:9](=[O:12])[C:10]=1[OH:11])=[O:2]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1nc2n(CC(=O)N3CC(C)CC(C)C3)cc(CSC)n2c(=O)c1O
Product: CSCc1cn(CC(=O)N2CC(C)CC(C)C2)c2nc(C(=O)NCc3ccc(Cl)c(Cl)c3)c(O)c(=O)n12
Yield: 76.4 %

Procedure:
Following the same procedure for Example 49 but using 1-[2-(3,5-dimethyl-piperidin-1-yl)-2-oxo-ethyl]-6-hydroxy-3-methylsulfanylmethyl-5-oxo-1,5-dihydro-imidazo[1,2-a]pyrimidine-7-carboxylic acid methyl ester from step 2 and 3,4-dichlorobenzylamine, the title product was obtained in 76.4% yield as a yellowish amorphous solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:6][N:5]=[CH:4][N:3]=1.[C-:15]#[N:16].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[C:15]([C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:6][N:5]=[CH:4][N:3]=1)#[N:16]
Reactant: [C-]#N
Reactant: Cc1ccc(-c2cncnc2Cl)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(-c2cncnc2C#N)cc1

Procedure:
A mixture of 4-chloro-5-(p-tolyl)pyrimidine (7.4 g, 36 mmol), potassium cyanide (4.74 g, 72 mmol) and 18-crown-6 ether (0.48 g, 2 mmol) in acetonitrile (130 ml) was heated under reflux for 17 hours. After removal of insoluble materials by filtration from the reaction mixture, the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel to give crystals. Recrystallization from ethyl acetate-hexane afforded pale yellow needles (4.17 g, 59%), m.p. 107°-109° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:42])=[N:14][C:15]([CH3:41])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CCO.O>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:42])=[N:14][C:15]([CH3:41])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCc3ccc(Cl)cc3)cc2)c1N1CCC(C)(C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CCC(C)(C)CC2)c1-c1ccc(OCc2ccc(Cl)cc2)cc1
Yield: 79.3 %

Procedure:
A mixture of (S)-ethyl 2-(tert-butoxy)-2-(5-(4-((4-chlorobenzyl)oxy)phenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetate (0.0344 g, 0.058 mmol) and LiOH (0.014 g, 0.580 mmol) in 9:1 EtOH/H2O (2 mL0 was refluxed for 3 h. Then, cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(5-(4-((4-chlorobenzyl)oxy)phenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid (0.0258 g, 0.046 mmol, 79% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.38-7.44 (m, 4H), 7.15-7.20 (m, 1H), 7.01-7.10 (m, 3H), 5.99 (br. s., 1H), 5.08-5.16 (m, 2H), 3.57 (br. s., 1H), 2.90 (br. s., 1H), 2.64 (s, 3H), 2.24-2.32 (m, 1H), 2.22 (s, 3H), 1.97-2.13 (m, 1H), 1.25 (s, 9H), 0.88 (br.s., 3H), 0.64 (br. s., 3H). 4H of piperidine were not resolved. LCMS (M+H)=565.3.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.CCN(C(C)C)C(C)C.[CH:16]1([CH2:21][CH:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23](Cl)=[O:24])[CH2:20][CH2:19][CH2:18][CH2:17]1>C(Cl)Cl>[CH:16]1([CH2:21][CH:22]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:23]([NH:1][C:2]2[S:3][CH:4]=[N:5][N:6]=2)=[O:24])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(Cl)C(CC1CCCC1)c1ccccc1
Reactant: Nc1nncs1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1nncs1)C(CC1CCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To 2-amino-1,3,4-thiadiazole (220 mg, 21 mmol), 0.4 mL DIEA and 7 mL of DCM is added a solution of the title C compound, 3-cyclopentyl-2-phenylpropionyl chloride (500 mg, 21 mmol) in 2 mL of DCM. The mixture is stirred at ambient temperature for 2-3 h, the mixture is evaporated, and the residue is treated with 10 mL 1 N HCl and extracted twice with ethyl acetate. The combined extracts are washed with brine, saturated sodium bicarbonate solution, and brine and dried over anhydrous magnesium sulfate. Filtration and evaporation afford 3-cyclopentyl-2-phenyl-N-[1,3,4]thiadiazol-2-yl-propionamide as an orange foam: 1H NMR (400 MHz, DMSO-d6) δ 11 (m, 2H), 1.4 (m, 2H), 1.5 (m, 3H), 1.7(m, 3H), 2.1 (ddd, J=13.3, 7.8, 7.7 Hz, 1H), 4.0 (dd, J=8.1, 7.1 Hz, 1H), 7.2 (s, 1H), 7.3 (m, 4H), 9.1 (s, 1H), 12.8 (s, 1H); LC/MS 302 (M+1), 300 (M−1).
Reaction SMILES: O.[OH:2][CH2:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>C(Cl)Cl.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>[CH:3]([C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
To a water cooled (25° C.) solution of 10.0 g of (R)-2-(hydroxymethyl)-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester in 250 ml of dry methylene chloride is added in one portion 16.0 g of pyridinium chlorochromate, 36.0 g of dried, crushed 4 Å molecular sieves and 4.5 ml of glacial acetic acid. The resulting mixture is stirred at 25° C. for one hour. Twenty-five grams of diatomaceous earth and 500 ml of diethyl ether is added, the suspension is filtered through a pad of diatomaceous earth and the filtrate concentrated in vacuo. The residue is dissolved in diethyl ether and is passed through a short column of silica gel using diethyl ether as the eluant. The first two 500 ml fractions contain the desired aldehyde. The solvent is concentrated in vacuo to give 10.1 g of desired product.