Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:22][C:23]2[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=2)[C:26](OC)=[O:27])[CH2:15][CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:34][NH:35][O:36][CH3:37].C([Mg]Cl)(C)C>O1CCCC1>[CH3:37][O:36][N:35]([CH3:34])[C:26](=[O:27])[C:25]1[CH:30]=[CH:31][CH:32]=[C:23]([CH2:22][N:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=2)[CH2:15][CH:16]([OH:21])[C:17]([F:20])([F:18])[F:19])[CH:24]=1
Reactant: CNOC
Reactant: COC(=O)c1cccc(CN(CC(O)C(F)(F)F)c2cccc(Oc3ccccc3)c2)c1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)c1cccc(CN(CC(O)C(F)(F)F)c2cccc(Oc3ccccc3)c2)c1
Temperature: -15 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
Ex-620A) To a slurry of methyl 3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzoate (1.03 g, 0.0023 mol) and N,O-dimethyl-hydroxylamine hydrochloride (386 mg, 0.0040 mol) in 4.6 mL of tetrahydrofuran at −15° C. was added a 2.0 M solution of isopropylmagnesium chloride in THF (4.6 mL, 0.0092 mol) over 15 min. The reaction was stirred for 1 h at −15° C., then quenched with 20% aqueous ammonium chloride and extracted with ethyl acetate. The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 1:1 ethyl acetate:hexane to afford 0.72 g (66%) of the desired N-methoxy-N-methyl-3-[[(3-phenoxyphenyl)-(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzamide product as an off-white solid. HRMS calcd. for C25H25N2O4F3: 475.1845 [M+H]+, found: 475.1840.
Reaction SMILES: [OH:1][C:2]1([CH2:13][NH2:14])[CH2:8][O:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][CH2:3]1.[S:15]([OH:19])([OH:18])(=[O:17])=[O:16].CS[C:22](=[NH:24])[NH2:23].CN(C)C=O>O>[S:15]([OH:19])([OH:18])(=[O:17])=[O:16].[OH:1][C:2]1([CH2:13][NH:14][C:22]([NH2:24])=[NH:23])[CH2:3][O:4][C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[O:7][CH2:8]1
Reactant: CSC(=N)N
Reactant: NCC1(O)COc2ccccc2OC1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CN(C)C=O
Product: N=C(N)NCC1(O)COc2ccccc2OC1

Procedure:
3-hydroxy-3-aminomethyl-3,4-dihydro-2H-1,5-benzodioxepin from Example 1, Step E, (1.95 g., 10 millimoles) and 2.78 g. (10 millimoles) of S-methylisothiourea sulfate in 15 mls. of dimethylformamide and 2 mls. of water is heated at 90°-100° C. for 5 hours. The solvent is evaporated in vacuo and the residue recrystallized from ethanol to give 3-hydroxy-3-guanidinomethyl-3,4-dihydro-2H-1,5-benzodioxepin sulfate.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][C:19]([CH3:22])(C)[CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:27].[CH:28]1(O)[CH2:33]CCC[CH2:29]1>CCO.CCO.CCO.CCO.[Ti]>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH:19]3[CH2:22][CH2:33][CH2:28][CH2:29][CH2:20]3)=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:27]
Reactant: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c-2ccc(F)c1Cl
Reactant: OC1CCCCC1
Agent: [Ti]
Solvent: CCO
Product: O=C(OC1CCCCC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c-2ccc(F)c1Cl
Reaction time: 8 h

