Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[C:13]3[CH2:15][CH2:16][CH2:17][C:12]3=[C:11]([NH:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([CH2:25][C:26]#[N:27])[CH2:21][CH2:20]3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C([O-])(O)=[O:29].[Na+]>S(=O)(=O)(O)O>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[C:13]3[CH2:15][CH2:16][CH2:17][C:12]3=[C:11]([NH:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([CH2:25][C:26]([NH2:27])=[O:29])[CH2:21][CH2:20]3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: N#CC[C@H]1CC[C@H](Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)CC1
Reactant: O=C([O-])O
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)C[C@H]1CC[C@H](Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Trans-2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)cyclohexyl)acetonitrile hydrochloride (0.056 g, 0.14 mmol) was suspended in sulfuric acid (2 mL) at 0° C. The reaction was warmed to rt and stirred for 16 h. After this time, the mixture was added dropwise to a saturated NaHCO3 solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, dichloromethane/methanol), followed by formation of the hydrochloride salt to afford the title compound (0.048 g, 82%) as a white solid. MW=420.38. 1H NMR (DMSO-d6, 500 MHz) δ 13.50 (s, 1H), 7.99-7.96 (m, 1H), 7.86-7.82 (m, 1H), 7.71-7.67 (m, 1H), 7.62-7.58 (m, 2H), 7.27 (s, 1H), 7.10 (s, 1H), 6.73 (s, 1H), 3.89-3.79 (m, 1H), 3.06 (t, J=7.5 Hz, 2H), 2.78 (t, J=7.5 Hz, 2H), 2.17 (quin, J=7.5 Hz, 2H), 1.96 (d, J=7.0 Hz, 2H), 1.92-1.85 (m, 2H), 1.78-1.71 (m, 2H), 1.70-1.60 (m, 1H), 1.50-1.38 (m, 2H), 1.21-1.09 (m, 1H); APCI MS m/z 384 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[CH3:27][C@H:28]1[O:33][CH2:32][CH2:31][NH:30][C@@H:29]1[C:34]([OH:36])=[O:35]>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:30]2[CH2:31][CH2:32][O:33][C@H:28]([CH3:27])[C@H:29]2[C:34]([OH:36])=[O:35])=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: C[C@H]1OCCN[C@@H]1C(=O)O
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Product: CCOC(=O)C1=C(CN2CCO[C@H](C)[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Yield: 42 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.9 g, 1.9 mmol) was reacted with (2R,3S)-2-methyl morpholine-3-carboxylic acid (0.28 g, 1.9 mmol) according to the procedure as described in Example 34, Step D to give the title compound as a yellow solid (0.43 g, 42%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([NH2:9])[CH2:7][N:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5]1)=[N+:2]=[N-:3].[Br:17][CH2:18][C:19]([F:26])([F:25])[CH2:20][CH2:21][C:22](O)=[O:23].C(N(CC)CC)C>C(OCC)(=O)C>[N:1]([C@H:4]1[CH2:5][N:6]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:7][C@@H:8]1[NH:9][C:22](=[O:23])[CH2:21][CH2:20][C:19]([F:26])([F:25])[CH2:18][Br:17])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@H]1CN(Cc2ccccc2)C[C@@H]1N
Reactant: O=C(O)CCC(F)(F)CBr
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: [N-]=[N+]=N[C@H]1CN(Cc2ccccc2)C[C@@H]1NC(=O)CCC(F)(F)CBr
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.6 %

