Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](I)([C:4]([C:7]([C:10]([C:13]([C:16]([C:19]([C:22]([F:25])([F:24])[F:23])([F:21])[F:20])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].I[C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1.CS(C)=O.CCOCC>[Cu].N1C=CC=CC=1C1C=CC=CN=1.O>[F:2][C:1]([F:3])([C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1)[C:4]([F:6])([F:5])[C:7]([F:9])([F:8])[C:10]([F:12])([F:11])[C:13]([F:15])([F:14])[C:16]([F:18])([F:17])[C:19]([F:21])([F:20])[C:22]([F:25])([F:24])[F:23]
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Agent: [Cu]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCOCC
Product: FC(F)(F)c1ccc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.2 %

Procedure:
A solution of C8F17I (12 g, 22 mmol) was added dropwise over 10 min to a stirred mixture of 4-iodobenzotrifluoride (3 g, 11 mmol), copper powder (5.6 g, 0.088 mmol), 2,2′-bipyridine (120 mg, 0.8 mmol), and DMSO (30 mL) at 70° C. The reaction mixture was subsequently stirred for a further 72 h at this temperature. After cooling to room temperature, it was poured into a beaker containing ether (100 mL) and water (100 mL). After filtering, the organic layer was separated, washed with water (3×50 mL) and dried over MgSO4. Sublimation gave the product 210 as a white solid (5.6 g, 90%): 1H NMR (300 MHz, CDCl3): 7.77 (4H, dd, J=8.1 and 8.4 Hz); 19F NMR (282 MHz, CDCl3): −64.0, −81.4, −111.6, −121.4, −122.0, −122.1, −122.9, −126.3.
Reaction SMILES: [OH:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([CH2:15][OH:16])=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19].N1C=CN=C1>CN(C=O)C>[OH:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([CH2:15][O:16][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:25])[CH3:24])=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2cc(CO)ccc2-c2c(O)cccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc2c(c1)C(=O)c1cccc(O)c1-2
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 89.4 %

Procedure:
A mixture of 332.2 mg (1.47 mmol) of the diol from Step H, 243.5 mg (1.61 mmol) of t-butyldimethylchlorosilane, and 120 mg (1.76 mmol) of imidazole in 8 mL of sieve dried DMF was stirred at 100° C. for 45 minutes. The mixture was partitioned between EtOAc, ice-water and 2N HCl, and the organic phase was separated, washed twice with ice-water, and then with brine, dried over Na2SO4, filtered, evaporated, and dried in vacuo. Purification by PLC using CH2Cl2-EtOAc (50:1) gave 447.4 mg of the title material.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5](N)=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].N([O-])=O.[Na+].S(=O)(=O)(O)O.[C:22]([OH:26])(=[O:25])[CH:23]=[CH2:24]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([CH:24]=[CH:23][C:22]([OH:26])=[O:25])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10]
Reactant: C=CC(=O)O
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)C=Cc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
4-Chloro-3-trifluoromethyl aniline was converted to the diazonium salt with sodium nitrite and sulfuric acid and this was reacted with acrylic acid (Meerwein reaction) to give 4-chloro-3-trifluoromethyl cinnamic acid. This acid was hydrogenated, reduced with lithium aluminum hydride to the alcohol and reacted with phosphorus tribromide to give 3(4-chloro-3-trifluoromethylphenyl)propyl bromide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.C(O)(=O)[C@@H](C(C(O)=O)O)O.C([O-])(=O)C(C(C([O-])=O)O)O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]2[CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(N2CCNCC2Cc2ccccc2)cc1
Agent: O=C(O)C(O)[C@@H](O)C(=O)O
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Product: Clc1ccc(N2CCNC[C@H]2Cc2ccccc2)cc1
Yield: 6.3 %