Procedure:
A mixture of 4.0 g (10 mmol) of tert.butyl (S)-8-chloro-7-fluoro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 0.8 g (3 mmol) of tetraethyl orthotitanate and 15 ml of cyclohexanol is stirred at 120° overnight, evaporated to dryness, the residue is taken up in methylene chloride, the solution obtained is washed successively with 40 ml of 5N hydrochloric acid, water and saturated sodium bicarbonate solution, dried over magnesium sulphate and evaporated. There is obtained cyclohexyl (S)-8-chloro-7-fluoro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 163°-166°.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[O:11][CH2:10][C:9]([CH3:13])([CH3:12])[O:8][C:6]=2[N:7]=1.C(O[C:25](=O)[N:26](C)[C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][C:9]1([CH3:13])[O:8][C:6]2[N:7]=[C:2]([C:30]3[CH:31]=[CH:32][C:27]([NH:26][CH3:25])=[N:28][CH:29]=3)[N:3]=[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:5]=2[O:11][CH2:10]1
Reactant: CC1(C)COc2c(nc(Cl)nc2N2CCOCC2)O1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CNc1ccc(-c2nc3c(c(N4CCOCC4)n2)OCC(C)(C)O3)cn1
Temperature: 120 °C
Yield: 31.1 %

Procedure:
A microwave vial was charged with 2-chloro-7,7-dimethyl-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine from Example 104 (50 mg, 0.18 mmol), methyl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-carbamic acid tert-butyl ester (88 mg, 0.26 mmol), Pd(PPh3)2Cl2 (12 mg, 0.02 mmol) and sodium carbonate (0.5 mL, 0.5 mmol, 1M aqueous solution) in acetonitrile (1.5 mL) then evacuated and back filled with nitrogen before being heated at 120° C. for 30 minutes using microwave irradiation. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with methanol and the product eluted with 2M ammonia in methanol. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% HCO2H in water on a gradient of acetonitrile 5-98%) affording 113 as a white solid (20 mg, 32%). LCMS: RT=2.79 min, [M+H]+=358. 1H NMR (400 MHz, CDCl3): δ 9.04 (1H, d, J=2.4 Hz), 8.35 (1H, dd, J=2.4, 8.6 Hz), 6.39 (1H, d, J=8.6 Hz), 4.84 (1H, broad s), 3.89 (2H, s), 3.85-3.76 (8H, m), 2.97 (3H, d, J=5.2 Hz), 1.45 (6H, s)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([OH:14])[CH2:10][C@@H:9]1[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](F)[CH:20]=1>CN1CCCC1=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([O:14][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([Br:18])[CH:20]=2)[CH2:10][C@@H:9]1[CH3:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1C[C@H](O)CCN1C(=O)OC(C)(C)C
Reactant: Fc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: C[C@H]1C[C@H](Oc2cccc(Br)c2)CCN1C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
Dissolve 4-hydroxy-trans-2-methyl-piperidine-1-carboxylic acid tert-butyl ester isomer 1 (preparation 2, 3.03 g, 14.07 mmol) in 1-methyl-2-pyrrolidinone (50 mL), treat with 95% sodium hydride (0.33 g, 12.93 mmol), stir and beat at 70° C. After 1 hr., add 1-bromo-3-fluoro-benzene (1.73 mL, 15.5 mmol), stir, and heat at 100° C. After 16 hr., cool to ambient temperature and quench with water (100 mL). Extract with 4:1 hexane:ethyl acetate (2×100 mL), combine the organic layers and wash with aqueous NaCl solution (75 mL), dry over sodium sulfate, filter and concentrate. Purify the residue by silica gel flash chromatography eluting with 4:1 hexanes:ethyl acetate to obtain of the title compound (2.42 g, 46%). 1H NMR (CDCl3): 7.1 (m, 3H), 6.8 (m, 1H), 4.55 (m, 1H), 4.5 (m, 1H), 4.1 (m, 1H), 2.95 (m, 1H), 2.1 (m, 1H), 1.95 (m, 1H), 1.7 (m, 1H), 1.5 (m, 1H), 1.45 (s, 9H), 1.2 (d, 3H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH2:25][CH:26]1[CH2:28][CH2:27]1>>[CH:26]1([CH2:25][NH:24][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[CH2:28][CH2:27]1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: NCC1CC1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCC2CC2)cn1
Yield: 78 %

