Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:13](=[O:29])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[C:21]2[CH:22]=[N:23][C:24]([O:27][CH3:28])=[N:25][CH:26]=2)[CH3:10])[C:5]([C:36]#[N:37])=[CH:4][N:3]=1.C(=N[OH:41])C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:13](=[O:29])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[C:21]2[CH:26]=[N:25][C:24]([O:27][CH3:28])=[N:23][CH:22]=2)[CH3:10])[C:5]([C:36]([NH2:37])=[O:41])=[CH:4][N:3]=1
Reactant: COc1ncc(-c2cccc3cc([C@H](C)Nc4nc(N)ncc4C#N)n(-c4ccccc4)c(=O)c23)cn1
Reactant: CC=NO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1ncc(-c2cccc3cc([C@H](C)Nc4nc(N)ncc4C(N)=O)n(-c4ccccc4)c(=O)c23)cn1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-2-amino-4-((1-(8-(2-methoxypyrimidin-5-yl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrimidine-5-carbonitrile 5 (34 mg, 0.070 mmol) in anhydrous toluene (4 mL) under argon, acetaldoxime (13 μL, 0.21 mmol), palladium(II) acetate (5 mg, 0.01 mmol) and triphenyl phosphine (5 mg, 0.017 mmol) were added and the resulting mixture was stirred at 80° C. for 3 h. The mixture was allowed to cool to RT and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried with Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by ISCO column chromatography (silica gel cartridge, 0-10% MeOH/DCM) to afford the product, (S)-2-amino-4-((1-(8-(2-methoxypyrimidin-5-yl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)amino)pyrimidine-5-carboxamide 11. ESI-MS m/z: 509.2 [M+H]+.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH:7]=O)[C:4]([OH:9])=[CH:3][CH:2]=1.[OH:10][C:11]1[C:12]([C:21]([NH:23][NH2:24])=[O:22])=[CH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2>>[OH:9][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[CH:7]=[N:24][NH:23][C:21]([C:12]1[C:11]([OH:10])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)=[O:22]
Reactant: O=Cc1ccccc1O
Reactant: NNC(=O)c1cc2ccccc2cc1O
Product: O=C(NN=Cc1ccccc1O)c1cc2ccccc2cc1O
Yield: 94 %

Procedure:
Following the general procedure of Example 1, condensation of salicylic aldehyde and 3-hydroxy-2-naphthoic hydrazide gave a pale yellow solid (94%): mp >285° C.; 1H NMR d 11.69 (br s, 1H), 10.97 (br s, 1 H), 10.79 (s, 1 H), 8.24 (s, 1 H), 8.02 (s, 1 H), 7.45 (d, 1 H, J=8.1 Hz), 7.31 (d, 1 H, J=8.1 Hz), 7.12 (dd, 1 H, J=7.8, 0.9 Hz), 7.05 (t, 1 H, J=7.5 Hz), 6.89 (s, 1 H), 6.86 (m, 2H), 6.51 (d, 1 H, J=8.1 Hz), 6.48 (t, 1H, J=7.5 Hz); 13C NMR d 163.62, 157.54, 154.08, 148.83, 135.94, 131.64, 130.37, 129.49, 128.70, 128.33, 126.79, 125.89, 123.86, 119.99, 119.44, 118.68, 116.48, 110.63; HRMS Calcd for C18H14N2O3 :306.1004, found 306.0977; Anal. (C18H14N2O3) C, H, N.
Reaction SMILES: [O:1]([CH2:8][CH2:9]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:12].Cl>N1C=CC=CC=1>[Br:12][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCOc1ccccc1
Reactant: BrP(Br)Br
Agent: Cl
Solvent: c1ccncc1
Product: BrCCOc1ccccc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 118.1 %

