Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[CH2:27])[C:11]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])([OH:18])[CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)=[CH:6][CH:5]=1.[OH-].[Na+]>CO>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[C:11]([OH:18])([C:10]([C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:28])=[O:2])=[CH:9][CH:8]=1)=[CH2:27])[CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: C=C(c1ccc(C(=O)OC)cc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=C(c1ccc(C(=O)O)cc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 95.7 %

Procedure:
A solution of 4-(2-[2,4-difluorophenyl]-2-hydroxy-1-(1,2,4-triazol-1-yl)-3-buten-3-yl) benzoic acid methyl ester (see Preparation 23 part (i)) (3.44 g, 9 mmol) in a mixture of methanol (50 ml) and aqueous sodium hydroxide (2M, 9 ml, 18 mmol) was heated under reflux for 3 hours. The cooled solution was evaporated under reduced pressure and the residue was dissolved in water (30 ml). The aqueous solution was extracted with ethyl acetate (3×30 ml) before acidification with hydrochloric acid (2M). The aqueous phase was further extracted with ethyl acetate (3×30 ml). The combined organic extracts were washed with brine (3×20 ml), dried (Na2SO4) and evaporated under reduced pressure to yield 4-{2-[2,4-difluorophenyl]-2-hydroxy-1-(1,2,4-triazol-1-yl)-3-buten-3-yl} benzoic acid (3.2 g, 96%). Recrystallisation of a sample from ethyl acetate/hexane/methanol afforded an off-white solid, m.p. 189-190° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:12]3[N:13]=[C:14]([CH2:17][N:18]4[CH:22]=[C:21]([C:23]([O:25]CC)=[O:24])[CH:20]=[N:19]4)[S:15][CH:16]=3)[CH:9]=[CH:10][CH:11]=2)[CH2:3][CH2:2]1.[OH-].[Na+].O>C(O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:12]3[N:13]=[C:14]([CH2:17][N:18]4[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[CH:20]=[N:19]4)[S:15][CH:16]=3)[CH:9]=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cccc(OCC4CC4)c3)cs2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cnn(Cc2nc(-c3cccc(OCC4CC4)c3)cs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
To a solution (4 mL) of the compound (340 mg, 0.89 mmol) obtained in Example 47a in ethanol was added 2N aqueous sodium hydroxide solution (1.8 mL, 3.6 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the aqueous layer was washed with diethyl ether, neutralized with 1N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was recrystallized (ethyl acetate-hexane) to give the title compound (180 mg, 57%) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3](Cl)=[N:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.[C:16]([O:20][CH3:21])(=[O:19])[C:17]#[CH:18].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[I-].[K+]>C(#N)C.[Cu]I.O>[F:1][C:2]([F:15])([F:14])[C:3](=[N:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[C:18]#[C:17][C:16]([O:20][CH3:21])=[O:19]
Reactant: C#CC(=O)OC
Reactant: COc1ccc(N=C(Cl)C(F)(F)F)cc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CC#N
Product: COC(=O)C#CC(=Nc1ccc(OC)cc1)C(F)(F)F
Temperature: 60 °C