Procedure:
As described for example 12, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (155 mg, 0.50 mmol) was converted using aminomethylcyclopropane instead of 2,2,2-trifiuoroethylamine to the title compound (SiO2, heptane:ethyl acetate=80:20 to 50:50, 142 mg, 78%) which was obtained as a white foam. MS: m/e=364.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([C:15]2[CH:16]=[C:17]([CH:27]=[CH:28][CH:29]=2)[C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])(=[O:14])=[O:13])=[CH:7][CH:6]=1)=[O:4].[C:30](#N)[CH3:31].C(=O)([O-])[O-].[K+].[K+].ICC>O>[CH2:30]([N:11]([C:8]1[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=1)[S:12]([C:15]1[CH:16]=[C:17]([CH:27]=[CH:28][CH:29]=1)[C:18]([O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:25])[CH3:26])=[O:19])(=[O:14])=[O:13])[CH3:31]
Reactant: COC(=O)c1ccc(NS(=O)(=O)c2cccc(C(=O)OCC[Si](C)(C)C)c2)cc1
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCI
Solvent: O
Product: CCN(c1ccc(C(=O)OC)cc1)S(=O)(=O)c1cccc(C(=O)OCC[Si](C)(C)C)c1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To a mixture of 320 mg of 2-(trimethylsilyl)ethyl 3-{[4-(methoxycarbonyl)phenyl]sulfamoyl}benzoate and 5 mL of acetonitrile were added 203 mg of potassium carbonate and 0.119 mL of iodoethane. After stirring at 70° C. for 5 hours, 102 mg of potassium carbonate and 0.059 mL of iodoethane were added thereto, followed by stirring at 70° C. for 10 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 334 mg of a 2-(trimethylsilyl)ethyl 3-{ethyl[4-(methoxycarbonyl)phenyl]sulfamoyl}benzoate as a colorless oily substance. ESI+: 464
Reaction SMILES: [C:1]([CH:6]1[CH2:13][C:9]2=[CH:10][S:11][CH:12]=[C:8]2[CH2:7]1)([O:3]CC)=[O:2].[OH-].[K+]>C(O)C.O>[C:1]([CH:6]1[CH2:13][C:9]2=[CH:10][S:11][CH:12]=[C:8]2[CH2:7]1)([OH:3])=[O:2]
Reactant: CCOC(=O)C1Cc2cscc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1Cc2cscc2C1

Procedure:
Dissolve 5-(carboethoxy)-2,4,5,6-tetrahydrocyclopenta[c]thiophene (6.68 g, 34.1 mmol) in ethanol (95%, 150 mL) and water (75 mL). Add potassium hydroxide (9.5 g, 0.17 mol) and stir at room temperature for 1 hour. Partition between water (150 mL) and ethyl ether (2×150 mL). Acidifythe aqueous phase with hydrochloric acid to pH 1. Extract with methylene chloride (2×150 mL), dry (Na2SO4) and evaporate the solvent in vacuo to give 5-(carboxy)-2,4,5,6-tetrahydrocyclopenta[c]thiophene.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]#[N:11])=[N:4][N:5]([CH:7]([CH3:9])[CH3:8])[N:6]=1.F[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20].O.[OH-].[Li+]>CS(C)=O>[CH:7]([N:5]1[N:4]=[C:3]([C:10]#[N:11])[C:2]([NH:1][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])=[N:6]1)([CH3:9])[CH3:8]
Reactant: CC(C)n1nc(N)c(C#N)n1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)n1nc(C#N)c(Nc2ccccc2[N+](=O)[O-])n1
Reaction time: 1 h
Yield: 92.7 %

