Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]2[C:10]([C:13]3[CH:14]=[CH:15][C:16]([F:27])=[C:17]([C:19]4[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:18]=3)=[CH:11][N:12]=[C:6]2[N:5]=1)(=O)[CH3:2].[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[C:49]([NH2:52])(=[S:51])[CH3:50].C(OCC)C>C(Cl)(Cl)Cl>[F:27][C:16]1[CH:15]=[CH:14][C:13]([C:10]2[N:7]3[CH:8]=[CH:9][C:4]([C:1]4[S:51][C:49]([CH3:50])=[N:52][CH:2]=4)=[N:5][C:6]3=[N:12][CH:11]=2)=[CH:18][C:17]=1[C:19]1[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(N)=S
Reactant: CC(=O)c1ccn2c(-c3ccc(F)c(-c4ccccc4C#N)c3)cnc2n1
Agent: [Br-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Cc1ncc(-c2ccn3c(-c4ccc(F)c(-c5ccccc5C#N)c4)cnc3n2)s1
Temperature: 50 °C
Reaction time: 16 h
Yield: 11 %

Procedure:
5′-(7-Acetylimidazo[1,2-α]pyrimidin-3-yl)-2′-fluorobiphenyl-2-carbonitrile (80 mg, 0.22 mmol) and pyridinium tribromide (110 mg, 0.34 mmol) in chloroform (5 ml) was stirred at 50° C. for 3 h. Thioacetamide (33 mg, 0.44 mmol) was then added and the reaction stirred at 50° C. for 16 h. The resulting mixture was partitioned between dichloromethane and saturated aqueous sodium hydrogencarbonate solution. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The residue was purified by preparative thin-layer chromatography eluting with dichloromethane containing 5% methanol and 1% conc. ammonia to give a foam. Trituration with diethyl ether afforded 2′-fluoro-5′-[7-(2-methylthiazol-5-yl)imidazo[1,2-α]pyrimidin-3-yl]biphenyl-2-carbonitrile as a yellow solid (10 mg, 11%): δH (400 MHz, DMSO) 2.75 (3H, s), 7.56-7.68 (5H, m), 7.81-7.92 (3H, m), 7.98-8.05 (2H, m), 8.40 (1H, s), 9.12 (1H, s); m/z (ES+) 412 (M++H).
Reaction SMILES: [Na].[C@@H:2]1([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13]([OH:14])[C:12]=3[N:11]=[CH:10]2)[O:8][C@H:5]([CH2:6][OH:7])[CH:4]=[CH:3]1.[H][H]>[Ni].O>[CH:10]1[N:9]([C@@H:2]2[O:8][C@H:5]([CH2:6][OH:7])[CH2:4][CH2:3]2)[C:18]2[N:17]=[CH:16][NH:15][C:13](=[O:14])[C:12]=2[N:11]=1
Reactant: OC[C@@H]1C=C[C@H](n2cnc3c(O)ncnc32)O1
Reactant: [H][H]
Agent: [Ni]
Agent: [Na]
Solvent: O
Product: O=c1[nH]cnc2c1ncn2[C@H]1CC[C@@H](CO)O1
Temperature: 30 °C
Reaction time: 0.33 h
Yield: 66.4 %