Procedure:
To 3.25 ml (0.04 mmol) of pyridine were added 13.82 g (0.1 mol) of 2-phenoxy ethanol and 10.83 g (0.04 mol) of phosphorus tribromide, followed by reacting at 0° C. for 1 hour while stirring. The reaction solution was warmed up to 50° C. and then reacted for 1 hour while stirring. After completion of the reaction, excess 1N hydrochloric acid (0° C.) were added to the reaction solution and then subjected to an extraction procedure using chloroform. The resulting organic layer was washed with 1N hydrochloric acid, water and an aqueous solution of sodium hydrogen carbonate, then dried on magnesium sulfate and concentrated under a reduced pressure. An obtained crude product was purified by distillation to obtain 9.5 g of a desired 2-bromoethylphenyl ether (yield 47%).
Reaction SMILES: [S:1]1C=C[CH:3]=[C:2]1CC([O-])=O.[K+].[PH:11](=[O:14])([OH:13])[OH:12].[CH2:15]([C:17]([CH2:45][CH3:46])([CH:19](Br)[C:20]1[N:24]=[CH:23][N:22]([C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:21]=1)[CH3:18])[CH3:16].[OH2:47]>O1CCCC1.C1OCCOCCOCCOCCOCCOC1>[PH:11](=[O:12])([OH:14])[OH:13].[CH2:15]([C:17]([CH2:45][CH3:46])([CH:19]([S:1][C:2](=[O:47])[CH3:3])[C:20]1[N:24]=[CH:23][N:22]([C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:21]=1)[CH3:18])[CH3:16]
Reactant: O
Reactant: CCC(C)(CC)C(Br)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=C([O-])Cc1cccs1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=[PH](O)O
Agent: [K+]
Solvent: C1CCOC1
Product: CCC(C)(CC)C(SC(C)=O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 48 h

Procedure:
A stirred solution of 18-crown-6 (0.04 g) in dry tetrahydrofuran (25 ml) was treated successively with potassium thiolacetate (0.59 g) and diethyl 3-bromo-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (1.94 g, prepared as described in Example 29). The mixture was allowed to stand for two days, poured into water and extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulphate and evaporated under reduced pressure. The residue was chromatographed on silica, using dichloromethane-ethanol (49:1) as eluant, to give diethyl 3-acetylthio-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (1.51 g) as a pale yellow oil. NMR(CDCl3): δ 1.3(6H,m), 1.6-1.9(2H,m), 2.2-2.3(2H,m), 2.4(3H,s), 4.0(4H,m), 4.9(1H,t), 7.15(6H,m), 7.3(9H,m), 7.9(1H,s), M/S: M+ 563.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=O.C(OCC)(=O)C>O>[CH2:1]([O:8][C:9]([N:11]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN(CCC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: O=CO
Product: CCOC(=O)CN(CCC(=O)O)C(=O)OCc1ccccc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
To tert-butyl 3-{N-benzyloxycarbonyl-N-(ethoxycarbonylmethyl)amino}propionate (500 mg, 1.37 mmol) was added formic acid (2.5 mL, 66.3 mmol), followed by stirring at an outer temperature set of 40° C. for 3 hours. After leaving to be cooled, to the reaction mixture were added ethyl acetate (10 mL) and water (10 mL), and the organic layer was collected by separation. To the aqueous layer was added ethyl acetate (10 mL), the organic layer was collected by separation, and then the organic layer was combined, washed with saturated brine (10 mL), then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained concentrated residue was dried at room temperature under reduced pressure to obtain 421 mg (yield 99%) of a title compound as colorless oil.
Reaction SMILES: [F:1][CH:2]([F:11])[C:3]([CH:8]([F:10])[F:9])([OH:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23].C(=O)(O)[O-].[Na+]>CC(N(C)C)=O.O>[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:4](=[O:5])[C:3]([OH:7])([CH:8]([F:10])[F:9])[CH:2]([F:11])[F:1])=[CH:27][CH:26]=1)(=[O:23])=[O:24]
Reactant: Nc1ccc(S(=O)(=O)c2ccccn2)cc1
Reactant: O=C(O)C(O)(C(F)F)C(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccc(S(=O)(=O)c2ccccn2)cc1)C(O)(C(F)F)C(F)F
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 42.8 %