Procedure:
In a typical reaction, 2,2,2-trifluoro-N-(4-methoxyphenyl)acetimidoyl chloride and a slight excess of methyl propiolate are mixed with about 0.3 equivalents of copper (I) iodide and slight excesses of potassium phosphate and potassium iodide in anhydrous acetonitrile. The mixture is heated at about 60° C. under a nitrogen atmosphere until the reaction is complete. After cooling, an extraction solvent like a halogenated hydrocarbon is added to the mixture along with water. The organic layer is recovered, washed with brine and dried. The solvent is evaporated to provide crude methyl 5,5,5-trifluoro-4-((4-methoxyphenyl)imino)pent-2-ynoate.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.ClC1N=C2C(C(=O)CC(C)C)=CNC2=NC=1.C(=O)([O-])[O-].[K+].[K+].[CH3:39][O:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[C:45]([O:49][CH3:50])[C:46]=1[O:47][CH3:48]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:14][CH:13]([CH3:15])[CH2:12][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:43]3[CH:44]=[C:45]([O:49][CH3:50])[C:46]([O:47][CH3:48])=[C:41]([O:40][CH3:39])[CH:42]=3)[N:3]=2)[NH:8][CH:9]=1)=[O:16]
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: CC(C)CC(=O)c1c[nH]c2ncc(Br)nc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)CC(=O)c1c[nH]c2ncc(Cl)nc12
Solvent: ClCCl
Product: COc1cc(-c2cnc3[nH]cc(C(=O)CC(C)C)c3n2)cc(OC)c1OC
Temperature: 150 °C

Procedure:
A mixture of 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-3-methyl-butan-1-one and 1-(2-chloro-5H-pyrrolo[2,3-b]pyrazin-7-yl)-3-methyl-butan-1-one (55 mg), potassium carbonate (95 mg, 0.69 mmol), 3,4,5-trimethoxyphenylboronic acid (47 mg, 0.22 mmol) and Pd(dppf)Cl2-DCM (16 mg, 0.02 mmol) was placed in a 5 ml microwave vial. The vial was capped and purged with nitrogen. Solvent was added (2 ml of 20% aqueous dioxane) and the vial was purged again with nitrogen. The reaction mixture was heated in a microwave reactor at 150° C. for 30 min. The solvents were evaporated and the crude product was purified by flash chromatography using a gradient of 20% ethyl acetate in hexanes up to 50% to yield 30 mg of 3-methyl-1-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-butan-1-one. MS: (M+H)+=370, MP=210.0-211.4° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[C:10]1[S:11][CH:12]=[CH:13][CH:14]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O>[N:15]1([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=2[C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCNC1
Reactant: O=Cc1ccc(F)c(-c2cccs2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(N2CCCC2)c(-c2cccs2)c1
Temperature: 25 °C
Yield: 28.9 %

Procedure:
Ex-20B: A solution of 4-fluoro-3-(thiophen-2-yl)-benzaldehyde (1.11 g, 5.38 mmol) from Ex-20A and pyrrolidine (13.0 g, 183.0 mmol) in dimethylformamide (30 mL) was treated with solid K2CO3 (1.7 g, 12.3 mmol), and the resulting mixture was stirred at reflux for 1 week. Upon cooling to room temperature, the reaction was poured into water (100 mL) and extracted with ethyl acetate (2×100 mL). The organic phase was dried over magnesium sulfate, and the solvent was removed under reduced pressure. Silica gel chromatography (hexane/ethyl acetate, 2:1) gave 400 mg (29%) of the desired 4-pyrrolidin-1-yl-3-(thiophen-2-yl)-benzaldehyde product as a yellow oil. 1H-NMR (300 MHz, CDCl3) δ 9.75 (s, 1H), 7.71–7.74 (m, 2H), 7.30 (dd, 1H, J=5.1 and 1.6 Hz), 7.02 (dd, 1H, J=5.1 and 3.7 Hz), 6.96 (m, 1H), 6.81 (d, 1H, J=10.1 Hz), 3.15 (m, 4H), 1.84 (m, 4H).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[Na+].[Na+].Br[C:17]1[NH:22][C:21](=[N:23][C:24]2[C:29]([CH:30]([CH3:32])[CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=2[CH:33]([CH3:35])[CH3:34])[CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.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>[C:1]1([C:17]2[NH:22][C:21](=[N:23][C:24]3[C:29]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:27]=[CH:26][C:25]=3[CH:33]([CH3:35])[CH3:34])[CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1N=c1cccc(Br)[nH]1
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: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1N=c1cccc(-c2ccccc2)[nH]1
Temperature: 70 °C

