Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N-]C(C)C)([CH3:3])[CH3:2].[Li+].C([O:12][C:13](=[O:24])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)C=C.Cl[Si](C)(C)C.[OH-].[Na+].ClC1C=C(C=CC=1Cl)OCC(O)=O>O1CCCC1.C(N(CC)CC)C>[Cl:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[Cl:22])[O:15][CH:14]([CH2:3][CH:1]=[CH2:2])[C:13]([OH:12])=[O:24]
Reactant: C=CCOC(=O)COc1ccc(Cl)c(Cl)c1
Reactant: CC(C)[N-]C(C)C
Agent: C[Si](C)(C)Cl
Agent: O=C(O)COc1ccc(Cl)c(Cl)c1
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCC(Oc1ccc(Cl)c(Cl)c1)C(=O)O
Temperature: -100 °C
Reaction time: 1 h

Procedure:
To a stirred solution of anhydrous tetrahydrofuran (100 cm3) cooled to −100° C. in an ethyl ether/liquid nitrogen bath under an atmosphere of dry nitrogen was added a 2M solution of lithium diisopropylamide (6.30 cm3, 12.7 mmol) in tetrahydrofuran followed by dropwise addition at −100° C. of a solution of (3,4-dichloro-phenoxy)-acetic acid allyl ester (3.00 g, 11.5 mmol) in anhydrous tetrahydrofuran (15 cm3) over 5 minutes. The solution was stirred at −100° C. for 1 hour and the supernatant (3.30 cm3, 11.8 mmol) of a centrifuged 1:1 mixture of chlortrimethylsilane and triethylamine was added dropwise over 5 minutes at −100° C. The solution was stirred an additional 1 hour at −100° C. and allowed to warm to ambient temperature. To the solution was added 1 N sodium hydroxide (250 cm3) and the mixture stirred 10 minutes at ambient temperature. The aqueous layer was separated, extracted with ethyl ether (2×50 cm3) and acidified with 1 N HCl to pH 1.0. The acidified aqueous was extracted with ethyl ether (3×50 cm3), the combined ethyl ether extracts washed with brine (50 cm3), dried over magnesium sulfate, vacuum filtered and the filtrate volatile fractions removed in vacuo to afford a 4:1 mixture of the title compound and (3,4-dichloro-phenoxy)-acetic acid as a pale yellow solid (1.12 g, 37.3%) with negative ESI (M−H)−260.1.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=CC=1)([O-])=O.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH:34]=1>O1CCCC1>[CH3:23][O:22][C:18]1[CH:17]=[C:16]([C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:43][CH2:42][CH2:41][CH2:40][CH2:39][C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: NCCCCc1cccnc1
Reactant: COc1cccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cccc(OC)c2)c1
Solvent: C1CCOC1
Product: COc1cccc(C(=C/C=C/C(=O)NCCCCc2cccnc2)c2cccc(OC)c2)c1
Yield: 89.2 %

Procedure:
As in Example 134, a solution of (E)-5,5-bis(3-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (32.36 g) and 3-pyridinebutanamine (11.4 g) in tetrahydrofuran (120 mL) Was stirred for 18 hours at room temperature and was worked up in the usual manner. The crude material was purified by HPLC (ethyl acetate) and then triturated with ether-hexane to furnish 29.6 g of (E)-5,5-bis (3-methoxyphenyl)-N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide mp 84°-86° C. Crystallization of the product from ethyl acetate-ether provided 29.0 g of amide, mp 86°-88° C. Anal. Calculated for C28H3N2O3 : C, 75.99; H, 6.83; N, 6.33 Found: C, 75.85; H, 6.84; N, 6.27.
Reaction SMILES: [F:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1>>[CH:19]1([NH:22][CH:15]2[CH2:16][CH2:17][N:12]([C:3]3[C:2]([F:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=3)[CH2:13][CH2:14]2)[CH2:21][CH2:20]1
Reactant: O=C1CCN(c2ncc(C(F)(F)F)cc2F)CC1
Reactant: NC1CC1
Product: Fc1cc(C(F)(F)F)cnc1N1CCC(NC2CC2)CC1

