Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][C:3]1([CH2:12][CH3:13])[C:9](=[O:10])[N:8]=[C:7]([O-:11])[NH:6][C:4]1=[O:5].[Na+].[CH2:15]([O:27][CH2:28]Cl)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CN(C)C=O>[CH2:15]([O:27][CH2:28][N:8]1[C:9](=[O:10])[C:3]([CH2:12][CH3:13])([CH2:2][CH3:1])[C:4](=[O:5])[N:6]([CH2:28][O:27][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:7]1=[O:11])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCOCCl
Reactant: CCC1(CC)C(=O)N=C([O-])NC1=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOCN1C(=O)N(COCCCCCCCCCCCC)C(=O)C(CC)(CC)C1=O
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Sodium barbital (4.0 g.) was suspended in 50 ml of dimethylformamide. To the suspension was added, over a period of 5 minutes, chloromethyl n-dodecyl ether (10 g.). The suspension was heated at 110° C. for a period of 1 hour and then allowed to stand overnight without heating. The suspension was poured into 500 ml of ice water and the resulting aqueous emulsion was extracted with ethyl acetate. The ethyl acetate solution was dried and the ethyl acetate was evaporated under reduced pressure to yield an oil, which was purified by column chromatography using silica gel (70-325 mesh). Elution with benzene provided 1,3-di-n-dodecyloxymethyl-5,5-diethyl barbituric acid.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([O:13][C:14]([F:17])([F:16])[F:15])[C:5]=1[O:18][CH3:19])[CH:2]=[CH2:3].[ClH:20]>CO.[Pd]>[ClH:20].[CH3:19][O:18][C:5]1[C:6]([O:13][C:14]([F:15])([F:17])[F:16])=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: C=CCc1cc([N+](=O)[O-])cc(OC(F)(F)F)c1OC
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCc1cc(N)cc(OC(F)(F)F)c1OC
Reaction time: 17 h

Procedure:
To a stirred solution of 1-allyl-2-methoxy-5-nitro-3-trifluoromethoxybenzene (1.9 g, 6.86 mmol, 1 eq.) in MeOH (26 mL) at room temperature was added aqueous HCl solution (3.4 mL, 3.0 M) followed by 10% Pd/C (256 mg). The reaction mixture was stirred under H2 atmosphere for 17 h, filtered through a pad of celite and concentrated in vacuo to give 4-methoxy-3-propyl-5-trifluoromethoxyphenylamine hydrochloride (1.6 g). The product was used without further purification.
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:20][CH2:19][C:18]2[C@@:5](O)([CH2:6][CH2:7][C@@H:8]3[C:17]=2[C@@H:16]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]4OCC(C)(C)C[O:28]4)=[CH:23][CH:22]=2)[CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[O:35])[CH2:4]1.[BH4-].[Na+].O>CO.C1COCC1>[OH:35][C@H:12]1[CH2:11][CH2:10][C@H:9]2[C@H:8]3[C:17]([C@@H:16]([C:21]4[CH:22]=[CH:23][C:24]([CH:27]=[O:28])=[CH:25][CH:26]=4)[CH2:15][C@:13]12[CH3:14])=[C:18]1[C:5](=[CH:4][C:3](=[O:2])[CH2:20][CH2:19]1)[CH2:6][CH2:7]3
Reactant: COC1(OC)CCC2=C3[C@@H](CC[C@@]2(O)C1)[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]3c1ccc(C2OCC(C)(C)CO2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[C@]12C[C@H](c3ccc(C=O)cc3)C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1CC[C@@H]2O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 73 %

Procedure:
2.1 g of 3,3-dimethoxy-11β-[4-(5,5-dimethyl-1,3-dioxan-2-yl)phenyl]-5α-hydroxy-estr-9-en-17-one is dissolved in 25 ml of methanol/THF (1:1, V/V) and reduced at 23° C. with 303 mg of sodium borohydride. After 45 minutes, it is stirred into water, and the aqueous phase is extracted several times with methylene chloride. The organic phase is dried and evaporated under reduced pressure. The crude product [4-(3,3-dimethoxy-5α,17β-dihydroxy-estr-9-en-11β-yl)benzaldehyde-neopentylketal] is dissolved in 25 ml of acetone, and stirred with 2 ml of water and 283 mg of p-toluenesulfonic acid at room temperature for 8 hours. Then, it is poured into water and the precipitate is suctioned off. The purification of the crude product is carried out by chromatography with a toluene/acetone gradient on silica gel. 1.1 g of 4-(17β-hydroxy-3-oxoestra-4,9-dien-11β-yl)benzaldehyde is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([CH2:8][C:9]#[N:10])=[O:7])=[CH:4][CH:3]=1.[S:13]1CC(O)S[CH2:15][CH:14]1O.C(N(CC)CC)C>C(O)C>[NH2:10][C:9]1[S:13][CH:14]=[CH:15][C:8]=1[C:6]([C:5]1[CH:11]=[CH:12][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:7]
Reactant: OC1CSC(O)CS1
Reactant: Cc1ccc(C(=O)CC#N)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc(C(=O)c2ccsc2N)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 130.2 %