Procedure:
Phenylboronic acid (316 mmol) and Na2CO3 (792 mmol) are dissolved into 200 mL of degassed 1:1 H2O/ethanol. This solution is added to a toluene solution (500 mL) of 6-bromo-2-(2,6-diisopropylphenyl)iminopyridine (109 g, 316 mmol). Inside of a dry box 1 g (0.86 mmol) of tetrakis(triphenylphosphine)palladium(0) is dissolved in 50 mL of degassed toluene. The solution is removed from the dry box and charged into the N2 purged reactor. The biphasic solution is vigorously stirred and heated to 70° C. for 4-12 h. After cooling to room temperature, the organic phase is separated, the aqueous layer is washed with toluene (3×75 mL), and the combined organic extracts are washed with H2O (3×200 mL) and dried over MgSO4. After removing the volatiles under reduced pressure, the resultant light yellow oil is purified via recrystallization from methanol to give a yellow solid. Yield is 109 g, 87.2 percent; mp 142-144° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[CH:4][CH:3]=1.[C-:10]#[N:11].[Na+].C(OCC)=O>C(O)C>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:10]#[N:11])=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: OCc1ccc(O)cc1
Agent: [Na+]
Solvent: CCO
Solvent: CCOC=O
Product: N#CCc1ccc(O)cc1
Yield: 94 %

Procedure:
A mixture of 4.96 g. para-hydroxybenzyl alcohol 2.4 g. sodium cyanide 12 ml. ethanol and 12 ml. ethyl formate is heated with stirring under reflux for a period of ninety minutes. The reaction product is then subjected to the same isolation process as in Example 1 to give a 94% yield of crude product showing a melting point of 58°-61° C. uncorrected.
Reaction SMILES: [OH:1]O.[CH2:3]([S:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][C:14]3[C:19]([N:20]=2)=[CH:18][N:17]=[N:16][CH:15]=3)=[C:8]([O:21][CH3:22])[CH:7]=1)[CH3:4]>C(O)C>[CH2:3]([S:5]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:20][C:19]3[C:14]([N:13]=2)=[CH:15][N:16]=[N:17][CH:18]=3)=[C:8]([O:21][CH3:22])[CH:7]=1)=[O:1])[CH3:4]
Reactant: CCSc1ccc(-c2nc3cnncc3[nH]2)c(OC)c1
Reactant: OO
Solvent: CCO
Product: CCS(=O)c1ccc(-c2nc3cnncc3[nH]2)c(OC)c1
Reaction time: 3 h

Procedure:
10 ml of 30% strength H2O2 are added to a boiling solution of 2.84 g of 2-(4-ethylthio-2-methoxyphenyl)-1,3,5,6-tetraazaindene in 50 ml of ethanol, and the mixture is then boiled for 3 hours. Cooling down and customary working up gives 2-(4-ethylsulfinyl-2-methoxyphenyl)-1,3,5,6-tetraazaindene.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C@@H:18]3[CH:23]4[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]4)[CH2:19]3)=[O:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH:26]([N:29]=[C:30]=[O:31])([CH3:28])[CH3:27]>C1COCC1.CN(C=O)C>[CH:26]([NH:29][C:30](=[O:31])[O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C@@H:18]3[CH:23]4[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]4)[CH2:19]3)=[O:17])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1)([CH3:28])[CH3:27]
Reactant: CC(C)N=C=O
Reactant: O=C(Nc1ccc(-c2ccc(CO)cc2)cc1)[C@H]1CN2CCC1CC2
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)NC(=O)OCc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
35 mg (0.10 mmol) of (3R)-N-[4′-(hydroxymethyl)-1,1′-biphenyl-4-yl]-1-azabicyclo-[2.2.2]octane-3-carboxamide are dissolved in 1 ml of a 1:1 THF/DMF mixture. 17 mg (0.21 mmol) of isopropyl isocyanate are added, and the mixture is stirred at 60° C. overnight. The solvent is removed under reduced pressure, and the crude product is purified by preparative HPLC. 23 mg (52% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([NH:19][C@H:20]([C:27]([NH:29][C@@H:30]([CH2:54][CH:55]1[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]1)[C@@H:31]([OH:53])[CH2:32][C@@H:33]([CH:50]([CH3:52])[CH3:51])[CH2:34][CH2:35][NH:36][C:37]([NH:39]C(=O)OCC1C=CC=CC=1)=[NH:38])=[O:28])[CH2:21][C:22]1[N:26]=[CH:25][NH:24][CH:23]=1)=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[ClH:61].N1C=CC=CC=1>CO.[Pd]>[ClH:61].[CH:55]1([CH2:54][C@H:30]([NH:29][C:27]([C@@H:20]([NH:19][C:17]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:18])[CH2:21][C:22]2[N:26]=[CH:25][NH:24][CH:23]=2)=[O:28])[C@@H:31]([OH:53])[CH2:32][C@@H:33]([CH:50]([CH3:52])[CH3:51])[CH2:34][CH2:35][NH:36][C:37]([NH2:39])=[NH:38])[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]1
Reactant: CC(C)[C@@H](CCNC(=N)NC(=O)OCc1ccccc1)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CC(C)[C@@H](CCNC(=N)N)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 76.4 %