Procedure:
2′,3′-Dideoxy-2′,3′-didehydroinosine sodium salt (50 gm) is added to water (180 ml) and stirred for 20 minutes at 25-35° C. Then the contents are hydrogenated under nitrogen atmosphere at 1.5-2.0 kg/cm2 hydrogen pressure at 15-20° C. using raney nickel catalyst for 7-8 hours. The reaction mass is filtered on a celite bed and washed with water (25 ml). To the filtrate activated carbon (2 gm) is added and stirred for 20 minutes. The mass is filtered on a celite bed and washed with water (25 ml). The filtrate is cooled to 5-15° C., the pH is adjusted to 7.0-8.0 with dilute hydrochloric acid (13 ml water+13 ml conc. HCl) at 5-15° C. and stirred for 2 hours 30 minutes. Filtered the mass, washed with water (40 ml). The resulting wet cake is added to water (120 ml), the temperature is raised to 65-75° C. and stirred for 20 minutes at the same temperature. The resulting solution is cooled to 25-35° C. and stirred for 1 hour 30 minutes. The reaction mass is then cooled to 10-15° C. and stirred for 1 hour 30 minutes. Filtered the solid, washed with the 40 ml of water and dried at 55-60° C. to give 30.5 gm of didanosine (HPLC Purity: 99.85%).
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([C:19]([F:22])([F:21])[F:20])[C:10]=1[N+:23]([O-])=[O:24])([C:3]([O:5]CC)=O)=[O:2].CN(C)C=O.N>O1CCCC1.[Pd]>[F:16][C:15]([F:17])([F:18])[C:13]1[CH:14]=[C:9]2[C:10](=[C:11]([C:19]([F:20])([F:21])[F:22])[CH:12]=1)[N:23]([OH:24])[C:3](=[O:5])[C:1](=[O:2])[NH:8]2
Reactant: CCOC(=O)C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1[N+](=O)[O-]
Agent: [Pd]
Agent: N
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc(C(F)(F)F)cc(C(F)(F)F)c2n(O)c1=O
Yield: 70 %

Procedure:
0.20 g (0.5 mmol) N-ethoxalyl-3,5-bistrifluoromethyl-2-nitroaniline in 10 ml tetrahydrofuran:dimethylformamide:25% aqueous ammonia (30:10:0.7) was hydrogenated at atm. pressure by using 5% Pd-C (0.02 g) as a catalyst. The reaction mixture was filtered and evaporated in vacuo. The residue was stirred with water, and the precipitate was filtered off to give 0.11 g (84%) of 6,8-bistrifluoromethyl-1-hydroxyquinoxaline- 2,3(1H,4H)-dione. M.p. decomp. 1H-NMR (DMSO-d6): 8.1 (s). MS (m/e): 314 (M+, 40%), 173 (45%), 69 (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].F[C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: COC(=O)c1ccc(F)cc1
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 130 °C
Reaction time: 17 h
Yield: 95.8 %

Procedure:
4-Chloro-3-(trifluoromethyl)phenol (1.19 g, 6.06 mmol), methyl 4-fluorobenzoate (0.934 g, 6.06 mmol) and potassium carbonate (2.51 g, 18.2 mmol) were stirred in dimethylsulfoxide (10 mL) at 120° C. overnight under an atmosphere of nitrogen. The temperature was then increased to 130° C. and the reaction mixture stirred for a further 17 hours. The reaction mixture was cooled to room temperature. Water (100 mL) was added and the mixture extracted with ethyl acetate (3×50 mL). The combined organic phase was washed sequentially with water (50 mL) and brine (50 mL), dried over magnesium sulphate, filtered and concentrated in vacuo to afford the title compound as a yellow oil (1.92 g, 96%, contains residual dimethylsulfoxide). This material was taken on crude in subsequent steps.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[C:38](C1C=C(B(O)O)C=CC=1)#[N:39]>>[NH2:37][C:9]1[C:8]([C:5]2[CH:6]=[C:7]([CH:2]=[CH:3][CH:4]=2)[C:38]#[N:39])=[C:13]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:33])([F:35])[F:34])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)[N:12]=[CH:11][N:10]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2cccc(C#N)c2)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 3-cyanophenylboronic acid instead of 4-fluorophenylboronic acid. LC-MS: (M+1=522, obsd.=522).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=O)[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([O:27][CH3:28])=[O:26])[C:20]=2[OH:29])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>C(O)(=O)CC.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[O:29][C:20]3[C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(NC(=O)C2CCN(C(=O)OCc3ccccc3)CC2)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(=O)O
Solvent: O
Product: COC(=O)c1cccc2nc(C3CCN(C(=O)OCc4ccccc4)CC3)oc12
Yield: 42.4 %