Procedure:
The title compound is prepared from 1-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperidin-4-one and cyclopropylamine following a procedure analogous to that described for Intermediate 66.
Reaction SMILES: [CH3:1][C@@H:2]1[C@:26]2([O:32][CH2:31][C@H:29]([CH3:30])[CH2:28][CH2:27]2)[O:25][C@H:4]2[CH2:5][C@@H:6]3[C@@:20]([CH3:21])([C@@H:3]12)[C@H:19]([OH:22])[C:18](=[O:23])[C@H:17]1[C@H:7]3[CH2:8][CH2:9][C@@H:10]2[C@:15]1([CH3:16])[CH2:14][CH2:13][C@H:12]([OH:24])[CH2:11]2.[Li].N>>[CH3:1][C@@H:2]1[C@:26]2([O:32][CH2:31][C@H:29]([CH3:30])[CH2:28][CH2:27]2)[O:25][C@H:4]2[CH2:5][C@@H:6]3[C@@:20]([CH3:21])([C@@H:3]12)[C@H:19]([OH:22])[C@@H:18]([OH:23])[C@H:17]1[C@H:7]3[CH2:8][CH2:9][C@@H:10]2[C@:15]1([CH3:16])[CH2:14][CH2:13][C@H:12]([OH:24])[CH2:11]2
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4C(=O)[C@@H](O)[C@]3(C)[C@H]1[C@@H]2C
Agent: N
Agent: [Li]
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4[C@H](O)[C@@H](O)[C@]3(C)[C@H]1[C@@H]2C

Procedure:
(3β,5α,12β,25R)spirostan-3,12-diol-11-one was converted into the title compound via reduction with lithium and ammonia according to the procedure described in J. Am. Chem. Soc., 1953, 75, 1282.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[CH:4]=[CH:3][C:2]=1[C:11]([O:13]C)=[O:12].[OH:15]O>C(O)(=O)C>[CH3:10][O:9][C:7]([C:5]1[CH:6]=[N+:1]([O-:15])[C:2]([C:11]([OH:13])=[O:12])=[CH:3][CH:4]=1)=[O:8]
Reactant: COC(=O)c1ccc(C(=O)OC)nc1
Reactant: OO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C(=O)O)[n+]([O-])c1
Temperature: 20 °C

Procedure:
12 g (60 mmol) of dimethyl pyridine-2,5-dicarboxylate were suspended in 30 ml of glacial acetic acid and treated with 13 ml of hydrogen peroxide (35%) at 20° C. with stirring. The mixture was then heated with stirring to 100° C. (internal temperature), a clear solution being formed at 50° C. After the mixture had been stirred at 100° C. for 90 min, it was allowed to cool to 20° C., the crystalline precipitate was filtered off with suction and washed with water and, after drying, 7.5 g of product were obtained, m.p. 160° C. (dec.).
Reaction SMILES: [P:1]([OH:4])([OH:3])[OH:2].[NH2:5][CH2:6][CH2:7][C:8]([OH:10])=O.N1CCOCC1.P(Cl)(Cl)Cl>>[CH2:7]([C:8]([P:1]([OH:4])([OH:3])=[O:2])([P:1]([OH:4])([OH:3])=[O:2])[OH:10])[CH2:6][NH2:5]
Reactant: OP(O)O
Reactant: NCCC(=O)O
Solvent: ClP(Cl)Cl
Solvent: C1COCCN1
Product: NCCC(O)(P(=O)(O)O)P(=O)(O)O
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
The mixture of 5 eq. phosphorous acid and β-alanine is heated to form a melt. Morpholine (1 eq.) is slowly added. The reaction is cooled to about 70° C. and 2 eq. of PCl3 are added. The mixture is heated for about 3.5 hours. Then the reaction is hydrolyzed in aqueous acid at about 75° C. for about 0.5 hours. Crystallization from aqueous acid/IPA, affords pamidronate.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][CH2:12][CH2:13][C@H:14]([NH2:18])[C:15](=O)[NH2:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B>C1COCC1>[CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][CH2:12][CH2:13][C@H:14]([NH2:18])[CH2:15][NH2:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)[C@@H](N)CCCNC(=O)OCc1ccccc1
Agent: B
Solvent: C1CCOC1
Product: NC[C@@H](N)CCCNC(=O)OCc1ccccc1
Temperature: 10 °C
Reaction time: 3 h

