Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([NH2:15])[CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:16]1[CH2:20][CH2:19][N:18]=[C:17]1S(O)(=O)=O>CC(O)CC.O>[NH:16]1[CH2:20][CH2:19][NH:18][C:17]1=[N:15][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1
Reactant: O=S(=O)(O)C1=NCCN1
Reactant: NC(Cc1ccncc1)c1ccccc1
Solvent: O
Solvent: CCC(C)O
Product: c1ccc(C(Cc2ccncc2)N=C2NCCN2)cc1
Temperature: 110 °C

Procedure:
A mixture of 1-phenyl-2-(pyridin-4-yl)ethanamine (0.23 g, 1.18 mmol), and 4,5-dihydro-1H-imidazole-2-sulfonic acid (0.18 g, 1.16 mmol) in 2-butanol (5 mL), water (1 mL) were heated at 110° C. for 3 hours. The solution was cooled to room temperature. The solvents were removed under vacuum. The residue was dissolved in methanol, and added amino modified silica gel. The solvent was removed under vacuum. Purification by chromatography on amino modified silica gel (100% ethyl acetate to 7% methanol in dichloromethane) gave N-(imidazolidin-2-ylidene)-1-phenyl-2-(pyridin-4-yl)ethanamine Compound 3 as a while solid (0.21 g, 0.80 mmol, 67% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].C([Li])(C)(C)C.[B:14](OC)([O:17]C)[O:15]C.Cl>O1CCCC1.CCCCC>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:14]([OH:17])[OH:15]
Reactant: COB(OC)OC
Reactant: Cc1ccccc1Br
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: Cc1ccccc1B(O)O
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-bromotoluene (1.0 g) in dry tetrahydrofuran (50 ml) was cooled to -70° C. under an atmosphere of argon. A solution of tert-butyl lithium in pentane (1.7M, 7.6 ml) was added dropwise to the mixture whilst maintaining the temperature below -60° C. The reaction mixture was stirred at -70° C. for 0.5 hours. Trimethyl borate (0.73 ml) was added and the mixture allowed to warm to ambient temperature. The mixture was poured onto a mixture of aqueous 2M hydrochloric acid and ice, and the mixture extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried (MgSO4) and evaporated to give 2-methylphenylboronic acid as a white solid (0.48 g) which was used without further purification.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][N:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)C.[OH-].[K+].[O-][Si]([O-])=O.[Mg+2]>C(O)C.O.CO>[OH2:3].[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:7]2[N:6]([CH2:5][C:4]([OH:22])=[O:3])[C:14]3[C:9]([N:8]=2)=[N:10][CH:11]=[CH:12][CH:13]=3)=[CH:16][CH:17]=1
Reactant: CCOC(=O)Cn1c(-c2ccc(Cl)cc2)nc2ncccc21
Agent: O=[Si]([O-])[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: O
Solvent: CCO
Solvent: CO
Product: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2ncccc21
Yield: 3.9 %

Procedure:
A mixture of 2-(4-chlorophenyl)-1H-imidazo[4,5-b]pyridine-1-acetic acid ethyl ester (8.4 g, 0.027 mole) and potassium hydroxide (2.25 g, 0.04 mole) in 95% ethanol (75 ml) and water (5 ml) was heated at reflux for 2.5 hours. The mixture was evaporated to dryness. The residue was dissolved in water and acidified with glacial acetic acid. The precipitate was collected by filtration, washed with water, and dried under high vacuum overnight at 60° C. to give 7.4 g (95% yield). A 1.4-g sample was dissolved in ~450 ml of boiling methanol, and the solution was treated with Florisil® and filtered. The filtrate was concentrated and diluted with water. A crystalline precipitate was collected by filtration, washed with water, and dried under high vacuum at 60° C. for 4 hours, then at room temperature over the weekend to give 0.16 g of solids, mp. 194°-96° C.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([CH2:13][CH2:14]Br)[CH2:5]1)(=[O:3])[CH3:2].[CH2:16]([C:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:17].C(O)(=O)/C=C/C(O)=O>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([CH2:13][CH2:14][N:21]2[CH2:22][CH2:23][C:18]([CH2:16][CH3:17])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:20]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCC1(c2ccccc2)CCNCC1
Reactant: CC(=O)N1CC(CCBr)c2ccccc21
Agent: O=C(O)/C=C/C(=O)O
Product: CCC1(c2ccccc2)CCN(CCC2CN(C(C)=O)c3ccccc32)CC1