Procedure:
Combine 5-amino-2-isopropyl-2H-1,2,3-triazole-4-carbonitrile (44.2 g, 0.292 mol) and 2-fluoronitrobenzene (41.25 g, 0.292 mol) in dimethylsulphoxide (590 ml) and stir in the presence of lithium hydroxide monohydrate (24.56 g;0.584 mol) for eighteen hours at 55° C. Pour the reaction mixture onto ice-water, stir for one hour, filter and wash the filter pad well with water to leave a yellow crystalline solid to give 2-isopropyl-5-(2-nitroanilino)-2H-1,2,3-triazole4-carbonitrile (73.7 g, 93% yield): 1HNMR/c: 1.6 ppm (d, 6H), 4.8 ppm (m, 1H), 7.05 ppm (tr, 1H), 7.64 ppm (tr, 1H), 8.2 ppm (dd, 1H), 8.28 ppm (dd, 1H), 10.25 ppm (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][N:10]=[N:9]2)=[C:4]([O:14][CH:15]([CH3:17])[CH3:16])[CH:3]=1.[C:18]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH3:18])[N:10]=[N:9]2)=[C:4]([O:14][CH:15]([CH3:17])[CH3:16])[CH:3]=1
Reactant: CC(C)Oc1cc(F)ccc1-n1nn[nH]c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)Oc1cc(F)ccc1-n1nnn(C)c1=O
Temperature: 25 °C
Yield: 80.7 %

Procedure:
A mixture of 1-(4-fluoro-2-isopropoxyphenyl)-1H-tetrazol-5(4H)-one (4.10 g, 17.2 mmol, 1 equiv), K2CO3 (7.15 g, 52.0 mmol, 3 equiv), and iodomethane (3.25 mL, 52.0 mmol, 3 equiv) in DMF (40 mL) was stirred at RT ON. The reaction mixture was partitioned between water and EtOAc, then the layers were separated. The aqueous layer was extracted with EtOAc 2×, and the combined organic layer was washed with brine 1×. The organic layer was dried over Na2SO4, filtered, and concentrated to dryness to provide 1-(4-fluoro-2-isopropoxyphenyl)-4-methyl-1H-tetrazol-5(4H)-one (3.50 g, 81%) as a brown oil that was used without further purification. 1H NMR (300 MHz; d6-DMSO) δ 7.46-7.51 (dd, 1H, J=6.3 Hz, 8.4 Hz), 7.20-7.25 (dd, 1H, J=2.7 Hz, 11 Hz), 6.87-6.94 (td, 1H, J=2.7 Hz, 8.1 Hz), 4.63-4.75 (hept, 1H, J=6.0 Hz), 3.59 (s, 3H), 1.16-1.18 (d, 6H, J=6.0 Hz); 19F NMR (282 MHz; d6-DMSO) δ −107.0 (sextet); m/z=253 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH2:22])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].[C:38](O)(=[O:41])[CH2:39][CH3:40]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH:22][C:38](=[O:41])[CH2:39][CH3:40])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[CH2:27][CH2:26]1)=[O:24]
Reactant: CCC(=O)O
Reactant: Cc1ccc(F)c(Nc2c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc3c(S(N)(=O)=O)cnn23)c1
Product: CCC(=O)NS(=O)(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 28.9 %

Procedure:
Using 7-(2-fluoro-5-methylphenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.10 g, 0.19 mmol) obtained in step 5 and propionic acid (0.071 mL, 0.95 mmol) instead of cyclopropanecarboxylic acid, and in the same manner as in Example 1 step 6, the title compound (0.032 g, 40%) was obtained.
Reaction SMILES: Cl.Cl.[N:3]1[N:7]2[CH2:8][CH2:9][CH2:10][NH:11][C:6]2=[C:5]([CH2:12][CH2:13][NH2:14])[CH:4]=1.[CH:15](OCC)=[O:16].C[O-].[Na+]>CO>[N:3]1[N:7]2[CH2:8][CH2:9][CH2:10][NH:11][C:6]2=[C:5]([CH2:12][CH2:13][NH:14][CH:15]=[O:16])[CH:4]=1
Reactant: NCCc1cnn2c1NCCC2
Reactant: CCOC=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=CNCCc1cnn2c1NCCC2
Yield: 62.6 %

