Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC1C=C(O)C=CC=1C(C1C=CC(O)=CC=1O)=O.OC1C=C(OC)C=CC=1C(C1C=CC=CC=1)=O.[OH:36][C:37]1[CH:53]=[C:52](OC)[CH:51]=[CH:50][C:38]=1[C:39]([C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][C:42]=1[OH:49])=[O:40].COC1C=C(O)C(C(C2C(O)=CC(OC)=C(S([O-])(=O)=O)C=2)=O)=CC=1S([O-])(=O)=O.[Na+].[Na+].OC1C(C(=O)C2C=CC=CC=2)=CC(S(O)(=O)=O)=C(OC)C=1.NC1C=CC=CC=1C(C1C=CC=CC=1)=O>>[OH:49][C:42]1[CH:43]=[C:44]([O:47][CH3:48])[CH:45]=[CH:46][C:41]=1[C:39]([C:38]1[CH:50]=[CH:51][CH:52]=[CH:53][C:37]=1[OH:36])=[O:40]
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2O)c(O)c1
Agent: COc1cc(O)c(C(=O)c2cc(S(=O)(=O)[O-])c(OC)cc2O)cc1S(=O)(=O)[O-]
Agent: COc1cc(O)c(C(=O)c2ccccc2)cc1S(=O)(=O)O
Agent: COc1ccc(C(=O)c2ccccc2)c(O)c1
Product: COc1ccc(C(=O)c2ccccc2O)c(O)c1

Procedure:
2,2′,4,4′-tetrahydroxybenzophenone (benzophenone-2, Uvinul® D-50); 2-hydroxy-4-methoxybenzophenone (oxybenzone, benzophenone-3); 2,2′-dihydroxy-4,4′-dimethoxybenzophenone (benzophenone-6); 2,2′-dihydroxy-4,4′-dimethoxybenzophenone-5,5′-disulphonic acid sodium salt (benzophenone-9); 4-hydroxy-2-methoxy-5-(oxo-phenylmethyl)benzenesulfonic acid (sulisobenzone, benzophenone-4); 2-hydroxy-4-methoxybenzophenone-5-sulphonic acid sodium salt (benzophenone-5), 2-aminobenzophenone;
Reaction SMILES: [CH3:1][Si:2]([CH3:38])([CH3:37])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:21][CH:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:19][CH2:18]2)[CH:9]=1.[I:39]N1C(=O)CCC1=O>C(#N)C>[CH3:34][Si:33]([CH3:36])([CH3:35])[CH2:32][CH2:31][O:30][CH2:29][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:37])[CH3:38])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:39])=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:21][CH:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:19][CH2:18]2)[CH:9]=1
Reactant: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.1 %

Procedure:
A 50 mL roundbottom flask was charged ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)-methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate (381 mg, 0.68 mmol) and acetonitrile (10 mL). To this solution was added N-Iodosuccinimide (167 mg, 0.74 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the crude oil was purified via silica gel chromatography (0% to 30% ethyl acetate in hexanes gradient) to yield ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate (335 mg, 0.49 mmol, 72% yield) as clear oil.
Reaction SMILES: [CH2:1]([CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:2]=[CH2:3].P(Cl)(Cl)(Cl)=O.[Cl:20][C:21]([Cl:26])(Cl)[C:22](Cl)=[O:23]>CCOCC.[Cu].[Zn]>[Cl:20][C:21]1([Cl:26])[C:22](=[O:23])[CH2:3][CH:2]1[CH2:1][CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C=CCC(C(=O)OCC)C(=O)OCC
Agent: [Cu]
Agent: [Zn]
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)C(CC1CC(=O)C1(Cl)Cl)C(=O)OCC
Temperature: 25 °C