Procedure:
To a suspension of 4-methylbenzoylacetonitrile (0.325 g; 2.042 mmol) and p-dithiane-2,5-diol (0.155 g; 1.018 mmol) in ethanol (4.3 mL) cooled at 0° C. was added triethylamine (0.283 mL; 2.042 mmol). After 10 min at room temperature, the reaction mixture was heated under reflux for 2 h. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulphatesulphate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate (10-25%) in heptane to afford the title compound (0.288 g; 65%) as a yellow solid.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.COC1C=CC([Mg]Br)=CC=1.O=[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:23]1[C:37]([O:39]CC)=[O:38]>C1COCC1.CCOCC.CCOCC>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:23]2[C:37]([OH:39])=[O:38])=[CH:4][CH:5]=1
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1=O
Reactant: COc1ccc(Br)cc1
Agent: COc1ccc([Mg]Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(C2c3ccccc3C(c3ccccc3)C2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Ethyl (1RS)[1-Hydroxy-1-(4-methoxyphenyl)]-3-phenylindene-2-carboxylate. To dry magnesium turnings (0.88 g, 36 mmol) under an argon atmosphere was added, portionwise, a solution of p-bromoanisole (4.5 ml, 36 mmol) in 5% THF/Et2O (37 ml). The resulting p-methoxyphenyl magnesium bromide solution was added to a solution of ethyl 1-oxo-3-phenylindene-2-carboxylate (5.0 g, 18 mmol) in Et2O (300 ml) under an argon atmosphere at 0° C. The resulting mixture was allowed to warm to room temperature and was stirred for 10 min. The mixture was partitioned between 3M HCl (100 ml) and EtOAc (200 ml). The organic extract was washed successively with H2O, aqueous NaHCO3, H2O and saturated aqueous NaCl and dried (Na2 SO4). The solvent was removed in vacuo to provide a yellow oil which was treated with Et2O/hexanes. The solid which formed was collected by filtration (3.47 g). The filtrate was concentrated under reduced pressure and purified by flash chromatography. The material which was isolated was treated with Et2O/hexanes, and the additional solid which formed (1.76 g, 75% total yield) was collected by filtration to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH:17]=[N:16][N:15]=[N:14]2)=[CH:8][C:4]=1[C:5](O)=[O:6].C(Cl)(=O)C([Cl:21])=O>CN(C)C=O.ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH:17]=[N:16][N:15]=[N:14]2)=[CH:8][C:4]=1[C:5]([Cl:21])=[O:6]
Reactant: COc1ccc(Cn2cnnn2)cc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(Cn2cnnn2)cc1C(=O)Cl
Reaction time: 4 h

Procedure:
Combine 2-methoxy-5-(1H-tetrazol-1-ylmethyl)benzoic acid (0.35 g, 1.5 mmol) and dichloromethane (25 mL). Add dropwise oxalyl chloride (0.21 mL, 2.35 mmol) followed by dimethylformamide (5 drops). After 4 hours, evaporate in vacuo and dry to give the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:16]=[CH:15][C:14]2[C:10](=[CH:11][N:12]([CH3:17])[N:13]=2)[C:9]=1[C:18](OC)=[O:19].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[Br:7][C:8]1[CH:16]=[CH:15][C:14]2[C:10](=[CH:11][N:12]([CH3:17])[N:13]=2)[C:9]=1[CH2:18][OH:19]
Reactant: COC(=O)c1c(Br)ccc2nn(C)cc12
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc2c(CO)c(Br)ccc2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.8 %