Procedure:
0.110 g (0.132 mmol) of benzyl [N-[(3S,5S,6S)-6-[[N-[N-(t-butoxycarbonyl)-3-phenyl-L-alanyl]-L-histidyl]amino]-7-cyclohexyl-5-hydroxy-3-isopropylheptyl]amidino]carbamate and 0.015 mg (0.132 mmol) of pyridine hydrochloride are dissolved in 2.4 ml of methanol and hydrogenated in the presence of 20 mg of palladium on charcoal (5%) for 3 hours at room temperature and atmospheric pressure. After completion of the hydrogen uptake the catalyst is filtered off and the filtrate is evaporated under reduced pressure. In this manner there is obtained 0.074 g of t-butyl [(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-6-guanidino-2-hydroxy-4-isopropylhexyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]carbamate hydrochloride as an amorphous solid, MS: 697 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:17]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc([N+](=O)[O-])cc1
Yield: 98.8 %

Procedure:
A solution of 4-nitrophenol (10 g, 71.9 mmol), ethyl bromoacetate (13.5 g, 80.8 mmol) and potassium carbonate (12.0 g, 86.8 mmol) in N,N-dimethylformamide (100 mL) was stirred at room temperature for 18 hr. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, washed successively with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with diethyl ether-hexane to give the title compound (16.0 g, yield 99%) as colorless needle crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C@@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=[C:6]([O:9][CH3:10])[CH2:7][N:8]=1.C([Li])CCC.I[CH2:20][C@@H:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:22][CH3:23]>O1CCCC1>[CH:11]([C@@H:4]1[C:3]([O:2][CH3:1])=[N:8][C@@H:7]([CH2:20][C@@H:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH3:23])[C:6]([O:9][CH3:10])=[N:5]1)([CH3:13])[CH3:12]
Reactant: CC[C@@H](CI)c1ccccc1
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC[C@@H](C[C@@H]1N=C(OC)[C@@H](C(C)C)N=C1OC)c1ccccc1
Reaction time: 1 h
Yield: 64.2 %

