Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].O.[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[CH2:20]([O:11][C:10](=[O:12])[C@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[N:1]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 90 °C

Procedure:
A solution containing L-phenylalanine (161 kg, 975 moles), potassium carbonate (445 kg, 3220 moles), water (675 L), ethanol (340 L), and benzyl chloride (415 kg, 3275 moles) was heated to 90±15° C. for 10-24 hours. The reaction mixture was cooled to 60° C. and the lower aqueous layer was removed. Heptane (850 L) and water (365 L) were added to the organics, stirred, and the layers separated. The organics were then washed once with a water/methanol mixture (150 L/150 L). The organics were then stripped to give the desired product as an oil, which was carried on in the next step without purification.
Reaction SMILES: [BrH:1].[CH2:2]([C:4]1[N:9]=[C:8]([NH2:10])[C:7]([CH2:11][Br:12])=[CH:6][N:5]=1)[CH3:3].[CH3:13][C:14]1[S:23][C:17]2=[C:18]([CH3:22])[N:19]=[CH:20][CH:21]=[C:16]2[CH:15]=1>CN(C)C=O>[BrH:12].[Br-:1].[NH2:10][C:8]1[C:7]([CH2:11][N+:19]2[C:18]([CH3:22])=[C:17]3[S:23][C:14]([CH3:13])=[CH:15][C:16]3=[CH:21][CH:20]=2)=[CH:6][N:5]=[C:4]([CH2:2][CH3:3])[N:9]=1
Reactant: CCc1ncc(CBr)c(N)n1
Reactant: Cc1cc2ccnc(C)c2s1
Agent: Br
Solvent: CN(C)C=O
Product: CCc1ncc(C[n+]2ccc3cc(C)sc3c2C)c(N)n1
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
891 Mg of 2-ethyl-4-amino-5-bromomethyl pyrimidine hydrobromide is dissolved in 5 ml. of dimethylformamide (DMF), 1.95 g. of 2,7-dimethylthieno[2,3-c]-pyridine is added; a precipitate forms immediately. The precipitate is collected, washed with DMF, and discarded. The filtrates are stirred at room temperature overnight, diluted with ether, and the off-white precipitate collected and washed with ether. The solid is dissolved in methanol, hydrogen bromide gas introduced, and the colorless product isolated from methanol-isopropanol. 270 Mg. of product, 6-[(4-amino-2-ethyl-5-pyrimidinyl)methyl]2,7-dimethylthieno[2,3-c]pyridinium bromide hydrobromide is recovered, m.p. 215°-216° C., dec., 20% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10](Cl)=[O:11])[CH:6]=[CH:7][CH:8]=1.C(#N)C.C[Si]([CH:20]=[N+:21]=[N-:22])(C)C.C(OCC)C>C1COCC1>[N+:21](=[CH:20][C:10](=[O:11])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[N-:22]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1cccc(CC(=O)Cl)c1
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cccc(CC(=O)C=[N+]=[N-])c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Under an argon atmosphere, 3-methoxyphenylacetyl chloride (81) (952 mg, 5.16 mmol) was dissolved in THF (2.5 mL) and acetonitrile (2.5 mL) and cooled to 0° C. To this was slowly added a solution of trimethylsilyldiazomethane in diethyl ether (2.0 M, 5.00 mL, 10.0 mmol), which was stirred overnight (15 hours) after warming up to room temperature. After concentrating under reduced pressure, the residue was purified by silica gel flash column chromatography (n-hexane/diethyl ether=3/2) to give 1-diazo-3-(3-methoxyphenyl)propan-2-one (82) as a pale yellow oily substance (650 mg, 3.42 mmol, 66.3%).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:7])([CH3:6])[CH3:5])#[N:2].N1C=CC=CC=1.[C:14](Cl)([Cl:16])=[O:15]>ClCCl>[C:1]([CH2:3][C:4]([O:7][C:14]([Cl:16])=[O:15])([CH3:6])[CH3:5])#[N:2]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(O)CC#N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(CC#N)OC(=O)Cl
Temperature: 25 °C