Procedure:
To a solution of 2,2-bis-difluoromethyl-2-hydroxyacetic acid (0.5 g, 2.84 mmole) in dimethylacetamide (10 ml) at -10° C. was added thionyl chloride (0.34 g, 2.84 mmol) dropwise. The resulting solution was stirred at -10° C. for approximately 30 min. 4-(2-Pyridylsulfonyl)aniline (0.58 g, 2.5 mmol) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then poured into water, and sodium bicarbonate solution was added to give a pH of 7-7.5. A brown colored precipitate was formed. The solid was filtered, washed with water, and dried. Crystallization and decoloration (charcoal) from ethyl acetate/methanol/hexane gave the title compound (0.42 g, 43%) as off-white leaves; mp 200°-202° C. 1H-NMR(300 MHz, d6 -DMSO): 6.45 (t, J=54.09 Hz, 2H, HCF2), 7.68(t, J=6.24 Hz, 1H, ArH), 7.92-8.03 (m, 5H, ArH, OH), 8.11-8.21 (m, 2H, ArH), 8.68 (d, J=4.47 Hz, 1H, ArH), 10.54 (s, 1H, NH). MS(CI,CH4): 393 (M+1, 100%).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[CH3:16][NH:17][C:18]([NH:20][CH2:21][CH:22]([O:24][CH3:25])[CH3:23])=[S:19]>>[BrH:1].[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2([OH:4])[CH2:2][S:19][C:18](=[N:20][CH2:21][CH:22]([O:24][CH3:25])[CH3:23])[N:17]2[CH3:16])=[CH:6][C:7]=1[S:12](=[O:15])(=[O:14])[NH2:13]
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Reactant: CNC(=S)NCC(C)OC
Product: Br
Product: COC(C)CN=C1SCC(O)(c2ccc(Cl)c(S(N)(=O)=O)c2)N1C

Procedure:
4.7 g of 2-bromo-4'-chloro-3'-sulfamoylacetophenone and 2.19 g of 1-methyl-3-(2-methoxypropyl)-thiourea were reacted as prescribed in Example 23 and the crystalline end product was filtered off. Colorless solid crystals: melting point: 167° C. (decomposition).
Reaction SMILES: [ClH:1].Cl.C(OC([N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([N:37]4[CH2:42][CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39][CH2:38]4)=[O:36])=[CH:30][CH:29]=3)([CH3:27])[CH3:26])=[CH:21][CH:20]=2)=[O:17])[CH2:12][CH2:11]1)=O)(C)(C)C.Cl>O1CCOCC1.C1(C)C=CC=CC=1>[ClH:1].[ClH:1].[N:13]1([C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([C:28]3[CH:29]=[CH:30][C:31]([O:34][C:35]([N:37]4[CH2:38][CH2:39][NH:40][CH2:41][CH2:42]4)=[O:36])=[CH:32][CH:33]=3)([CH3:27])[CH3:26])=[CH:21][CH:20]=2)=[O:17])[CH2:12][CH2:11][NH:10][CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Oc2ccc(C(C)(C)c3ccc(OC(=O)N4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CC(C)(c1ccc(OC(=O)N2CCNCC2)cc1)c1ccc(OC(=O)N2CCNCC2)cc1

Procedure:
8.3 g of 2,2-bis[4-(4-tert-butoxycarbonyl-1-piperazinylcarbonyloxy)phenyl]propane dihydrochloride are dissolved in 50 ml of abs. dioxane, and 9.5 ml of an approx. 20% solution of hydrogen chloride in dioxane are added to this solution while stirring. The mixture is stirred overnight, after which it is diluted with toluene and the precipitate is filtered off with suction. After drying in vacuo, 5.7 g of the title compound, having a m.p. of from 200° C. (decomposition), are obtained.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:12][O:11][CH2:10][CH2:9][C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH2:13]([NH2:18])[CH2:14][CH2:15][CH2:16][CH3:17]>>[NH2:8][C:6]1[N:7]=[C:2]([NH:18][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:3]2[CH2:12][O:11][CH2:10][CH2:9][C:4]=2[N:5]=1
Reactant: Nc1nc(Cl)c2c(n1)CCOC2
Reactant: CCCCCN
Product: CCCCCNc1nc(N)nc2c1COCC2
Yield: 59 %