Procedure:
To a stirred suspension of Cu.Zn (1.771 g, 13.73 mmol) and diethyl 2-allylmalonate (1.084 mL, 5.49 mmol) in anhydrous Et2O (20 mL) at reflux was added a solution of phosphorus oxychloride (1.127 mL, 12.09 mmol) and 2,2,2-trichloroacetyl chloride (1.357 mL, 12.09 mmol) in Et2O (10 mL) dropwise through an addition funnel over 2 h. The resulting mixture was then heated at reflux overnight. After cooling to room temperature, the mixture was filtered through CELITE® and washed with EtOAc. The filtrate was concentrated and the residue was purified by silica gel column chromatography (80 g, EtOAc/hexane=0-50%) to afford Preparation 7A (1.59 g, 93%).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH3:27][O:28][CH2:29][C:30](O)=[O:31]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:30](=[O:31])[CH2:29][O:28][CH3:27])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: COCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, white solid (59 mg, 59%), MS (ISP) m/z=399.3 [(M+H)+], mp 115° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 2-methoxy-acetic acid.
Reaction SMILES: [CH2:1]([N:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]#[N:31])=[CH:20][CH:19]=1)[C:6](=[O:16])[C@@H:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])[CH2:2][CH2:3][CH3:4].C([Sn]([N:45]=[N+:46]=[N-:47])(CCCC)CCCC)CCC>>[CH2:1]([N:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]2[NH:47][N:46]=[N:45][N:31]=2)=[CH:20][CH:19]=1)[C:6](=[O:16])[C@@H:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]([CH3:9])[CH3:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CCCCN(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)[C@@H](NS(C)(=O)=O)C(C)C
Product: CCCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)[C@@H](NS(C)(=O)=O)C(C)C

Procedure:
Analogously to Example 20 and using 2.2 g (5 mmol) of 2-(S)-methanesulfonylamino-3-methylbutanoic acid N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)amide and 2.5 g (7.5 mmol) of tributyltin azide, the title compound is obtained in the form of a light-coloured foam that has an Rf value of 0.45 [toluene/isopropanol/glacial acetic acid (170:30:2)].
Reaction SMILES: C(Cl)CCl.[C:5]([C:8]1[CH:9]=[CH:10][C:11]2[NH:17][C@@H:16]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=2[CH:25]=1)([OH:7])=O.Cl.Cl.[NH2:28][CH2:29][C:30]1[NH:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1.C1C=CC2N(O)N=NC=2C=1.O.C(N(C(C)C)CC)(C)C>CN(C=O)C>[N:31]1[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[NH:34][C:30]=1[CH2:29][NH:28][C:5]([C:8]1[CH:9]=[CH:10][C:11]2[NH:17][C@@H:16]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=2[CH:25]=1)=[O:7]
Reactant: COC(=O)C[C@@H]1Nc2ccc(C(=O)O)cc2CN(C)C1=O
Reactant: NCc1nc2ccccc2[nH]1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C[C@@H]1Nc2ccc(C(=O)NCc3nc4ccccc4[nH]3)cc2CN(C)C1=O
Reaction time: 21 h
Yield: 52 %

