Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]2[S:15][C:14]([N:16]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:17][C@@H:18]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[N:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.C(O)(=O)C>CO.[Pd]>[OH:1][C:2]1[CH:3]=[C:4]([C:11]2[S:15][C:14]([N:16]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:17][C@@H:18]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:35])[CH3:36])[CH2:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=3)=[N:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)CN(C(=O)OC(C)(C)C)c1nnc(-c2ccc([N+](=O)[O-])c(O)c2)s1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)CN(C(=O)OC(C)(C)C)c1nnc(-c2ccc(N)c(O)c2)s1
Reaction time: 2 h
Yield: 52.5 %

Procedure:
tert-Butyl (S)-1-(5-(3-hydroxy-4-nitrophenyl)-1,3,4-thiadiazol-2-yl-boc-amino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (400 mg, 625 μmol) was dissolved in 100 mL MeOH in a 500 mL round bottom flask. To this flask was added 10% Pd/C (100 mg pre-wet with water) and 1.5 mL acetic acid. The mixture was stirred under an atmosphere of hydrogen under balloon pressure for 2 hours. After filtration through a pad of celite, the solution was evaporated to dryness. The residue was re-dissolved in 150 mL EtOAc. The solution was washed with saturated ammonia chloride twice and dried over sodium sulfate. After removing the solvent, the remaining residue was subjected to silica gel column chromatograph separation using 20% to 40% EtOAc in hexane as the eluant. After removing the solvent, the desired product (200 mg, 53%) was obtained as a tan solid. LCMS (API-ES) m/z (%): 610.0 (100%, M++H); 1H NMR (400 MHz, CD3OD) δ ppm 1.21 (s, 9H) 1.55 (s, 9H) 2.80-2.95 (m, 1H) 2.95-3.06 (m, 1H) 4.00-4.25 (m, 1H) 4.25-4.57 (m, 2H) 6.77 (d, J=8.22 Hz, 1H) 7.18 (dd, J=8.02, 1.96 Hz, 1H) 7.25 (d, J=1.76 Hz, 1H) 7.44-7.53 (m, 2H) 7.60 (d, J=8.02 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:12]2[NH:11][CH2:10][CH2:9][O:8][C:7](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:14](N1C=CN=C1)(N1C=CN=C1)=[O:15]>C1COCC1>[NH:1]1[C:2]2=[CH:3][CH:4]=[CH:5][C:6]3=[C:12]2[N:11]([CH2:10][CH2:9][O:8][C:7]3=[O:13])[C:14]1=[O:15]
Reactant: Nc1cccc2c1NCCOC2=O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C1OCCn2c(=O)[nH]c3cccc1c32
Temperature: 25 °C
Reaction time: 8 h
Yield: 123.9 %

Procedure:
To a solution of 200 mg (1.13 mmol) of 9-amino-2,3-dihydro-4,1-benzoxazepin-5(1H)-one in 20 mL of THF was added 280 mg (2 mmol) of 1,1′-carbonyldiimidazole and the reaction mixture was stirred overnight at room temperature. The reaction mixture was heated at 50° C. for 4 h and allowed to cool to room temperature. The reaction was concentrated in vacuo and the residue was dissolved in a mixture of ethyl acetate/n-hexane (1:1) and washed with water. The organics were dried over sodium sulfate, filtered, and concentrated in vacuo to give 286 mg (1.40 mmol, 70%) of the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([CH3:24])([S:20]([CH3:23])(=[O:22])=[O:21])[C:17](O)=[O:18])=[CH:10][CH:9]=1.CN(C=O)C.[Si]([O:34][NH2:35])(C)(C)C>C(Cl)Cl>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([CH3:24])([S:20]([CH3:23])(=[O:22])=[O:21])[C:17]([NH:35][OH:34])=[O:18])=[CH:10][CH:9]=1
Reactant: CC(CCc1ccc(Br)cc1)(C(=O)O)S(C)(=O)=O
Reactant: C[Si](C)(C)ON
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(CCc1ccc(Br)cc1)(C(=O)NO)S(C)(=O)=O
Yield: 96.8 %