Procedure:
A mixture of benzyl-4-(2-hydroxy-3-(methoxycarbonyl)phenylcarbamoyl)piperidine-1-carboxylate (400 mg, 0.61 mmol) in propionic acid (5 mL) was heated to reflux for 4 days. The mixture was diluted with water (50 mL), neutralized with sodium bicarbonate, and then extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by pre-HPLC to afford methyl 2-(1-(benzyloxycarbonyl)piperidin-4-yl)benzo[d]oxazole-7-carboxylate (102 mg) as a yellow oil. LC-MS (ESI) m/z: 395 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16](I)[C:15]([C:19]([F:22])([F:21])[F:20])=[N:14]1.[CH:23]([Sn](CCCC)(CCCC)CCCC)=[CH2:24]>CN(C)C=O.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>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]([CH:23]=[CH2:24])[C:15]([C:19]([F:22])([F:21])[F:20])=[N:14]1
Reactant: FC(F)(F)c1cc(Cl)c(-n2cc(I)c(C(F)(F)F)n2)c(Cl)c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C(F)(F)F
Temperature: 75 °C
Reaction time: 3 h

Procedure:
A solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodo-3-trifluoromethylpyrazole (1 g) in dimethylformamide (5 ml) containing vinyltri-n-butyltin (2 ml) and tetrakis(triphenylphosphine)palladium(0) (0.1 g) was stirred at 75° C. for 3 hours. The reaction mixture was evaporated and then partitioned between water and ether. The organic layer was separated, washed with water (×5), dried (Na2SO4) and evaporated. The residue was crystailised from hexane and further purified by column chromatography on silica gel eluted with ether. Combination and evaporation of appropriate fractions gave a yellow solid which was further purified by reverse phase high performance chromatography on C18 silica eluted with acetonitrile: methanol: water (40:10:50). Combination and evaporation of appropriate fractions, followed by recrystallisation from propan-2-ol, gave the title compound as a light yellow solid, m.p.95-98° C.
Reaction SMILES: [CH:1]([CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)=[O:26])([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[O:15])[C:5]1=[O:35])=[O:2].[CH2:36](O)[CH2:37][OH:38].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:34][C:31]1[CH:30]=[CH:29][C:28]([NH:27][C:25]([CH2:24][C:6]2([NH:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[O:15])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:4]([CH2:3][CH:1]3[O:38][CH2:37][CH2:36][O:2]3)[C:5]2=[O:35])=[O:26])=[CH:33][CH:32]=1
Reactant: Cc1ccc(NC(=O)CC2(NC(=O)Nc3ccc(C)cc3)C(=O)N(CC=O)c3ccccc32)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)CC2(NC(=O)Nc3ccc(C)cc3)C(=O)N(CC3OCCO3)c3ccccc32)cc1
Yield: 68 %

Procedure:
To a solution of 0.294 g of (RS)-1-(formylmethyl)-3-((4-methylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one in 50 ml of toluene were added 0.5 ml of ethylene glycol and 10 mg of p-toluenesulfonic acid. The mixture was heated under reflux for 6 hours while azeotropically removing produced water together with toluene. The reaction mixture was washed with saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to give 0.220 g (68%) of the title compound.
Reaction SMILES: O.[CH3:2][C:3]1O[C:5]([CH3:14])=[CH:6][C:7](=[O:13])[C:8]=1[C:9]([O:11][CH3:12])=[O:10].[NH2:15][CH:16]1[CH2:21][C:20]([CH3:23])([CH3:22])[NH:19][C:18]([CH3:25])([CH3:24])[CH2:17]1>C1(C)C=CC=CC=1>[CH3:2][C:3]1[N:15]([CH:16]2[CH2:17][C:18]([CH3:25])([CH3:24])[NH:19][C:20]([CH3:23])([CH3:22])[CH2:21]2)[C:5]([CH3:14])=[CH:6][C:7](=[O:13])[C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: COC(=O)c1c(C)oc(C)cc1=O
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1c(C)n(C2CC(C)(C)NC(C)(C)C2)c(C)cc1=O
Temperature: 25 °C