Procedure:
Chloroformic cyanotert. butyl ester is prepared by reacting cyanotert butanol (10 g, 100 mMole) and pyridine (10 g, 125 mmole) in dichloromethane (150 ml) at about -40° C. together with liquid phosgene (-70° C., 40 ml, 600 mMole). The mixture is allowed to warm to room temperature and stirred over night. It is then extracted with ice cold aqueous hydrochloric acid (1N) washed twice with ice water immediately dried by shaking several times with fresh anhydrous sodium sulfate, the aqueous phases and the sodium sulfate are twice reextracted with a small amount of dichloromethane, and the combined organic phases are evaporated under reduced pressure (20° C. bath) to yield the product (17 g, 100% yield).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:4]([C:9]2[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][C:10]=2[F:17])[C:5](=O)[NH:6][N:7]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:5]1[N:6]=[N:7][C:2]([CH3:1])=[C:3]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]=1[C:9]1[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][C:10]=1[F:17]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1n[nH]c(=O)c(-c2c(F)cc(F)cc2F)c1-c1ccccc1
Product: Cc1nnc(Cl)c(-c2c(F)cc(F)cc2F)c1-c1ccccc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
1.67 g of 6-methyl-5-phenyl-4-(2,4,6-trifluorophenyl)-2H-pyridazin-3-one and 10 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. The reaction mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 1.74 g of 3-chloro-6-methyl-5-phenyl-4-(2,4,6-trifluorophenyl)pyridazine (hereinafter, referred to as compound (xxi) of the present invention).
Reaction SMILES: [CH3:1][N:2]([CH2:16][C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)[C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[C:6]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:5]=1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.Cl>O>[CH3:1][N:2]([CH2:16][C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)[C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([N:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)=[C:6]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:5]=1
Reactant: CN1CCNCC1
Reactant: CN(Cc1ccco1)C(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Agent: Cl
Solvent: O
Product: CN1CCN(c2ccc(C(=O)N(C)Cc3ccco3)cc2S(N)(=O)=O)CC1
Reaction time: 72 h

Procedure:
103 Grams of 4-chloro-3-sulfamoylbenzoic acid-N-methyl-2-furylmethylamide (0.3 mole) were heated under reflux with 0.3 l of N-methylpiperazine for 5 hours. After the reaction solution had been poured into 2 l of water, the pH value of the mixture was adjusted to 8.0 with 5N HCl. After standing at room temperature for 3 days, the separated yellow resin had crystallized. The reaction product was suction-filtered, washed thoroughly with water and was recrystallized from a mixture of methanol and water.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][NH:5][C:4]1=[O:8].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:17][CH2:18][CH2:19]Cl)=[CH:12][CH:11]=1>CN(C=O)C>[F:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[CH2:17][CH2:18][CH2:19][N:3]2[CH2:7][CH2:6][NH:5][C:4]2=[O:8])=[CH:14][CH:15]=1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Reactant: O=C1NCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1NCCN1CCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a suspension of sodium hydride (0.72 g, 18 mmol) in DMF (20.0 mL) was added a solution of imidazolidin-2-one (1) (2.5 g, 30.0 mmol, Aldrich) in DMF (10.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 45 minutes and then a solution of 4,4-bis(4-fluorophenyl)butyl chloride (2) (5.6 g, 10 mmol) in DMF (10.0 mL) was added. Then the mixture was stirred at 60° C. for 4 hours. After this period, the mixture was cooled to room temperature and quenched with water (20 mL). The mixture was extracted with ethyl acetate (100 mL×3). The organic layer was dried with anhydrous Na2SO4 and concentrated to give a crude sample. The crude sample was purified by column chromatography using ethyl acetate/hexane gradient as an eluent to give the title compound 3. MS: m/z 331. 1H NMR (CDCl3): δ 7.16 (m, 4H), 6.96 (t, J=8 Hz, 4H), 4.36 (br, 1H), 3.91 (t, J=8 Hz, 1H), 3.38 (m, 2H), 3.32 (m, 2H), 3.21 (t, J=8 Hz, 2H), 2.00 (dd, J=8, 12 Hz, 2H), 1.45 (m, 2H).
Reaction SMILES: [CH3:1]I.[CH3:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[C:9]2[C:13]([OH:15])=[O:14].[OH-].[K+].O>CC(C)=O>[CH3:1][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:3])[C:9]([C:13]([OH:15])=[O:14])=[CH:10]1
Reactant: CI
Reactant: Cc1cccc2c(C(=O)O)c[nH]c12
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cccc2c(C(=O)O)cn(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
Methyl iodide (30 g) was added to a stirred mixture of 7-methylindole-3-carboxylic acid (4.3 g) and powdered potassium hydroxide (20 g) in anhydrous acetone at 0° C. The resulting suspension was then stirred at room temperature overnight, then poured into water (500 ml), washed with dichloromethane (3×100 ml) and the aqueous phase acidified to pH 2 with hydrochloric acid. The product was isolated by filtration and dried under vacuum to afford white crystals (4.5 g); m.p. 243° C.; δH (360 MHz, DMSO-d6) 2.72 (3H, s, CH3), 4.09 (3H, s, NCH3), 6.92 (1H, d, J=6 Hz, H-6), 7.02 (1H, t, J=6 Hz, H-5), 7.87 (1H, d, J=6, H-4), 7.92 (1H, s, H-2); m/z 189 (M+, 100%), 172 (40), 144 (30), 91 (55).
Reaction SMILES: [NH:1]([C:53]([CH3:55])=[O:54])[C@@H:2]([C:14]([NH:16][C@@H:17]([C:25]([NH:27][C@@H:28]([C:36]([NH:38][C@H:39]([C:46]([O:48]C(C)(C)C)=[O:47])[CH2:40][O:41]C(C)(C)C)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[CH:11]2)=[CH:6][CH:5]=1>FC(F)(F)C(O)=O.SCCS>[NH:1]([C:53]([CH3:55])=[O:54])[C@@H:2]([C:14]([NH:16][C@@H:17]([C:25]([NH:27][C@@H:28]([C:36]([NH:38][C@H:39]([C:46]([OH:48])=[O:47])[CH2:40][OH:41])=[O:37])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:26])[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:15])[CH2:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[CH:11]2)=[CH:6][CH:5]=1
Reactant: CC(=O)N[C@H](Cc1ccc2ccccc2c1)C(=O)N[C@H](Cc1ccccc1)C(=O)N[C@H](Cc1ccccc1)C(=O)N[C@@H](COC(C)(C)C)C(=O)OC(C)(C)C
Agent: SCCS
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N[C@H](Cc1ccc2ccccc2c1)C(=O)N[C@H](Cc1ccccc1)C(=O)N[C@H](Cc1ccccc1)C(=O)N[C@@H](CO)C(=O)O
Reaction time: 1 h