Procedure:
According to the process disclosed in GB Patent No. 2 225 321, racemic 1-(4-chlorophenyl)-phenylmethyl-piperazine is resolved using 2 molar equivalent amount of (R)-tartaric acid and the tartarate salt having unsatisfactory optical purity obtained after three recrystallizations was neutralized. The thus obtained base was crystallized three times from hexane. The process provided (R)-(−)-1-(4-chlorophenyl)-phenylmethyl-piperazine in the yield of 6.3%. This method is not suitable for the use in the pharmaceutical industry since neither the product purity nor the yield are satisfactory.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])=[CH:11][CH:10]=2)[CH:3]=1.[C:23]([O:26][CH2:27][C:28]1[C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=[CH:30][C:29]=1[N:43]1[N:52]=[CH:51][C:50]2[C:45](=[C:46]([F:57])[CH:47]=[C:48]([C:53]([CH3:56])([CH3:55])[CH3:54])[CH:49]=2)[C:44]1=[O:58])(=[O:25])[CH3:24].C([O-])([O-])=O.[Na+].[Na+].O>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>[C:53]([C:48]1[CH:49]=[C:50]2[C:45](=[C:46]([F:57])[CH:47]=1)[C:44](=[O:58])[N:43]([C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([C:2]3[CH:3]=[C:4]([NH:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]([N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)=[O:16])=[CH:13][N:14]=4)[N:5]=[CH:6][N:7]=3)[C:28]=1[CH2:27][O:26][C:23](=[O:25])[CH3:24])[N:52]=[CH:51]2)([CH3:54])([CH3:55])[CH3:56]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Reactant: O=C(c1ccc(Nc2cc(Cl)ncn2)nc1)N1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)ncn2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 80 °C
Reaction time: 13 h
Yield: 30.7 %

Procedure:
To a stirred solution of (6-(6-chloropyrimidin-4-ylamino)pyridin-3-yl)(morpholino)methanone (0.15 g, 0.45 mmol) in 1,4-dioxane (5 mL) was added 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (0.250 g, 0.5 mmol), Pd(PPh3)4 (30 mg, 0.08 mmol), Na2CO3(212 mg, 2 mmol) and H2O (2 mL). The mixture was stirred at 80° C. for 13 hrs under N2. The mixture was evaporated and ethyl acetate (50 mL) and H2O (20 mL) were added to the resulting residue. The organic phase was washed with H2O (2×20 mL), brine (2×20 mL) and dried over Na2SO4. After filtration and concentration, the final product (90 mg, 30%) was obtained as yellow solid. LC-MS: 652.2 [M+H]+, tR=1.499 min.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=2)([C:13]([F:16])([F:15])[F:14])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.O>ClCCCl.CO>[Cl:23][C:21]1[CH:22]=[C:17]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:18]=[C:19]([Cl:24])[CH:20]=1
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CCN(Cc2ccccc2)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Solvent: O
Solvent: ClCCCl
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CCNC1
Yield: 89.3 %

Procedure:
To a stirred solution of 1-benzyl-3-(3,5-dichloro-phenyl)-3-trifluoromethyl-pyrrolidine (Preparation 34, 7.5 g, 20.1 mmol) in 1.2-dichloroethane (50 mL) was added 1-chloroethyl chloroformate (3.87 mL, 36.19 mmol) at room temperature. Resulting reaction mixture was refluxed for 3 hours. After complete consumption of starting material, reaction mixture was concentrated under reduced pressure to afford brown thick oil, which was dissolved in MeOH (50 mL) and refluxed for 2 hours. After complete consumption of starting material, reaction mixture was concentrated in vacuo to afford brown oil, to which water was added (100 mL) and extracted with hexane (2×50 mL). Aqueous layer was basified by saturated sodium bicarbonate solution and extracted by ethyl acetate (3×50 mL). Combined organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo to afford brown oil (7.5 g, crude). Crude compound was purified by column chromatography (100-200 mesh silica). Desired product was eluted in 25% ethyl acetate in hexane to afford product as brown oil (5.1 g, 89.32%). 1H-NMR (400 MHz, DMSO-d6) δ: 2.33-2.39 (m, 1H), 2.40-2.45 (m, 1H), 2.85-2.98 (m, 2H), 3.34 (d, 1H, J=12.72 Hz), 3.52 (d, 1H, J=12.56 Hz), 7.28-7.34 (m, 1H), 7.46-7.52 (m, 2H), 7.64 (d, 1H J=1.25 Hz). (m/z): 284.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N+:11]([O-:13])=[O:12])[C:5]([NH2:10])=[N:6][C:7]=1[NH:8][NH2:9].[CH2:14](OC(OCC)OCC)C>>[Cl:1][C:2]1[C:7]2[N:6]([CH:14]=[N:9][N:8]=2)[C:5]([NH2:10])=[C:4]([N+:11]([O-:13])=[O:12])[N:3]=1
Reactant: CCOC(OCC)OCC
Reactant: NNc1nc(N)c([N+](=O)[O-])nc1Cl
Product: Nc1c([N+](=O)[O-])nc(Cl)c2nncn12
Yield: 77 %

