Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[C:38]([O:42][C:43](=[O:58])[NH:44][C:45]1([C:48]2[CH:53]=[CH:52][C:51]([C:54]([NH:56][NH2:57])=[O:55])=[CH:50][N:49]=2)[CH2:47][CH2:46]1)([CH3:41])([CH3:40])[CH3:39]>CN(C=O)C.O>[C:38]([O:42][C:43](=[O:58])[NH:44][C:45]1([C:48]2[CH:53]=[CH:52][C:51]([C:54]([NH:56][NH:57][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:6])=[O:55])=[CH:50][N:49]=2)[CH2:47][CH2:46]1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)NN)cn2)CC1
Reactant: O=C(O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)NNC(=O)C3CC3)cn2)CC1
Temperature: 25 °C
Reaction time: 21 h
Yield: 94.1 %

Procedure:
To a solution of cyclopropyl carboxylic acid (0.20 g, 0.68 mmol) in DMF (2 mL) was added HATU (0.26 g, 0.68 mmol), Et3N (0.10 mL, 0.75 mmol) and the reaction mixture was allowed to stir at room temperature for 20 min. [1-(5-Hydrazinocarbonyl-pyridin-2-yl)-cyclopropyl]-carbamic acid tert-butyl ester (0.20 g, 0.68 mmol) in DMF (1 mL) was added and the reaction allowed to stir at room temperature for 21 h. The mixture was diluted with water and extracted with EtOAc (3×100 mL). The combined extracts were washed with satd NaHCO3, brine and dried with MgSO4. The mixture was filtered and concentrated to give {1-[5-(N′-cyclopropane-carbonyl-hydrazinocarbonyl)-pyridin-2-yl]-cyclopropyl}-carbamic acid tert-butyl ester (0.23 g, 0.64 mmol) as a light brown solid, m/z 361.7 [M+H]+.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][C:15]([O:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[CH:16][CH:17]=2)[N:12]=1.C(#N)C>O>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][C:15]2[N:14]=[C:13]3[C:18]([CH:19]=[CH:20][C:11]([NH:10][C:1](=[O:9])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[N:12]3)=[CH:17][CH:16]=2)=[CH:23][CH:24]=1
Reactant: COc1ccc(Oc2ccc3ccc(N)nc3n2)cc1
Reactant: O=C(O)c1ccccc1
Solvent: CC#N
Solvent: O
Product: COc1ccc(Oc2ccc3ccc(NC(=O)c4ccccc4)nc3n2)cc1
Temperature: 4 °C
Yield: 73.8 %

Procedure:
The procedure is similar to that described in Example 1, but starting with benzoic acid (11 g), N,N'carbonyldiimidazole (16.2 g) and 2-amino-7-(4-methoxyphenoxy)-1,8-naphthyridine (26.7 g). The product produced by precipitation in water (30.8 g; m.p. approximately 110° C.) is dissolved in boiling acetonitrile (150 cc). After 3 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (2×5 cc) and dried at 50° C. under reduced pressure (0.067 kPa). N-[7-(4-methoxyphenoxy)-1,8-naphthyridin-2-yl]benzamide (24.7 g) is produced, m.p. 171° C. 2-Amino-7-(4-methoxyphenoxy)-1,8-naphthyridine can be prepared in the following manner:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)[N:3]=1.[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([C:27]2[N:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[C:22]([CH:26]=1)[C:23](O)=[O:24].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C=O)C>[CH3:8][C:6]1[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][N:14]([C:23]([C:22]4[CH:26]=[C:18]([CH3:17])[CH:19]=[CH:20][C:21]=4[C:27]4[N:28]=[CH:29][CH:30]=[CH:31][N:32]=4)=[O:24])[CH2:15]3)[CH2:10]2)[N:5]=1
Reactant: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Reactant: Cc1ccc(-c2ncccn2)c(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ncccn2)c(C(=O)N2CC[C@H]3CN(c4nc(C)cc(C)n4)[C@H]3C2)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 20.7 %