Procedure:
To a solution of the product from Step 5 (17.5 g, 80.6 mmol), 5-bromo-4,4-difluoropentanoic acid (17.5 g, 80.6 mmol) from Preparation 3 and triethylamine (32.6 g, 323 mmol) in ethyl acetate (250 mL) was added a 50% solution of propanephosphonic acid cyclic anhydride in ethyl acetate (48.0 mL, 80.6 mmol). The reaction was warmed to reflux and stirred for 16 hours. The reaction was cooled to room temperature and partitioned between ethyl acetate and H2O. The organic phase washed with saturated sodium carbonate solution and saturated sodium chloride solution and then dried over sodium sulfate and concentrated to provide 22.0 g (65%) of the product as an oil. MS m/z 416. (MH+).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(OC([N:19]1[C:24](=[O:25])[CH:23]2[CH:21]([CH:22]2[C:26]([O-:28])=[O:27])[CH:20]1[C:29]([O-:31])=[O:30])=O)(C)(C)C.O>C(Cl)Cl>[C:26]([CH:22]1[CH:23]([C:24]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:25])[CH:21]1[CH:20]([C:29]([OH:31])=[O:30])[NH2:19])([OH:28])=[O:27]
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C(=O)C2C(C(=O)[O-])C2C1C(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: NC(C(=O)O)C1C(C(=O)O)C1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.3 %

Procedure:
To a solution of AlCl3 (53.8 mg, 0.40 mmol) in dry CH2Cl2 (1 mL) at 0° C., aniline (70 μl, 0.77 mmol) in CH2Cl2 (0.5 mL) was added dropwise. The mixture was stirred at room temperature for 10 min, and then ethyl (1SR, 2 SR, 5RS, 6RS) 3-tert-butoxycarbonyl-4-oxo-3-azabicyclo[3.1.0)hexane-2,6-dicarboxylate (106 mg 0.31 mmol) in dry CH2Cl2 (0.5 mL) was added. After stirring at room temperature for 4 h, a mixture of ice and water was added. The layers were separated and the aqueous phase was extracted with CH2Cl2 (X3). The combined organic layers were dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by flash chromatography (hexane/ethyl acetate 1/1) to give 67.5 mg of the desired compound (50% yield).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:23]1[N:24]=[C:25]([NH2:41])[C:26]2[N:27]=[CH:28][N:29]([C:39]=2[N:40]=1)[C@@H:30]1[O:38][C@H:35]([CH2:36][OH:37])[C@@H:33]([OH:34])[C@H:31]1[OH:32]>>[N+:19]([C:16]1[CH:15]=[CH:14][C:13]([O:12][C:10]([N:7]2[CH2:8][CH2:9][CH:4]([CH2:1][C:2]#[C:3][C:23]3[N:24]=[C:25]([NH2:41])[C:26]4[N:27]=[CH:28][N:29]([C:39]=4[N:40]=3)[C@@H:30]3[O:38][C@H:35]([CH2:36][OH:37])[C@@H:33]([OH:34])[C@H:31]3[OH:32])[CH2:5][CH2:6]2)=[O:11])=[CH:18][CH:17]=1)([O-:21])=[O:20]
Reactant: C#CCC1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: Nc1nc(C#CCC2CCN(C(=O)Oc3ccc([N+](=O)[O-])cc3)CC2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
Batch: AB-9-149. 4-nitrophenyl 4-(prop-2-ynyl)piperidine-1-carboxylate, batch JR28-97 (0.630 g, 2.185 mmol) was added to a solution of 2-iodoadenosine (0.727 g, 1.849 mmol) according to general procedure 2. Yield: 1.192 g, 65%. %. 1H NMR (CD3OD) δ 8.26 (m, 1H), 8.25-7.34 (2×m, 4H), 5.94 (d, 1H), 4.72 (m, 2H), 4.32-4.14 (2×m, 3H), 3.91-3.71 (2×d, 2H), 3.17-2.90 (2×bt, 4H), 2.48 (d, 5H), 1.45 (m, 5H). m/z MH+=554.15. HPLC rt=7.3 mm.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[N+:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)([O-:27])=[O:26]>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:9]=[C:4]([C:3]([OH:2])=[O:24])[C:5]([C:32]4[CH:31]=[CH:30][CH:29]=[C:28]([N+:25]([O-:27])=[O:26])[CH:33]=4)=[CH:6][CH:7]=3)[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1cccc([N+](=O)[O-])c1
Yield: 38.2 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 3-nitrophenylboronic acid (available from Aldrich Chemical Company, Inc.; 67 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-3′-nitro-biphenyl-2-carboxylic acid (36 mg, 38%). 1H NMR (400 MHz, DMSO-d6) δ 8.46-8.51 (m, 2H), 8.18-8.39 (m, 4H), 8.06-8.15 (m, 1H), 7.87 (d, J=7.0 Hz, 1H), 7.73-7.79 (m, 2H), 7.63-7.68 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[O:7][CH2:8][C:9]1[N:10]=[CH:11][C:12]([C:15]([OH:17])=O)=[N:13][CH:14]=1.Cl.[CH3:24][O:25][C:26](=[O:42])[C@@H:27]([NH2:41])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:31][CH:30]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:24][O:25][C:26](=[O:42])[C@@H:27]([NH:41][C:15]([C:12]1[CH:11]=[N:10][C:9]([CH2:8][O:7][C:6]2[CH:18]=[CH:19][CH:20]=[C:4]([O:3][C:2]([F:1])([F:22])[F:21])[CH:5]=2)=[CH:14][N:13]=1)=[O:17])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:31][CH:30]=1
Reactant: O=C(O)c1cnc(COc2cccc(OC(F)(F)F)c2)cn1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnc(COc2cccc(OC(F)(F)F)c2)cn1
Yield: 53.2 %