Procedure:
A 500 ml, 3-neck, round-bottom flask is equipped with a mechanical stirrer, thermometer and a Dean-Stark water trap topped with a water cooled condenser. The flask is charged with a mixture of 45.5 g (0.25 moles) of the methyl 2,6-dimethyl-4-oxopyran-3-carboxylate prepared as described above, 39.1 g (0.25 m) 4-amino-2,2,6,6-tetramethylpiperidine, and 300 ml toluene. The stirred mixture in the flask is heated to boiling by means of an oil bath and the water formed during the reaction is collected in the trap. After 4 hours of reflux a total of 3.8 ml water is collected and the flask and its contents are cooled to room temperature. The toluene is removed by means of a rotary evaporator. On standing and cooling the residue deposits crystals of the title product which are further purified by fractional crystallization.
Reaction SMILES: [C:1]1([C:7]2([C:10]3[NH:15][C:14](=[S:16])[C:13]([NH:17][C:18]([C:20]4[CH:21]=[C:22]5[C:26](=[CH:27][CH:28]=4)[CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]5)=O)=[CH:12][CH:11]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:25]1[C:26]2[C:22](=[CH:21][C:20]([C:18]3[S:16][C:14]4[C:13]([N:17]=3)=[CH:12][CH:11]=[C:10]([C:7]3([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH2:8][CH2:9]3)[N:15]=4)=[CH:28][CH:27]=2)[CH2:23][NH:24]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(C(=O)Nc3ccc(C4(c5ccccc5)CC4)[nH]c3=S)cc2C1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: c1ccc(C2(c3ccc4nc(-c5ccc6c(c5)CNC6)sc4n3)CC2)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
tert-Butyl 5-(6-(1-phenylcyclopropyl)-2-thioxo-1,2-dihydropyridin-3-ylcarbamoyl)i-soindoline-2-carboxylate (213 mg, 0.437 mmol) was dissolved in toluene (4.4 mL) before camphor sulfonic acid (91 mg, 0.393 mmol) was added and stirred at 100° C. for 3 h. The reaction mixture was diluted with 75 mL of EtOAc, added to a separatory funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed with sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated via rotovap to give 2-(isoindolin-5-yl)-5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine after flash chromatography. MS (ESI) m/z: Calculated: 369.1; Observed: 370.4 (M++H).
Reaction SMILES: N[C@H:2](C(O)=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-:13].[Na+]>>[CH2:2]([OH:13])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: [OH-]
Agent: [Na+]
Product: OCCc1ccccc1

Procedure:
Referring to FIG. 1, L-phenylalanine is provided as a solution 10, wherein the solution comprises fermentation media 12 containing L-phenylalanine. Alternatively, the fermentation media is combined with a solution of L-phenylalanine. The combined fermentation solution is added 20 to a fermentation bath, which fermentation bath is then inoculated with at least one species of yeast 22. The pH of the fermentation solution is adjusted 40 to a pH of about 7.0 with a base (e.g., NaOH) after which the fermentation solution is allowed to ferment under fermentation conditions 30, providing phenethyl alcohol.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[N:20][S:17]([C:14]1[CH:13]=[CH:12][C:11]([Cl:10])=[CH:16][CH:15]=1)(=[O:19])=[O:18]
Reactant: O=Cc1cccc(O)c1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=S(=O)(N=Cc1cccc(O)c1)c1ccc(Cl)cc1

