Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:26]([S:34][CH2:35][CH2:36][C:37](=[O:41])[N:38]([CH3:40])[CH3:39])[S:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:23]=[CH:24][CH:25]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>C1COCC1>[OH:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:26]([S:34][CH2:35][CH2:36][C:37](=[O:41])[N:38]([CH3:40])[CH3:39])[S:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)CCSC(SCCC(=O)N(C)C)c1cccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CCSC(SCCC(=O)N(C)C)c1cccc(CO)c1

Procedure:
To a solution of (-)-methyl 5-(3-(t-butyldiphenylsilyloxymethyl)phenyl)-8-dimethylcarbamyl-4,6-dithiaoctanoate (step 5) (1.377 g, 2.26 mmol.) in THF (25 mL) at room temperature was slowly added tetra-n-butylammonium fluoride (1M) in THF (2.34 mL). The solution was stirred 2 hrs at room temperature Ethyl acetate was added to the reaction mixture, and the organic layer it was washed with brine (3×), dried over sodium sulfate, filtered and evaporated to dryness. Purification by flash chromatography using 40% acetone in hexane afforded the title compound.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH2:2][CH2:3][CH3:4].C(Cl)CCl.O[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:29]([NH:31][C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[CH:38]=[N:37][CH:36]=[CH:35]3)=[O:30])[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:15][CH:14]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:1]([O:6][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]([CH2:20][NH:21][C:22]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:28])[C:29]([NH:31][C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[CH:38]=[N:37][CH:36]=[CH:35]3)=[O:30])=[CH:17][CH:18]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)O
Reactant: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(CO)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CCCC(=O)OCc1ccc(C(CNC(=O)OC(C)(C)C)C(=O)Nc2ccc3cnccc3c2)cc1
Reaction time: 8 h

Procedure:
To butyric acid in pyridine was added EDC, DMAP, and tert-butyl 2-(4-(hydroxymethyl)phenyl)-3-(isoquinolin-6-ylamino)-3-oxopropylcarbamate (E139), and the solution was capped and stirred overnight. The mixture was poured into EtOAc/NaHCO3(sat) and the aqueous layer was further extracted with EtOAc. The organics were dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 0-5% MeOH/CH2Cl2 gradient) gave pure 4-(3-(tert-butoxycarbonylamino)-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl butyrate (E148).
Reaction SMILES: C[Si]([CH:5]=[N+:6]=[N-:7])(C)C.C([Li])CCC.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)#[N:14].[F-].[K+].C(=O)(O)[O-].[Na+]>Cl.C(O)C.CCOCC>[N:6]1[CH:5]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[NH:14][N:7]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: N#Cc1ccccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [F-]
Solvent: CCOCC
Solvent: CCO
Product: c1ccc(-c2cnn[nH]2)nc1
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A 250 ml reaction flask is dried under vacuum and baked by fire and then cooled by nitrogen gas flow. 50 ml of anhydrous ether is added into the flask and (trimethylsilyl)diazomethane (6 ml, 12.0 mmol) is also added. At −78° C., n-butyl lithium agent (6 ml, 14.4 mmol) is added. After reacting for 0.5 hrs, 2-cyanopyridine (1.04 g, 10.0 mmol) is added. The reaction is then carried out for 12 hrs. After the reaction is finished, ether extraction is carried out and the organic layer is collected and then concentrated to obtained white solids. The white solids are placed in a 50 ml reaction flask, potassium fluoride (0.58 g, 10.0 mmol) is added, 10 ml of ethanol is added, and a few drops of hydrochloride are added. Hot reflux is carried out for 2 hrs. After the reaction is finished, the reaction solution is neutralized by saturated sodium bicarbonate solution. Ether extraction is carried out and the organic layer is collected and then concentrated to obtain white solids. After purified by silicone chromatographic column, the product pytz is obtained. The yield is about 60%. 1H NMR (500 MHz, CDCl3): δ 8.70 (s, 1 H), 8.36 (s, 1 H), 7.99 (s, 1 H), 7.82 (t, 1 H, J=8.0 Hz), 7.32-7.29 (m, 1 H). HRMS (EI) m/z:calculated value C7H6N4 146.0592; experimental value 146.0593.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[CH2:14][C:13](=[O:15])[NH:12][C:11]3[CH:16]=[C:17]([N:20]4[CH:24]=[CH:23][CH:22]=[CH:21]4)[CH:18]=[CH:19][C:10]=3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C[N:45]([CH:47]=[O:48])C>CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[O:15]=[C:13]1[CH2:14][C:8]([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[C:47]([NH2:45])=[O:48])=[N:9][C:10]2[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[CH:23][CH:22]=[CH:21]3)=[CH:16][C:11]=2[NH:12]1
Reactant: CN(C)C=O
Reactant: O=C1CC(c2cccc(I)c2)=Nc2ccc(-n3cccc3)cc2N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc(C2=Nc3ccc(-n4cccc4)cc3NC(=O)C2)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A mixture of 4-(3-iodo-phenyl)-8-pyrrol-1-yl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 7) (214 mg, 0.5 mmol), Pd(OAc)2 (4 mg, 3 mol %), PPh3 (8mg, 8 mol %) and HDMS (0.52 mL, 2.5 mmol) in DMF (2 mL) was stirred under CO atmosphere at 60° C. for 4 h. The mixture was taken up in EtOAc, washed with 1 N HCl, sat. NaHCO3-sol. and brine, dried over MgSO4. Removal of the solvent in vacuum left a dark brown solid, which was purified by silica gel column chromatography with EtOAc/MeOH 95:5. Obtained as a yellow-brown solid (97 mg).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@H:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:27]1[N:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][N:28]=1>>[CH2:33]([C:30]1[CH:29]=[N:28][C:27]([N:23]2[CH2:24][CH2:25][CH:20]([C@H:18]3[O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH:7]=5)[CH:12]=[C:13]4[CH2:19]3)[CH2:21][CH2:22]2)=[N:32][CH:31]=1)[CH3:34]
Reactant: CCc1cnc(Cl)nc1
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@H](C2CCNCC2)C3)CC1
Product: CCc1cnc(N2CCC([C@@H]3Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O3)CC2)nc1