Procedure:
A solution of 5-(3-trifluoromethoxy-phenoxymethyl)-pyrazine-2-carboxylic acid (0.182 g, 0.579 mmol) was treated with 2(S)-amino-3-biphenyl-4-yl-propionic acid methyl ester hydrochloride (0.162 g, 0.637 mmol), HBTU (0.440 g, 1.158 mmol), and DIEA (0.310 g, 1.737 mmol) by the general procedure A. The crude crude product was purified by flash column chromatography on silica gel to give 0.170 g of 3-biphenyl-4-yl-2(S)-{[5-(3-trifluoromethoxy-phenoxymethyl)-pyrazine-2-carbonyl]-amino}-propionic acid methyl ester. LCMS: 553 (M+2)+
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[C:10](=[O:16])[NH:11][CH2:12]2)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:9]12[NH:8][CH:13]([CH2:14][CH2:15]1)[CH2:12][NH:11][C:10]2=[O:16]
Reactant: CC(C)(C)OC(=O)N1C2CCC1C(=O)NC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCC2CCC1N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-oxo-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (108 mg, 0.48 mmol) in DCM (0.5 mL) at 0° C. was added dropwise, TFA (0.5 ml) and the reaction mixture stirred for 30 min. The reaction was warmed to RT and stirred for 1 h before being concentrated in vacuo and triturated with diethyl ether. The resultant residue was subjected to flash chromatography (Isolute NH2, 50% methanol in DCM) to give 3,8-Diaza-bicyclo[3.2.1]octan-2-one as a white solid (69 mg, quantitative). LCMS): RT=0.32 min, [M+H]+=127. 1H NMR 400 MHz (DMSO-d6) δ: 7.02 (1 H, br, s), 3.53 (1 H, m), 3.24 (1 H, dd, J=11.00, 4.14 Hz), 2.80-2.79 (1 H, m), 2.77 (1 H, m), 1.78 (3 H, m), 1.57-1.56 (1 H, m).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2.[CH3:15][O-:16].[Na+]>CO>[CH3:15][O:16][CH2:3][C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2
Reactant: C[O-]
Reactant: Oc1ccc(CCl)c2cccnc12
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCc1ccc(O)c2ncccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5-Chloromethyl-8-hydroxyquinoline hydrochloride (2.145 g; 9.3 mmol) was added to a mixture of sodium methoxide (1.763 g; 32.6 mmol) in MeOH (40 ml). The reaction mixture was stirred for about 4 h at room temperature, and then evaporated to dryness. The residue was dissolved in CHCl3 (100 ml, the solution was washed with water until a neutral pH was obtained, and was then washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was extracted with hexane (100 ml). The hexane solution was evaporated to give the title product, 0.36 g (20%). M.p. 75-760° C. TLC (CHCl3/MeOH/NH3.9.5:0.5:0.1). Rf=0.36.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:15][C@@H:16]([CH3:20])[CH2:17][O:18][CH3:19])[CH:14]=1)[C:9]([OH:11])=O.[CH2:25]([O:27][C:28](=[O:37])[CH2:29][S:30][C:31]1[S:35][C:34]([NH2:36])=[N:33][CH:32]=1)[CH3:26]>>[CH2:25]([O:27][C:28](=[O:37])[CH2:29][S:30][C:31]1[S:35][C:34]([NH:36][C:9](=[O:11])[C:8]2[CH:12]=[C:13]([O:15][C@@H:16]([CH3:20])[CH2:17][O:18][CH3:19])[CH:14]=[C:6]([O:5][C:4]3[CH:21]=[CH:22][C:23]([F:24])=[C:2]([F:1])[CH:3]=3)[CH:7]=2)=[N:33][CH:32]=1)[CH3:26]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(F)c(F)c2)cc(C(=O)O)c1
Reactant: CCOC(=O)CSc1cnc(N)s1
Product: CCOC(=O)CSc1cnc(NC(=O)c2cc(Oc3ccc(F)c(F)c3)cc(O[C@@H](C)COC)c2)s1