Procedure:
10 g of Ac-D-Nal(2)-D-Phe-D-Phe-Ser(tBu)-OtBu are dissolved in a mixture of 40 ml of 90% strength aqueous trifluoroacetic acid and 1.6 ml of 1,2-dimercaptoethane. The mixture is left to stand at room temperature for one hour and is concentrated. The residue is triturated with water and dried under high vacuum.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@:4]([CH3:21])([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]>C(O)C.CCOC(C)=O.CCCCCC>[CH3:1][O:2][C:3](=[O:22])[C@:4]([CH3:21])([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:13][CH2:4][CH2:3][OH:2])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: COC(=O)[C@](C)(Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)[C@](C)(Cc1ccc(OCCCO)cc1)NC(=O)OC(C)(C)C

Procedure:
The N-t-butyloxycarbonyl-α-methyltyrosine methylester (1.70 g) from the previous synthesis was dissolved in 25 ml of absolute ethanol and treated with dry sodiun ethoxide (742 mg). 3-Bromopropanol (924 mg, 0.6 ml) was added and the solution was refluxed for 5 hours. The ethanol was then evaporated, 100 ml of dichloromethane added and the solution washed with 100 ml of water. After drying over MgSO4 the solvent was evaporated to yield two spots on a TLC plate developed in EtOAc:Hexane 1:1. The first spot was product and the second was starting material. The product was purified on a silica gel column using EtOAc:Hexane (1:1) A yield of 620 mg (MW 367.2, 31%) was obtained.
Reaction SMILES: Cl[C:2]1[C:7]2[NH:8][C:9]([CH:11]([CH3:13])[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-:15].[K+].[K+].Br[CH2:21][C:22]1[CH:31]=[C:30]2[C:25]([CH:26]=[CH:27][C:28]([C:32]3[N:36]=[C:35]([CH3:37])[O:34][N:33]=3)=[CH:29]2)=[CH:24][CH:23]=1>CN(C=O)C>[CH:11]([C:9]1[N:8]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]3[C:30](=[CH:29][C:28]([C:32]4[N:36]=[C:35]([CH3:37])[O:34][N:33]=4)=[CH:27][CH:26]=3)[CH:31]=2)[C:7]2[C:2](=[O:15])[NH:3][CH:4]=[CH:5][C:6]=2[N:10]=1)([CH3:13])[CH3:12]
Reactant: Cc1nc(-c2ccc3ccc(CBr)cc3c2)no1
Reactant: CC(C)c1nc2ccnc(Cl)c2[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc3ccc(Cn4c(C(C)C)nc5cc[nH]c(=O)c54)cc3c2)no1
Reaction time: 16 h