Procedure:
((S)-4-Amino-4-carbamoyl-butyl)-carbamic acid benzyl ester (1.87 g, 7.071 mmol) is suspended in dry THF (40 ml) and cooled to 10° C. in an ice bath under nitrogen. Borane (28.3 ml of a 1 M solution in THF, 28.3 mmol) is added. The ice bath is removed and the suspension heated to 70° C. and then left to stir at this temperature for 3 hours. Further borane (28.3 ml of a 1 M solution in THF, 28.3 mmol) is added and then after an hour the same amount of 1M borane in THF is added again. After a final hour at 70° C. the reaction mixture is quenched with MeOH (40 ml). The solvent is reduced in vacuo to approximately 50 ml. This is diluted with 5 M HCl (100 ml) and washed with diethyl ether (3×100 ml). The aqueous phase is basified to pH 12 with 2N NaOH and product extracted into EtOAc (3×100 ml). The organic phases are combined, dried over MgSO4 and the solvent evaporated in vacuo to yield the title compound as a colourless oil.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:19][C:20]1[N:24]([CH2:25][CH2:26][CH3:27])[CH:23]=[N:22][CH:21]=1.O>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([S:1][CH2:19][C:20]2[N:24]([CH2:25][CH2:26][CH3:27])[CH:23]=[N:22][CH:21]=2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CCCn1cncc1CCl
Reactant: O=[N+]([O-])c1ccc(S)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1cncc1CSc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 40 h
Yield: 70.7 %

Procedure:
2-mercapto-5-nitropyridine (2.3 g) was dissolved in DMF (47 ml), potassium carbonate (6.2 g) and 5-chloromethyl-1-propylimidazole hydrochloride (3.5 g) was added to the mixture, and the mixture was stirred for 40 hours at room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 5-nitro-2-[[(1-propylimidazol-5-yl)methyl]sulfanyl]pyridine (2.9 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[CH3:21])[CH:8]([OH:22])[CH2:7]1)=[O:5])[CH3:2].[OH:23]O>>[CH2:1]([O:3][C:4]([N:6]1[CH2:20][CH2:19][C:18]2[C:9](=[N+:10]([O-:23])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]=2[CH3:21])[CH:8]([OH:22])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2c(nc3ccccc3c2C)C(O)C1
Reactant: OO
Product: CCOC(=O)N1CCc2c(C)c3ccccc3[n+]([O-])c2C(O)C1
Yield: 17 %

Procedure:
5-Hydroxy-1,2,4,5-tetrahydro-11-methyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester-6-oxide was prepared from 5-hydroxy-1,2,4,5-tetrahydro-11-methyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester and hydrogen peroxide analogous to Example 163.
Reaction SMILES: [N+:1]1([O-:10])[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:23][C:24]1[CH:25]=[C:26]([NH2:31])[CH:27]=[CH:28][C:29]=1[Cl:30]>CN(C)C=O>[Cl:23][C:24]1[CH:25]=[C:26]([NH:31][C:7]([C:4]2[CH:3]=[CH:2][N+:1]([O-:10])=[CH:6][CH:5]=2)=[O:9])[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1cc[n+]([O-])cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)c(Cl)c1)c1cc[n+]([O-])cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 70.6 %

Procedure:
A suspension of 4-pyridinecarboxylic acid-1-oxide (3.74 g, 26.9 mmol) and 1,1'-Carbonyldiimidazole (4.80 g, 29.6 mmol) in dry dimethylformamide (50 ml) was stirred for 40 minutes under an air-lock and treated with 3,4-dichlorobenzenamine (4.79 g, 29.6 mmol). The reaction mixture was heated at 100° for 5.3 hours and cooled to room temperature. The solution was evaporated in vacuo and the residue triturated with ethanol (80 ml) to give the title compound (5.38 g), m.p. 259°-265°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:15](F)=[CH:14][CH:13]=[CH:12][N:11]=2)=O)[CH:5]=[CH:6][CH:7]=1.O.[NH2:18][NH2:19].O>CO>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[NH:19][N:18]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1cccc(F)c1)c1ncccc1F
Reactant: NN
Solvent: CO
Solvent: O
Product: Fc1cccc(-c2n[nH]c3cccnc23)c1
Temperature: 80 °C

