Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:31])[N:15]([CH2:17][C:18]4[C:19]([C:28](Cl)=[O:29])=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=4)[N:16]=[C:10]3[C:9]=2[C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)=[CH:4][CH:3]=1.[OH-].[NH4+:39]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:31])[N:15]([CH2:17][C:18]4[C:19]([C:28]([NH2:39])=[O:29])=[N:20][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:22][CH:23]=4)[N:16]=[C:10]3[C:9]=2[C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=C(Cl)c1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirring solution of 3-((7-(4-chlorophenyl)-3-oxo-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)methyl)-6-(trifluoromethyl)picolinoyl chloride (36 mg, 0.066 mmol) in anhydrous THF (1 mL) at room temperature was added 28% aqueous ammonium hydroxide solution (1 mL). The resulting mixture was stirred at room temperature for 10 min. Analysis by HPLC/MS indicated the starting acid chloride had been consumed and the desired product had formed. The reaction mixture was diluted with water and extracted with EtOAc (15 mL×2). The combined EtOAc extracts were washed with saturated aqueous NaCl, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified using preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 50% to 100% B over 8 min (A=0.1% trifluoroacetic acid, 90% water, 10% methanol and B=0.1% trifluoroacetic acid, 90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3 once, water twice, then saturated aqueous NaCl, dried over Na2SO4 and evaporated. The residue was dissolved in acetonitrile, frozen and lyophilized to afford 20 mg (57%) of the title compound as a pale yellow powder. HPLC/MS: retention time=2.75 min, [M+H]+=525.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:10]([C:11]([CH2:13][CH2:14][CH3:15])=[CH2:12])[O:9][CH:8]=[N:7]1)=[O:5])[CH3:2].C(OC(=O)C(NC=O)C(O)C(CCC)=C)C.S(Br)(Br)=O.[P:36]([O:41]C)([O:39][CH3:40])[O:37][CH3:38]>>[CH2:1]([O:3][C:4](=[O:5])[CH:6]([NH:7][CH:8]=[O:9])/[CH:10]=[C:11](\[CH2:13][CH2:14][CH3:15])/[CH2:12][P:36]([O:39][CH3:40])([O:37][CH3:38])=[O:41])[CH3:2]
Reactant: C=C(CCC)C1OC=NC1C(=O)OCC
Reactant: COP(OC)OC
Agent: C=C(CCC)C(O)C(NC=O)C(=O)OCC
Agent: O=S(Br)Br
Product: CCC/C(=C\C(NC=O)C(=O)OCC)CP(=O)(OC)OC

Procedure:
The starting material is manufactured as follows: Reaction of 2-methylene-pentanal with isocyanoacetic acid ethyl ester analogously to Example 1 yields 5-(penten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester. By hydrolysis of the 5-(penten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester in a manner analogous to that described in Example 15, 2-formylamino-3-hydroxy-4-propyl-4-pentenoic acid ethyl ester is obtained.Reaction of the 2-formylamino-3-hydroxy-4-propyl-4-pentenoic acid ethyl ester with thionyl bromide and subsequent treatment with trimethyl phosphite in a manner analogous to that described in Example 1 yields E-2-formylamino-4-propyl-5-dimethylphosphono-3-pentenoic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([O:24][CH2:25][C:26]4([OH:34])[CH2:31][CH2:30][S:29](=[O:33])(=[O:32])[CH2:28][CH2:27]4)=[CH:19][C:18]=3[CH3:35])[C:13]([CH3:16])=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[CH2:36][CH2:37][C:38]([OH:40])=[O:39].[OH-].[Na+].[Cl-].[Ca+2:44].[Cl-]>CO>[Ca+2:44].[F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([O:24][CH2:25][C:26]4([OH:34])[CH2:27][CH2:28][S:29](=[O:33])(=[O:32])[CH2:30][CH2:31]4)=[CH:19][C:18]=3[CH3:35])[C:13]([CH3:16])=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[CH2:36][CH2:37][C:38]([O-:40])=[O:39].[F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([O:24][CH2:25][C:26]4([OH:34])[CH2:27][CH2:28][S:29](=[O:33])(=[O:32])[CH2:30][CH2:31]4)=[CH:19][C:18]=3[CH3:35])[C:13]([CH3:16])=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[CH2:36][CH2:37][C:38]([O-:40])=[O:39]
Reactant: Cc1ccc(CNc2ccc(CCC(=O)O)c(F)c2)cc1-c1c(C)cc(OCC2(O)CCS(=O)(=O)CC2)cc1C
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(CNc2ccc(CCC(=O)[O-])c(F)c2)cc1-c1c(C)cc(OCC2(O)CCS(=O)(=O)CC2)cc1C
Yield: 54.7 %