Procedure:
In the manner described in Example 1, treatment of 1-acetyl-3-(2-bromoethyl)indoline with 4-ethyl-4-phenylpiperidine gives an oil. On reaction with molar equivalent of fumaric acid, a crystalline fumarate results. After recrystallization from acetone-hexane it melts at 173°-178°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[C:12][C:13]2[C:21]3[C:16](=[N:17][CH:18]=[N:19][C:20]=3[NH2:22])[NH:15][N:14]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CS(O[CH:28]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[NH2:22][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[N:15]([CH:32]3[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31]3)[N:14]=[C:13]([C:12]#[C:11][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=3)[C:21]=12
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)C1
Reactant: COc1cc(C#Cc2n[nH]c3ncnc(N)c23)cc(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C#Cc2nn(C3CCN(C(=O)OC(C)(C)C)C3)c3ncnc(N)c23)cc(OC)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A suspension of 3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (62 mg) obtained in Step 1, tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate (217 mg) obtained in Step 2, and potassium carbonate (221 mg) in DMF (2.0 ml) was stirred at 70° C. for 1 hour. Ethyl acetate and water were added thereto to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a light-yellow, amorphous substance (36.2 mg). Physical properties: m/z [M+H]+ 465.1
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[CH2:3][CH2:4][N:5]([CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26](OC)=[O:27])=[CH:24][CH:23]=1)[C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:10]=1.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:1][CH:2]([CH3:32])[CH2:3][CH2:4][N:5]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][OH:27])=[CH:30][CH:31]=1)[C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[N:10]=1
Reactant: COC(=O)c1ccc(CN(CCC(C)C)c2nc(-c3ccc(C(F)(F)F)cc3)cs2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CCN(Cc1ccc(CO)cc1)c1nc(-c2ccc(C(F)(F)F)cc2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
To a solution of methyl 4-[((3-methylbutyl){4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}amino)methyl]benzoate (1.34 g, 2.90 mmol) in tetrahydrofuran (10 mL) was added dropwise 1.0 M diisobutylaluminum hydride toluene solution (6.38 mL, 6.38 mmol) under ice-cooling. The reaction mixture was stirred at room temperature for 2 hr, sodium sulfate decahydrate was added and the mixture was further stirred at room temperature for 1 hr. The insoluble material was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90-60/40) to give the title compound (950 mg, yield 75%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:6][C:5]([C:15]#[N:16])=[CH:4][C:3]=1[NH:17][C:18]1[N:23]=[C:22]([N:24]([CH:34]2[CH2:36][CH2:35]2)CC2C=CC(OC)=CC=2)[C:21]2=[N:37][CH:38]=[C:39]([C:40]#[N:41])[N:20]2[N:19]=1.[F:42][C:43]1([F:48])[CH2:46][CH:45]([NH2:47])[CH2:44]1.C(OC)(OC)OC.C([BH3-])#N.[Na+]>CO.O1CCCC1.O>[Cl:1][C:2]1[C:7]([N:8]2[CH2:9][CH2:10][CH:11]([NH:47][CH:45]3[CH2:46][C:43]([F:48])([F:42])[CH2:44]3)[CH2:12][CH2:13]2)=[CH:6][C:5]([C:15]#[N:16])=[CH:4][C:3]=1[NH:17][C:18]1[N:23]=[C:22]([NH:24][CH:34]2[CH2:35][CH2:36]2)[C:21]2=[N:37][CH:38]=[C:39]([C:40]#[N:41])[N:20]2[N:19]=1
Reactant: NC1CC(F)(F)C1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCC(=O)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(N2CCC(NC3CC(F)(F)C3)CC2)c1
Temperature: 25 °C