Procedure:
1.5 g of (3-fluorophenyl)-(3-fluoropyridin-2-yl)-methanone was dissolved in 5 mL of methanol, added with 1.0 mL of hydrazine monohydrate, and heated at 80° C. for 4 hours. The reaction solution was added with water, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:4), to afford 240 mg of the title compound as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:28]/[O:29][CH3:30])/[C:8]([NH:10][C@@H:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([OH:25])=[O:24])=[C:15]([CH2:18]OC(=O)C)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.CN([Si](C)(C)C)C(=O)C(F)(F)F.[I:43][Si](C)(C)C>C(Cl)Cl>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:28]/[O:29][CH3:30])/[C:8]([NH:10][C@@H:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([OH:25])=[O:24])=[C:15]([CH2:18][I:43])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C[Si](C)(C)I
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Agent: CN(C(=O)C(F)(F)F)[Si](C)(C)C
Solvent: ClCCl
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CI)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
7β-[(Z)-2-(2-Aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid (240 mg) was suspended in methylene chloride (4 ml), followed by an addition of N-methyl-N-(trimethylsilyl) trifluoroacetamide (330 μl). The resulting mixture was stirred at room temperature for 30 minutes. After ice-cooling, iodotrimethylsilane (200 μl) was added to the solution, and the resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure to obtain the silylated derivative of 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-iodomethyl-3-cephem-4-carboxylic acid.
Reaction SMILES: [NH:1]([C:8]1[CH:16]=[C:15]([C:17](O)=[O:18])[C:14]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(NC2C=C(C(O)=O)C(NC3C=CC(OC)=CC=3)=CC=2C(O)=O)=CC=1>CO>[CH:24]1[CH:25]=[C:26]2[C:17]([C:15]3[C:14]([NH:20][C:21]2=[CH:22][CH:23]=1)=[CH:13][C:9]1[C:10]([C:7]2[C:2]([NH:1][C:8]=1[CH:16]=3)=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:11])=[O:18]
Reactant: O=C(O)c1cc(Nc2ccccc2)c(C(=O)O)cc1Nc1ccccc1
Agent: COc1ccc(Nc2cc(C(=O)O)c(Nc3ccc(OC)cc3)cc2C(=O)O)cc1
Solvent: CO
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 112 °C

Procedure:
A mixture (one part) of 2,5-dianilino-terephthalic acid (96%) and 2,5-dianisidino-terephthalic acid (4%) was dissolved in polyphosphoric acid (4 parts at 117.5%). The solution was heated and drowned into methanol as described in Example 3. The mixture was then heated for 4 hours at 112° C. to produce a transparent, beta-phase quinacridone pigment, which exhibited an X-ray diffraction spectrum identical to that of Examples 5 thus confirming the product to be a pure beta-phase quinacridone.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[CH:29]12[CH2:35][CH:32]([NH:33][CH2:34]1)[CH2:31][NH:30]2.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.N#N>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:29]12[CH2:35][CH:32]([NH:33][CH2:34]1)[CH2:31][N:30]2[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1
Reactant: C1NC2CNC1C2
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(N4CC5CC4CN5)ccc2OCC3)c(F)c1
Temperature: 120 °C
Reaction time: 0.1 h
Yield: 13 %