Procedure:
To a solution of 3-{2-fluoro-4-[({4′-[(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy]-2′,6,6′-trimethylbiphenyl-3-yl}methyl)amino]phenyl}propanoic acid (57.0 mg, 0.10 mmol) in methanol (1 mL) was added 1 M aqueous sodium hydroxide solution (0.10 mL). Successively, an aqueous solution of calcium chloride (6.2 mg, 0.05 mmol) was gradually added. The precipitated solid was collected by filtration, washed with water and vacuum dried to give the title compound (32.2 mg, yield 55%) as a colorless amorphous powder.
Reaction SMILES: C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([CH2:27][CH2:28][CH2:29][NH:30][C:31]([CH:33]3[CH2:35][CH2:34]3)=[O:32])[C:21]=2[CH2:20][CH2:19]1>C(O)(=O)C>[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([CH2:27][CH2:28][CH2:29][NH:30][C:31]([CH:33]3[CH2:34][CH2:35]3)=[O:32])[C:21]=2[CH:20]=[CH:19]1
Reactant: O=C(NCCCc1cccc2c1CCO2)C1CC1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CC(=O)O
Product: O=C(NCCCc1cccc2occc12)C1CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 15.1 %

Procedure:
Lead tetraacetate (194 mg) was added to a solution of cyclopropanecarboxylic acid [3-(2,3-dihydro-benzofuran-4-yl)-propyl]-amide (100 mg) in acetic acid (1.5 ml) at 10°. The mixture was stirred at room temperature for 4 h and at 50° for 24 h. The solvent was evaporated and the residue purified by chromatography on silica. Elution with hexane/ethyl acetate gave the title compound as an oil (15 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1.[CH3:10][O-:11].[Na+].[Na]>CO>[NH2:1][C:2]1[C:7]([O:11][CH3:10])=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: Cc1cnc(N)c(Br)n1
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1nc(C)cnc1N
Temperature: 25 °C
Yield: 75 %

Procedure:
2-Amino-3-bromo-5-methylpyrazine (0.374 g) was added to a freshly prepared solution of sodium methoxide in methanol (made by addition of sodium (0.115 g) to methanol (6 ml). The reaction mixture was heated under reflux for 18 hours, cooled to ambient temperature and the solvent removed by evaporation. Water (5 ml) was added to the residue and extracted with dichloromethane (3×20 ml). The combined organic extracts were dried (MgSO4) and the solvent removed by evaporation. The residue was purified by chromatography on silica gel, eluting with dichloromethane to give 2-amino-3-methoxy-5-methylpyrazine as a white crystalline solid (0.208 g, 75%), m.p. 67°-69° C.; mass spectrum (+ve CI): 140 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:38])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([O:36]C)=[O:35])=[CH:23][CH:22]=2)[C:7]([CH2:11][NH:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].CO>O>[CH2:1]([C:5]1[N:6]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:38])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([OH:36])=[O:35])=[CH:23][CH:22]=2)[C:7]([CH2:11][NH:12][S:13]([C:16]([F:17])([F:18])[F:19])(=[O:14])=[O:15])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CNS(=O)(=O)C(F)(F)F)n1Cc1ccc(C(=O)c2ccccc2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCc1nc(Cl)c(CNS(=O)(=O)C(F)(F)F)n1Cc1ccc(C(=O)c2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2-Butyl-1-[4-(2-carbomethoxybenzoyl)benzyl]-4-chloro-5-[(trifluoromethylsulfonamido)methyl]imidazole (150 mg, 0.26 mmol, 1 eq), 1.000N NaOH (0.55 mL, 0.55 mmol, 2.1 eq), methanol (20 mL), and water (0.5 mL) were mixed and stirred for 5 hours at room temperature under N2. The solvent was removed in vacuo. Water (50 mL) was added and the pH was adjusted to 4 with 1N HCl. Tan solids precipitated. These were collected and dried to yield 89 mg. NMR (200 MHz, DMSO-d6) δ7.98 (d, 1H, J=7 Hz); 7.70 (t, 1H, J=7 Hz); 7.68 (t, 1H, J=7 Hz); 7.63 (d, 2H, J=10 Hz); 7.37 (d, 1H, J=7 Hz); 7.10 (d, 2H, J=10 Hz); 5.34 (s, 2H); 4.20 (s, 2H); 2.50 (t, 2H, J=7 Hz); 1.49 (t, of t, 2H, J=7,7 Hz); 1.27 (t of q, 2H, J=7,7 Hz); 0.80 (t, 3H, J=7 Hz). Mass calcd. for C24H23ClF3N3O5S: 557.0999. Found: 557.0988
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH:22]([CH3:24])[CH3:23])[C:4]([N:6]1[CH2:11][CH2:10][C@@:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)([OH:12])[C:8]([CH3:21])([CH3:20])[CH2:7]1)=[O:5].ClC1N=[C:30]([O:32]C)N=C(OC)N=1.C(O)=O.CN1CCOCC1>CN(C1C=CN=CC=1)C>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C@@:9]2([OH:12])[CH2:10][CH2:11][N:6]([C:4](=[O:5])[C@H:3]([NH:2][CH:30]=[O:32])[CH:22]([CH3:24])[CH3:23])[CH2:7][C:8]2([CH3:20])[CH3:21])=[CH:18][CH:17]=1
Reactant: COc1nc(Cl)nc(OC)n1
Reactant: CC(C)[C@@H](N)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O=CO
Solvent: CN1CCOCC1
Product: CC(C)[C@@H](NC=O)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.9 %