Procedure:
In a similar manner to Example 2, 1.24 g (10 mmol) of 3-hydroxybenzaldehyde, 1.94 g (10 mmol) of 4-chlorobenzenesulfonamide and 20 mg of TsOH in 150 mL of toluene were heated for 12 hours to give 0.29 g (10%) of SULF-9 as a brown powder: IR (Nujol) 3400, 1658, 1556, 1458, 1155, 1025 cm-1 ; 1H NMR (DMSO-d6, TMS ext std) δ8.85 (s,1), 8.73 (s, 1), 7.7-7.2 (m, 8).
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)O1.Cl.[S:11]([N:21]1[C:25]2[N:26]=[CH:27][C:28]3[N:29]([C:30]([C@@H:33]4[CH2:37][CH2:36][C@H:35]([NH2:38])[CH2:34]4)=[N:31][N:32]=3)[C:24]=2[CH:23]=[CH:22]1)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12].CC([O-])=O.[Na+]>O.C(Cl)Cl>[N:38]1([C@H:35]2[CH2:36][CH2:37][C@@H:33]([C:30]3[N:29]4[C:24]5[CH:23]=[CH:22][N:21]([S:11]([C:14]6[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=6)(=[O:13])=[O:12])[C:25]=5[N:26]=[CH:27][C:28]4=[N:32][N:31]=3)[CH2:34]2)[CH:3]=[CH:7][CH:6]=[CH:5]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@@H]4CC[C@H](N)C4)n23)cc1
Reactant: COC1CCC(OC)O1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@@H]4CC[C@H](n5cccc5)C4)n23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.3 %

Procedure:
A solution of 2,5-dimethoxytetrahydrofuran (0.14 g, 1.1 mmol) in water (3 mL) was heated at about 100° C. for about 1.5 h. The solution was cooled to ambient temperature. A suspension of (1S,3R)-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclo-pentanamine hydro-chloride (0.10 g, 0.21 mmol, prepared using E from Preparation #B.1 and HCl) and NaOAc (0.05 g, 0.61 mmol) in DCM (5 mL) was added to the aqueous solution. The reaction mixture was stirred at ambient temperature for about 1 h followed by addition of additional 2,5-dimethoxytetrahydrofuran (0.14 g, 1.1 mmol). The reaction mixture was heated to about 40° C. for about 15 h. Additional 2,5-dimethoxytetrahydrofuran (0.14 g, 1.1 mmol) was added and the reaction mixture was stirred at about 40° C. for about 8 h then at about 35° C. for about 48 h. The reaction was diluted with DCM (10 mL) and water (10 mL). The layers were separated and the organic layer was washed with water (2×10 mL) and brine (10 mL), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure to give 1-((1R,3S)-3-(1H-pyrrol-1-yl)cyclopentyl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.095 g, 99%) as a yellow residue: LC/MS (Table 1, Method a) Rt=2.42 min; MS m/z: 447 (M+H)+.
Reaction SMILES: [CH2:1](I)[CH2:2][CH3:3].[C:5]1([C:11]2[C:16](=[O:17])[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][NH:13][N:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[C:5]1([C:11]2[C:16](=[O:17])[C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][N:13]([CH2:1][CH2:2][CH3:3])[N:12]=2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCCI
Reactant: O=c1c(-c2ccccc2)c[nH]nc1-c1ccccc1
Product: CCCn1cc(-c2ccccc2)c(=O)c(-c2ccccc2)n1
Yield: 95 %

Procedure:
Propyl iodide was reacted with 3,5-diphenyl-4(1H)-pyridazinone according to the process of Example 4 to produce 3,5-diphenyl-1-propyl-4(1H)-pyridazinone, m.p. 94°-96° C. in 95% yield.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[N:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=1>CN(C)C=O>[N:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])=[CH:14][CH:13]=1
Reactant: NCc1ccncc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccncc1
Yield: 71.4 %