Procedure:
A mixture of 4-chloro-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine-2-ylamine (29.3 mg, 0.158 mmol) and amylamine (1.0 ml) was refluxed for 2.5 hours. After reaction, the procedure according to pro-treatment of Example 7 was carried out to give the object compound (22.3 mg, 59%).
Reaction SMILES: [S:1]1[C:5]([C:6]2([OH:23])[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[CH2:9][CH:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:7]2)=[CH:4][N:3]=[CH:2]1>C1C=CC2C(=CC=CC=2O)C=1>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1([OH:23])[C:15]2[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[CH2:9][CH:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:7]1.[S:1]1[C:5]([C:6]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[CH:9]=[C:8]([C:18]([O:20][CH3:21])=[O:19])[CH:7]=2)=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)C1Cc2cc(OC)ccc2C(O)(c2cncs2)C1
Agent: Oc1cccc2ccccc12
Product: CCOC(=O)C1Cc2cc(OC)ccc2C(O)(c2nccs2)C1
Product: COC(=O)c1cc(-c2cncs2)c2ccc(O)cc2c1

Procedure:
Following the procedure described in Naphthol 5, Steps 5-8, but substituting 1-(5-thiazolyl)-3-carbethoxy-6-methoxy-1,2,3,4-tetrahydro-1-naphthol from Step 1, for 1-(2-thiazolyl)-3-carbethoxy-6-methoxy-1,2,3,4-tetrahydro-1-naphthol, the title product was obtained as an orange solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:18][C:19]([F:23])([F:22])[CH2:20][NH2:21].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[C:15](=[O:17])[NH:21][CH2:20][C:19]([F:23])([F:22])[F:18])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1C(=O)O
Reactant: NCC(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To a mixture of cis-2-tertbutoxycarbonylamino-cyclohexanecarboxylic acid (Acros, 2 g, 8.22 mmol), 2,2,2-trifluoroethylamine (0.969 mL, 12.33 mmol), HOBT (1.888 g, 12.33 mmol) and DIPEA (4.31 mL, 24.66 mmol) in DMF (10 mL) was added EDC (2.364 g, 12.33 mmol) and the mixture allowed to stir at RT for 1 hr. The reaction was quenched into 10% aq. KHSO4 (100 mL) and product extracted with ethyl acetate (100 mL). Organic washed with aq. NaHCO3 (50 mL) and then brine (50 mL). Aqueous extracts backwashed with ethyl acetate (50 mL) and organic extracts combined, dried over sodium sulfate, filtered and concentrated to give 2.55 gm of a white solid, I-5a. 1H NMR (600 MHz, CDCl3) δ 6.18 (m, 1H), 5.07 (m, 1H), 3.75-4.0 (m 3H), 2.62 (m, 1H), 1.3-2.0 (br m, 8H), 1.40 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([Mg]Br)=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Br[Mg]c1cc2cc(OCc3ccccc3)ccc2[nH]1
Reactant: ClCc1cccnc1
Product: c1ccc(COc2ccc3[nH]cc(Cc4cccnc4)c3c2)cc1

Procedure:
The above mentioned compound was prepared similarly to the procedure described in Arch. Pharm. 308, 209 (1975) from 5-benzyloxy-indolyl-magnesium bromide and 3-chloromethyl-pyridine. After recrystallization from acetonitrile, the desired compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[F:8].FC(F)(F)S(O[C:18]1[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH:19]=1)(=O)=O.C([O-])([O-])=O.[Na+].[Na+].CCO>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.COCCOC>[Cl:1][C:2]1[CH:3]=[C:4]([C:18]2[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH:19]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CCOC(=O)C1CC=C(OS(=O)(=O)C(F)(F)F)CC1
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: CCO
Solvent: COCCOC
Product: CCOC(=O)C1CC=C(c2ccc(F)c(Cl)c2)CC1
Temperature: 100 °C