Procedure:
To 5.0 g (0.024 mole) 5-chloro-6-hydrazino-3-nitropyrazinamine was added 50 ml of triethylorthoformate and the resulting suspension was heated at 100° for 1 hour. The reaction mixture was cooled, filtered and the dark brown solid washed with chloroform to give 3.9 g (77%) of 8-chloro-6-nitro-1,2,4-triazolo[4,3-a]pyrazine-5-amine as a brown solid, m.p. 220°, H' nmr (DMSO-d6): 9.65 (2H, broad singlet), 9.95 (1H, singlet); ms:m/e 214.
Reaction SMILES: C(OP([CH:9]([F:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[CH3:16][C:17]1([CH3:25])[CH:19]([CH:20]=O)[CH:18]1[C:22]([OH:24])=[O:23].[H-].[Na+].P(O)(O)([O-])=O.[Na+]>COCCOC>[CH3:16][C:17]1([CH3:25])[CH:19](/[CH:20]=[C:9](/[F:15])\[C:10](=[O:11])[O:12][CH2:13][CH3:14])[CH:18]1[C:22]([OH:24])=[O:23]
Reactant: CC1(C)C(C=O)C1C(=O)O
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)/C(F)=C\C1C(C(=O)O)C1(C)C
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
A solution of 7.7 g of ethyl diethyl-phosphono-fluoro-acetate (prepared by process of Ann. Chem., 1964, p. 674), 60 ml of 1,2-dimethoxyethane and 4 g of (1R, trans) 2,2-dimethyl-3-formyl-cyclopropane-carboxylic acid was added over 30 minutes at 2° to 10° C. to a suspension of 2.6 g of a 60% sodium hydride in oil suspension and 60 ml of 1,2-dimethoxyethane and the mixture was stirred at 5° C. for 15 minutes, and then at room temperature for 3 hours. The resulting solution was poured into aqueous monosodium phosphate solution at 5° C. and the mixture was stirred for 10 minutes. The mixture was extracted with ethyl acetate and the organic phase was washed with water, dried and evaporated to dryness at 40° C. under reduced pressure to obtain 6.5 g of an oil residue. The latter was chromatographed over silica gel and was eluted with a 70-30-1 hexane-ethyl acetate-acetic acid mixture to obtain 4 g of (1R,trans) 2,2-dimethyl-3(E)-[2-fluoro-3-oxo-3-ethoxypropenyl]-cyclopropane-1-carboxylic acid
Reaction SMILES: C(O)(=O)C.[C-:5]#[N:6].[Na+].[CH2:8]1[N:19]2[C:20]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=[N:16][C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=32)[CH2:9]1>C(OCC)(=O)C>[C:5]([CH:15]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]3[CH2:9][CH2:8][N:19]([C:20]=23)[C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[NH:16]1)#[N:6]
Reactant: C1=Nc2ccccc2N2CCc3cccc1c32
Reactant: [C-]#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: N#CC1Nc2ccccc2N2CCc3cccc1c32
Reaction time: 18 h
Yield: 69.4 %

Procedure:
Acetic acid (30 ml) was added to a slurry consisting of sodium cyanide (10 g), 1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]-benzodiazepine (19 g) and ethyl acetate (250 ml) dropwise at room temperature. The mixture was stirred for 18 hours and thereafter diluted with ethyl acetate to 1 liter and washed with 1N sodium hydroxide (2×500 ml), water (2×600 ml) and brine (2×600 ml) The solution was dried over anhydrous magnesium sulfate and concentrated to a solid. The solid was triturated with ether (2×150 ml). Recrystallization from hot toluene (450 ml) yielded 14.8 g of crystals, m.p. 185°-186.5° C.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.II.C1OC1C>C(#N)C>[CH:10]1[C:9]2[CH:8]=[CH:7][C:1]3[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: C(=Cc1ccccc1)c1ccccc1
Agent: CC1CO1
Agent: II
Solvent: CC#N
Product: c1ccc2c(c1)ccc1ccccc12
Reaction time: 0.17 h