Procedure:
The title compound is prepared from (S)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 37, the configuration of the stereocenter is arbitrarily assigned) and 2-chloro-5-ethylpyrimidine following a procedure analogous to that described in Example 1. LC (method 5): tR=0.87 min; Mass spectrum (ESI+): m/z=470 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.Cl.[C:15]1([N:21]2[C:25](=[O:26])[CH2:24][C:23]3([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:29]3[CH2:28][CH2:27][C:23]4([CH2:22][N:21]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[C:25](=[O:26])[CH2:24]4)[CH2:31][CH2:30]3)=[CH:7][CH:6]=2)[O:12][N:11]=1
Reactant: O=C1CC2(CCNCC2)CN1c1ccccc1
Reactant: Cc1noc(-c2ccc(Cl)nn2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1noc(-c2ccc(N3CCC4(CC3)CC(=O)N(c3ccccc3)C4)nn2)n1

Procedure:
The object product (142 mg, 64%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridazine (111 mg) obtained in Example 43(2), 2-phenyl-2,8-diazaspiro[4.5]decan-3-one hydrochloride (150 mg) and potassium carbonate (155 mg).
Reaction SMILES: C([O-])(=O)C.[CH:5]1[N:10]=[C:9]([NH2:11])[C:8]2[N:12]=[CH:13][N:14]([C@@H:15]3[O:19][C@H:18]([CH2:20][O:21][P:22]([OH:25])([OH:24])=[O:23])[C@@H:17]([OH:26])[C@H:16]3[OH:27])[C:7]=2[N:6]=1.C(SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)C[O:43][P:44]([OH:73])(=[O:72])[O:45][P:46](O)(=[O:70])[O:47]C[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1OP(O)(O)=O)(=O)C>>[P:22]([O:21][CH2:20][C@H:18]1[O:19][C@@H:15]([N:14]2[C:7]3[N:6]=[CH:5][N:10]=[C:9]([NH2:11])[C:8]=3[N:12]=[CH:13]2)[C@H:16]([OH:27])[C@@H:17]1[OH:26])([O:25][P:46]([O:45][P:44]([OH:73])([OH:72])=[O:43])([OH:70])=[O:47])(=[O:24])[OH:23]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O
Reactant: CC(=O)SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O
Agent: CC(=O)[O-]
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O