Procedure:
9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (416 mg, 1.0 mmol), Pd(OAc)2 (22.4 mg, 0.1 mmol), 2,5-Diaza-bicyclo[2.2.1]heptane (120 mg, 1.2 mmol), X-phos (47 mg, 0.10 mmol), tert-butoxide (200 mg, 20 mmol) in dioxane (2 mL) was bubbled N2 for 10 min and then stirred at 120° C. for 6 min under the irradition of microwave. The mixture was filtered over ceilite. The filtrate was concentrated to dryness and purified by pre-HPLC to afford 310. (61.4 mg, yield=13%). 1H NMR (CDCl3, 400 MHz): δ 8.27 (s, 1H), 7.89-7.88 (m, 1H), 7.72-7.99 (m, 1H), 7.41-7.39 (m, 1H), 7.28-7.16 (m, 2H), 6.39 (d, J=8.8 Hz, 1H), 4.41 (s, 1H), 4.16 (s, 2H), 3.46-3.41 (m, 6H), 2.74 (s, 2H), 1.06 (t, J=6.8 Hz, 2H). LC-MS (ESI): m/z=479 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([OH:13])=[N:11][N:10]=[C:9]2[CH3:14])=[N:6][CH:7]=1.[C:15]([N:19]=[C:20]=[O:21])([CH3:18])([CH3:17])[CH3:16].C[O-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([O:13][C:20]([NH:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])=[N:11][N:10]=[C:9]2[CH3:14])=[N:6][CH:7]=1
Reactant: CC(C)(C)N=C=O
Reactant: Cc1nnc(O)n1-c1ccc(Cl)cn1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nnc(OC(=O)NC(C)(C)C)n1-c1ccc(Cl)cn1
Reaction time: 24 h

Procedure:
19.6 g (0.09 mol) of 4-(5-chloropyridin-2-yl)-5-hydroxy-3-methyl-1,2,4-triazole are suspended in 600 ml of absolute tetrahydrofuran. The mixture is heated to boiling and 20 g (0.2 mol) of tert-butylisocyanate are added, the mixture is heated for 10 minutes and 4 ml of a 5% methanolic sodium methoxide solution are added to the reaction mixture. It is then stirred for 24 hours under reflux conditions, then the suspension is concentrated and the residue is dissolved in methylene chloride and the insoluble components are removed by suction filtering. The organic phase is washed successively with 2 N hydrochloric acid, with sodium hydrogen carbonate solution and with water, dried with magnesium sulphate and evaporated in vacuo. After the addition of ether, 25 g (87% of theory) of the title compound were isolated in the form of crystals, m.p. 132°-134° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:12]=[C:13]([OH:18])[CH:14]=[CH:15][C:16]=1[F:17].C([O-])([O-])=O.[K+].[K+]>>[F:10][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][C:16]=1[F:17])[O:18][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)c(F)c1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=Cc1ccc(Oc2ccc(F)c(F)c2)cc1
Temperature: 25 °C

Procedure:
4-Fluorobenzaldehyde (5.32 mL, 49.6 mmol), 3,4-difluorophenol (7.10 g, 54.6 mmol) and K2CO3 (8.31 g, 60.1 mmol) were combined in a flask, which was immediately flushed with argon. DMF (50.0 mL) was added and the mixture was heated at reflux under argon for 6 h. Upon cooling to room temperature, EtOAc (100 mL) and H2O (100 mL) were added; the ethyl acetate layer was separated and washed with H2O (2×100 mL). The combined organic layers were washed with brine, dried over MgSO4, and the solvent was removed in vacuo. The desired product was obtained (11.4 g, 98.0%): 1H NMR (400 MHz, CDCl3) δ 9.95 (s, 1H), 7.88 (dd, 2H, J=0.8 Hz, 8.8 Hz) 7.24–7.17 (m, 1H), 7.07 (d, 2H, J=8.8 Hz), 6.97–6.92 (m, 1H), 6.86–6.82 (m, 1H); ESMS m/e: 235.0 (M+H)+.
Reaction SMILES: Br.Br.[N:3]1([C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.O.C(=O)([O-])O.[Na+].[C:22](OC(=O)C)(=[O:24])[CH3:23]>ClC(Cl)Cl>[C:22]([N:6]1[CH2:5][CH2:4][N:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[CH2:8][CH2:7]1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1cccc(N2CCNCC2)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(=O)N1CCN(c2cccc(O)c2)CC1
Temperature: 10 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a stirred solution of 80 parts of 3-(1-piperazinyl)phenol dihydrobromide in 360 parts of water and 180 parts of trichloromethane are added portionwise 42 parts of sodium hydrogen carbonate at 10° C. Then there are added dropwise, during a 15 minutes-period, 26 parts of acetic acid anhydride while cooling at 10° C. Upon completion, stirring is continued for 3 hours at room temperature. The precipitated product is filtered off, washed with water and crystallized from 2-propanol, yielding 37 parts (70%) of 1-acetyl-4-(3-hydroxyphenyl)piperazine; mp. 186.1° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[N:13]=[CH:12][C:11]([I:14])=[CH:10][C:6]=1[C:7]([OH:9])=O)[CH2:2][CH3:3].[NH2:15][C:16]1[C:17]([CH2:24][CH3:25])=[N:18][NH:19][C:20]=1[C:21]([NH2:23])=[O:22]>>[NH2:23][C:21]([C:20]1[C:16]([NH:15][C:7](=[O:9])[C:6]2[CH:10]=[C:11]([I:14])[CH:12]=[N:13][C:5]=2[O:4][CH2:1][CH2:2][CH3:3])=[C:17]([CH2:24][CH3:25])[NH:18][N:19]=1)=[O:22]
Reactant: CCCOc1ncc(I)cc1C(=O)O
Reactant: CCc1n[nH]c(C(N)=O)c1N
Product: CCCOc1ncc(I)cc1C(=O)Nc1c(C(N)=O)n[nH]c1CC