Procedure:
To a vial charged with 2-((2-chloro-5-cyano-3-(4-oxopiperidin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 13) (30 mg, 0.053 mmol) and 3,3-difluorocyclobutanamine (6.79 mg, 0.063 mmol) in methanol (132 μl) and tetrahydrofuran (132 μl) was added trimethyl orthoformate (58.4 μl, 0.528 mmol). The reaction mixture was stirred at room temperature. Sodium cyanoborohydride (6.64 mg, 0.106 mmol) was added and the reaction mixture was stirred at room temperature 6 h. The reaction mixture was diluted with water and methanol and filtered. The solid was taken up in DMF and partitioned between water and ethyl acetate. The aqueous layer was washed with ethyl acetate (3×). The combined organics were washed with 10% lithium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was taken forward as is.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31]CC1C=CC=CC=1>[Pd].C(O)(=O)C.C(O)C>[F:1][C:2]([F:39])([F:40])[CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31]
Reactant: FC(F)(F)COCCOCCOCCOCCOCCOCCOCCOCCOCCOCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: OCCOCCOCCOCCOCCOCCOCCOCCOCCOCC(F)(F)F
Yield: 95 %

Procedure:
A stirred solution of the product of step (b) (0.97 g) and 10% palladium on carbon (100 mg) in acetic acid:ethanol (1:9, 20 mL) was placed under an atmosphere of hydrogen at 20° C. for 2 hours. The reaction mixture was filtered through a pad of celite and the solvent was removed in vacuo to give the title compound (780 mg). LC retention time 2.45 mins
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[CH:19]=2)([CH3:17])[CH3:16])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pt]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[CH:19]=2)([CH3:17])[CH3:16])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CC(C)(Oc1ccc([N+](=O)[O-])c2ccccc12)c1ccnc(N)c1
Agent: [Pt]
Solvent: CO
Product: CC(C)(Oc1ccc(N)c2ccccc12)c1ccnc(N)c1
Yield: 99.1 %

Procedure:
A solution of 4-(2-(4-nitronaphthalen-1-yloxy)propan-2-yl)pyridin-2-amine (41) (282 mg, 0.87 mmol) in MeOH (45 mL) was passed through a Thales H-cube (1.0 mL·min−1, 30° C., 55 mm 10% Pt/C Cat-Cart, full hydrogen mode). The reaction mixture was evaporated in vacuo to afford the title compound (42) (253 mg, 89%) as a brown foam: m/z 294 (M+H)+ (ES+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:18][C:17]([O:19][C@H:20]3[CH2:25][O:24][C@H:23]([CH2:26][OH:27])[C@@H:22]([OH:28])[CH2:21]3)=[N:16][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]#[CH:15])=[CH:10][CH:9]=1.Br[C:30]1[N:31]=[N:32][N:33]([CH3:35])[N:34]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1.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.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:18][C:17]([O:19][C@H:20]3[CH2:25][O:24][C@H:23]([CH2:26][OH:27])[C@@H:22]([OH:28])[CH2:21]3)=[N:16][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:30]2[N:31]=[N:32][N:33]([CH3:35])[N:34]=2)=[CH:10][CH:9]=1
Reactant: Cn1nnc(Br)n1
Reactant: C#Cc1ccc(-c2nc3nc(O[C@H]4CO[C@H](CO)[C@@H](O)C4)[nH]c3cc2Cl)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cn1nnc(C#Cc2ccc(-c3nc4nc(O[C@H]5CO[C@H](CO)[C@@H](O)C5)[nH]c4cc3Cl)cc2)n1