Procedure:
A mixture of (1R,6S)-8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane (60 mg, 0.28 mmol), 5-methyl-2-pyrimidin-2-yl-benzoic acid (61.82 mg, 0.29 mmol), HOAT (56.12 mg, 0.41 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (79.1 mg, 0.41 mmol), TEA (83.5 mg, 0.83 mmol) was taken into DMF (5 mL) and stirred at 50° C. for 4 h. The reaction mixture was cooled and diluted with ethyl acetate (50 mL). It was washed with sat. aqueous NaHCO3 solution (2×25 mL) and with water (2×60 mL). The ethyl acetate layer was dried over Na2SO4, filtered and concentrated. The crude product was purified three times on Agilent Basic HPLC system to yield the title compound (24 mg, 21%). MS (ESI) mass calcd. for C24H26N6O, 414.51; m/z found 415.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 9.17-5.47 (m, 7H), 4.89-1.08 (m, 19H).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]3[C:13]4[CH2:20][CH2:19][NH:18][C:17](=[O:21])[C:14]=4[C:15]([OH:16])=[C:9]3[C:8]2=[O:22])=[CH:4][CH:3]=1.C(N([CH2:30][CH3:31])CC)C.[C:32]1(C)[CH:37]=C[C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]3[C:13]4[CH2:20][CH2:19][NH:18][C:17](=[O:21])[C:14]=4[C:15]([O:16][S:38]([C:35]4[C:30]([CH3:31])=[CH:37][CH:32]=[CH:33][CH:34]=4)(=[O:40])=[O:39])=[C:9]3[C:8]2=[O:22])=[CH:23][CH:24]=1
Reactant: CCN(CC)CC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1NCCc2c1c(O)c1n2CCN(Cc2ccc(F)cc2)C1=O
Solvent: ClCCl
Product: Cc1ccccc1S(=O)(=O)Oc1c2c(n3c1C(=O)N(Cc1ccc(F)cc1)CC3)CCNC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 8-(4-fluorobenzyl)-10-hydroxy-3,4,7,8-tetrahydropyrido-[3′,4′:4,5]pyrrolo[1,2-a]pyrazine-1,9(2H,6H)-dione (1.0 g, 3.0 mmol) and triethylamine (0.64 mL, 4.6 mmol) in dichloromethane (30 mL), p-toluenesulfonyl chloride (0.64 g, 3.34 mmol) was added. The reaction mixture was stirred at rt overnight and concentrated under vacuum. The residue was subjected to reverse phase preparative HPLC purification. Collection and lyophilization of appropriate fractions provided the titled compounds.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mn]([O-])(=O)(=O)=[O:15].[K+].[OH2:20]>>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]([OH:15])=[O:20])=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1ccc(-c2ccccc2)nc1
Reactant: O
Agent: [K+]
Product: O=C(O)c1ccc(-c2ccccc2)nc1
Temperature: 25 °C

Procedure:
A suspension of 2-phenyl-5-methyl pyridine (1.03 g, 6.09 mmol) and potassium permanganate (2.89 g, 18.3 mmol), in water (25 mL) was heated at reflux for 2 hours. The reaction was allowed to cool to ambient temperature and filtered through celite to remove the solids. Acetic acid (1 mL) was added to the colourless filtrate and the product was collected as a white solid by filtration.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:3]([CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:2]1.C(C1NC=CN=1)([C:17]1[NH:18][CH:19]=CN=1)=O.CNC>O1CCCC1>[CH3:17][N:18]([CH3:19])[C:12](=[O:14])[CH2:11][CH2:10][C:3]1[C:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=2[NH:1][CH:2]=1
Reactant: O=C(O)CCc1c[nH]c2c1CCCC2
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)CCc1c[nH]c2c1CCCC2
Reaction time: 2 h
Yield: 70 %

Procedure:
3-(4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid (9.7 g) in 100 mL of tetrahydrofuran was stirred with 8.1 g of carbonyl diimidazole for 1 hour. Dimethylamine (2.5 g) was added and the mixture stirred for 2 hours. The solvent was evaporated and the residue taken up in ethyl acetate, washed with water, 0.1 N hydrochloric acid, water, and brine, dried over sodium sulfate and evaporated to give 7.7 g (70% yield) of 3-(4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid dimethyl amide.
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2([CH:32]=[C:33]([F:36])[CH2:34]O)[CH2:31][CH2:30]2)=[CH:25][CH:24]=1>C(Cl)(Cl)(Cl)Cl>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2([CH:32]=[C:33]([F:36])[CH2:34][Br:1])[CH2:31][CH2:30]2)=[CH:25][CH:24]=1
Reactant: OCC(F)=CC1(c2ccc(Cl)cc2)CC1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: FC(=CC1(c2ccc(Cl)cc2)CC1)CBr
Temperature: 25 °C
Yield: 63 %