Procedure:
The title compound was prepared from 2-propoxy-5-iodonicotinic acid (see Preparation 2(h) and 4-amino-3-ethyl-1H-pyrazole-5-carboxamide (prepared as described in WO 98/49166) according to the method described in Preparation 2(g)(i).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[Mg].C[O:12][B:13](OC)[O:14]C>C1COCC1>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([B:13]([OH:14])[OH:12])=[CH:3][CH:4]=1)=[CH2:7]
Reactant: COB(OC)OC
Reactant: C=Cc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: C=Cc1ccc(B(O)O)cc1
Yield: 93.3 %

Procedure:
The procedure of Example 9 was repeated with the following reagents: 4-bromostyrene (9.15 g, 0.05 mol), magnesium turnings (1.46 g, 0.06 mol), THF (40 mL), and trimethylborate (6.24 g, 0.06 mol in 30 mL of THF). After work-up, an off-white solid (6.9 g, 93 percent) was isolated. 1H and 13C NMR spectra were consistent with the following structure. ##STR13##
Reaction SMILES: C(CC1C=CC(C[CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C@@H:19]2[CH2:28][CH2:27][C:26]3[CH:25]=[C:24]([O:29]C(=O)C(C)(C)C)[CH:23]=[CH:22][C:21]=3[CH2:20]2)=CC=1)(O)=O.[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH2:11]([N:12]([CH2:25][C:26]1[CH:27]=[CH:28][C:19]([CH2:14][CH2:13][N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[CH:20][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C@@H:19]1[CH2:28][CH2:27][C:26]2[CH:25]=[C:24]([OH:29])[CH:23]=[CH:22][C:21]=2[CH2:20]1)[CH3:10]
Reactant: C1CCNCC1
Reactant: CC(C)(C)C(=O)Oc1ccc2c(c1)CC[C@@H](c1ccccc1NCCCc1ccc(CC(=O)O)cc1)C2
Product: CCN(Cc1ccc(CCN2CCCCC2)cc1)c1ccccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 57.9 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]phenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (28 mg) and piperidine (24 mg) according to an analogous synthetic method to Example 715 and purified by LC-MS, the title compound (7.6 mg) was obtained.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH:19]1[CH2:21][CH2:20]1)[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]#[N:18])[CH2:13][CH2:12]1)=[O:10])(C)(C)C.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>ClCCl>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[NH2:7][C@H:8]([CH:19]1[CH2:21][CH2:20]1)[C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]#[N:18])[CH2:15][CH2:16]1)=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC(C#N)CC1)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC1CCN(C(=O)[C@H](N)C2CC2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a round-bottomed flask, [(R)-2-(4-cyanopiperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-carbamic acid tert-butyl ester (2.71 g, 7.93 mmol) was dissolved in dichloromethane (50 ml). The solution was cooled to 0° C. and trifluoroacetic acid (18 ml, 234 mmol) was slowly added. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to provide 1-((R)-2-amino-2-cyclopropyl-acetyl)-piperidine-4-carbonitrile trifluoroacetate as a yellow oil which was used without further purification.