Procedure:
To a solution of (R)-2-amino-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methylbutan-1-one hydrochloride (111 mg, 0.296 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (57.1 mg, 0.325 mmol), formic acid (0.012 mL, 0.325 mmol) and NMM (0.068 mL, 0.62 mmol) CH2Cl2 (10 mL), was added DMAP (3.61 mg, 0.03 mmol). The mixture was stirred at rt for 3 h. The reaction was filtered and the filtrate was washed with Na2CO3, 0.5N HCl, and brine. The organic layer was dried over Na2SO4 and Concentrated to give N—((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)formamide (76 mg, 0.207 mmol, 70.0% yield).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:30])[CH:17]=[C:18](F)[CH:19]=3)[O:14]2)(=O)=O)=CC=1.[N-:31]=[N+:32]=[N-:33].[Na+]>CS(C)=O>[N:31]([CH2:12][CH:13]1[CH:22]=[CH:21][C:20]2[C:15](=[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH:17]=[CH:18][CH:19]=2)[O:14]1)=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2C=Cc3cc(F)cc(-c4ccccc4Cl)c3O2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NCC1C=Cc2cccc(-c3ccccc3Cl)c2O1
Reaction time: 0.08 h
Yield: 87.8 %

Procedure:
A solution of [8-(2-chlorophenyl)-6-fluoro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate prepared in Example 61, step 1 (204 mg, 0.459 mmol) and sodium azide (119 mg, 1.834 mmol) in anhydrous dimethyl sulfoxide (8 mL) was heated at 70° C. under nitrogen for 19 hours. The cooled reaction mixture was quenched by the addition of water (30 mL) and the resulting suspension stirred vigorously for 5 minutes. The mixture was then partitioned between ethyl acetate (100 mL) and water (100 mL), the organic phase separated, washed with water (100 mL) and saturated brine (100 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford 120 mg (67%) of 2-azidomethyl-8-(2-chloro-phenyl)-2H-chromene as a yellow syrup that was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([C:18]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:19])[CH:15]=[CH:14][C:13]=1[OH:26])([O-])=O.C1(C)C=CC=CC=1.CNC.[H][H]>[C].[Pd].O.CC(O)C>[OH:26][C:13]1[CH:14]=[CH:15][C:16]([C:18]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:19])=[CH:17][C:12]=1[N:11]1[N:10]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[N:1]1
Reactant: [H][H]
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Agent: [Pd]
Agent: CNC
Solvent: CC(C)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)CC(C)(C)c1ccc(O)c(-n2nc3ccccc3n2)c1
Yield: 82.9 %