Procedure:
EDC (1.15 g, 6.02 mmol) was added to a solution of methyl (2S)-7-carboxy-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (2.11 g, 5.02 mmol), 2-aminomethylbenzimidazole dihydrochloride (1.15 g, 6.02 mmol), HOBT.H2O (811 mg, 6.02 mmol), and diisopropylethylamine (1.76 mL, 10 mmol) in anhydrous DMF (25 mL) at RT. After 21 h, the reaction was concentrated on the rotavap (high vacuum), and the residue was taken up in CH2Cl2 (240 mL) and washed with H2O. The organic layer was dried (Na2SO4), dissolved in xylenes, and reconcentrated to remove residual DMF. The crude product was chromatographed on silica gel (MeOH/CHCl3) to give the title compound (1.1 g, 52%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][C:3]=1[O:10][CH3:11].CCN(C(C)C)C(C)C.[CH2:21]([O:23][CH:24]([O:29][CH2:30][CH3:31])[C:25](=[NH:28])OC)[CH3:22]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:25](=[NH:28])[CH:24]([O:29][CH2:30][CH3:31])[O:23][CH2:21][CH3:22])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(CN)ccc1Cl
Reactant: CCOC(OCC)C(=N)OC
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(OCC)C(=N)NCc1ccc(Cl)c(OC)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a mixture of (4-chloro-3-methoxyphenyl)methanamine (392 mg, 2.284 mmol) (as the hydrochloride salt), Hunig's Base (0.5 mL, 2.86 mmol), and MeOH (2 mL) was added a solution of methyl 2,2-diethoxyacetimidate (295 mg, 1.83 mmol) in MeOH (1 mL) and the resulting mixture was heated with stirring in an oil bath at 70° C. for 2 hrs and allowed to cool to room temperature over 3 days. The solvent was removed in vacuo and the residue was used without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH3:40])[CH:3]([NH:20][C:21]1[CH:39]=[CH:38][C:24]([C:25]([N:27]2[CH2:32][CH2:31][CH2:30][C@@H:29]([C:33]([O:35]CC)=[O:34])[CH2:28]2)=[O:26])=[CH:23][CH:22]=1)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][CH2:15][CH2:16]3)=[N:11]2)=[CH:6][C:5]=1[CH3:19].C1COCC1.[OH-].[Na+]>C(O)C>[CH3:1][CH:2]([CH3:40])[CH:3]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([N:27]2[CH2:32][CH2:31][CH2:30][C@@H:29]([C:33]([OH:35])=[O:34])[CH2:28]2)=[O:26])=[CH:38][CH:39]=1)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][CH2:15][CH2:16]3)=[N:11]2)=[CH:6][C:5]=1[CH3:19]
Reactant: CCOC(=O)[C@@H]1CCCN(C(=O)c2ccc(NC(c3ccc(-n4cc5c(n4)CCCC5)cc3C)C(C)C)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(-n2cc3c(n2)CCCC3)ccc1C(Nc1ccc(C(=O)N2CCC[C@@H](C(=O)O)C2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a mixture of ethyl (3R)-1-(4-((2-methyl-1-(2-methyl-4-(4,5,6,7-tetrahydro-2H-indazol-2-yl)phenyl)propyl)amino)benzoyl)piperidine-3-carboxylate (152.3 mg), THF (0.56 mL) and ethanol (0.56 mL) was added 1M aqueous sodium hydroxide solution (0.561 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, the reaction mixture was neutralized with 1M hydrochloric acid (0.561 mL), and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (140.4 mg).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19][C:7]1=2)C.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1.ClCCl>[OH:3][CH2:4][CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19][C:7]1=2
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)CC2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCO)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A chilled (0° C.) mixture of tert-butyl 6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate in tetrahydrofuran (30 mL) was treated over 1 h with 1 M diisobutylaluminum hydride (19.0 mL, 19.0 mmol) in dichloromethane. After 1.5 h, ice was added and the mixture was allowed to warm to rt. The mixture was evaporated in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was filtered through celite, dried, and evaporated in vacuo to provide 2.479 g of the title compound, the structure of which is shown in FIG. 6 as (24) (where n=1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=NNS(C4C=CC(C)=CC=4)(=O)=O)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl.[C:39](#[N:42])[CH:40]=[CH2:41]>O1CCOCC1.[Cl-].[Na+].O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH2:41][CH:40]4[C:39]#[N:42])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)NN=C(c2ccccc2)c2ccc3c(cnn3-c3ccc(F)cc3)c2)cc1
Reactant: C=CC#N
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#CC1CC1(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 1 h
Yield: 20.6 %

Procedure:
(c)(d) N′-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methylene)-4-methylbenzenesulfonohydrazide (1.82 g, 3.77 mmol) was dissolved in 20 mL of dioxane and 20 mL of a 50% aqueous NaOH solution and heated at 85 C. After 1 h, the reaction mixture was adjusted to pH 4-5 with conc HCl and extracted 2× EtOAc. The organic layers were dried over MgSO4, filtered, concentrated, and the crude product was taken to the next step. Crude residue was dissolved in 20 mL of benzene and acrylonitrile (4 mmol) was added. The reaction mixture was heated to reflux. After 2 h, the reaction was poured into brine and extracted 2× EtOAc. The organic layers were dried over MgSO4, filtered, concentrated, and then purified by HPLC to give 275 mg (21% yield) of 2-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-phenylcyclopropanecarbonitrile. MS found: (M+H)+=354.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=1.[I:15]N1C(=O)CCC1=O.O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[C:9]=1[I:15]
Reactant: O=C1CCC(=O)N1I
Reactant: O=Cc1c[nH]c(-c2ccccc2F)c1
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1c[nH]c(-c2ccccc2F)c1I
Reaction time: 12 h
Yield: 13.5 %

Procedure:
5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde (2.0 g) was dissolved in N,N-dimethylformamide (60 mL), N-iodosuccinimide (2.38 g) was added and the mixture was stirred at for 12 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed successively with a saturated aqueous sodium hydrogencarbonate solution, a 3% aqueous potassium hydrogensulfate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3→1:1) to give the title compound as a pale-brown powder (yield 450 mg, 14%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][CH:9]([NH:18][CH:19]([C:28]([O:30]CC2C=CC=CC=2)=[O:29])[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:8]1=[O:38])=[O:5])[CH3:2].CCOCC>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][CH:9]([NH:18][CH:19]([C:28]([OH:30])=[O:29])[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:8]1=[O:38])=[O:5])[CH3:2]
Reactant: CCOC(=O)CN1C(=O)C(NC(CCc2ccccc2)C(=O)OCc2ccccc2)CCc2ccccc21
Agent: [Pd]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)CN1C(=O)C(NC(CCc2ccccc2)C(=O)O)CCc2ccccc21