Procedure:
A column (inside diameter: 1.8 cm, length: 12 cm) was packed with 2,000 units of immobilized acetate kinase, 200 units of immobilized adenylate kinase and 10 units of immobilized acetyl CoA synthetase which were obtained by the same methods as in Example 11, and 4 mM of AMP, 1.0 mM of ATP (25% based on the concentration of AMP), 25 mM of acetyl phosphate, 2.5 mM of potassium acetate and 2.5 mM of reduction type CoA lithium salt which were dissolved in a 100 mM imidazole hydrochloride buffer solution containing 10 mM magnesium chloride were fed thereto at a flow rate of 50 ml/hour. The reaction temperature in the column was kept at 37° C. AMP was separated from the solution eluted from the column by the same method as in Example 1 and it was sent back to the inlet for substrates. After 40 minutes from the initiation of the reaction, the formed acetyl CoA became 1.6 mM, and thereafter a stabilized state was kept over 15 hours.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([CH:11]([C:20]#[N:21])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])[CH2:8][CH2:9][CH3:10].[Cl-].[NH4+].Cl>CCOCC>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[CH:11]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:20][NH2:21]
Reactant: CCCCC(C#N)c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: CCCCC(CN)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.7 %

Procedure:
To a suspension of 9.0 g (0.24 mole) of lithium aluminum hydride in 200 ml of anhydrous ether is added 57 g (0.24 m) of α-n-butyl-2,4-dichlorobenzyl cyanide dropwise at 10°. The reaction mixture is stirred at room temperature for 30 minutes and at 35° overnight. Excess lithium aluminum hydride is then decomposed by addition of saturated ammonium chloride solution (50 ml), followed by 20% hydrochloric acid (300 ml) at 0°. The acidic aqueous layer is separated and extracted with ether. The combined ether portions are washed with water and dried over MgSO4. When ether is evaporated under vacuo, there is obtained 63 g of a yellow solid. The solid is then dissolved in 20% sodium hydroxide solution and extracted with ether. The combined ether extracts are dried over MgSO4. Solvent is evaporated to give 48 g of an oil. Vacuum distillation (101°-104°/0.1 mm) gives 38.3 g of pure product.
Reaction SMILES: C(OC)(=O)[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Na+].Cl.C([O-])(=O)C.[Na+].[F:17][C:18]1[CH:19]=[C:20]([S:24][CH:25]([CH3:29])[CH2:26][CH:27]=[O:28])[CH:21]=[CH:22][CH:23]=1>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[F:17][C:18]1[CH:19]=[C:20]([S:24][CH:25]([CH3:29])[CH2:26][CH:27]([OH:28])[CH2:2][C:3](=[O:4])[CH3:5])[CH:21]=[CH:22][CH:23]=1
Reactant: CC(CC=O)Sc1cccc(F)c1
Reactant: COC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)CC(O)CC(C)Sc1cccc(F)c1
Reaction time: 3 h
Yield: 87.4 %

Procedure:
10 9 86 Grams of methyl acetoacetate were dissolved in 15 ml of water, and 12.67 g of a 30% aqueous sodium hydroxide solution were added thereto by drops while cooling the mixture to 25° C. or less. After having been stirred at 30°-35° C. for 3 hours, the mixture was adjusted to pH 7.0 with a concentrated aqueous hydrochloric acid solution. Thereafter, 0.62 g of sodium acetate and 2.42 g of tetrabutylammonium bromide were added thereto and then an additional concentrated aqueous hydrochloric acid solution was added thereto so that the mixture had a pH of 6.9. Further, 27.4 g of a toluene solution containing 36.6% of 3-(3-fluorophenylthio)butanal were added thereto and the resulting mixture was stirred at 45°-50° C. for 9 hours. The organic layer separated from the mixture was washed with a 5% aqueous acetic acid solution and then with a saturated aqueous sodium chloride solution. Then it was dried over anhydrous magnesium sulfate. Removing the solvent from the layer under reduced pressure gave 12.49 g of crude-6-(3-fluorophenylthio)-4-hydroxy-2-heptanone (purity: 90.8%, yield: 87.4%). A purified product was obtained by column chromatography. The purified product had an nD21 of 1.5342.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:23])([F:22])[S:20]Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][NH:11][C:12]=2[S:20][C:19]([F:23])([F:22])[F:18])=[CH:4][CH:3]=1
Reactant: FC(F)(F)SCl
Reactant: CCOC(=O)c1c[nH]cc1-c1ccc(Cl)cc1
Solvent: ClCCl
Product: CCOC(=O)c1c[nH]c(SC(F)(F)F)c1-c1ccc(Cl)cc1
Temperature: -30 °C
Reaction time: 0.75 h
Yield: 95.3 %