Procedure:
Under a nitrogen atmosphere, a solution of bromine (0.767 g, 4.8 mmol) in carbon tetrachloride at ice-water bath temperature is treated sequentially with a solution of triphenylphosphine (1.26 g, 4.8 mmol) in carbon tetrachloride and a solution of 3-[1-(p-chlorophenyl)-cyclopropyl]-2-fluoro-2-propen-1-ol, (Z)- (0.907 g, 4 mmol) in carbon tetrachloride, heated to and stirred at reflux for 70 minutes, cooled to room temperature, and poured into petroleum ether. The resultant mixture is filtered, and the filtrate is concentrated in vacuo to obtain a residue: The residue is dissolved in petroleum ether and passed through a plug of silica gel (eluted with hexanes) to obtain an oil. Flash column chromatography of the oil using silica gel and a 3:20 methylene chloride/hexanes solution gives the title product as a colorless oil (0.73 g, 63% yield) which is identified by NMR spectral analyses.
Reaction SMILES: COC(=O)CN1CC(CNCC2C=CC=CC=2)=CCC(N[C:22]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][N:25]=2)=[O:23])C1=O.[Li+].[OH-:37]>C1COCC1.O>[C:24]1([C:22]([OH:23])=[O:37])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1
Reactant: [OH-]
Reactant: COC(=O)CN1CC(CNCc2ccccc2)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nccc2ccccc12
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution containing {6-(benzylamino-methyl)-3-[(isoquinoline-1-carbonyl)-amino]-2-oxo-2,3,4,7-tetrahydro-azepin-1-yl}-acetic acid methyl ester, 24, (82 mg, 0.14 mmol) in THF/H2O (4 mL of 3:1) is treated with excess LiOH and stirred for 2.5 hours at room temperature. The solution is acidified to pH 7 and concentrated in vacuo. The residue is purified by HPLC to afford the desired product which is used directly for the next step.
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH2:52][OH:53])[C:11]([CH3:51])([CH3:50])[O:12]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([CH2:52][OH:53])([C:11]([CH3:51])([CH3:50])[O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC(C)(C)[C@](CO)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: Clc1ccccc1Cl
Product: CCOc1ccc(Cc2cc([C@]34OC(C)(C)[C@](CO)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.9 %

Procedure:
To a solution of [(1R,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-7,7-dimethyl-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanol 9d (50.00 mg, 0.07 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 5 mL) were added o-dichlorobenzene (0.04 mL, 0.35 mmol) and 10% Pd/C (42.40 mg, 0.04 mmol) at room temperature. The mixture was stirred at room temperature under H2 for 2 hours and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluted with EtOAc to give the title compound 9 as colorless oil (13.00 mg, 46.0%, HPLC: 94.04%). The compound was characterized by the following spectroscopic data: MS (ESI, neg. ion) m/z: 509 [M+HCOO]−; and 1H NMR (400 MHz, DMSO-d6) δ(ppm): 7.40 (m, 2H), 7.29 (dd, 1H), 7.10 (d, 2H), 6.84 (d, 2H), 5.00 (d, 1H), 4.93 (d, 1H), 4.82 (d, 1H), 4.63 (t, 1H), 3.99 (s, 2H), 3.96 (m, 1H), 3.92 (m, 1H), 3.79 (m, 1H), 3.60 (m, 1H), 3.42 (m, 2H), 3.28 (m, 1H), 1.42 (s, 3H), 1.30 (t, 3H), 0.95 (s, 3H).
Reaction SMILES: P(O)(O)(O)=O.[F:6][C:7]1[CH:8]=[C:9]([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[CH:10]=[C:11]2[C:16]=1[C@H:15](NC)[CH2:14][CH2:13][CH2:12]2.[NH2:27][C:28]([NH2:30])=[O:29].O.[CH3:32]N1CCCC1=O>>[F:6][C:7]1[CH:8]=[C:9]([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[CH:10]=[C:11]2[C:16]=1[C@H:15]([CH2:32][NH:27][C:28]([NH2:30])=[O:29])[CH2:14][CH2:13][CH2:12]2
Reactant: NC(N)=O
Reactant: CN1CCCC1=O
Reactant: CN[C@@H]1CCCc2cc(Sc3cccc(F)c3)cc(F)c21
Agent: O=P(O)(O)O
Solvent: O
Product: NC(=O)NC[C@@H]1CCCc2cc(Sc3cccc(F)c3)cc(F)c21
Temperature: 70 °C
Yield: 93.8 %