Procedure:
1-Ethoxycarbonylmethyl-3-(1-benzyloxycarbonyl-3-phenylpropylamino-2,3,4,5-tetrahydro-1H-[1]-benzazepine-2-one (isomer B of Example 20, 1.1 g) in ethanol (150 ml) was hydrogenated at room temperature and atmospheric pressure using palladium on charcoal (0.5 g) as catalyst. After uptake of hydrogen had terminated, the catalyst was filtered off, and the solvent removed under reduced pressure to give a semi-solid. Trituration with ether (30 ml) yielded isomer B of the title compound, m.p. 175°-177° C.
Reaction SMILES: C(OC([O:6][C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23](=[O:27])[C:24]([CH3:26])=[CH2:25])=[O:16])=[CH:9][CH:8]=1)=O)C.CC(C)=O.N>N1C=CC=CC=1>[OH:6][C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23](=[O:27])[C:24]([CH3:26])=[CH2:25])=[O:16])=[CH:9][CH:8]=1
Reactant: C=C(C)C(=O)OCCCCOC(=O)/C=C/c1ccc(OC(=O)OCC)cc1
Agent: N
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: C=C(C)C(=O)OCCCCOC(=O)/C=C/c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
5 g of 4-methacryloyloxybutyl (E)-3-(4-ethoxycarbonyloxyphenyl)acrylate were dissolved in 40 ml of pyridine and treated at room temperature with a mixture of 60 ml of acetone and 7 ml of 25% aqueous ammonia solution. The reaction mixture was stirred at room temperature for 12 hours. After distillation of the acetone the mixture was neutralized with 2N hydrochloric acid, diluted with 100 ml of water and subsequently extracted 3 times with 100 ml of diethyl ether each time. The combined organic phases were dried over sodium sulphate, filtered and concentrated. Chromatographic purification of the residue on silica gel with hexane/ethyl acetate (vol. 7:3) gave 4-methacryloyloxybutyl (E)-3-(4-hydroxyphenyl)acrylate.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][Si:8]([CH3:23])([CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH:14]1[CH2:16][O:15]1>C(O)C>[CH3:23][Si:8]([CH3:7])([CH2:17][CH2:18][Si:19]([CH3:20])([CH3:22])[CH3:21])[CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH:14]([OH:15])[CH2:16][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: C[Si](C)(C)CC[Si](C)(C)CCCOCC1CO1
Solvent: CCO
Product: C[Si](C)(C)CC[Si](C)(C)CCCOCC(O)CN1CCOCC1
Temperature: 70 °C

Procedure:
Morpholine (0.634 g; 7.28 mMol) and 40 mL of ethanol were charged to a 100 mL RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 70° C. 2-{3-[Dimethyl-(2-trimethylsilanyl-ethyl)-silanyl]-propoxymethyl}-oxirane 8 (2 g; 7.28 mMol) mixed with 10 g ethanol was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 70° C. for an additional 4 hours. Ethanol was stripped off on the rotovap. The mixture was distilled under vacuum to remove impurities.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[NH2:30][CH:31]1[CH2:34][N:33]([C:35]2[S:36][C:37]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:38][N:39]=2)[CH2:32]1.[Cl:45][C:46]1[N:47]=[C:48]([C:53](O)=[O:54])[NH:49][C:50]=1[CH2:51][CH3:52]>CC(N(C)C)=O.ClCCl.C(OCC)(=O)C>[Cl:45][C:46]1[N:47]=[C:48]([C:53]([NH:30][CH:31]2[CH2:34][N:33]([C:35]3[S:36][C:37]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:38][N:39]=3)[CH2:32]2)=[O:54])[NH:49][C:50]=1[CH2:51][CH3:52]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCOC(=O)c1cnc(N2CC(N)C2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(N2CC(NC(=O)c3nc(Cl)c(CC)[nH]3)C2)s1
Temperature: 25 °C
Reaction time: 19 h
Yield: 63.7 %