Procedure:
A solution of ethyl 4-(p-chlorophenyl)-pyrrole-3-carboxylate (9.0 g, 0,036 mol) in methylene chloride (180 mL) is treated with trifluoromethylsulfenyl chloride (4.9 g, 0.036 mol) with stirring for 45 minutes at -30° C. The reaction mixture is warmed to room temperature and stirred for several hours. Since a TLC shows some starting material present, the reaction mixture is cooled to -30° C., treated with additional trifluoromethylsulfenyl chloride (1.3 g, 0.0095 mol), warmed to room temperature overnight with stirring, washed with water, saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title product as an off-white solid (12.0 g, mp 161.5°-164.0° C.) which is identified by 1HNMR, 19FNMR and 13CNMR spectral analyses.
Reaction SMILES: CN1C=CN=C1.[CH:7]1([CH2:12][C@H:13]([CH2:34][N:35]([CH:44]=[O:45])[O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:14]([N:16]2[C@H:20]([C:21](O)=[O:22])[CH2:19][CH2:18][N:17]2[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8]1.S(Cl)(C)(=O)=O.[N:51]1[CH:56]=[CH:55][C:54]([NH2:57])=[N:53][CH:52]=1>CN(C)C=O>[CH:7]1([CH2:12][C@H:13]([CH2:34][N:35]([CH:44]=[O:45])[O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:14]([N:16]2[C@H:20]([C:21]([NH:57][C:54]3[CH:55]=[CH:56][N:51]=[CH:52][N:53]=3)=[O:22])[CH2:19][CH2:18][N:17]2[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: Nc1ccncn1
Agent: CS(=O)(=O)Cl
Agent: Cn1ccnc1
Solvent: CN(C)C=O
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)Nc2ccncn2)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
1-Methylimidazole (0.53 ml, 6.7 mmol) was added into a solution of (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (1.2 g, 2.23 mmol) in N,N-dimethylformamide (DMF) (15.9 ml). The resulting solution was cooled to 0° C., and then mesyl chloride (0.18 ml, 2.34 mmol) was added dropwise at 0° C. Then 4-pyrimidinamine (0.255 g, 2.68 mmol) was added, and the reaction mixture was stirred for 1 h at room temperature. The reaction solution was purified via reverse phase HPLC (Gilson) to yield phenylmethyl (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-3-[(4-pyrimidinylamino)carbonyl]-1-pyrazolidinecarboxylate (1.21 g, 88% yield).
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20]([C:22]3[CH:23]=[N:24][N:25]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:26]=3[C:27]([F:30])([F:29])[F:28])=[O:21])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[OH-].[Na+].Cl>C1COCC1.O>[C:31]1([N:25]2[C:26]([C:27]([F:30])([F:28])[F:29])=[C:22]([C:20]([NH:19][CH2:18][C:15]3[CH:16]=[CH:17][C:12]([C:9]4[CH:8]=[CH:7][C:6]([O:5][CH2:4][C:3]([OH:37])=[O:2])=[CH:11][CH:10]=4)=[CH:13][CH:14]=3)=[O:21])[CH:23]=[N:24]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COC(=O)COc1ccc(-c2ccc(CNC(=O)c3cnn(-c4ccccc4)c3C(F)(F)F)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(-c2ccc(CNC(=O)c3cnn(-c4ccccc4)c3C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
A mixture of methyl({4′-[({[1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbonyl}amino)methyl][1,1′-biphenyl]-4-yl}oxy)acetate (284 mg, 0.557 mmol), prepared in the previous step, and 1 N NaOH (668 μL, 0.668 mmol) in 20 mL of THF and 10 mL of water was stirred at room temperature for 20 h (overnight). The reaction was acidified by the addition of 668 μL of 1 N HCl and then concentrated under reduced pressure to remove the THF. The solid that formed was collected by filtration and dried under reduced pressure to give the title compound (249 mg, 89%) as a white solid, MS (APCI) m/z 496 [M+H]+. Elemental Analysis for C26H20F3N3O4+0.38 H2O. Calc'd: C, 62.17; H, 4.17; N, 8.37Found: C, 61.91; H, 4.08; N, 8.00
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl-].[CH3:12][O:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:34]12[S:42][CH:38]([CH2:39][CH2:40][CH2:41]1)[CH2:37][C:36](=O)[CH2:35]2>C1COCC1>[CH3:12][O:13][CH:14]=[C:36]1[CH2:37][CH:38]2[S:42][CH:34]([CH2:41][CH2:40][CH2:39]2)[CH2:35]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CC2CCCC(C1)S2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC=C1CC2CCCC(C1)S2
Reaction time: 16 h