Procedure:
A mixture of “AB” and 4-chloro-2-isopropyl-3H-imidazo[4,5-c]pyridine is found in the mother liquor. A solution of 0.877 g of “AB” and 0.691 g of potassium carbonate in 30 ml of DMF is stirred at room temperature for 30 minutes. 1.5 g of 3-(7-bromomethylnaphthalen-2-yl)-5-methyl[1,2,4]oxadiazole (m.p. 149-150°) are added and the mixture is stirred for 16 hours and worked up in the customary manner. After chromatography on silica gel, in addition to the two regioisomeric dialkylation products, the compound 2-isopropyl-3-[7-(5-methyl[1,2,4]oxadiazol-3-yl)naphth-2-ylmethyl]-5H-imidazo[4,5-c]pyridin-4-one (“BB”), m.p. 214-215° EI 399 is obtained
Reaction SMILES: CN(C)C=O.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:28](#[N:31])[CH:29]=[CH2:30].[NH2:32][C:33]1[C:42]2[N:43]=[C:44]([CH2:51][O:52][CH3:53])[N:45]([CH2:46][C:47]([CH3:50])([OH:49])[CH3:48])[C:41]=2[C:40]2[CH:39]=[CH:38][C:37](Br)=[CH:36][C:35]=2[N:34]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[NH2:32][C:33]1[C:42]2[N:43]=[C:44]([CH2:51][O:52][CH3:53])[N:45]([CH2:46][C:47]([OH:49])([CH3:50])[CH3:48])[C:41]=2[C:40]2[CH:39]=[CH:38][C:37]([CH:30]=[CH:29][C:28]#[N:31])=[CH:36][C:35]=2[N:34]=1
Reactant: COCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)(C)O
Reactant: C=CC#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CN(C)C=O
Product: COCc1nc2c(N)nc3cc(C=CC#N)ccc3c2n1CC(C)(C)O
Temperature: 120 °C
Yield: 74.7 %

Procedure:
A thick walled glass tube, equipped with a stir bar, was charged with palladium (II) acetate (225 mg, 1.00 mmol), acetonitrile (50 mL), N,N-dimethylformamide (20 mL) triethylamine (8.25 mL, 59.3 mmol), tri-o-tolylphosphine (900 mg, 2.97 mmol), acrylonitrile (770 mg, 21.8 mmol) and 1-[4-amino-7-bromo-2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (7.50 g, 19.8 mmol). The reaction mixture was purged with nitrogen and the tube was sealed and heated at 120° C. in an oil bath for 18 hours. The reaction was cooled to ambient temperature and then concentrated under reduced pressure. The resulting solid was partitioned between chloroform (300 mL) and aqueous 1% sodium carbonate (100 mL). The fractions were separated and the aqueous fraction was extracted with chloroform (4×100 mL). The combined organic fractions were concentrated under reduced pressure and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0-7% gradient of methanol in dichloromethane) to provide 5.2 g of 3-[4-amino-1-(2-hydroxy-2-methylpropyl)-2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]prop-2-enenitrile as an off-white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[CH2:15]([C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1)[C:16]([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl.O>[CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][NH:5][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([CH2:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[CH:21][CH:22]=1
Reactant: CC(C)(C)CCN
Reactant: CC(C)(C)Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)CCNC(=O)c1ccc(CC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a cold solution of 5.26, g of 3,3-dimethylbutylamine and 21.0 ml of triethylamine in 180 ml of methylene chloride was added dropwise a solution of p-neopentylbenzoylchloride in 20 ml of methylene chloride. The resulting mixture was stirred at room temperature for 5 hours and diluted with water. The organic layer was washed with 3N hydrochloric acid, water, 1N sodium hydroxide, brine, dried, and evaporated to yield a solid. The solid was recrystallized from ethylacetate:hexane to yield N-(3,3-dimethylbutyl)-4-(2,2-dimethylpropyl)benzamide as a beige solid, mp 124°-126° C.
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]2[C:11](=O)[NH:12][N:13]=[C:6]2[C:5]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]#[N:29])=[CH:18][CH:17]=1)[CH2:2][CH3:3].C[Sn]([N:34]=[N+:35]=[N-:36])(C)C>C1(C)C=CC=CC=1>[CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]2[CH:11]=[N:12][N:13]=[C:6]2[C:5]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[NH:29][N:36]=[N:35][N:34]=2)=[CH:18][CH:17]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc(C)n2c(=O)[nH]nc2c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCCc1nc(C)n2cnnc2c1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 8 h
Yield: 35 %