Procedure:
The title compound was prepared from 3-(3,4-Difluoro-phenoxy)-5-((S)-2-methoxy-1-methyl-ethoxy)-benzoic acid and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester following general procedure A
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([C:8]([OH:10])=[O:9])[CH2:3]1.C(N(CC)CC)C.[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.Cl>ClCCl>[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([N:2]2[CH2:7][CH2:6][CH2:5][C@H:4]([C:8]([OH:10])=[O:9])[CH2:3]2)=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(O)[C@H]1CCCNC1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)[C@H]1CCCN(C(=O)c2ccc(F)cc2)C1
Reaction time: 8 h
Yield: 92.3 %

Procedure:
To a suspension of (S)-piperidine-3-carboxylic acid hydrochloride (0.75 g, 4.53 mmol) in dry dichloromethane (30 mL), triethylamine (1.97 mL, 14.0 mmol) and 4-fluorobenzoyl chloride (543 mL, 4.53 mmol) were added dropwise at 0° C. The resulting solution was kept under stiffing overnight at room temperature, under nitrogen atmosphere, then HCl 1N (30 mL) was added and the phases were separated. The organic layer was washed with HCl 1N (30 mL), with water (30 mL), dried over Na2SO4 and evaporated under reduced pressure to provide 1.05 g of 1-(4-fluoro-benzoyl)-(S)-piperidine-3-carboxylic acid as a yellow oil, used for the next step without further purification.
Reaction SMILES: [O-]CC.[K+].[C:5]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:17][C:18]([CH3:20])=O.C(Br)C>CN(C)C=O>[C:18](=[C:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([O:14][CH2:15][CH3:16])=[O:13])([CH3:20])[CH3:17]
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: CC(C)=O
Agent: CC[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCBr
Product: CCOC(=O)CC(C(=O)OCC)=C(C)C
Temperature: 60 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
52.5 mmol of potassium ethoxide were suspended in 100 mL of N,N-dimethylformamide in a 250 mL round bottom flask. To this slurry, heated up to 60° C., a mixture of 50 mmol of diethyl succinate and 57.5 mmol of acetone was added dropwise in 10 minutes. The course of the reaction was detected by GC. After 60 minutes the reaction was completed with a conversion of 97.2% (determined by GC). Then 87.5 mmol of ethyl bromide were added to the reaction mixture at 60° C. The slurry was stirred for 60 minutes at 60° C. The reaction was complete, giving the product isomers with a yield of 95% (determined by GC).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:21])[CH2:4][C:5]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7][CH2:6]1.[C:22](OC(=O)C)(=[O:24])[CH3:23].CCCCCC>C(OCC)(=O)C>[C:22]([O:1]/[N:2]=[C:3](\[NH2:21])/[CH2:4][C:5]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:6][CH2:7][C:8]2([O:9][CH2:10][CH2:11][O:12]2)[CH2:13][CH2:14]1)(=[O:24])[CH3:23]
Reactant: N=C(CC1(c2ccccc2)CCC2(CC1)OCCO2)NO
Reactant: CC(=O)OC(C)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)O/N=C(\N)CC1(c2ccccc2)CCC2(CC1)OCCO2
Yield: 85.17 %