Procedure:
35.5 g (0.1 mol) of 2-nitro-2'-hydroxy-5'-t-octylazobenzene, 0.125 g of 5% palladium carbon, 100 ml of toluene, 100 ml of IPA, 50 ml of water and 7 g of 50% dimethylamine were charged into a 500-ml stainless autoclave with an agitator. Reaction was effected in the same way as that employed in Example 1 and stopped when no more hydrogen was absorbed by the reaction solution. After the reaction had been completed, after treatment was performed in the same way as in Example 1 to obtain 26.8 g of 2-(2'-hydroxy-5'-t-octylphenyl)benzotriazole (yield, 82.9%; melting point, 103° to 105° C.).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH:11]=[CH:10]1>N(C(C)(C)C#N)=NC(C)(C)C#N.C1(C)C=CC=CC=1>[CH:1]([C:10]1=[CH:11][C:12]([O:14][C:9]1=[O:15])=[O:13])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1C=CC(=O)O1
Reactant: C=Cc1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Cc1ccccc1
Product: O=C1C=C(C=Cc2ccccc2)C(=O)O1
Temperature: 90 °C
Yield: 98.4 %

Procedure:
A flask similar to that used in Example A was charged with 156.0 g of styrene, 147.0 g of maleic anhydride, 2.0 g of azobisisobutyronitrile and 2,400 ml of toluene. The mixture was heated at 90° C. for 1 hour while agitated under a nitrogen atmosphere so as to carry out the required reaction. After the reaction, the reaction mixture was condensed and petroleum ether about 10 times as much as the condensed mixture by volume was added to the condensed reaction mixture so as to precipitate the resultant cooligomer. The cooligomer thus obtained was washed with 500 g of petroleum ether three times and, then, dried, thereby obtaining 295 g of styrene-maleic anhydride cooligomer having a number average molecular weight of 8,500.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:8])=[N:4][NH:5][C:6]=1[CH3:7].C([O-])([O-])=O.[K+].[K+].Cl[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([O:32][CH3:33])[CH:26]=2)[CH2:21][CH2:20]1)=[O:18].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[NH2:8][C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[N:5]([CH2:16][C:17]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([O:32][CH3:33])[CH:26]=3)[CH2:23][CH2:24]2)=[O:18])[N:4]=1
Reactant: Cc1[nH]nc(N)c1Cl
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COc1cc(N2CCN(C(=O)Cn3nc(N)c(Cl)c3C)CC2)ccc1Cl

Procedure:
Protocol T was followed using 4-Chloro-5-methyl-1H-pyrazol-3-ylamine, K2CO3, 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/4) afforded the title compound as colorless oil. 1H NMR (400 MHz, CDCl3): 7.18-7.22 (d, 1H), 6.44-6.48 (d, 1H), 6.36-6.42 (dd, 1H), 5.0 (s, 2H), 4.24 (s, 2H), 2.4 (s, 3H), 3.76-3.86 (m, 4H), 3.12-3.18 (m, 4H). 13C NMR (400 MHz, CDCl3): 164.6, 154.8, 144.6, 130.2, 130, 128.8, 109.2, 102, 56, 51, 49.6, 45.6, 42.
Reaction SMILES: C[Al](C)C.[C:5]1([SH:11])[CH:10]=[CH:9][CH:8]=CC=1.[OH:12][CH:13]([CH3:18])[CH2:14][C:15]([O-:17])=[O:16].Cl>ClCCl>[S:11]1[CH:8]=[CH:9][CH:10]=[C:5]1[O:17][C:15](=[O:16])[CH2:14][CH:13]([OH:12])[CH3:18]
Reactant: CC(O)CC(=O)[O-]
Reactant: Sc1ccccc1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: CC(O)CC(=O)Oc1cccs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a dry flask on ice, 6 ml of dehydrated dichloromethane was stirred and 2 ml of 2M trimethyl aluminum was slowly added thereto under a nitrogen stream. After that, 2 mmol of thiophenol was slowly added thereto. The mixture was stirred at room temperature for 30 minutes and then 3-hydroxybutyrate dissolved in 6 ml of dehydrated dichloromethane was added thereto. The reaction was monitored by a TLC. To this mixed solution was added 20 ml of dichloromethane and, until generation of bubbles stopped, 20 ml of 3% hydrochloric acid solution was added. The mixed solution was transferred to a separating funnel, washed with 3% hydrochloric acid solution for two times and with saturated saline for two times, dried over magnesium sulfate and evaporated in vacuo to give 532 mg of crude oily 3-hydroxybutyrate thiophenyl ester in dark yellow color. This was purified by a column chromatography (20 cm×1 cm diameter; eluent was hexane:ethyl acetate=2:1) using silica gel 60 to give 125 mg of pure 3-hydroxybutyrate thiophenyl ester as a transparent oil. The yield to the unpurified substance was 24%. Result of NMR analysis of this compound is as follows.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([NH:13][CH3:14])[CH2:10][CH:9]1[C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[C:25]#[N:26])[CH2:19][CH2:18]1)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH:35]=O>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:35][C:34]2[CH:37]=[CH:38][CH:39]=[C:32]([F:31])[CH:33]=2)[CH3:14])[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[C:25]#[N:26])[CH2:19][CH2:18]1)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(F)c1
Reactant: CNC1CC(C(=O)N2CCN(c3ccccc3C#N)CC2)N(Cc2ccccc2)C1
Product: CN(Cc1cccc(F)c1)[C@H]1C[C@@H](C(=O)N2CCN(c3ccccc3C#N)CC2)N(Cc2ccccc2)C1