Procedure:
4 g of 7-n-propyl-5-methyl-8-[(2'-cyano-4-biphenylyl)methyl]-1,2,4-triazolo[4,3-c]pyrimidin-3(2H)-one, prepared in Example 15, are dissolved in 100 ml of toluene. 2.8 g of trimethyltin azide are added and the mixture is heated to reflux for 24 hours. The crystals formed are drained in the heated state and washed with ether, then suspended in 100 ml of tetrahydrofuran. Hydrogen chloride gas is bubbled into the mixture and, after the reactants have passed completely into solution, a precipitate appears. The mixture is left overnight at room temperature and the crystals formed are drained, washed with ether and dissolved in dilute sodium hydroxide solution. This solution is washed with ether, then acidified by bubbling in sulphur dioxide and extracted with chloroform. The organic phase is dried over magnesium sulphate and evaporated under vacuum, and the residue crystallises in an ether/acetone mixture to give 1.5 g of 7-n-propyl-5-methyl-8-{[2'-(5-tetrazolyl)-4-biphenylyl]methyl}-1,2,4-triazolo[4,3-c]pyrimidin-(3(2H)-one in the form of crystals of melting point 248°-249° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[C:4]([F:15])[CH:3]=1.[CH2:16]([O:18][C:19]([C@H:21]1[CH2:23][O:22]1)=[O:20])[CH3:17].[O-]S(C(F)(F)F)(=O)=O.[Li+]>C(#N)C>[CH2:16]([O:18][C:19](=[O:20])[C@H:21]([OH:22])[CH2:23][NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:9]=[CH:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[C:4]([F:15])[CH:3]=1)[CH3:17]
Reactant: CCOC(=O)[C@H]1CO1
Reactant: Nc1ccc(N2C=CC(=O)CC2)c(F)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Product: CCOC(=O)[C@H](O)CNc1ccc(N2C=CC(=O)CC2)c(F)c1
Yield: 45 %

Procedure:
A solution of 1-(4-amino-2-fluorophenyl)-2,3-dihydro-1H-pyridin-4-one (Step 4, 0.412 g, 2.0 mmol) and oxirane-2(R)-carboxylic acid ethyl ester (0.394 g, 3.4 mmol) with lithium triflate (0.360 g, 3.0 mmol) in dry acetonitrile (5.0 mL) is heated at 50-60° C. for 24 h. Volatiles are removed under vacuum, and the crude material purified by silica gel flash chromatography (eluent: 5% acetone in CH2Cl2) to afford the title compound (290 mg, 45%) as a viscous yellow oil, MS (m/z): 323 [M +H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[N:9][N:8]([CH3:11])[C:7]=1[N:12]1[CH:16]=[CH:15][CH:14]=[N:13]1)=[O:5])C.[Li+].[OH-]>CO.O>[CH3:11][N:8]1[C:7]([N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=[N:9]1
Reactant: CCOC(=O)c1cnn(C)c1-n1cccn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1ncc(C(=O)O)c1-n1cccn1
Yield: 101.4 %