Procedure:
A mixture of N-hydroxy-2-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-acetamidine (266) (600 mg, 2.01 mmol) and acetic anhydride (2 mL) was stirred at room temperature for 16 h (TLC, ethyl acetate:hexane=7:3/UV/SiO2, Rf=0.4). The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (2×25 mL), brine (25 mL), dried and concentrated in vacuo to get crude mass which was purified by CombiFlash using a gradient eluent mixture of ethyl acetate and hexane to get pure (Z)-(1-amino-2-{8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl}ethylidene)amino acetate (267) (585 mg, 85.17%) as a white sticky solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Br[CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH3:14][C:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: CC(C)(C)CCBr
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)CCOc1ccc(C#N)cc1
Temperature: 25 °C
Yield: 88.5 %

Procedure:
Mix 4-cyanophenol (1.2 g, 10 mmol), 1-bromo-3,3-dimethylbutane (5.3 g, 32 mmol), powdered potassium carbonate (4.14 g, 30 mmol), and powdered potassium iodide (166 mg, 1 mmol) in acetone (60 mL). Stir under inert atmosphere and heat at reflux for 48 h. Cool the reaction mixture to ambient temperature. Dilute with acetone, filter and evaporate. Purify by chromatography on silica gel eluting with hexane/EtOAc (10 and 9:1) to obtain the desired intermediate (1.8 g, 89%). MS (ES+) m/z: 221 (M+NH4)+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[N:4][N:3]=1.[Cl:13][CH:14]([Cl:33])[C:15]([NH:17][C@H:18]([CH2:31][F:32])[C@H:19]([OH:30])[C:20]1[CH:25]=[CH:24][C:23]([Sn](C)(C)C)=[CH:22][CH:21]=1)=[O:16]>>[Cl:13][CH:14]([Cl:33])[C:15]([NH:17][C@H:18]([CH2:31][F:32])[C@H:19]([OH:30])[C:20]1[CH:21]=[CH:22][C:23]([C:2]2[S:6][C:5]([CH2:7][NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[N:4][N:3]=2)=[CH:24][CH:25]=1)=[O:16]
Reactant: C[Sn](C)(C)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Reactant: CS(=O)(=O)NCc1nnc(Br)s1
Product: CS(=O)(=O)NCc1nnc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)s1

Procedure:
Following the general procedure of Example 9—Step 2 and making non-critical variations but using N-((5-bromo-1,3,4-thiadiazol-2-yl)methyl)methane-sulfonamide and 2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(trimethyl-stannyl)phenyl)-propan-2-yl)acetamide the title compound is obtained (11.8 mg): 1H NMR (400 MHz, DMSO-d6) 3.0 (s, 3H), 4.2-4.4 (m, 1.5H), 4.45 (t, 1H), 4.55-4.6 (m, 0.5H), 4.65 (d, 2H), 4.7-4.75 (m, 0.5H), 4.95 (bt, 0.5H), 6.1 (d, 1H), 6.5 (s, 1H), 7.5 (d, 2H), 7.95 (d, 2H), 8.15 (t, 1H), 8.6 (d, 1H). m/z (C1) M+H 471.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:38]1[CH:43]=[C:42]([CH3:44])[N+:41]([O-:45])=[C:40]([CH3:46])[CH:39]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([C:38]4[CH:43]=[C:42]([CH3:44])[N+:41]([O-:45])=[C:40]([CH3:46])[CH:39]=4)=[CH:21][CH:22]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Reactant: Cc1cc(Br)cc(C)[n+]1[O-]
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccc(F)cc4)OC3=O)cc2)cc(C)[n+]1[O-]