Procedure:
As described for Example 75d, 2-[4-(1-benzyl-4-methylamino-pyrrolidine-2-carbonyl)-piperazin-1-yl]-benzonitrile was converted, using 3-fluorobenzaldehyde instead of 3,4-dichlorobenzaldehyde, to the title compound. MS m/e=512.5 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][CH:8]2[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:20][CH2:21][C:22]([CH3:28])([CH3:27])[C:23]([O:25][CH3:26])=[O:24].B(F)(F)F.CCOCC>C(OCC)C>[OH:13][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[O:20][CH2:21][C:22]([CH3:28])([CH3:27])[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)C(C)(C)CO
Reactant: COC(=O)C1OC1(c1ccccc1)c1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Product: COC(=O)C(O)C(OCC(C)(C)C(=O)OC)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
12.7 g (50 mmol) of methyl 3,3-diphenyl-2,3-epoxypropionate were dissolved in 50 ml of diethyl ether, 6.6 g (50 mmol) of methyl 3-hydroxy-2,2-dimethylpropionate and 1 ml of BF3.Et2O were added, and the mixture was stirred at room temperature for 18 h. The solvent was evaporated off, and the oily residue was reacted without further purification and characterization.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[OH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1>>[Cl:1][C:2]1[N:3]=[N:4][C:5]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:6][CH:7]=1
Reactant: OCc1ccccn1
Reactant: Clc1ccc(Cl)nn1
Product: Clc1ccc(OCc2ccccn2)nn1

Procedure:
3,6-Dichloropyridazine (1.0 g, 6.712 mmol) was reacted analogously to example 4a with 2-hydroxymethylpyridine (732 mg, 6.712 mmol). Yield: 1.26 g (85%), M+H+: 222.1.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].C[O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.[F-].[Cs+]>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].ClCCl.COCCOC>[C:5]([C:4]1[CH:3]=[C:2]([C:15]2[CH:16]=[CH:17][C:12]([OH:11])=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)#[N:6]
Reactant: COc1ccc(B(O)O)cc1
Reactant: N#Cc1cccc(I)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: COCCOC
Solvent: ClCCl
Product: N#Cc1cccc(-c2ccc(O)cc2)c1
Temperature: 25 °C
Yield: 619.2 %