Procedure:
To a suspension of lithium aluminum hydride (152 mg, 4.00 mmol) in tetrahydrofuran (15 mL) was added a solution of methyl 5-bromo-2-methyl-2H-indazole-4-carboxylate (534 mg, 2.00 mmol) in tetrahydrofuran (5 mL) at 0° C., and the mixture was stirred at room temperature for 15 min. To the reaction solution was added sodium sulfate decahydrate (1.5 g), and the mixture was stirred for 15 min and filtered through celite. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=40/60→80/20) to give the title compound (351 mg, yield 73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:4]=1[CH2:5][N:6]([C:32]1[CH:37]=[CH:36][N:35]=[CH:34][N:33]=1)[S:7]([C:10]1[C:11]([F:31])=[CH:12][C:13]([O:19][C@H:20]2[CH2:24][CH2:23][CH2:22][C@@H:21]2[C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)=[C:14]([CH:18]=1)[C:15]([NH2:17])=O)(=[O:9])=[O:8].C(N(CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[C:15]([C:14]1[C:13]([O:19][C@H:20]2[CH2:24][CH2:23][CH2:22][C@@H:21]2[C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)=[CH:12][C:11]([F:31])=[C:10]([S:7]([N:6]([CH2:5][C:4]2[CH:38]=[CH:39][C:40]([O:42][CH3:43])=[CH:41][C:3]=2[O:2][CH3:1])[C:32]2[CH:37]=[CH:36][N:35]=[CH:34][N:33]=2)(=[O:8])=[O:9])[CH:18]=1)#[N:17]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(C(N)=O)c(O[C@H]3CCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(C#N)c(O[C@H]3CCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.9 %

Procedure:
To a solution of the 5-{[(2,4-dimethoxybenzyl)(pyrimidin-4-yl)amino]sulfonyl}-4-fluoro-2-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzamide (64.3 mg, 0.107 mmol) prepared in Example 62c in dichloromethane (2.0 mL), triethylamine (41.0 μL, 0.300 mmol) and trifluoroacetic acid (21.0 μL, 0.150 mmol) were added with cooling on ice, and the reaction solution was stirred at room temperature for 2 hours. To the reaction solution, triethylamine (41.0 μL, 0.300 mmol) and trifluoroacetic acid (21.0 μL, 0.150 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was purified with silica gel chromatography (ethyl acetate) to yield the title compound (32.3 mg, 53%) as a colorless oil.
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:17]2[C:16](=[O:20])[C:15]3[C:6](=[CH:7][C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5](=[O:21])[C:4]=2[CH:3]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[N:22]1([C:2]2[CH:19]=[CH:18][C:17]3[C:16](=[O:20])[C:15]4[C:6](=[CH:7][C:8]5[C:13]([CH:14]=4)=[CH:12][CH:11]=[CH:10][CH:9]=5)[C:5](=[O:21])[C:4]=3[CH:3]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C1c2ccc(F)cc2C(=O)c2cc3ccccc3cc21
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1c2ccc(N3CCCCC3)cc2C(=O)c2cc3ccccc3cc21

Procedure:
1 g (3.62 mmol) of 2-fluoro-naphthacene-5,12-dione, 0.92 g (10.86 mmol) of piperidine, 1.50 g (10.86 mmol) of potassium carbonate and 10 ml of DMSO are stirred at a bath temperature of 60° C. for 45 minutes. After cooling, the mixture is poured onto water and the orange product is filtered off. The crystals are dissolved in tetrahydrofuran (THF)/toluene and the solution is dried over sodium sulfate and evaporated. The residue is recrystallized from toluene/pentane. Yield: 1.11 g (90%); melting point 230°-233° C.
Reaction SMILES: [F:1][C:2]1([CH3:19])[CH2:7][C:6]([F:9])([F:8])[C@:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])([CH3:10])[NH:4][C:3]1=[O:18].FC(F)(F)C(O)=O.OS(O)(=O)=O.[N+:32]([O-])([OH:34])=[O:33].[OH-].[Na+]>>[F:1][C:2]1([CH3:19])[CH2:7][C:6]([F:9])([F:8])[C@:5]([C:11]2[CH:16]=[C:15]([N+:32]([O-:34])=[O:33])[CH:14]=[CH:13][C:12]=2[F:17])([CH3:10])[NH:4][C:3]1=[O:18]
Reactant: CC1(F)CC(F)(F)[C@@](C)(c2ccccc2F)NC1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CC1(F)CC(F)(F)[C@@](C)(c2cc([N+](=O)[O-])ccc2F)NC1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.2 %