Procedure:
(R)-8-Fluoro-6-(3-fluorophenylsulfanyl)-1,2,3,4-tetrahydronaphthalen-1-yl-methylamine phosphate salt was treated with urea (27.5 g) in anhydrous N-methylpyrrolidinone (140 ml) at 100° C. for 18 hours. The reaction was cooled to 70° C. and water (360 ml) was added dropwise while allowing the temperature to decline to to room temperature. The resulting solids were collected and washed with water. The crude filter cake (46 g) was recrystallized from toluene (160 ml) and n-heptane (60 ml) to afford [(R)-8-fluoro-6-(3-fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-urea (37.27 g) in 93.8% yield, 99.8% pure by HPLC: MP=130.7-132.4° C.; MS (M+1)=349; H1 NMR (300 MHz): δ (DMSO): 1.49-1.99 (4H, m), 2.57-2.83 (2H, dt/m), 3.99-3.27 (3H, m), 5.43 (2H, bs, NH), 6.20 (1H, bt, J=6.03), 6.96-7.04 (2H, m), 7.1-7.17 (3H, m), 7.37-7.47 (1H, m); [α]D=24.2° (MeOH).
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8].CO[C:13]([CH:15]1[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17][CH2:16]1)=[O:14]>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[CH2:1]([O:10][C:13]([CH:15]1[CH2:16][CH2:17][CH:18]([C:21]([O:23][CH2:24][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])=[O:22])[CH2:19][CH2:20]1)=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)CCCCCCO
Reactant: COC(=O)C1CCC(C(=O)OC)CC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: CC(C)CCCCCCOC(=O)C1CCC(C(=O)OCCCCCCC(C)C)CC1
Temperature: 185 °C

Procedure:
Isononyl alcohol (8.1 mol), dimethylcyclohexane-1,4-dicarboxylate (DMCD, cis 1.7%, trans 98.3%, Eastman, 3.0 mol) and tetraisopropyl titanate catalyst (0.85 g) were added to a 2.5 L reactor equipped with a stirrer and two condensers and heated to 185° C. Di(isononyl)cyclohexane-1,4-dicarboxylate (cis 3%, trans 97%) was obtained with a purity of 99.7% in the same manner as in Example 1.
Reaction SMILES: [CH:1](Cl)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]([C:19]1[N:20]=[CH:21][NH:22][C:23]=1[C:24]([O:26][CH3:27])=[O:25])=[O:18]>C(#N)C.C(N(CC)CC)C>[CH:1]([N:20]1[C:19]([C:17]([O:16][CH3:15])=[O:18])=[C:23]([C:24]([O:26][CH3:27])=[O:25])[N:22]=[CH:21]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1nc[nH]c1C(=O)OC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1ncn(C(c2ccccc2)c2ccccc2)c1C(=O)OC
Temperature: 80 °C