Procedure:
A solution of (2R)-(−)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (4.25 g, 23.1 mmol) in tetrahydrofuran (30 ml) was cooled to −78° C., then n-butyllithium (1.6 M in hexane, 15.1 ml, 24.2 mmol) was added and the mixture was stirred for 1 hour. A solution of ((R)-1-iodomethyl-propyl)-benzene (6.30 g, 24.2 mmol) in tetrahydrofuran (30 ml) was added dropwise over 30 min and the mixture was stirred overnight while being allowed to warm slowly from −70° C. to room temperature. The reaction was quenched by addition of saturated aqueous ammonium chloride solution and the mixture was extracted with ether. The organic layer was separated, washed with saturated brine, then dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, heptane/EtOAc) to yield a light yellow oil (4.69 g, 64%); MS (ISP): 317.0 ([M+H]+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8]/[CH:9]=[CH:10]/[C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(OCC)=O.C(N(CC)CC)C.[CH:27]1([NH2:30])[CH2:29][CH2:28]1.[Cl-].[Na+]>>[CH:27]1([NH:30][C:11](=[O:13])/[CH:10]=[CH:9]/[CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:29][CH2:28]1
Reactant: NC1CC1
Reactant: O=C(O)/C=C/CCc1ccccc1
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: O=C(/C=C/CCc1ccccc1)NC1CC1
Yield: 85 %

Procedure:
5-Phenyl-2E-pentenoic acid 1 eq, ethyl chloroformate 1.5 eq, triethylamine 1.5 eq, cyclopropylamine 1.5 eq, quench with 10% sodium chloride solution, yield=85%.
Reaction SMILES: [CH2:1]([C:5](O)([CH2:13][CH2:14][CH2:15][CH3:16])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[Br-].[Br:19][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.S([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C>CN(C=O)C>[CH2:1]([C:5]([Br:19])([CH2:13][CH2:14][CH2:15][CH3:16])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(O)(CCCC)c1ccc(F)cc1
Reactant: Br[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S([O-])[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCC(Br)(CCCC)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 126.1 %

Procedure:
To a solution of 8.1 g (25 mmol) of benzyl alcohol obtained from Step 2 in 100 mL of DMF at -40 C. was added 47 g (50 mmol) of bromotriphenyphosphonium bromide (Aldrich). The resulting solution was stirred cold for 30 min, then was allowed to warm to 0° C. To the mixture was added 10% solution of sodium sulfite and ethyl acetate. The extract was washed a few times with water, dried (MgSO4), and concentrated in vacuo. The mixture was stirred in small amount of ethyl acetate/hexane mixture (1:4 ratio) and filtered through a pad of silica gel, eluting with same solvent mixture. The combined filtrate was concentrated in vacuo to give 9.5 g (98%) of the desired product as a colorless oil: 1H NMR (CDCl3) d 0.88 (t, J=7.05 Hz, 6H), 1.0-1.4 (m, 8H), 1.55-1.78 (m, 4H), 3.11 (s, 2H), 4.67 (s, 2H), 7.02 (dt, J=8.46, 3.02 Hz, 1H), 7.15 (dd, J=9.47, 2.82 Hz, 1H), 7.46 (dd, J=8.67, 5.64, 1H), 9.45 (s, 1H).
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[CH:27]([CH3:29])[CH3:28])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[CH:27]([CH3:29])[CH3:28]
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(C(C)(C)O[SiH2]C(C)(C)C)c(C(C)C)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(C#Cc2ccc(CO)c(C(C)C)c2)cc1
Reaction time: 0.25 h
Yield: 84.6 %