Procedure:
A solution of sodium bis(trimethylsilyl)amide 1M in THF (37.9 ml, 37.9 mmol) was added dropwise to a suspension of (methoxymethyl)triphenylphosphonium chloride (13.40 g, 37.9 mmol) in THF (60 ml) at −10° C., followed by the addition of 9-thia-bicyclo[3.3.1]nonan-3-one (3.95 g, 25.3 mmol) at −10° C. The suspension was allowed to warm to Rt and stirring was continued for 16 hrs.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.C(N(CC)C(C)C)(C)C.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1>ClCCl>[CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:30]([CH:27]4[CH2:29][CH2:28]4)=[O:31])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: Cc1nnc2ccc(-c3cccc(N)c3)nn12
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnc2ccc(-c3cccc(NC(=O)C4CC4)c3)nn12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 7.6 g of 3-methyl-6-(3-aminophenyl)-1,2,4-triazolo[4,3-b]pyridazine in 1.5 liters of dichloromethane was added 6 ml of N,N-diisopropylethylamine and 3.1 ml of cyclopropane carboxylic acid chloride. The solution was stirred at room temperature for 4 hours, washed with 200 ml of saturated sodium bicarbonate solution, dried and the solvent removed in vacuo. The residue was crystallized from dichloromethane-hexane to give 2.24 g of tan crystals, mp 255°-258° C. A sample recrystallized from dichloromethane-hexane gave white crystals, mp 259°-262° C.
Reaction SMILES: C1C2C(CC=CC=2)CCC1=O.C1C2C(=CC=CC=2)CCC1.[CH3:22][C:23]1([CH3:47])[CH2:32][CH2:31][C:30](=[O:33])[C:29]2[CH:28]=[C:27](/[CH:34]=[CH:35]/[C:36]3[CH:46]=[CH:45][C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:38][CH:37]=3)[CH:26]=[CH:25][C:24]1=2.Br[CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51]>[Zn]>[CH3:47][C:23]1([CH3:22])[CH2:32][CH2:31][C:30]([OH:33])([CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])[C:29]2[CH:28]=[C:27](/[CH:34]=[CH:35]/[C:36]3[CH:37]=[CH:38][C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:45][CH:46]=3)[CH:26]=[CH:25][C:24]1=2
Reactant: CCOC(=O)c1ccc(/C=C/c2ccc3c(c2)C(=O)CCC3(C)C)cc1
Reactant: CCOC(=O)CBr
Agent: O=C1CCC2CC=CC=C2C1
Agent: [Zn]
Solvent: c1ccc2c(c1)CCCC2
Product: CCOC(=O)CC1(O)CCC(C)(C)c2ccc(/C=C/c3ccc(C(=O)OCC)cc3)cc21