Procedure:
To a solution of 2′-methyl-2′H-[1,3′]bipyrazolyl-4′-carboxylic acid ethyl ester (340 mg, 1.54 mmol) in CH3OH (5 mL) and water (55 mL) was added LiOH (41 mg, 1.71 mmol). The reaction mixture was stirred at reflux for 4 h, and then the solution was concentrated under reduced pressure to remove the methanol. The residue was diluted with water and the solution was acidified to pH 2 with concentrated HCl. The resulting mixture was then extracted three times with ethyl acetate. The combined organic extracts were concentrated in vacuo to give 2′-methyl-2′H-[1,3′]bipyrazolyl-4′-carboxylic acid (300 mg, quantitative), which was used without further purification.
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].[F:9][C:10]([F:21])([F:20])[C:11](=O)[CH2:12][C:13](=O)[C:14]([F:17])([F:16])[F:15].CCOCC.CCCCCC>CS(C)=O>[F:9][C:10]([F:20])([F:21])[C:11]1[CH:12]=[C:13]([C:14]([F:15])([F:16])[F:17])[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: N=C(N)N
Reactant: O=C(CC(=O)C(F)(F)F)C(F)(F)F
Agent: O=C(O)O
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CS(C)=O
Product: Nc1nc(C(F)(F)F)cc(C(F)(F)F)n1
Temperature: 110 °C
Yield: 49.8 %

Procedure:
A mixture of guanidine carbonate (180 mmol) and 1,1,1,5,5,5-hexafluoro-2,4-pentanedione (120 mmol) was dissolved in 60 ml of DMSO and warmed to 110° C. for 2 to 3 hours. Flash chromatography of the crude reaction product with ether/hexane (50:50) afforded 13.8 g of the title compound as a white crystalline solid, m.p. 94.5°-96° C. NMR (60 MHz, CDCl3): δ 6.5 (br. s, 2H); 7.2 (s, 1H). A second product isolated was the hydroxypyrimidine (A is A-3): m.p. 116°-118.5° C. NMR (90 MHz, CDCl3): δ 7.1 (br. s, 3H); 7.3 (s, 1H).
Reaction SMILES: [ClH:1].[NH:2]([CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([OH:15])=[O:14])[CH2:9][CH2:8]1)[C:3]([NH2:5])=[NH:4].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1O.S(=O)(=O)(O)O.B(O)(O)O>CS(C)=O.C1(C)C(C)=CC=CC=1>[ClH:1].[NH:2]([CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([O:15][C:18]2[CH:17]=[CH:16][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)=[O:14])[CH2:9][CH2:8]1)[C:3]([NH2:5])=[NH:4]
Reactant: Oc1ccc2ccccc2c1
Reactant: N=C(N)NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: OB(O)O
Solvent: CS(C)=O
Solvent: Cc1ccccc1C
Product: N=C(N)NC[C@H]1CC[C@H](C(=O)Oc2ccc3ccccc3c2)CC1

Procedure:
A suspension of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride(1.8 g), β-naphtol(1.44 g), sulfuric acid(0.05 g) and boric acid(0.03 g) in a mixture of dimethylsulfoxide(10 ml) and xylene(50 ml) was heated under reflux conditions for 20 hours. The resulting water was removed by azeotropy with xylene. Following concentration of the reaction mixture, the residue was chromatographed on a column of silica gel with chloroform/methanol as eluent to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([F:22])[CH:20]=3)[C:15](=[O:23])[N:14]2[CH3:24])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:25][C:26]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([F:22])[CH:20]=3)[C:15](=[O:23])[N:14]2[CH3:24])[CH2:10][CH2:11][N:29]2[CH2:30][CH2:31][C:26]([OH:25])([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:27][CH2:28]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: CN1C(=O)c2ccc(F)cc2C1C(CC=O)c1ccc(Cl)c(Cl)c1
Product: CN1C(=O)c2ccc(F)cc2C1C(CCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 129.9 %

Procedure:
3-(3,4-Dichlorophenyl)-3-(6-fluoro-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (2.05 g) was coupled to 4-hydroxy-4-phenylpiperidine (1.0 g) by a method similar to that described in Example 8. The reaction product was purified by chromatography and converted to the corresponding hydrochloride salt as described in the Example 8 to afford the title compound (2.05 g); mp 160°-205° C.; MS: m/z=527(M+1); NMR(CD3SOCD3): 1.78 (m,2), 2.17 (m,1), 3.12 (s,3), 4.89 (m,1), 6.88 (d,1, J=8.3), 7.10-7.59 (m,9), 7.84 (d,1, J=8.7). Analysis for C29H29Cl2N2O2F.1.0 HCl.1.0 H2O: Calculated: C, 59.85; H, 5.54, N, 4.81; Found: C, 60.15; H, 5.39; N, 4.81.