Procedure:
In a photoreaction container, argon was infused into a solution of 5.5 g (20.75 mmol) of stilbene in 7 L of acetonitrile at room temperature while stirring. After 10 minutes, 5.27 g (20.75 mmol, 1.0 eq.) of iodine and 58 mL (830 mmol, 40 eq.) of propylene oxide were added, followed by irradiation of light at room temperature while stirring. After 72 hours of irradiation, the disappearance of the raw materials was confirmed, and the resulting reaction liquid was concentrated. The residual product was dissolved in 500 mL of chloroform, followed by washing with 1 L of saturated sodium thiosulfate and 500 mL of brine. The organic layer was dried over magnesium sulfate, and then the solvent was distilled under reduced pressure to give a solid. The solid was collected by suction filtration using a Büchner funnel and a filtering flask, which was then washed with 50 mL of methanol twice. The solid was dried under reduced pressure at 60° C. to give 4.70 g (86.0%) of light brown powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[NH:11][CH2:12][CH2:13][OH:14].[CH:15](O)=O>[Pd]>[F:1][C:2]1[C:3]2[N:11]([CH2:12][CH2:13][OH:14])[CH:15]=[N:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: O=CO
Reactant: O=[N+]([O-])c1cccc(F)c1NCCO
Agent: [Pd]
Product: OCCn1cnc2cccc(F)c21
Reaction time: 8 h
Yield: 64 %

Procedure:
2-[(2-fluoro-6-nitrophenyl)amino]ethanol (18.3 g, 91.5 mmol) dissolved in 90 mL of formic acid is added to a suspension of Pd—C 10% (300 mg) in 10 ml of formic acid. The mixture is shaken in a Parr apparatus under atmospheric pressure of H2 overnight. The reaction mixture is filtered over Celite, the solvent is evaporated under vacuum and the resulting residue dissolved in NH3 2M in ethanol. This solution is stirred at room temperature for 1 h (to cleave the formic acid adduct). A precipitate forms. This mixture is evaporated to dryness and purified by column chromatography (SiO2, DCM/MeOH 10:1 to 5:1), giving the desired product as a white solid (10.5 g, 64%) TLC: DCM/MeOH 5:1, Rf=0.23.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][N:9]=2)[CH2:3][CH2:2]1.CCN(CC)CC.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([N:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][N:9]=2)[CH2:3][CH2:2]1)(=[O:25])=[O:24]
Reactant: Clc1ccc(OC2CCNCC2)nc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(Oc2ccc(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.6 %

Procedure:
To a solution 2-(4-piperidinyloxy) -5-chloropyridine(12.9 g, 0.06 mol) and Et3N (25.4 ml, 0.182 mol) in dry dichloromethane (400 ml) at 0° C. and under Argon, was added methanesulfonyl chloride (5.3 ml, 0.067 mol) in dry dichloromethane (100 ml), dropwise. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with dichloromethane (250 ml), then washed with water (×3) then brine. The organic layers were dried with Na2SO4 and evaporated in vacuo. The residue was triturated and washed with diethylether to give 2-(N-methanesulfonyl-4-piperidinyloxy)-5-chloropyridine (15.1 g) as a pale yellow solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]([NH2:9])=[O:8])=[O:5])[CH3:2].[CH2:10](O)C>C1C=CC=CC=1>[CH2:1]([N:3]1[CH:10]=[N:9][C:7](=[O:8])[NH:6][C:4]1=[O:5])[CH3:2]
Reactant: CCO
Reactant: CCNC(=O)NC(N)=O
Solvent: c1ccccc1
Product: CCn1cnc(=O)[nH]c1=O
Temperature: 60 °C
Yield: 58.7 %