Procedure:
Oxalyl chloride (4.50 mL, 50 mmol) was added to a solution of 4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)butanoic acid (II) (14.69 g, 43.82 mmol) in DCM (300 mL) under nitrogen at ambient temperature, followed by DMF (340 ul). The reaction was stirred until effervescence ceased and then was allowed to stir for 1 hour. O-TMS-hydroxylamine (16.0 mL, 130 mmol) was added via syringe and the suspension was stirred for 1 hour. The reaction was quenched with methanol (60 mL), stirred for 1 hour and concentrated in vacuo to afford a yellow-white solid. The solid was triturated in DCM (200 mL) overnight. The solid was collected by filtration, washed with 1:1 DCM:heptane (2×100 mL), and dried under vacuum to afford the title compound as a white solid (14.85 g, 96.76%). LC-MS m/z 350.0 (M+1). 1H NMR (500 MHz, METHANOL-d4) δ ppm 1.64 (s, 3H) 2.00-2.10 (m, 1H) 2.44-2.58 (m, 2H) 2.61-2.77 (m, 1H) 3.04 (s, 3H) 7.18 (d, J=8.29 Hz, 2H) 7.44 (d, J=8.29 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:26]=[C:25]([CH3:27])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[N:17]=1>>[N:19]1[CH:20]=[CH:21][N:22]=[CH:23][C:18]=1[C:16]1[N:17]=[C:12]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:13]2[CH:26]=[C:25]([CH3:27])[S:24][C:14]=2[N:15]=1
Reactant: Cc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: Cc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyrazin-2-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-dichlorobenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[F:9][C:10]1[CH:11]=[CH:12][C:13](B2OC(C)(C)C(C)(C)O2)=[C:14]([CH:17]=1)[C:15]#[N:16]>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].O>[Br:8][C:6]1[CH:7]=[C:2]([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:17][C:14]=2[C:15]#[N:16])[CH:3]=[N:4][CH:5]=1
Reactant: CC1(C)OB(c2ccc(F)cc2C#N)OC1(C)C
Reactant: Brc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1cc(F)ccc1-c1cncc(Br)c1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
A solution of 3,5-dibromopyridine (1.0 g, 4.2 mmol) and 5-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile (0.95 g, 3.8 mmol) in 1,2-dimethoxyethane (20 ml) and 2N sodium carbonate solution (10 ml) was degassed with nitrogen for 30 min. Tetrakis-(triphenylphosphine)palladium(0) (89 mg, 0.08 mmol) was added and the mixture heated under reflux for 18 h. The mixture was allowed to cool to ambient temperature, diluted with water (10 ml) then extracted with ethyl acetate (2×100 ml). The organics were combined, dissolved in phophorus oxychloride (50 ml) and heated at 100° C. for 2 h. The reaction mixture was allowed to cool to ambient temperature and concentrated. The residue was treated with ice, and the resulting solution was layered with ethyl acetate (30 ml) and made basic by the addition of solid sodium hydrogencarbonate. The layers were separated, and the aqueous extracted further with ethyl acetate (75 ml). The organics were combined, washed with brine (20 ml), dried over anhydrous magnesium sulfate, filtered and evaporated to give a colourless oil. The oil was purified by flash column chromatography on silica, eluting with isohexane on a gradient of ethyl acetate (20-50%), to give 2-(5-bromopyridin-3-yl)-5-fluorobenzonitrile (0.95 g, 81%) as a white solid: δH (360 MHz, CDCl3) 7.44-7.46 (1H, m), 7.49-7.54 (2H, m), 8.02 (1H, s), 8.67 (1H, d, J 1.8), 8.78 (1H, d, J 1.8).
Reaction SMILES: [CH2:1]([S:4][CH2:5][CH2:6][O:7][N:8]=[C:9]([C:15]1[N:16]=[C:17]([NH:20][CH:21]=[O:22])[S:18][CH:19]=1)[C:10]([O:12]CC)=[O:11])[CH:2]=[CH2:3].CO.[OH-].[Na+]>O1CCCC1>[CH2:1]([S:4][CH2:5][CH2:6][O:7][N:8]=[C:9]([C:15]1[N:16]=[C:17]([NH:20][CH:21]=[O:22])[S:18][CH:19]=1)[C:10]([OH:12])=[O:11])[CH:2]=[CH2:3]
Reactant: C=CCSCCON=C(C(=O)OCC)c1csc(NC=O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=CCSCCON=C(C(=O)O)c1csc(NC=O)n1
Temperature: 35 °C
Reaction time: 5.5 h
Yield: 43.3 %