Procedure:
The title compound was prepared from (S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one one and 4-bromo-2,6-dimethylpyridine-N-oxide following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.354, m/z=493; 1H NMR (CDCl3) 1.18 (d, 6H), 1.48 (d, 3H), 2.08-2.21 (m, 5H), 2.36 (m, 1H), 2.53 (s, 6H), 2.82 (m, 1H), 5.65 (m, 1H), 6.98 (m, 4H), 7.18 (m, 4H), 7.28 (m, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[N:11]([C:12](=[O:15])[CH2:13]Cl)[CH2:10][CH2:9][NH:8][C:7]1=[O:16].N.[NH:18]1CCOCC1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[N:11]([C:12](=[O:15])[CH2:13][NH2:18])[CH2:10][CH2:9][NH:8][C:7]1=[O:16]
Reactant: O=C1NCCN(C(=O)CCl)C1c1cccs1
Reactant: C1COCCN1
Agent: N
Product: NCC(=O)N1CCNC(=O)C1c1cccs1

Procedure:
Reacting the compound obtained in Example 21 with ammonia or morpholine, as described in Example 7, gives 3-(2-thienyl)-4-aminoacetylpiperazin-2-one: melting point: 130° C. (decomposition), or 3-(2-thienyl)-4-(morpholinomethylcarbonyl)-piperazin-2-one: melting point: 144°-146° C., respectively.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:14][CH2:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH3:18][S:19]([O:22][C:23]1[CH:24]=[C:25]([CH2:29][CH2:30]CS([O-])(=O)=O)[CH:26]=[CH:27][CH:28]=1)(=[O:21])=[O:20]>>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:14][CH2:15][CH3:16])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:30][CH2:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([O:22][S:19]([CH3:18])(=[O:20])=[O:21])[CH:24]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: CS(=O)(=O)Oc1cccc(CCCS(=O)(=O)[O-])c1
Product: CCOC(=O)C(Cc1ccc(OCCc2cccc(OS(C)(=O)=O)c2)cc1)OCC

Procedure:
2-Ethoxy-3-{4-[2-(3-methanesulfonyloxyphenyl)ethoxy]phenyl}propanoic acid ethyl ester was synthesized using the same method as in example 1(b) from 2-ethoxy-3-(4-hydroxyphenyl)propanoic acid ethyl ester (described in Example 20b) and 2-(3-methanesulfonyloxyphenyl)-ethylmethanesulfonate.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:35])[CH:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:53])[C@@H:15]2[CH2:36][CH2:37][C@H:38]2[O:43][C:42](=[O:44])[CH2:41][C@H:40]([O:45][Si](C(C)(C)C)(C)C)[CH2:39]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:35])[CH:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([CH3:33])([CH3:34])[CH3:32])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:53])[C@@H:15]2[CH2:36][CH2:37][C@H:38]2[O:43][C:42](=[O:44])[CH2:41][C@H:40]([OH:45])[CH2:39]2)=[CH:10]1
Reactant: CCC(Oc1ccccc1C(C)(C)C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(Oc1ccccc1C(C)(C)C)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Yield: 40.6 %

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 1.40 g of (4R,6R)-6-([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-[(2RS)-2-(2-t-butylphenoxy)butyryloxy]-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 133, above] and 43.7 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 0.40 g of the title compound as white crystals, melting at between 176° and 178° C.