Procedure:
The ethylbiuret prepared in Part A, above, [592 gm., 4.7 mole] is dispersed in 24 l. absolute ethanol and 1.6 l. benzene. This reaction mixture is heated to the reflux temperature and 3.5 l. of solvent medium is removed by distillation. The solution is cooled to 60° C. and 2090 gm. of a 25 percent solution of sodium methoxide in methanol is slowly added over an interval of five minutes. That addition is followed by the addition of 820 gm. of ethylformate. This reaction mixture is heated at the reflux temperature for three (3) hours, whereupon the solution is cooled to 38° C. and concentrated hydrochloric acid is added slowly until the pH of the solution is 2. To the acidified solution is added more (3.4 l.) benzene. Then 2 l. of the solvent medium is removed by distillation under reduced pressure and 50° C. The mixture is then heated to 75° C. and filtered in order to remove the sodium chloride produced by the reaction. The filter cake of salt is washed with hot absolute ethanol and the washings are added to the filtrate. The volume of the combined filtrate and absolute ethanol washings is reduced to 5 l. by evaporation under reduced pressure at 50° C. The resulting concentrate is cooled at 5° C. for 18 hours while crystals form. The crystals are collected on a filter and washed with cold (5° ) ethanol. The washed crystals are dried in an oven under reduced pressure at 50° C. for 18 hours. There is thus obtained 408 gm. of crude product having a melting point at 137° to 139° C. A further purification is achieved by dissolving the 408 gm in 4 l. methanol at reflux temperature. This solution is concentrated by allowing the methanol to evaporate to a volume of 2 l. while being heated on a steam bath. The concentrated solution is allowed to cool slowly to 25° C. It is then chilled to 5° C. for two hours. The crystals that form are collected on a filter and the filter cake is washed with ice-cold methanol. After drying there is obtained 389 gm. (58.7 percent yield) of 1-ethyl-5-azauracil having a melting point of 141° to 142° C. A second crop of crystals is recovered from the mother liquor after further concentration and cooling.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[N:8]=1)=O.[C:23]1([NH:29]N)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO>[O:13]=[C:12]1[CH:11]=[CH:10][N:9]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[N:8]=[C:7]1[C:5]1[N:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:2]=[CH:3][CH:4]=1
Reactant: CN(C)C=CC(=O)c1nn(-c2ccc(C#N)cc2)ccc1=O
Reactant: NNc1ccccc1
Solvent: CO
Product: N#Cc1ccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3)n2)cc1
Yield: 4.6 %

Procedure:
To a solution of 4-{3-[3-(dimethylamino)prop-2-enoyl]-4-oxopyridazin-1(4H)-yl}benzonitrile (crude, 340 mg, 1.16 mmol) in 20 mL of methanol was added phenylhydrazine (500 mg, 4.62 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 4-[4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]benzonitrile (18 mg, 4% for two steps) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[N:12]=[CH:11][C:5]2[NH:6][C:7](=O)[N:8]=[CH:9][C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[C:17]([C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])[NH2:22])#[CH:18]>CN(C=O)C.CC(N(C)C)=O>[C:17]([C:19]1[CH:20]=[C:21]([NH:22][C:9]2[C:4]3[CH:3]=[C:2]([F:1])[N:12]=[CH:11][C:5]=3[N:6]=[CH:7][N:8]=2)[CH:23]=[CH:24][C:25]=1[F:26])#[CH:18]
Reactant: O=c1ncc2cc(F)ncc2[nH]1
Reactant: C#Cc1cc(N)ccc1F
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: C#Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1F
Temperature: 25 °C
Reaction time: 45 h
Yield: 84.7 %