Procedure:
To a solution of 2-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)ethylamine dihydrochloride (2.36 g) and ethyl formate (40 g) in methanol (20 ml) was added 28% sodium methoxide solution in methanol (4.0 g), and the mixture was stirred under reflux for 16 hours. The insoluble materials were filtered off using Celite, and the filtrate was concentrated in vacuo. The residue was triturated with acetonitrile and dried in vacuo to give N-[2-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)ethyl]formamide (1.2 g) as a solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH2:21][OH:22])[CH:7]=[N:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1.Cl[C:24]1[CH:25]=[C:26]2[N:33]([CH3:34])[CH2:32][CH2:31][N:27]2[C:28](=[O:30])[N:29]=1>C1COCC1>[Br:3][C:4]1[CH:5]=[C:6]([CH2:21][O:22][C:24]2[CH:25]=[C:26]3[N:33]([CH3:34])[CH2:32][CH2:31][N:27]3[C:28](=[O:30])[N:29]=2)[CH:7]=[N:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: OCc1cnc(Oc2cccc(C(F)(F)F)c2)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCn2c1cc(OCc1cnc(Oc3cccc(C(F)(F)F)c3)c(Br)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using NaH (6.89 mg, 0.172 mmol), (5-bromo-6-(3-(trifluoromethyl)phenoxy)pyridin-3-yl)methanol (60 mg, 0.17 mmol) in THF (8 mL) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (32.0 mg, 0.172 mmol).
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[NH:17][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:15][CH2:14]1)C>O.C1COCC1.CO>[C:18]1([C:16]2[NH:17][N:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:24])=[O:5])[CH2:14][N:15]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)CCCCCCN1CN=C(c2ccccc2)N1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCCN1CN=C(c2ccccc2)N1
Yield: 99.9 %

Procedure:
Add a solution of potassium hydroxide (1.8 g, 32 mmol) in water (70 mL) to a solution of 7-(5-phenyl-4H-[1,3,4]triazol-3-yl)heptanoic acid ethyl ester (4.9 g, 16 mmol) in THF (50 mL) and methanol (50 mL) at room temperature under nitrogen and heat the mixture at reflux for 3 hours. Remove the solvent under reduced pressure, dilute the residue with water (200 mL) and wash with ethyl acetate (200 mL). Adjust the pH of the aqueous layer to 3 with concentrated HCl and extract with ethyl acetate (3×200 mL). Wash the combined organic extracts with brine (200 mL), dry over sodium sulfate and remove the solvent under reduced pressure to afford 7-(5-phenyl-4H-[1,3,4]triazol-3-yl)heptanoic acid (4.4 g, 99%). APCI mass spectrum m/z 273 [C15H19N3O2]−.
Reaction SMILES: O[C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:14])=O>O>[CH3:11][C:9]1[C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=[C:2]([Cl:14])[CH:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)ncc1C(=O)O
Solvent: O
Product: Cc1cc(Cl)ncc1C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
6-Hydroxy-4-methylnicotinic acid (10 g, 65.3 mmol) and phosphorus oxychloride (33 mL) were combined and refluxed for 3 hours. The reaction solution was poured into 300 mL of ice and then 600 mL of water was added. The solution was boiled for 30 minutes before cooling and extracting the product into ether. The solvent was removed and the residue was recrystallized from 900 mL of hot water. Yellow solid, 9.06 g (81% yield). Mp 170-172° C. 1H NMR (CD3OD): δ 2.61 (s, 3H), 7.41 (s, 1H), 8.80 (s, 1H). LC-MS, M+1=172.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH2:18])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=O.Cl.[NH2:20][OH:21].C[O-].[Na+].CO.Cl>O1CCOCC1>[OH:21][NH:20][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][NH2:18])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:2]
Reactant: NO
Reactant: COC(=O)c1cnc(N2CCN(CCN)CC2)s1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: NCCN1CCN(c2ncc(C(=O)NO)s2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound 15d (125 mg, 0.462 mmol) in 1,4-dioxane (2 mL) were added hydroxylamine hydrochloride (321 mg, 4.62 mmol) and a freshly prepared solution of sodium methoxide in methanol (159 mg, 6.91 mmol of sodium dissolved in 1.5 mL of methanol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was acidified to pH˜6 with 1M HCl and the formed precipitates were filtered off. The filtrate was diluted with ethylacetate (5 mL) and water (2 mL) and the organic layer was separated. The aqueous layer was washed with ethylacetate (5 mL) and the combined organic layers were dried on sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 16d.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[O:15][CH2:16][CH2:17][CH2:18][Br:19])(C)(C)C>Cl.O1CCOCC1>[Br:19][CH2:18][CH2:17][CH2:16][O:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:8]=1[NH2:7]
Reactant: Cc1cccc(OCCCBr)c1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cccc(OCCCBr)c1N