Procedure:
A mixture of ethyl 2-(2-allylthioethoxyimino)-2-(2-formamidothiazol-4-yl)acetate (syn isomer, 5.1 g.), methanol (37.2 ml.), 1 N-aqueous sodium hydroxide (37.2 ml.) and tetrahydrofuran (35 ml.) was stirred at 35° C. for 5.5 hours. After concentrating the resultant solution in vacuo, the residue was washed with ethyl acetate twice. The aqueous solution was adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate twice. The extract was washed with a saturated aqueous solution of sodium chloride dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with n-hexane and the precipitates were collected by filtration to give 2-(2-allylthioethoxyimino)-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer, 2.03 g.), mp. 70° to 78° C.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Br[CH2:15][C:16]#[C:17][CH3:18].Cl>C1COCC1>[CH2:15]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[C:16]#[C:17][CH3:18]
Reactant: CC#CCBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC#CCC(C(=O)OCC)C(=O)OCC
Reaction time: 0.83 h
Yield: 115.3 %

Procedure:
To a stirring mixture consisting of diethyl malonate (24.3 g, 141 mmol) in THF (140 mL) was added sodium hydride (60% dispersion in oil, 2.8 g, 70 mmol) and the resulting reaction mixture was stirred for 50 minutes. To the reaction mixture was added 1-bromobut-2-yne (GFS, 6.2 g, 47 mmol), and the mixture was stirred for two hours. The reaction mixture was treated carefully with 0.5 N HCl and extracted with ethyl acetate. The organic phase was washed with water, then brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography. Elution with ethyl acetate-heptane (5:95 to 15:85 v/v) afforded the title intermediate (11.5 g, quantitative yield) as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.C(N(CC)CC)C.[Cl:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][N:40]=1>O1CCCC1>[Cl:38][C:39]1[CH:47]=[CH:46][C:42]([C:43]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:29])[C:19]5[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=5)[CH:12]=4)=[N:6][N:5]3[CH:30]=2)=[O:44])=[CH:41][N:40]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)c4ccc(Cl)nc4)cn3n2)c1)c1cccc(C(F)(F)F)c1
Yield: 77.4 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (150 mg, 0.362 mmol), triethylamine (76 μL, 0.544 mmol), 6-chloronicotinoyl chloride (76 mg, 0.435 mmol) and tetrahydrofuran (5 mL) as starting materials and in the same manner as in Example 388, the title compound (155 mg, 77%) was obtained as a pale-yellow powder.
Reaction SMILES: [O:1]([CH2:5][CH3:6])[C:2]([S-:4])=[S:3].[K+].O.[CH2:9]([S:11][CH:12]1[N:15]([CH:16](Cl)[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[C:14](=[O:31])[CH2:13]1)[CH3:10]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.ClCCl>[CH2:9]([S:11][CH:12]1[N:15]([CH:16]([S:3][C:2]([O:1][CH2:5][CH3:6])=[S:4])[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:18])[C:14](=[O:31])[CH2:13]1)[CH3:10]
Reactant: CCSC1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=S)[S-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=S)SC(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1SCC
Reaction time: 1 h