Procedure:
A mixture of (2R,3 S,5R)-5-((6-chloro-5-(4-ethynylphenyl)-1H-imidazo[4,5-b]pyridin-2-yl)-oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3-ol (60 mg, 0.150 mmol), Pd(Ph3P)4(17.34 mg, 0.015 mmol), copper(I) iodide (2.85 mg, 0.015 mmol), 5-bromo-2-methyl-2H-tetrazole (48.9 mg, 0.300 mmol) and diisopropylethylamine (0.210 ml, 0.450 mmol) in dioxane (2 ml) was charged in a reaction tube. The tube was sealed and N2 was bubbled through for 5 min. The reaction was heated at 80 C for 18 h, and then concentrated. The resulting residue was purified on reverse phase HPLC eluting with 10-70% CH3CN/H2O with TFA as an additive to give the title compound. LC-MS: m/e: 481.97.53 (M+H)+ (Rt 1.70/4 min); 1H NMR δ (ppm) (CD3OD): 7.84-7.75 (m, 4H), 5.11 (septet, 1H, J=5 Hz)), 4.38-4.31 (m, 1H), 4.24 (s, 3H), 3.89 (dd, 1H, J=12, 2 Hz), 3.69-3.59 (m, 2H), 3.37 (t, 1H, J=11 Hz), 3.20-3.15 (m, 1H), 2.79-2.72 (m, 1H), 1.70 (dd, 1H, J=23, 12 Hz),
Reaction SMILES: C(OC(=O)CCC1C(C)=CC(C2N=C(C3SC(C=O)=C(C)C=3)ON=2)=CC=1CC)C.C(NC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)=O.C([O:54][C:55](=[O:84])[CH2:56][CH2:57][C:58]1[C:63]([CH3:64])=[CH:62][C:61]([C:65]2[N:69]=[C:68]([C:70]3[S:71][C:72]([CH2:76][N:77]([CH:79]([CH3:81])[CH3:80])[CH3:78])=[C:73]([CH3:75])[CH:74]=3)[O:67][N:66]=2)=[CH:60][C:59]=1[CH2:82][CH3:83])C>C(O)C.[OH-].[Na+]>[CH2:82]([C:59]1[CH:60]=[C:61]([C:65]2[N:69]=[C:68]([C:70]3[S:71][C:72]([CH2:76][N:77]([CH:79]([CH3:81])[CH3:80])[CH3:78])=[C:73]([CH3:75])[CH:74]=3)[O:67][N:66]=2)[CH:62]=[C:63]([CH3:64])[C:58]=1[CH2:57][CH2:56][C:55]([OH:84])=[O:54])[CH3:83]
Reactant: CCOC(=O)CCc1c(C)cc(-c2noc(-c3cc(C)c(CN(C)C(C)C)s3)n2)cc1CC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CCOC(=O)CCc1c(C)cc(-c2noc(-c3cc(C)c(C=O)s3)n2)cc1CC
Agent: CNC(C)C
Solvent: O=CO
Solvent: CCO
Product: CCc1cc(-c2noc(-c3cc(C)c(CN(C)C(C)C)s3)n2)cc(C)c1CCC(=O)O
Yield: 96.8 %

Procedure:
3-[2-Ethyl-4-(5-{5-[(isopropyl-methyl-amino)-methyl]-4-methyl-thiophen-2-yl}-[1,2,4]oxadiazol-3-yl)-6-methyl-phenyl]-propionic acid ethyl ester formate salt (86 mg) is obtained as a pale yellow oil starting from 3-{2-ethyl-4-[5-(5-formyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenyl}-propionic acid ethyl ester (100 mg, 0.242 mmol) and N-isopropyl-methylamine (709 mg, 9.70 mmol) using two portions of sodium triacetoxyborohydride (171 mg, 0.727 mmol) and following Method C; LC-MS: tR=0.71 min; [M+1]+=470.15; 1H NMR (D6-DMSO): δ1.05 (d, J=6.5 Hz, 6H), 1.17-1.26 (m, 6H), 2.23 (s, 6H), 2.39 (s, 3H), 2.44-2.50 (m, 2H), 2.72 (q, J=7.5 Hz, 2H), 2.89-3.01 (m, 3H), 3.70 (s, 2H), 4.10 (q, J=7.0 Hz, 2H), 7.69 (s, 2H), 7.80 (s, 1H), 8.15 (s, 1H). b) A solution of the above propionic acid ethyl ester (75 mg, 0.145 mmol) in ethanol (1.5 mL) and 2 N aq. NaOH (1.5 mL) is stirred at rt for 6 h. The ethanol is evaporated and the reaction mixture is acidified by adding formic acid before it is separated be prep. HPLC (column: Atlantis T3 C18, 30×75 mm, 10 μm, eluting with a gradient of acetonitrile in water containing 0.5% of formic acid) to give the title compound (62 mg) as its formate salt as a pale yellow solid; LC-MS*: tR=0.66 min; [M−1]−=440.02; 1H NMR (D6-DMSO): δ1.05 (d, J=6.5 Hz, 6H), 1.22 (t, J=7.3 Hz, 3H), 2.23 (s, 6H), 2.33-2.42 (m, 5H), 2.73 (q, J=7.5 Hz, 2H), 2.89-2.97 (m, 3H), 3.70 (s, 2H), 7.69 (s, 2H), 7.80 (s, 1H), 8.17 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][C:10]1[C:11]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=3)C(=O)[O:17][N:16]=2)=[N:12][O:13][N:14]=1.[N:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[C:30]=[O:31].[OH-].[Na+]>C(Cl)Cl.O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:32]([NH:29][C:30]([NH:8][CH2:9][C:10]1[C:11]([C:15](=[N:16][OH:17])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=2)=[N:12][O:13][N:14]=1)=[O:31])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)N=C=O
Reactant: NCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)NCc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.7 %