Procedure:
(6R)-3,5,5-Trifluoro-6-(2-fluorophenyl)-3,6-dimethylpiperidin-2-one (1.86 g, 6.76 mmol) (1:1.8 mixture of diastereomers) was suspended in trifluoroacteic acid (11.5 ml, 149 mmol). The mixture was cooled to 0° C. and concentrated H2SO4 (2.86 ml, 52.0 mmol, 97%) was added. Finally, fuming HNO3 (0.33 ml, 7.4 mmol) was added in a dropwise manner and the reaction was stirred at 0° C. for 10 min. The reaction mixture was poured onto 150 g ice and basified to pH>11 using 5 M NaOH. The resulting suspension was extracted with ethyl acetate (250 mL). The phases were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organics were washed with a solution of saturated aqueous NH4Cl (50 mL) and water (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to afford (6R)-3,5,5-trifluoro-6-(2-fluoro-5-nitrophenyl)-3,6-dimethylpiperidin-2-one (2.08 g, 6.50 mmol, 96% yield) (1:1.8 mixture of diastereomers) LC-MS (m/z) 321.1 (MH+) tR=0.62 minutes (Method B).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[CH2:11]([N:18]=[C:19]=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][C:19]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C=NCc1ccccc1
Reactant: NC(=O)CC[C@H](N)C(=O)O
Product: NC(=O)CC[C@H](NC(=O)NCc1ccccc1)C(=O)O
Yield: 67.9 %

Procedure:
Preparation from L-(+)-glutamine (5.39 g, 36.9 mmol) and benzyl isocyanate (4.96 g, 36.9 mmol) (final pH value after 24 h stirring: 8-9) gave N2-[(benzylamino)carbonyl]-L-glutamine (7.0 g, 68%, white solid).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[N:11][N:12]=2)=[CH:4][CH:3]=1.[CH:19]1([NH:22][C:23](=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:25]=2)[CH2:21][CH2:20]1>>[CH:19]1([NH:22][C:23]([C:24]2[CH:29]=[C:28]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:9][C:10]([CH2:13][N:14]5[CH2:18][CH2:17][CH2:16][CH2:15]5)=[N:11][N:12]=4)=[CH:4][CH:3]=3)[C:27]([CH3:30])=[CH:26][CH:25]=2)=[O:40])[CH2:20][CH2:21]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Ic1ccc(-c2nnc(CN3CCCC3)o2)cc1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN3CCCC3)o2)cc1

Procedure:
Example 12 was prepared from 2-(4-iodophenyl)-5-pyrrolidin-1-ylmethyl-[1,3,4]oxadiazole (Intermediate 8) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)benzamide (Intermediate 17).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:9]=[C:8]([C:10]([C:12]2[CH:20]=[C:19]3[C:15]([CH:16]=[C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[NH:18]3)=[CH:14][CH:13]=2)=[O:11])[S:7][C:6]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[OH-].[Na+]>CO.C1COCC1>[C:27]1([C:6]2[S:7][C:8]([C:10]([C:12]3[CH:20]=[C:19]4[C:15]([CH:16]=[C:17]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[NH:18]4)=[CH:14][CH:13]=3)=[O:11])=[CH:9][C:5]=2[CH2:4][C:3]([OH:33])=[O:2])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)Cc1cc(C(=O)c2ccc3cc(-c4ccccc4)[nH]c3c2)sc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cc1cc(C(=O)c2ccc3cc(-c4ccccc4)[nH]c3c2)sc1-c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.8 %

Procedure:
To a stirred solution of 0.44 g (0.97 mmol) of 23 in 7 mL of MeOH and 7 mL of THF was added 1.5 mL (1.5 mmol) of 1 N NaOH solution. The resulting solution was stirred at room temperature for 4 h. The solvent was removed in vacuo, and the residue was diluted with 10 mL of H2O, acidified to pH˜3 with 1N HCl, and extracted with 30 mL of EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/Hex 1:1) to afford 0.36 g (87%) of 8: mp 238-240° C.; 1H NMR (400 MHz, DMSO-d6) δ 12.5 (brs, 1H), 12.04 (s, 1H), 8.00 (s, 1H), 7.93 (d, J=7.4 Hz, 2H), 7.80 (s, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.59-7.48 (m, 9H), 7.38 (t, J=7.1 Hz, 1H), 7.07 (d, J=1.2 Hz, 1H), 3.69 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 186.6, 172.0, 147.4, 141.6, 141.0, 136.3, 132.6, 132.2, 131.9, 131.4, 130.4, 129.2, 129.1, 128.8, 128.3, 125.6, 125.4, 120.5, 99.3, 34.1; IR (KBr) cm−1 3417, 3054, 1713, 1596.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]3[CH2:16][CH2:15][CH:14]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH3:25])=[C:19]([F:26])[C:18]=4[F:27])[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.O.C(O)CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:24]([O:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]2[CH2:15][CH2:16][CH:11]([CH:8]3[CH2:9][CH2:10][C:5]4([O:1][CH2:2][CH2:3][O:4]4)[CH2:6][CH2:7]3)[CH2:12][CH:13]=2)=[C:18]([F:27])[C:19]=1[F:26])[CH3:25]
Reactant: CCOc1ccc(C2CCC(C3CCC4(CC3)OCCO4)CC2)c(F)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: OCCO
Product: CCOc1ccc(C2=CCC(C3CCC4(CC3)OCCO4)CC2)c(F)c1F