Procedure:
A flask was charged with (3-chloro-4-fluorophenyl)boronic acid (495 mg, 2.84 mmol), ethyl 4-{[(trifluoromethyl)sulfonyl]oxy}cyclohex-3-ene-1-carboxylate (686 mg, 2.27 mmol), Pd(PPh3)4 (262 mg, 0.227 mmol), 1M Na2CO3 (6.81 mL, 6.81 mmol), EtOH (2.8 mL), and DME (8.6 mL). The reaction was degassed with N2, the flask was sealed, and the reaction was heated to 100° C. for 2 hours. The reaction was then cooled to room temperature and diluted with hexanes (100 mL) and EtOAc (20 mL). The mixture was washed with water (2×25 mL) and brine (2×25 mL), and the organic layer was dried (Na2SO4), filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (0 to 10% EtOAc/hexanes) afforded ethyl 4-(3-chloro-4-fluorophenyl)cyclohex-3-ene-1-carboxylate. Rf=0.25 (5% EtOAc/hexanes). 1H NMR (500 MHz, CDCl3): δ 7.37 (dd, J=7.1, 2.3 Hz, 1H), 7.20 (m, 1H), 7.05 (t, J=8.8 Hz, 1H), 6.05 (s, 1H), 4.16 (q, J=7.1 Hz, 2H), 2.36-2.62 (m, 4H), 2.17 (m, 1H), 1.84 (m, 1H), 1.27 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([C:8]1[CH:9]=[C:10]([C:13]([NH:15][N:16]([CH2:32][C@@H:33]([OH:37])[C:34]([OH:36])=[O:35])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=3[F:31])=[CH:20][CH:19]=2)=[O:14])[NH:11][N:12]=1)(=[O:7])[CH3:6].C1COCC1>>[C:1]([O:37][C@H:33]([CH2:32][N:16]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=2[F:31])=[CH:20][CH:19]=1)[NH:15][C:13]([C:10]1[NH:11][N:12]=[C:8]([C:5](=[O:7])[CH3:6])[CH:9]=1)=[O:14])[C:34]([OH:36])=[O:35])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(=O)c1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)[nH]n1
Solvent: C1CCOC1
Product: CC(=O)O[C@H](CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(C(C)=O)n[nH]1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
Acetyl chloride (30 μL, 421.2 μmol) and (R)-3-[N′-(5-acetyl-2H-pyrazole-3-carbonyl)-N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid (20.0 mg, 42.1 μmol) were combined in THF (205 μL, 2.5 mmol), and stirred overnight at room temperature. The solvent was evaporated and the residue was purified (reverse phase HPLC column) to yield the title compound (12.2 mg) as a TFA salt. MS m/z [M+H]+ calc'd for C24H22ClFN4O6, 517.12. found 517.2.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH:20]2[CH2:25][CH2:24][C:23](C)(C)[CH2:22][CH2:21]2)[CH2:10][CH2:9]1)=O)(C)(C)C.F[C:29](F)(F)[C:30](O)=O.ClCCl.C(=O)([O-])[O-].[K+].[K+].[C:44](OCC)(=O)[CH3:45]>O>[CH2:44]([C:23]1([CH2:29][CH3:30])[CH2:22][CH2:21][CH:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:25][CH2:24]1)[CH3:45]
Reactant: O=C(O)C(F)(F)F
Reactant: CC1(C)CCC(c2ccccc2N2CCN(C(=O)OC(C)(C)C)CC2)CC1
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCC1(CC)CCC(c2ccccc2N2CCNCC2)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-[2-(4,4-dimethylcyclohexyl)phenyl]piperazine-1-carboxylic acid t-butyl ester (1.12 g, 2.80 mmol) produced in Example (38b), trifluoroacetic acid (10 mL, 130 mmol) and dichloromethane (10 mL) was stirred for 10 minutes at an external temperature of 0° C., and the temperature was raised to room temperature followed by stirring for 30 minutes. Potassium carbonate was then gradually added to the reaction mixture to make the mixture basic. Then, ethyl acetate and water were added and extraction was performed with ethyl acetate.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.Cl.Cl[CH2:10][C:11]1[CH:12]=[N+:13]([O-:17])[CH:14]=[CH:15][CH:16]=1>C(O)C>[CH:15]1[CH:14]=[N+:13]([O-:17])[CH:12]=[C:11]([CH2:10][S:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][N:3]=2)[CH:16]=1
Reactant: [O-][n+]1cccc(CCl)c1
Reactant: Sc1ccncn1
Agent: Cl
Solvent: CCO
Product: [O-][n+]1cccc(CSc2ccncn2)c1
Temperature: 25 °C
Yield: 70 %