Procedure:
3-[4-(Aminomethyl)-1,2,5-oxadiazol-3-yl]-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one trifluoroacetate (15 mg, 0.035 mmol) and TEA (15 μL, 0.10 mmol) were dissolved in DCM (0.5 mL) and then 2-isocyanato-2-methylpropane (24 μL, 0.21 mmol) was added. The reaction was stirred for 16 h at room temperature. A solution of sodium hydroxide in water (0.50 mL, 1.0 N) was added and the mixture stirred at room temperature for 2 h. Acidification with acetic acid and purification by preparative LCMS gave the desired product (12 mg, 68%). MF═C15H18ClFN6O3; LCMS calculated for C15H19ClFN6O3 (M+H)+: m/z=385.0.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:58][C:59]1[O:60][C:61]2[CH:67]=[CH:66][CH:65]=[CH:64][C:62]=2[N:63]=1.Cl>CN(C)C=O.O.C(OCC)(=O)C>[O:60]1[C:61]2[CH:67]=[CH:66][CH:65]=[CH:64][C:62]=2[N:63]=[C:59]1[NH:58][C:8](=[O:9])[CH:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=1)[CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1[N+](=O)[O-]
Reactant: Nc1nc2ccccc2o1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nc3ccccc3o2)cc1[N+](=O)[O-]
Yield: 18.9 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (prepared as in Example 32, 50 mg, 0.15 mmol), triethylamine (0.060 mL, 0.44 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (98 mg, 0.22 mmol), and 2-aminobenzoxazole (30 mg, 0.22 mmol) in N,N-dimethylformamide (3 mL) was stirred at 25° C. for 3 h. The reaction mixture was then diluted with water (25 mL), a 1N aqueous hydrochloric acid solution (5 mL), and ethyl acetate (25 mL). The layers were separated. The resulting organic layer was washed with a saturated aqueous sodium chloride solution (1×25 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) afforded N-benzooxazol-2-yl-3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-propionamide (13 mg, 19.5%) as a yellow solid: mp 106-110° C; EI-HRMS m/e calcd for C22H23N3O6S (M+) 457.1308, found 457.1323.
Reaction SMILES: [N+:1]([C:4]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:5]=1[CH:6]([Cl:8])[Cl:7])([O-:3])=[O:2].[N+](C1C(C)=CC=CC=1C[Cl:20])([O-])=O.C(Cl)Cl.[OH-].[Na+]>[Cl-].C([N+](C)(C)C)CCCCCCCCCCC.C(O)(C)(C)C.C(Cl)(Cl)(Cl)Cl>[N+:1]([C:4]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([Cl:20])([Cl:7])[Cl:8])([O-:3])=[O:2]
Reactant: Cc1cccc(CCl)c1[N+](=O)[O-]
Reactant: Cc1cccc(C(Cl)Cl)c1[N+](=O)[O-]
Agent: CCCCCCCCCCCC[N+](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)(C)O
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cccc(C(Cl)(Cl)Cl)c1[N+](=O)[O-]