Procedure:
250 g of crude 4-(1,4-dioxaspiro[4.5]dec-8-yl)-1-(4-ethoxy-2,3-difluorophenyl)cyclohexan in 1000 ml of toluene are heated on a water separator for 3 h together with 80.0 ml (1.43 mol) of ethylene glycol with addition of 12.0 g (0.06 mol) of p-toluenesulfonic acid monohydrate. After cooling, the batch is washed successively with water, sat. sodium hydrogencarbonate solution and sat. sodium chloride solution. The solution is dried using sodium sulfate and concentrated to dryness. The crude product is crystallised from acetonitrile, giving 8-[4-(4-ethoxy-2,3-difluorophenyl)cyclohex-3-enyl]-1,4-dioxaspiro[4.5]decane as colourless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:16])[CH:14]=O)[CH:7]=[CH:6]2.Cl.[NH2:18][C@H:19]([C:22]([OH:24])=[O:23])[CH2:20][SH:21].C([O-])(=O)C.[K+]>CC(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@@H:13]([CH:14]1[NH:18][C@H:19]([C:22]([OH:24])=[O:23])[CH2:20][S:21]1)[CH3:16])[CH:7]=[CH:6]2
Reactant: N[C@@H](CS)C(=O)O
Reactant: COc1ccc2cc([C@H](C)C=O)ccc2c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc2cc([C@H](C)C3N[C@H](C(=O)O)CS3)ccc2c1
Temperature: 25 °C

Procedure:
A solution of (2S)-2-(6-methoxy-2-napthyl)-propanal (8.2 g; 38.3 mmoles) in acetone (50 ml) is added dropwise to a solution of (R)-cysteine hydrochloride (5.94 g; 37.6 mmoles) and of potassium acetate (3.69 g; 37.6 mmoles) in 100 ml of water and acetone (1:1 v/v) kept under stirring at room temperature.
Reaction SMILES: [Cl-].[C:2]([O:6][C:7](=[O:10])[CH2:8][Zn+])([CH3:5])([CH3:4])[CH3:3].CCOCC.Br[C:17]1[C:43]([F:44])=[CH:42][C:20]([O:21][CH2:22][CH2:23][C@@H:24]2[CH2:26][C@@H:25]2[CH:27]2[CH2:32][CH2:31][N:30]([C:33]3[N:38]=[CH:37][C:36]([O:39][CH2:40][CH3:41])=[CH:35][N:34]=3)[CH2:29][CH2:28]2)=[CH:19][C:18]=1[F:45].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:40]([O:39][C:36]1[CH:35]=[N:34][C:33]([N:30]2[CH2:29][CH2:28][CH:27]([C@H:25]3[CH2:26][C@H:24]3[CH2:23][CH2:22][O:21][C:20]3[CH:42]=[C:43]([F:44])[C:17]([CH2:8][C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:10])=[C:18]([F:45])[CH:19]=3)[CH2:32][CH2:31]2)=[N:38][CH:37]=1)[CH3:41]
Reactant: CC(C)(C)OC(=O)C[Zn+]
Reactant: CCOc1cnc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(Br)c(F)c3)CC2)nc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOc1cnc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)OC(C)(C)C)c(F)c3)CC2)nc1
Temperature: 65 °C