Procedure:
To a stirred mixture of 3.2 g. of potassium ethyl xanthate, 5.4 g. of benzyltriethylammonium chloride, 100 ml. of water and 50 ml. of dichloromethane, at 0° C., was added a solution of 7.12 g. of p-nitrobenzyl 2-(4-ethylthio-2-oxo-1-azetidinyl)-2-chloroacetate in 75 ml. of dichloromethane. Stirring was continued at 0°-5° C. for 1 hour, and then the organic phase was removed. The aqueous phase was extracted with 100 ml. of dichloromethane, and then the combined dichloromethane layers were washed successively with 75 ml. of dilute hydrochloric acid, 75 ml. of saturated aqueous sodium bicarbonate and 75 ml. of water. The dichloromethane solution was dried with anhydrous sodium sulfate and evaporated to dryness in vacuo, and the residue was purified by column chromatography on 200 g. of silica gel, eluting with 95:5 chloroform-ethyl acetate. The product containing fractions were combined and concentrated in vacuo to give 4.3 g of the title compound. The IR spectrum (chloroform) showed an absorption at 5.66 microns. The NMR spectrum (deuterochloroform) showed peaks at 1.02-1.6 (m, 6H); 2.35-3.65 (m, 4H); 4.4-5.1 (m, 3H); 5.3 (s, 2H); 6.3 and 6.4 (ss, 1H); 7.4 (d, 2H); and 8.2 (d, 2H) ppm.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[NH2:11].[Cu][C:13]#[N:14].[NH4+].[OH-].ClCCl>CN(C=O)C>[NH2:11][C:3]1[CH:4]=[C:5]2[C:9]([CH2:8][CH2:7][CH2:6]2)=[CH:10][C:2]=1[C:13]#[N:14]
Reactant: Nc1cc2c(cc1I)CCC2
Reactant: N#C[Cu]
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cc2c(cc1N)CCC2
Temperature: 160 °C
Yield: 59 %

Procedure:
To a solution of 6-iodoindan-5-amine (135 mg, 0.52 mmol) in DMF (2 mL), was added copper (I) cyanide (93 mg, 1.04 mmol). The mixture was heated at 160° C. for 1.5 h. The reaction mixture was poured into 10% NH4OH. An equal amount of dichloromethane was added and resulting mixture was filtered. The filtrate was partitioned between two layers. The aqueous layer was extracted with dichloromethane (1×). The combined organic layers were concentrated in vacuo. The residue was dissolved in ethyl ether. The ether layer was washed with aqueous sodium bisulfite, dried with Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (Si, hexanes/EtOAc) yielding 6-aminoindane-5-carbonitrile (48.5 mg, 59%). LCMS calc.=158.08; found=159.1 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 7.22 (s, 1H), 6.64 (s, 1H), 4.25 (br, s, 2H), 2.85 (t, J=7.4 Hz, 2H), 2.80 (t, J=7.4 Hz, 2H), 2.09-2.03 (m, 2H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:3]([NH:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=2)[CH:7]=1)=[O:4].CCN(C(C)C)C(C)C.Br[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>CN(C=O)C>[Cl:18][C:14]1[CH:13]=[C:12]([C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:10]([CH3:11])[N:9]=2)[CH:17]=[CH:16][N:15]=1
Reactant: Cn1nc(-c2ccnc(Cl)c2)cc1NC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1nc(-c2ccnc(Cl)c2)cc1NC(=O)[C@H](Cc1ccccc1)NCC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a 500 ml flask was added 2000 mg of (2S)-2-amino-N-(3-(2-chloropyridin-4-yl)-1-methyl-1H-pyrazol-5-yl)-3-phenylpropanamide 17.7.E, 50 ml of DMF, 1.4 ml of DIEA and the reaction was cooled to 0° C. To the reaction was then added 953 μl of tert-butyl bromoacetate and the reaction was stirred at 22° C. for 16 hours at which time the crude was partitioned between 800 ml EtAc, 2×200 ml of saturated brine, and 2×200 ml of water. (Note: no product observed in aqueous layer). The organic solvent was removed by rotary evaporation and the crude purified with a silica gel column (eluting with 50% EtAc in Hexane) to give 1.8 g of 17.8.A as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:24][NH2:25])[N:13]=2)=[O:11])=[CH:5][CH:4]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](Cl)=[O:36])=[CH:30][CH:29]=1.CCN(C(C)C)C(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:24][NH:25][C:35](=[O:36])[CH2:34][C:31]3[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)[N:13]=2)=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: COc1ccc(NC(=O)c2cccc(-c3ccccc3CN)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CC(=O)NCc2ccccc2-c2cccc(C(=O)Nc3ccc(OC)cc3)n2)cc1
Reaction time: 8 h
Yield: 96.9 %