Procedure:
A mixture of 74 g (0.5 mole) of phthalic anhydride, 60 g (0.56 mole) of 4-pyridinemethylamine and 200 mL of dimethylformamide was heated under reflux for 2 hours. The cooled mixture was filtered and the solids were washed with ether and dried to give 85.1 g of 2-(4-pyridinylmethyl)-1H-isoindole-1,3(2H) -dione, m.p. 164°-165°. Another 24.0 g was obtained by crystallization of the concentrated mother liquors from dimethylformamide. Combined yield: 99.1 g (83%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[NH2:12][C:13]([CH3:17])([CH3:16])[CH2:14][OH:15]>C(Cl)Cl>[CH3:16][C:13]([NH:12][C:4](=[O:5])[C:3]1[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=1[F:11])([CH3:17])[CH2:14][OH:15]
Reactant: CC(C)(N)CO
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)c1c(F)cccc1F
Temperature: 25 °C
Yield: 95.4 %

Procedure:
A solution of 2,6-difluorobenzoyl chloride (50 g, 283 mmol) in CH2Cl2 (200 mL) was added rapidly dropwise to an ice water-cooled solution of 2-amino-2-methyl-1-propanol (63.1 g, 708 mmol) in CH2Cl2 (400 mL). The resulting mixture was stirred at RT and monitored to completion by GLC, then was extracted twice with 10% HCl and once with sat aq NaHCO3. The organic phase was dried (MgSO4), and concentrated to afford 61.9 g N-(1,1-dimethyl-2-hydroxyethyl)-2,6-difluorobenzamide as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)([CH2:12][CH2:13]S(C)(=O)=O)[C:8]1=[O:29].[F:37][C:38]1[CH:60]=[CH:59][C:41]([CH2:42][N:43]2[C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=3[N:45]=[C:44]2[C:52]2([OH:58])[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)=[CH:40][CH:39]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:55]2[CH2:56][CH2:57][C:52]([C:44]3[N:43]([CH2:42][C:41]4[CH:59]=[CH:60][C:38]([F:37])=[CH:39][CH:40]=4)[C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=4[N:45]=3)([OH:58])[CH2:53][CH2:54]2)([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:8]1=[O:29]
Reactant: OC1(c2nc3ccccc3n2Cc2ccc(F)cc2)CCNCC1
Reactant: COc1ccc(CC2(CCS(C)(=O)=O)CCN(Cc3cc(OC)c(OC)c(OC)c3)C2=O)cc1OC
Product: COc1ccc(CC2(CCN3CCC(O)(c4nc5ccccc5n4Cc4ccc(F)cc4)CC3)CCN(Cc3cc(OC)c(OC)c(OC)c3)C2=O)cc1OC

Procedure:
Prepare by the method of Example 6.6.2 using 1-(3,4,5-trimethoxy-benzyl)-3-(3,4-dimethoxy-phenylmethyl)-3-(2-methanesulfonyl-ethyl)-2-oxo-pyrrolidine and 4-[1-(4-fluoro-benzyl)-1H-benzoimidazol-2-yl]-4-hydroxy-piperidine to give the title compound: Rf=0.58 (silica gel, 10% methanol/ethyl acetate).
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[CH:4][NH:3]1.[OH-].[K+].I[CH3:14]>CO.O>[CH3:14][N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([OH:10])=[O:9])[C:2]1=[O:1]
Reactant: O=C(O)c1ccc[nH]c1=O
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1cccc(C(=O)O)c1=O

Procedure:
To 2-oxo-1H-pyridine-3-carboxylic acid (2.00 g, 14.4 mmol) in methanol (20 mL) was added a solution of KOH (1.60 g, 28.5 mmol) in water (3 mL) and the mixture was vigorously stirred until a thick suspension formed. Iodomethane (10 μL, 0.16 mmol) was added and the mixture was heated at reflux for 1.5 h. The mixture was concentrated to ⅓ volume and was acidified to pH 1 with 6N HCl. The solids were filtered off and were washed with water (3×2 mL) and acetonitrile (2×2 mL), and then dried in vacuo to give 1-methyl-2-oxo-pyridine-3-carboxylic acid as a white solid. ESI-MS m/z calc 153.0, found 154.1 (M−1)−. Retention time: 0.65 minutes (3 min run).