Procedure:
[2-(3-Bromo-propoxy)-6-methyl-phenyl]-carbamic acid tert-butyl ester was stirred in 4 M HCl in dioxane (50 mL) for 1.5 hrs with the formation of a white precipitation. Filtration, followed by several washes with ether, afforded 2-(3-bromo-propoxy)-6-methyl-phenylamine as a white solid (4.8 g). MS: 244.0 (M+H)+; tR=1.80 min (method 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH:55]1[C@@H:59]2[CH2:60][CH2:61][CH2:62][CH2:63][C@H:58]2[N:57]=[C:56]1[C:64]1[CH:69]=[CH:68][C:67]([CH2:70][CH2:71][NH2:72])=[CH:66][CH:65]=1>CN(C=O)C>[NH:57]1[C@@H:58]2[CH2:63][CH2:62][CH2:61][CH2:60][C@H:59]2[N:55]=[C:56]1[C:64]1[CH:65]=[CH:66][C:67]([CH2:70][CH2:71][NH:72][C:21]([C:18]2[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]3[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH3:24])(=[O:11])=[O:12])[CH3:14])[O:20][CH:19]=2)=[O:23])=[CH:68][CH:69]=1
Reactant: NCCc1ccc(C2=N[C@@H]3CCCC[C@H]3N2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NCCc3ccc(C4=N[C@@H]5CCCC[C@H]5N4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AG using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (56 mg, 0.16 mmol), EDCI (36 mg, 0.19 mmol), HOAt (26 mg, 0.19 mmol), DIPEA (0.084 mL, 0.48 mmol) and 2-{4-[(3aR,7aR)-3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl]phenyl}ethanamine (82 mg, 0.14 mmol) in DMF (1 mL). The crude product was purified using Ambersep resin, then using prep method C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[CH3:12][N:13](C=O)C>CCOC(C)=O.[C-]#N.[C-]#N.[Zn+2].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>[O:10]=[C:8]1[NH:7][C:6]2[CH:11]=[C:2]([C:12]#[N:13])[CH:3]=[CH:4][C:5]=2[O:9]1
Reactant: O=c1[nH]c2cc(Br)ccc2o1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1ccc2oc(=O)[nH]c2c1
Temperature: 150 °C
Reaction time: 24 h

Procedure:
To a solution of 5-bromo benzoxazolinone (1 g, 4.7 mmol) in DMF (15 mL), were added Zn(CN)2 (1 g, 9.4 mmol) and Pd(PPh3)4. The reaction was stirred at 150° C. for 24 h. The reaction progress was monitored by TLC (100% EtOAc). The reaction was diluted with EtOAc (10 mL) and filtered through Celite® brand filter agent. The organic layer was concentrated and purified by column chromatography (silica gel, 0-50% EtOAc in hexanes) to give the title compound. 1H NMR (400 MHz, CDCl3): δ 8.6 (br s, 1H), 7.5 (dd, J=1.8, 8.4 Hz, 1H), 7.3-7.4 (m, 2H).