Procedure:
39 mg (0.12 mmol) of 6-(2-Aminomethylphenyl)-pyridine-2-carboxylic acid-(4-methoxyphenyl)-amide were dissolved in 3 ml of dichloromethane, treated with 27 μl (0.144 mmol) of 4-methoxyphenylacetyl chloride and 19 mg (0.144 mmol) of DIPEA and the mixture was stirred overnight. It was diluted with 20 ml of dichloromethane and washed with an NaHCO3 solution. The organic phase was dried, concentrated and purified by RP-HPLC. 56 mg (78%) of the compound of Example 20 were obtained in the form of its trifluoroacetate.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[C:6]([CH2:12][CH2:13][CH3:14])[C:5]=1[OH:15])(=[O:3])[CH3:2].[NH2:16][C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1>C(#N)C>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=2)=[C:6]([CH2:12][CH2:13][CH3:14])[C:5]=1[OH:15])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CCCc1c(CCl)ccc(C(C)=O)c1O
Solvent: CC#N
Product: CCCc1c(CNc2ccc(C(=O)OCC)cc2)ccc(C(C)=O)c1O

Procedure:
A solution of 6.8 g. of 4-acetyl-3-hydroxy-2-propylbenzyl chloride and 14.9 g. of ethyl 4-aminobenzoate in 200 ml. of acetonitrile was heated to reflux for 48 hours. An additional 9.9 g. of ethyl 4-aminobenzoate were added and the reaction was refluxed an additional 120 hours. The reaction mixture was cooled and concentrated in vacuo. The residue was dissolved in methylene chloride. The organic solution was washed first with a saturated sodium carbonate solution and then with water. The organic solution was then dried over sodium sulfate and evaporated to dryness. Chromatography of the residue afforded 7.4 g. of the desired title product. NMR.
Reaction SMILES: [N:1]1([C:6]2[CH:32]=[CH:31][C:9]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([CH:18]4[CH2:23][CH2:22][N:21]([C:24](OC(C)(C)C)=O)[CH2:20][CH2:19]4)=[CH:14][N:13]=3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[CH2:33]([C:36]1[CH:37]=[N:38]C(Br)=[N:40][CH:41]=1)[CH2:34][CH3:35]>>[CH2:33]([C:36]1[CH:37]=[N:38][C:24]([N:21]2[CH2:22][CH2:23][CH:18]([C:15]3[CH:16]=[CH:17][C:12]([CH2:11][O:10][C:9]4[CH:31]=[CH:32][C:6]([N:1]5[CH:5]=[N:4][N:3]=[N:2]5)=[CH:7][CH:8]=4)=[N:13][CH:14]=3)[CH2:19][CH2:20]2)=[N:40][CH:41]=1)[CH2:34][CH3:35]
Reactant: CCCc1cnc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(COc3ccc(-n4cnnn4)cc3)nc2)CC1
Product: CCCc1cnc(N2CCC(c3ccc(COc4ccc(-n5cnnn5)cc4)nc3)CC2)nc1

Procedure:
The title compound was prepared from tert-butyl 4-[2-[4-(tetrazol-1-yl)phenoxymethyl]pyridin-5-yl]piperidine-1-carboxylate (Example 17) (56 mg, 0.13 mmol) and 5-propyl-2-bromopyrimidine (36 μL, 0.26 mmol) following a procedure analogous to that in Example 48 as a white crystal (6 mg, yield 10%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.Cl[C:19]([O:21][CH3:22])=[O:20]>C(Cl)(Cl)Cl>[CH3:22][O:21][C:19](=[O:20])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1
Reactant: COC(=O)Cl
Reactant: Nc1ccc(Br)cn1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Nc1ccc(Br)cn1
Temperature: 0 °C
Yield: 37 %