Procedure:
A heterogeneous mixture of 6-fluoropyrido[3,4-d]pyrimidin-4(3H)-one (200) (1.65 g, 10.0 mmol), thionyl chloride (20 mL) and a catalytic amount of DMF (2 drops) was stirred under reflux for 1 h to give a homogeneous mixture. It was evaporated under reduced pressure at 45° C. (bath temperature) to give a light brown solid. To this solid was added a solution of 3-ethynyl-4-fluoroaniline (J. Org. Chem., 1981, 46, 2280-2286) (1.49 g, 11.0 mmol) and dry DMA (15 mL). The residue of 3-ethynyl-4-fluoroaniline was washed down with more DMA (2×2 mL). The reaction mixture was stirred at room temperature for 45 h. It was poured into water (300 mL). The pH was adjusted to ca. 9 using an aqueous solution of Na2CO3 at room temperature. Petroleum ether (300 mL) was added and stirred at room temperature for 30 min. The petroleum ether layer was decanted. It was repeated once more with petroleum ether (300 mL). The solid was collected by filtration and washed with water (5×50 mL); ethyl acetate/petroleum ether (1:10) (4×50 mL) and dried to give N-(3-ethynyl-4-fluorophenyl)-6-fluoropyrido[3,4-d]pyrimidin-4-amine (208) (2.39 g, 85%) as a pale brown solid, mp 223-226° C.; 1H NMR δ [(CD3)2SO] 10.10 (s, 1H), 8.96 (s, 1H), 8.73 (s, 1H), 8.24 (br s, 1H),), 8.12 (dd, J=6.4, 2.8 Hz, 1H), 7.96-7.88 (m, 1H), 7.39 (t, J=9.1 Hz, 1H), 4.54 (s, 1H). Anal. Calcd for C15H8F2N4.1.8H2O: C, 57.25; H, 3.72; N, 17.80. Found C, 57.27; H, 3.49; N, 17.90.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1)[CH:13]=[CH2:14]>ClCCl>[O:6]1[CH2:14][CH:13]1[CH2:12][C:15]1[CH:16]=[CH:17][C:18]([C:19]#[N:20])=[CH:21][CH:22]=1
Reactant: C=CCc1ccc(C#N)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: N#Cc1ccc(CC2CO2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
Add a solution of 3-chloro-peroxybenzoic acid (5.44 g, 40.92 mmol), in 25 ml of dichloromethane to a solution of 4-allyl-benzonitrile (2.66 g, 18.60 mmol) in 50 ml of dichloromethane. stir at room temperature overnight. Quench with NaHCO3 (15 ml) saturated solution and wash the organic layer three times with NaHCO3 solution and dry over magnesium sulfate. Evaporate in vacuo, and purify by flash chromatography in Hexane-AcOEt (7:1, 1% Et3N) affording 1.44 g (49%) of the title compound. MS m/z 160 (M+H)+.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5](O)[CH2:4][C:3]1([CH3:12])[CH3:11].N(OC(C)(C)C)=O.[C:20]1([C:26](=[CH2:36])[CH2:27][O:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2N)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>N1C=CC=CC=1>[C:20]1([C:26]2([CH2:36][O:1][N:2]3[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]3([CH3:12])[CH3:11])[C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[O:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C=C(COc1ccccc1N)c1ccccc1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Agent: CC(C)(C)ON=O
Solvent: c1ccncc1
Product: CC1(C)CCCC(C)(C)N1OCC1(c2ccccc2)COc2ccccc21
Yield: 27.4 %

Procedure:
The procedure of Example 1 is repeated using 3.9 g (25 mmol) of 1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine, 6.18 g (60 mmol) of tert-butyl nitrite, 15 mg (0.025 mmol) of (S,S)-(+)-N,N-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt(II) mmol) in 100 mL of pyridine and 11.25 g (50 mmol) of 2-(2-phenylallyloxy)-aniline in 20 mL of pyridine. The crude product obtained is purified by liquid chromatography (2.5% ethyl acetate/heptane) to give 2.5 g of an off-white oil in 27.4% yield. MS [M+1] 366
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[NH:4][C:3]=1[C:15]([O:17]CC)=O.[CH:20](N)=[NH:21]>O1CCCC1.C(O)C>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[NH:4][C:3]3[C:15]([OH:17])=[N:21][CH:20]=[N:1][C:2]=3[CH:6]=2)=[CH:12][CH:11]=1
Reactant: N=CN
Reactant: CCOC(=O)c1[nH]c(-c2ccc(OC)cc2)cc1N
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(-c2cc3ncnc(O)c3[nH]2)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 11.5 %

Procedure:
Ethyl 3-amino-5-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (7.2 g) was dissolved in tetrahydrofuran (16 mL)/ethanol (32 mL), formamidine (3.46 g) was added, and the mixture was stirred at 90° C. for 16 hrs. After cooling to room temperature, tetrahydrofuran was evaporated under reduced pressure. The residue was diluted with ethanol (20 mL), and the precipitated powder was collected by filtration, washed with ethanol (15 mL) and dried under reduced pressure to give the title compound (769 mg).