Procedure:
Reaction Scheme 5 discloses another example for the preparation of compounds within the scope of Formula 3. In this example the substituent is introduced to replace the oxo function of tetrahydronaphthalene-2-one after the Z--Y(R)--A--B group has already been coupled to the tetrahydronaphthalene nucleus. Thus, ethyl (E)-4-[2-(5,6-dihydro-5,5-dimethyl-naphthalen-8(7H)-one-2-yl)ethenyl]-benzoate (Compound A2) is reacted with ethyl bromoacetate in the presence of zinc metal in a Reformatsky reaction to provide (+/-) ethyl (E)-4-[2-(5,6,7,8-tetrahydro-5,5-dimethyl-8-hydroxy-8-(carbethoxymethyl)naphthalen-2-yl)ethenyl]benzoate (Compound A32). Compound A32 is itself within the scope of the present invention, within the scope of Formula 1. Compound A32 is dehydrated, as shown in the example by treatment with (methoxycarbonyl sulfamoyl)triethylammonium hydroxide (Burgess reagent) to yield a mixture of ethyl (E)-4-[2-(5,6-dihydro-5,5-dimethyl-8-(carbethoxymethyl)naphthalen-2-yl)ethenyl]benzoate (Compound A33a), and ethyl (E)-4-[2-(5,6-dihydro-5,5-dimethyl-8(7H)-anti (carbethoxymethylidenyl)-naphthalen-2-yl)ethenyl]benzoate (Compound A33b). Compound A33a is within the scope of Formula 6, and Compound A33b is within the scope of Formula 3. ##STR20##
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:25][C:24]([OH:27])([CH3:26])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[OH:27][C:24]1([CH3:26])[CH2:25][N:22]([C:3]2[C:2]([C:32]3[CH:33]=[N:34][C:29]([CH3:28])=[CH:30][CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: CC1(O)CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC(C)(O)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 128 using 5-bromo-6-(3-hydroxy-3-methylazetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 128.1) and (6-methylpyridin-3-yl)boronic acid. HPLC (Condition 4) tR=4.22 min, UPLC-MS (Condition 3) tR=0.95 min, m/z=459.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.27 (s, 3H) 2.52 (s, 3H) 3.45-3.61 (m, 4H) 5.41 (s, 1H) 7.34 (dd, J=8.21, 5.47 Hz, 3H) 7.72 (dd, J=8.21, 2.35 Hz, 1H) 7.80-7.88 (m, 2H) 7.97 (d, J=2.35 Hz, 1H) 8.49 (d, J=1.96 Hz, 1H) 8.73 (d, J=2.35 Hz, 1H) 10.18 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH:11]1[CH2:15][C@@H:14]([C:16]([OH:18])=O)[C@H:13]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH2:12]1)(=[O:10])=[O:9].Cl.CN(C)CCCN=C=NCC.OC1[C:49]2[N:48]=N[NH:46][C:45]=2C=CC=1.C(N(C(C)C)C(C)C)C.NCC#N>CN(C)C=O>[C:45]([CH2:49][NH:48][C:16]([C@@H:14]1[CH2:15][CH:11]([S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:10])=[O:9])[CH2:12][C@H:13]1[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=[O:18])#[N:46]
Reactant: Oc1cccc2[nH]nnc12
Reactant: O=C(O)[C@@H]1CC(S(=O)(=O)c2ccccc2Cl)C[C@H]1COc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N#CCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#CCNC(=O)[C@@H]1CC(S(=O)(=O)c2ccccc2Cl)C[C@H]1COc1ccc(Cl)cc1
Reaction time: 0.75 h
Yield: 97.4 %

Procedure:
To a mixture of (1R,2R)-4-(2-Chloro-benzenesulfonyl)-2-(4-chloro-phenoxymethyl)-cyclopentanecarboxylic acid (epimeric mixture, 50 mg) in dimethylformamide (2 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (46 mg), hydroxybenzotriazole (24 mg) and ethyldiisopropylamine (61 mg). After 45 min, aminoacetonitrile (8 mg) was added and the reaction mixture was stirred for 2 days then partitioned between ethyl acetate and an aqueous saturated solution of sodium hydrogenocarbonate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water then dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with dichloromethane/methanol (19:1 v/v) as eluant to afford the title compound (53 mg, 97%) as light yellow oil. MS (EI): 467.0 (M+H)+.