Procedure:
A solution of 2-amino-5-bromopyridine (9.46 g, 20 mmol) and N,N-diisopropylethylamine (3.10 g) in chloroform (20 ml) was added to a solution of methyl chloroformate (2.30 g, 24 mmol) in chloroform (25 ml) dropwise with stirring at 0° C. The reaction mixture was stirred for 20 minutes, filtered and the precipitate was washed with chloroform and dried to afford 1.71 g (37%) of the title product as a white solid. mp 191-192° C. 1H NMR (CDCl3): δ=8.42 (d, 1 H); 8.30 (d, 1 H); 7.91 (d, 1 H); 7.77 (d of d, 1 H); 3.79 (s, 3 H). MS (El): m/z=230, 232 (M+, Br isotopes).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[O:18][N:17]=[C:16]([C:19]2[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=2)[C:22]([N:24]=[C:25]=[O:26])=[O:23])[N:15]=1>ClCCl>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[O:18][N:17]=[C:16]([C:19]2[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=2)[C:22]([NH:24][C:25]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:26])=[O:23])[N:15]=1
Reactant: O=C=NC(=O)c1cccc(-c2noc(-c3ccccc3F)n2)c1
Reactant: C1COCCN1
Solvent: ClCCl
Product: O=C(NC(=O)N1CCOCC1)c1cccc(-c2noc(-c3ccccc3F)n2)c1
Yield: 96.6 %

Procedure:
Morpholine (114 μL; 1.30 mmol, 2.0 eq.) is added to a solution of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]benzoyl isocyanate (Compound A4, 200 mg, 0.65 mmol) in anhydrous dichloromethane (4.0 mL) under nitrogen, and the reaction mixture is heated to reflux for 18 h. The resulting slurry is filtered and recrystallized from the minimum amount of dichloromethane in hexanes to afford 249 mg (97%) of morpholine-4-carboxylic acid 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]benzoylamide (Compound 25) as a white powder: mp 190-194° C.; 1H NMR (300 MHz, DMSO-d6) δ 3.05 (t, J=5.1 Hz, 2H), 3.46 (d, J=4.5 Hz, 2H), 3.61 (m, 2H), 3.76 (t, J=5.1 Hz, 2H), 7.46-7.90 (m, 4H), 7.59 (d, J=8.1 Hz, 1H), 8.22-8.29 (m, 2H), 8.53 (d, J=1.5 Hz, 1 H), 9.20 (br s, 1H); MS m/z 397.15, calcd for C20H17FN4O4 (MH+) 397.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[C:23]([N:24]2[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]2)=[C:22]2[C:17]([CH:18]=[CH:19][CH:20]=[N:21]2)=[C:16]([F:30])[CH:15]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[F:30][C:16]1[CH:15]=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[C:23]([N:24]2[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]2)=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[N:21]2
Reactant: CC(N)c1cc(F)c2cccnc2c1N1CC[C@@H](O)C1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(F)c2cccnc2c1N1CC[C@@H](O)C1

Procedure:
A mixture of 6-bromo-9H-purine (14.5 mg, 0.0727 mmol), (3R)-1-[7-(1-aminoethyl)-5-fluoroquinolin-8-yl]pyrrolidin-3-ol (10 mg, 0.04 mmol), and N,N-diisopropylethylamine (0.013 mL, 0.073 mmol) in isopropyl alcohol (0.1 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on a RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at a flow rate of 30 mL/min) to give the desired product. First peak retention time 1.32 minutes, LCMS calculated for C20H21FN7O (M+H)+: m/z=394.2; Found: 394.2. Second peak retention time 1.40 minutes, LCMS calculated for C20H21FN7O (M+H)+: m/z=394.2; Found: 394.2.
Reaction SMILES: [N:1]1O[C:3]([O-])=[C:4]2[CH2:9][CH2:8][CH2:7][CH2:6][N+:5]=12.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[C:12]#C>C1(C)C(C)=CC=CC=1>[N:1]1[N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]2=[CH:3][C:12]=1[C:11]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: C#CC(=O)OCC
Reactant: [O-]c1on[n+]2c1CCCC2
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cc2n(n1)CCCC2

Procedure:
A mixture of 4,5,6,7-tetrahydro[1,2,3]oxadiazolo[3,4-a]pyridin-8-ium-3-olate (Heterocycles; 1990; 31; 481), (13.0 g, 93 mmol), and ethyl propiolate (28.5 ml, 278 mmol), in xylene (250 ml) was heated under reflux for 2 hours. The cooled mixture was evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel using ether as the eluant, to afford the title compound as an oil, 5.82 g.