Procedure:
20.3 g of benzhydryl chloride were added dropwise to a suspension of 18.4 g (0.1 mol) of 4,5-dimethoxycarbonyl-imidazole in 60 cc of acetonitrile and 14 cc of triethylamine and the reaction mixture was heated for 8 hours at 80° C. The solvent was then removed under reduced pressure and triethylammonium chloride was separated by washing with water. 30 g (85% of the theory) of 1-benzhydryl-4,5-dimethoxycarbonyl-imidazole, m.p. 93° C., were obtained.
Reaction SMILES: [NH2:1][CH:2]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)[C:3]([N:5]1[CH2:10][C:9](=[O:11])[N:8]([CH2:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:7][CH:6]1[CH2:24][CH2:25][C:26]#[N:27])=[O:4].[C:36]([NH:39][C@H:40]([C:49](O)=[O:50])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=1)(=[O:38])[CH3:37].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.CN(C)CCCN=C=NCC>CN(C=O)C.O>[C:36]([NH:39][CH:40]([CH2:41][C:42]1[CH:43]=[CH:44][C:45]([OH:48])=[CH:46][CH:47]=1)[C:49]([NH:1][CH:2]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)[C:3]([N:5]1[CH2:10][C:9](=[O:11])[N:8]([CH2:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:7][CH:6]1[CH2:24][CH2:25][C:26]#[N:27])=[O:4])=[O:50])(=[O:38])[CH3:37]
Reactant: N#CCCC1CN(CCc2ccc3ccccc3c2)C(=O)CN1C(=O)C(N)Cc1ccc(F)cc1
Reactant: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: CC(=O)NC(Cc1ccc(O)cc1)C(=O)NC(Cc1ccc(F)cc1)C(=O)N1CC(=O)N(CCc2ccc3ccccc3c2)CC1CCC#N
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3-[1-[2-amino-3-(4-fluorophenyl)propionyl]-4-(2-naphthalen-2-ylethyl)-5-oxo-piperazin-2-yl]propionitrile, 33, (47.2 g, 100 mmol), N-acetyl-L-tyrosine (22.3 g, 120 mmol), 1-hydroxybenzotriazole (16.2 g, 120 mmol), and N-methylmorpholine (132 mL, 120 mmol) in DMF (150 mL) is cooled to 0° C. and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (24.9 g, 130 mmol) is slowly added. The resulting mixture is stirred for 2 hours at 0° C. then allowed to warm and stir at room temperature another 2 hours. The reaction solution is diluted with water and the resulting solid is collected by filtration, re-dissolved in EtOAc and extracted with water, dried and concentrated in vacuo to afford the crude product which is purified over silica gel.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]2([CH2:30][CH3:31])[CH2:21][O:20]C(=O)[N:18]2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].C(OCC)(=O)C>CO.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([NH:18][C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])([CH2:30][CH3:31])[CH2:21][OH:20])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC1(CCc2ccc(OCc3ccccc3)cc2)COC(=O)N1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCC(CO)(CCc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 142 %

Procedure:
To a solution of 4-(2-(4-benzyloxyphenyl)ethyl)-3-tert-butoxycarbonyl-4-ethyloxazolidin-2-one (18 g) in methanol (432 ml) was added a solution of lithium hydroxide monohydrate (9.1 g) in water (50 ml) and the mixture was stirred at room temperature for 3 hours. Ethyl acetate was added to the reaction mixture and the mixture was washed with water and a saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure to give the subject compound (24 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH:21]([OH:36])[CH2:22][N:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH3:35])[CH2:25][CH2:24]3)[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].CI.CO.[CH2:43](Cl)Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH:21]([O:36][CH3:43])[CH2:22][N:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH3:35])[CH2:25][CH2:24]3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(Cl)cc3)nn2CC(O)CN2CCN(c3ccccc3C)CC2)C1
Reactant: ClCCl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CO
Solvent: C1CCOC1
Product: COC(CN1CCN(c2ccccc2C)CC1)Cn1nc(-c2ccc(Cl)cc2)c2c1CCN(C(C)=O)C2
Reaction time: 0.33 h

Procedure:
A stirred solution of 1-{3-(4-chloro-phenyl)-1-[2-hydroxy-3-(4-o-tolyl-piperazin-1-yl)-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanone (25 mg, 0.05 mmol) in THF (0.2 mL) was treated with NaH (1.42 mg, 0.06 mmol) at 25° C. After 20 min, methyl iodide (3.7 μL, 0.06 mmol) was added and the reaction mixture was stirred for an additional 2 h. Preparative TLC (silica, 5% MeOH/CH2Cl2) afforded 14.6 mg (56%) of a colorless film. TLC (silica, 10% MeOH/CH2Cl2): Rf=0.38. MS (electrospray): m/z 522.2 ([M+H]+, C29H36ClN5O2 requires 521.3). 1H NMR (CDCl3, 400 MHz, a mixture of two rotamers): 7.62 and 7.37 (AB pattern, Jab=8.8 Hz, 2H), 7.55 and 7.40 (AB pattern, Jab=8.8 Hz, 2H), 7.18-7.14 (m, 2H), 7.02-6.95 (m, 2H), 4.82 and 4.75 (AB pattern, Jab=15.5 Hz, 1H), 4.62 (s,1H), 4.30-4.25 (m,1H), 4.09-3.73 (m, 4H), 3.29 (s, 1.5H), 3.27 (s, 1.5H), 2.93-2.55 (m, 12H), 2.30 (s, 3H), 2.21 (s, 1.5H), 2.16 (s, 1.5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[NH:12][NH:11][C:10]2=[O:15])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)CC)C.[CH3:23][N:24]=[C:25]=[O:26]>CN(C)C=O.O>[CH3:23][NH:24][C:25]([N:12]1[C:13](=[O:14])[N:9]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[C:10](=[O:15])[NH:11]1)=[O:26]
Reactant: O=c1[nH][nH]c(=O)n1-c1cc(Cl)cc(Cl)c1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)n1[nH]c(=O)n(-c2cc(Cl)cc(Cl)c2)c1=O