Procedure:
11.2 g (0.1 moles) 4-mercaptopyrimidine is dissolved in 100 ml ethanol containing 10.8 g sodium methoxide. 18 g (0.1 moles) 3-chloromethylpyridine-N-oxide hydrochloride is added; the mixture is heated under reflux for about one hours. The solution is cooled to ambient temperature, the sodium chloride filtered off, and the filtrate evaporated under vacuum to eliminate the solvent. The residue is crystallized from ethyl acetate to give 15.35 g of product (M.P.=105°-108° C.; yield=70%).
Reaction SMILES: [CH:1]1([N:7]([CH3:16])[C@@H:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]([OH:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:17](N(C(C)C)CC)(C)C.Br[CH:27]1[CH2:32][CH2:31][CH2:30][CH:29]=[CH:28]1>C1COCC1>[CH2:17]([O:10][C:9](=[O:11])[C@@H:8]([N:7]([C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1)[CH3:16])[CH2:12][CH:13]([CH3:14])[CH3:15])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: BrC1C=CCCC1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)OCc1ccccc1)N(C)C1=CCCCC1
Temperature: 50 °C
Yield: 57 %

Procedure:
The Preparation (S)-2-(Cyclohexyl-methyl-amino)-4-methyl-pentanoic Acid (IId) ##STR31## Step i: N-Me-O-Benzyl-L-Leucine (3.6 g, 15.3 mmol) was dissolved in THF (77 mL) and treated with diisopropylethylamine (21 mL, 122 mmol) and 3-bromo-cyclohexene (3.5 mL, 30.6 mmol). The reaction was heated to 50° C. for 2 days. The reaction was filtered, and the solution was concentrated. The residue was chromatographed on silica gel eluting with 8% ethyl acetate/hexanes to give 2.75 g (57%) of (S)-2-(cyclohexenyl-methyl-amino)-4-methyl-pentanoic acid benzyl ester.
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([CH2:17]P(=O)(OCC)OCC)=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].[Br:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH:35]=O.O>C1COCC1>[N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14](/[CH:17]=[CH:35]/[C:34]4[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=4[Br:32])=[N:15][N:16]=3)[N:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CCOP(=O)(Cc1nnc2ccc(N3CCCCCC3)nn12)OCC
Reactant: O=Cc1ccccc1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Brc1ccccc1/C=C/c1nnc2ccc(N3CCCCCC3)nn12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of diethyl [(6-azepan-1-yl-1,2,4-triazolo[4,3-b]pyridazin-3-yl)methyl]phosphonate (367 mg) in THF (10 ml), potassium tert-butoxide (127 mg) was added with cooling in an ice bath, and the mixture was stirred at room temperature for 40 minutes. The resultant red solution was combined with 2-bromobenzaldehyde (0.128 ml), and stirred at room temperature for further 1 hour. The reaction solution was combined with water, and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resultant white solids were recrystallized from methanol to obtain 6-azepan-1-yl-3-[(E)-2-(2-bromophenyl)vinyl]-1,2,4-triazolo[4,3-b]pyridazine (152 mg) as colorless crystals.
Reaction SMILES: [CH:1]1([C:4]([NH:6][NH2:7])=[O:5])[CH2:3][CH2:2]1.[C:8](=S)=[S:9]>CN(C)C=O>[SH:9][C:8]1[O:5][C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:6][N:7]=1
Reactant: NNC(=O)C1CC1
Reactant: S=C=S
Solvent: CN(C)C=O
Product: Sc1nnc(C2CC2)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 17.9 g (0.179 mole) cyclopropane carboxylic acid hydrazide (the product of Example 6) in about 75 ml dimethylformamide, 68.0 g (0.894 mole) carbon disulfide was added (and all solids dissolved). The solution turned orange and then green. The reaction mixture was stirred about 1 hour at room temperature, refluxed about 3 hours, and stirred overnight at room temperature. The mixture was added to an ice-water bath to give an oil. The mixture was extracted with methylene chloride. The methylene chloride fraction was dried over magnesium sulfate and stripped. Chromatography on silica gel, eluting with methylene chloride, gave the above-identified product as a solid, melting point 76°-78° C.