Procedure:
WSC hydrochloride (62 mg, 0.32 mmol), 1-hydroxybenzotriazole (36 mg, 0.27 mmol) and N-methylmorpholine (0.06 mL, 0.54 mmol) were added to a mixed solution of ethyl 2-(3-aminoazetidin-1-yl)-1,3-thiazole-5-carboxylate obtained in Example (217b) (61 mg, 0.27 mmol) and 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (47 mg, 0.27 mmol) in DMA/dichloromethane (2 mL/2 mL), and the mixture was stirred at room temperature for 19 hours. The reaction solution was diluted with ethyl acetate, and then the mixture was washed with brine and dried over anhydrous magnesium sulfate. Following filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: dichloromethane/methanol=20/1) to obtain 66 mg of the title compound as a white solid (64%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:15][C@H:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:18][C@H:17]1[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])(=O)C1C=CC=CC=1>O.C(O)C>[C:36]([O:35][C:33]([NH:32][C@H:17]1[C@@H:16]([OH:15])[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:18]1)=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@@H]1OC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@@H]1O
Temperature: 70 °C
Reaction time: 20 h
Yield: 88.6 %

Procedure:
A solution of potassium carbonate (3.70 g, 26.8 mmol) in water (80 mL) was added to a solution of cis-benzyl 4-(benzoyloxy)-3-((tert-butoxycarbonyl)amino)piperidine-1-carboxylate (8.11 g, 17.84 mmol) in ethanol (160 mL) and the mixture was stirred at 70° C. for 20 h. The reaction mixture was concentrated in vacuo to ⅓rd volume and the resultant suspension was diluted with water (50 mL) and extracted using DCM (3×70 mL). The collected organics were combined and dried (Na2SO4) and concentrated in vacuo to afford the crude product as a colourless oil. The crude product was then purified by column chromatography on a silica cartridge (340 g) using a 0-100% ethyl acetate/cyclohexane gradient. The appropriate fractions were combined and evaporated in vacuo to give the required product cis-benzyl 3-((tert-butoxycarbonyl)amino)-4-hydroxypiperidine-1-carboxylate (5.54 g, 15.81 mmol, 89% yield) as a white foam.
Reaction SMILES: [CH:1]([Si:4]([CH:9]([CH3:11])[CH3:10])([CH:6]([CH3:8])[CH3:7])[SH:5])([CH3:3])[CH3:2].[H-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19](I)[CH:18]=[CH:17][C:16]=1[NH:22][C:23](=[O:31])[C@:24]([OH:30])([CH3:29])[C:25]([F:28])([F:27])[F:26].C(OCC)(=O)C>C1COCC1.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>[Cl:14][C:15]1[CH:20]=[C:19]([S:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:6]([CH3:8])[CH3:7])[CH:9]([CH3:11])[CH3:10])[CH:18]=[CH:17][C:16]=1[NH:22][C:23](=[O:31])[C@:24]([OH:30])([CH3:29])[C:25]([F:26])([F:28])[F:27]
Reactant: C[C@@](O)(C(=O)Nc1ccc(I)cc1Cl)C(F)(F)F
Reactant: CC(C)[Si](S)(C(C)C)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)[Si](Sc1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1)(C(C)C)C(C)C
Temperature: 1 °C

Procedure:
Triisopropylsilanethiol (2.8 ml) was added to a stirred suspension of sodium hydride (60% mineral oil dispersion, 0.53 g) in anhydrous THF (40 ml) cooled to 1° C. under argon. After 15 minutes at this temperature tetrakis(triphenylphosphine)palladium (0) (1.21 g) was added and this solution was added to (R)-N-(2-chloro-4-iodophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 197) (5.2 g) in anhydrous toluene (40 ml) and the mixture was heated to 85° C. for 2 hours. The mixture was allowed to cool to ambient temperature, ethyl acetate (200 ml) was added and the mixture was washed with brine (100 ml) and dried. Volatile material was removed by evaporation and the residue was purified on a silica gel flash column eluting with 1-20% ethyl acetate/hexane to give the title compound (6.51 g) as a gum. NMR (CDCl3) 1.07-1.1 (d, 18H), 1.20-1.28 (m, 3H), 1.74 (s, 3H), 3.64 (s, 1H), 7.39-7.42 (m, 1H), 7.53 (s, 1H), 8.23 (d, 1H), 8.81 (s, 1H); MS (ESP−): 454.