Procedure:
To a solution of 2.5 g of 4-(3',5'-dichlorophenyl) urazole in 10 ml of N,N-dimethylformamide were added a drop of triethylamine and, in turn, 0.8 g of methyl isocyanate dropwise at room temperature with agitation. The reaction was continued for one additional hour under the same conditions and the reaction mixture was poured in water to precipitate crystals which were filtered and recrystallized from acetoneethanol to obtain 1-methylcarbamoyl-4-(3',5'-dichlorophenyl) urazole in an amount of 2.1 g (yield being 68%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]([CH2:7][C:8]2[CH2:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C([Li:21])CCC>CCCCCC>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:14]=[CH:13][C:6]([CH2:7][C:8]2([Li:21])[CH:12]=[CH:11][CH:10]=[CH:9]2)=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc(CC2=CC=CC2)cc1
Reactant: [Li]CCCC
Solvent: CCCCCC
Product: [Li]C1(Cc2ccc(C(F)(F)F)cc2)C=CC=C1
Yield: 80 %

Procedure:
2.5 g of 4-trifluoromethylbenzylcyclopentadiene (10 mmoles) and 30 ml of hexane are charged, in an argon atmosphere, into a tailed test-tube equipped with magnetic stirring. The same procedure is then carried out as in paragraph 2 of example 1 above, using 4.5 ml of a 2.5 M solution of butyllithium in hexane. At the end, 2.1 g of the desired salt are obtained with a yield of 80%.
Reaction SMILES: [N:1]([O-])=O.[Na+].[F:5][C:6]([F:15])([F:14])[C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=1)[NH2:10].Cl.[CH3:17][O:18][CH2:19][C:20](=[O:26])[CH2:21][C:22]([O:24][CH3:25])=[O:23].CC([O-])=O.[Na+]>O.CCO>[CH3:17][O:18][CH2:19][C:20](=[O:26])[C:21](=[N:1][NH:10][C:9]1[CH:11]=[CH:12][CH:13]=[C:7]([C:6]([F:14])([F:15])[F:5])[CH:8]=1)[C:22]([O:24][CH3:25])=[O:23]
Reactant: COCC(=O)CC(=O)OC
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COCC(=O)C(=NNc1cccc(C(F)(F)F)c1)C(=O)OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
A solution of NaNO2 (4.14 g, 60 mmol) in H2O (15 mL) was added dropwise at 0° C. to a mixture of 3-(trifluoromethyl)aniline (6.24 mL, 50 mmol) and 6 M HCl aqueous solution (50 mL, 300 mmol). After stirring for 15 min, the resulting aqueous solution was added to a suspension of methyl 4-methoxyacetoacetate (7.31 mL, 50 mmol) and NaOAc (24.6 g, 300 mmol) in EtOH (80 mL) pre-cooled at 0° C. The precipitate was collected by filtration, washed with water, and dissolved in AcOEt. The organic solution was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was crystallized from hexane/AcOEt to give the title compound (14.0 g, 88% yield) as pale yellow crystals: 1H NMR (300 MHz, CDCl3): δ ppm 3.51 (3H×0.36, s), 3.52 (3H×0.64, s), 3.90 (3H×0.36, s), 3.94 (3H×0.64, s), 4.68 (2H×0.64, s), 4.70 (2H×0.36, s), 7.41-7.59 (3H+1H×0.64, m), 7.71 (1H×0.36, s), 13.00 (1H×0.64, s), 14.87 (1H×0.36, s).