Procedure:
9.6 gms of 2-nitro-3-methyl benzal chloride (prepared by chlorination of 2-nitro-m-tolualdehyde with thionyl chloride), 9.6 gms of 2-nitro-3-methyl benzyl chloride, 0.6 gms of n-dodecyl trimethyl ammonium chloride, 160 ml of methylene chloride, 100 ml of carbon tetrachloride, 250 ml of 50% sodium hydroxide, and 10 gms of t-butyl alcohol were charged into a reaction vessel. The mixture was refluxed for 31/2 hours, cooled, solvent extracted, distilled and recrystallized to 16.0 gms of product as determined by GC-Mass spectral analysis.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9](=[O:12])[CH:8]=[CH:7]2.[CH3:14][C:15](O)([C:17]#[CH:18])[CH3:16].C1(C)C(C)=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:14][C:15]1([CH3:16])[O:13][C:3]2=[C:2]([CH3:1])[C:11]3[O:10][C:9](=[O:12])[CH:8]=[CH:7][C:6]=3[CH:5]=[C:4]2[CH:18]=[CH:17]1
Reactant: C#CC(C)(C)O
Reactant: Cc1c(O)ccc2ccc(=O)oc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: Cc1c2c(cc3ccc(=O)oc13)C=CC(C)(C)O2
Reaction time: 4 h
Yield: 33 %

Procedure:
A solution prepared from 5.0 mmol of 8-methyl-7-hydroxycoumarin and 6.0 mmol of 2-methyl-3-butyn-2-ol in 40 ml of xylene containing 0.095 g (0.50 mmol) of p-toluenesulfonic acid was refluxed with magnetic stirring for 4 hours. The solvent was distilled off in vacuo and the oily contents of the flask chilled in an ice-salt water bath to induce crystallization. The white microneedles, 33% yield, were recrystallized from methanol to analytical purity, m.p. 105°-107° C. (lit. m.p. 106°-107° C.). The 1H-NMR spectrum was also identical to that reported, see P. Rodighiero et al., reference cited above.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4].[Cl:20][S:21](O)(=[O:23])=[O:22]>ClCCl>[F:19][C:2]([F:1])([F:18])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([S:21]([Cl:20])(=[O:23])=[O:22])=[CH:16][CH:17]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(N1CCC(Cc2ccccc2)CC1)C(F)(F)F
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: O=C(N1CCC(Cc2ccc(S(=O)(=O)Cl)cc2)CC1)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.3 %

Procedure:
A mixture of 1-(trifluoroacetyl)-4-benzylpiperidine (29.2 g, 108 mmol) and dichloromethane (10 ml) was added dropwise to chlorosulfonic acid (36 ml, 539 mmol) over period of 1 h at −10° C. The mixture was stirred at 0° C. for 1 h and then at room temperature for 1 h. The whole was poured into ice-water (500 ml). The mixture was extracted with dichloromethane (200 ml×2). The extracts were washed with 5% aqueous sodium bicarbonate (500 ml), saturated sodium chloride solution (500 ml) successively. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel 100 g, ethyl acetate/hexane=1/20 to 1/5) to obtain the title compound (16.5 g, 41%) as a colorless crystalline powder.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][CH2:21][Cl:22].O>CS(C)=O>[Cl:22][CH2:21][CH2:20][CH2:19][CH2:18][N:6]1[CH:7]=[C:2]([CH3:1])[C:3]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:4][C:5]1=[O:8]
Reactant: Cc1c[nH]c(=O)nc1-c1cccnc1
Reactant: ClCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cn(CCCCCl)c(=O)nc1-c1cccnc1
Temperature: 60 °C
Yield: 67.9 %

Procedure:
To a solution of 5-methyl-4-pyridin-3-yl-1H-pyrimidin-2-one (100 mg, 0.53 mmol) in DMSO (2 ml), 60% NaH (23 mg, 0.59 mmol) was added portionwise. After heating the mixture at 60° C. for 1 hour, 1-bromo-4-chloro-butane (100 mg, 0.59 mmol) dissolved in DMSO (0.8 ml) was added at 60° C. and the heating was maintained for further 2 hours. After cooling to room temperature, water was added and the mixture extracted with diethyl ether to remove the dialkylated product and finally with ethyl acetate. Ethyl acetate was washed with brine, dried (Na2SO4) and evaporated to afford 100 mg of the title compound as yellow oil (68% yield).