Procedure:
A 250 mL flask was charged with 2.21 g (2.7 mmol) (1,1′-bis(diphenylphosphino) ferrocene) dichloropalladium (II)•dichloromethane, 6.26 g (2.73 mmol) 3-iodobenzonitrile, 6.0 g (3.95 mmol) 4-methoxyphenylboronic acid, and 12.45 g (8.20 mmol) cesium fluoride, followed by the addition of 180 mL 1,2-dimethoxyethane. The flask was flushed with N2 and the suspension heated to reflux which was maintained for 3 hours. The reaction mixture was cooled to room temperature, filtered through a pad of 300 g flash silica gel, and the pad was washed with 1 L ethyl acetate. The ethyl acetate was concentrated and the residue purified by flash chromatography on silica gel eluting with 10% hexanes/90% ethyl acetate to give 3.3 g of the desired product (58% yield). This material was dissolved in 50 mL anhydrous dichloromethane and the solution cooled in a dry ice-acetone bath and a solution of boron tribromide (40 mL, 4 mmol) was added dropwise under inert atmosphere. The reaction was then stirred at room temperature overnight. The solution was cooled in an ice bath and 5 mL of H2O was added dropwise, followed by the addition of 20 mL 1N HCl. The mixture was stirred for 1 hour and the resulting suspension was filtered and the filtrate transferred to a separatory funnel and the organic layer separated off and set aside. The filtered solid was washed with H2O and ethyl acetate and filtered and the filtrate transferred to the separatory funnel and the organic layer combined with the previous organic layer, dried over Na2SO4, filtered and the filtrate concentrated to provide 3.05 g of the desired product (99% yield).
Reaction SMILES: COP([CH2:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])(=O)OC.[H-].[Na+].[CH:20]([C:22]1[CH:23]=[C:24]([CH:32]=[CH:33][CH:34]=1)[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=O.O>O1CCCC1.C(OCC)(=O)C>[CH2:11]([O:10][C:8](=[O:9])/[CH:7]=[CH:20]/[C:22]1[CH:23]=[C:24]([CH:32]=[CH:33][CH:34]=1)[C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COP(=O)(CC(=O)OCc1ccccc1)OC
Reactant: CC(C)(C)OC(=O)c1cccc(C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cccc(/C=C/C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.9 %

Procedure:
To a solution of dimethyl(benzyloxycarbonyl)methylphosphonate (2.20 g) in tetrahydrofuran (32.0 mL) was added 55% sodium hydride (406 mg) under ice-cooling, followed by stirring at room temperature for 30 minutes. Subsequently, tert-butyl 3-formylbenzoate (1.60 g) was added thereto, followed by stirring at room temperature for 16 hours. To the reaction mixture were added water and ethyl acetate, and the organic layer was extracted. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 3-[(1E)-3-(benzyloxy)-3-oxopropa-1-en-1-yl]benzoate (1.60 g).
Reaction SMILES: [OH:1][N:2]1[C:11](=[O:12])[CH:10]2[CH:5]([CH:6]3[CH2:13][CH:9]2[CH:8]=[CH:7]3)[C:3]1=[O:4].N1C=CC=CC=1.[Cl:20][CH2:21][CH2:22][S:23](Cl)(=[O:25])=[O:24].Cl>C(Cl)Cl.C(OCC)(=O)C>[Cl:20][CH2:21][CH2:22][S:23]([O:1][N:2]1[C:11](=[O:12])[CH:10]2[CH:5]([CH:6]3[CH2:13][CH:9]2[CH:8]=[CH:7]3)[C:3]1=[O:4])(=[O:25])=[O:24]
Reactant: O=S(=O)(Cl)CCCl
Reactant: O=C1C2C3C=CC(C3)C2C(=O)N1O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1C2C3C=CC(C3)C2C(=O)N1OS(=O)(=O)CCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
A solution of 12.5 g (70.0 mmol) of N-hydroxy-5-norbornene-2,3-dicarboximide and pyridine (6.2 ml, 77.0 mmol) in CH2Cl2 (105 ml) is treated dropwise with 2-chloroethanesulfonyl chloride (7.36 ml, 70.0 mmol) at 0° C., according to the procedure of W. C. Groutas, M. A. Stanga, J. C. Castrisos, E. J. Schatz, M. J. Brubaker J. Pharm. Sci. 1990, 79, 886-88. After stirring overnight at room temperature, the reaction mixture is diluted with ethyl acetate (280 ml) and then treated with 5% aqueous HCl (130 ml). The layers are separated and the aqueous layer is extracted once with ethyl acetate (280 ml). The combined organic extracts are dried over Na2SO4 and evaporated under reduced pressure, leaving a colorless oil which solidifies when further dried under vacuum. 15.6 g (73%) of the product are obtained as a white solid.