Procedure:
To a solution of methyl {4-[4-(tert-butyl-dimethyl-silanyloxymethyl)-3-isopropyl-phenylethynyl]-phenyl}-acetate (Intermediate 154, 288.0 mg, 0.66 mmol) in 5 mL THF at 0° C. was added tetrabutylammonium fluoride (471.0 mg, 1.80 mmols; 1.8 mL of a 1M solution in THF). The pale-yellow solution was stirred for 15 minutes and quenched by the addition of ice cold H2O. The mixture was extracted with Et2O and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (Na2SO4) and concentrated under reduced pressure. Column chromatography (5-10% EtOAc-hexanes) afforded 180.0 mg (85%) of the title compound as a colorless solid.
Reaction SMILES: O1CCC[CH2:2]1.[C:6]([C:9]1[C:17]2[C:16](=[O:18])[NH:15][N:14]=[CH:13][C:12]=2[N:11]([CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:10]=1)(=[O:8])[CH3:7].C[Mg]Br.[Cl-].[NH4+]>C(OCC)C>[CH2:21]([O:20][CH2:19][N:11]1[C:12]2[CH:13]=[N:14][NH:15][C:16](=[O:18])[C:17]=2[C:9]([C:6]([OH:8])([CH3:2])[CH3:7])=[CH:10]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C1CCOC1
Reactant: CC(=O)c1cn(COCc2ccccc2)c2cn[nH]c(=O)c12
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(O)c1cn(COCc2ccccc2)c2cn[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
To 87 ml of tetrahydrofuran solution containing 1.69 g (5.7 mmol) of 3-acetyl-1-benzyloxymethyl-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 21-(c) was added dropwise 7.5 ml of 3M methyl magnesium bromide in diethyl ether solution under ice-cooling, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; toluene:ethyl acetate=7:3 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 1.66 g of the title compound as a white solid. (Yield: 93%)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.[I:11]I.[I+3]=O>C(O)C>[I:11][C:5]1[S:1][C:2]([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)=[CH:3][CH:4]=1
Reactant: II
Reactant: c1csc(-c2cccs2)c1
Agent: O=[I+3]
Solvent: CCO
Product: Ic1ccc(-c2cccs2)s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 157.5 %

Procedure:
To a solution of 2,2'-bithiophene (33.2 g) in ethanol (50 ml) was added iodine (20.3 g) in ethanol (200 ml). Then iodine (V) oxide (6.7 g) in ethanol (30 ml) was added dropwisely. The reaction mixture was further stirred at room temperature for 5 hours. Ethanol was removed and the residue was dissolved in dichloromethane. The solution was washed with sodium bicarbonate aqueous solution (10%, 150 ml×2) then water (200 ml×2). Dried over anhydrous magnesium sulfate and concentrated to give crude products. Distilled under vacuum (105°-110° C./0.1 mm Hg) to give 5-iodo-2,2'-bithiophene (36.8 g, 63%). The residue was then separated by silica gel chromatography eluted with n-hexane to give 5,5'-diiodo-2,2'-bithiophene (5.36 g, 6.4%), melting point 170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:14][C@H:13]([C:15]3[O:19][NH:18][C:17](=[O:20])[CH:16]=3)[CH2:12][CH2:11][N:10]2C(OC)=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Br>>[Cl:8][C:6]1[CH:5]=[C:4]([C@@H:9]2[CH2:14][C@H:13]([C:15]3[O:19][NH:18][C:17](=[O:20])[CH:16]=3)[CH2:12][CH2:11][NH:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@H]1c1cc(Cl)cc(Cl)c1
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@H](c3cc(Cl)cc(Cl)c3)C2)o[nH]1
Reaction time: 8 h
Yield: 60.4 %

Procedure:
(2S,4R)-Methyl 2-(3,5-dichlorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1 g, 2.69 mmol) (from example 55, step 3) was dissolved in hydrogen bromide (33% in AcOH, 4.67 mL, 80.82 mmol) and stirred overnight. Evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2S,4R)-2-(3,5-dichlorophenyl)piperidin-4-yl)isoxazol-3(2H)-one (509 mg, 60%). 1H NMR (600 MHz, dmso) δ 1.32 (q, 1H), 1.44 (dq, 1H), 1.84-1.89 (m, 1H), 1.97-2.02 (m, 1H), 2.70 (dt, 1H), 2.84 (tt, 1H), 3.07-3.12 (m, 1H), 3.67 (dd, 1H), 5.75 (s, 1H), 7.42 (d, 2H), 7.44 (t, 1H). HRMS Calculated for [C14H14Cl2N2O2+H]+: 313.0511. Found: 313.0516