Procedure:
A 0.5 M solution of 2-(tert-butyloxy)-2-oxoethylzinc chloride in Et2O (43 mL, 21.2 mmol) was added to a mixture of 2-(4-((1R,2S)-2-(2-(4-bromo-3,5-difluorophenoxy)ethyl)cyclopropyl)piperidin-1-yl)-5-ethoxypyrimidine (3.4 g, 7.05 mmol), Pd2(dba)3 (0.484 g, 0.529 mmol), and X-PHOS (504 mg, 1.06 mmol) in anhydrous THF (10 mL). The mixture was stirred and heated at 65° C. overnight. The mixture was cooled to rt and filtered through celite, washing the filtercake with excess EtOAc. The volatiles were removed and the residue was purified by column chromatography on silica gel (KP-Sil 100 g SNAP column, Biotage system) eluting with 5-40% EtOAc:hexanes over 12 CV to afford the title compound. LC/MS (m/z): 518 (M+H)+.
Reaction SMILES: [ClH:1].[O:2]([C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH2:18][C:19]2([C:28]([OH:30])=O)[CH2:24][CH2:23][N:22]([CH2:25][C:26]#[CH:27])[CH2:21][CH2:20]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.[NH2:50][OH:51]>CN(C=O)C.O>[ClH:1].[OH:51][NH:50][C:28]([C:19]1([CH2:18][S:15]([C:12]2[CH:13]=[CH:14][C:9]([O:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[CH:10][CH:11]=2)(=[O:16])=[O:17])[CH2:24][CH2:23][N:22]([CH2:25][C:26]#[CH:27])[CH2:21][CH2:20]1)=[O:30]
Reactant: C#CCN1CCC(CS(=O)(=O)c2ccc(Oc3ccccc3)cc2)(C(=O)O)CC1
Reactant: NO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C#CCN1CCC(CS(=O)(=O)c2ccc(Oc3ccccc3)cc2)(C(=O)NO)CC1
Reaction time: 48 h

Procedure:
Part H: To a solution of the carboxylic acid of Part G (460 mg, 1.1 mmol) in DMF (10 mL) was added N-hydroxbenzotriazole.H2O (180 mg, 1.33 mmol) and after 5 minutes of stirring was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (299 mg, 1.56 mmol). After 10 additional minutes 4-methylmorpholine (0.49 mL, 4.45 mmol) and 50% aqueous hydroxylamine (0.22 mL, 3.34 mmol) and the solution stirred for 24 hours. An additional aliquot of each reagent was added and the solution stirred for an additional 48 hours. The solution was diluted with H2O, extracted with chloroform, washed with satd. NaCl and dried over MgSO4. Reverse phase HPLC (acetonitrile/H2O) provided the hydroxamate compound as a white solid (N-hydroxy-4-[[(4-phenoxyphenyl)-sulfonyl]-methyl]-1-(2-propynyl)-4-piperidinecarboxamide, monohydrochloride; 200 mg, 42%). HRMS calc'd for C22H24N2O5S: 429.1489, found 429.1480. Anal. calc'd for C22H24N2O5S: C, 61.66; H, 5.64; N, 6.54; S, 7.48. Found: C, 61.33; H, 5.68; N, 6.36; S, 7.35.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.Cl.[C:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][CH:27]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:28]([OH:30])=[O:29])(=[O:19])[CH3:18].C1C=CC2N(O)N=NC=2C=1.[N:47]12[CH2:54][CH2:53][CH:50]([CH2:51][CH2:52]1)[C@@H:49](O)[CH2:48]2>C1COCC1>[N:47]12[CH2:54][CH2:53][CH:50]([CH2:51][CH2:52]1)[C@@H:49]([O:29][C:28](=[O:30])[CH:27]([NH:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:17](=[O:19])[CH3:18])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:48]2
Reactant: CC(=O)c1ccccc1NC(C(=O)O)c1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(=O)c1ccccc1NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107 %

Procedure:
PS-DCC (890 mg, 1.184 mmol, loading: 1.33 mmol/g) is suspended in dry THF (10 mL). (2-Acetyl-phenylamino)-phenyl-acetic acid hydrochloride (I63) (181 mg, 0.59 mmol), HOBt (181 mg, 1.18 mmol), and (R)-quinuclidin-3-ol (226 mg, 1.78 mmol) are added and the mixture is shaken at RT overnight. PS-DCC is filtered off and the filtrate is evaporated. The residue is dissolved in EtOAc and washed with sat. NaHCO3, water and brine, dried over Na2SO4, filtered and evaporated. The resulting crude oil is purified by flash chromatography (DCM/MeOH=9/1) to afford the title compound as a colorless oil (239 mg, quantitative yield, mixture of diastereoisomers).