Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH2:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13](=[N:17][O:18][CH3:19])[C:14]([OH:16])=O)[N:8]=1.[NH2:20][CH:21]1[C:39](=[O:40])[N:23]2[C:24]([C:36]([OH:38])=[O:37])=[C:25]([CH:28]([S:30][C:31]3[NH:35][N:34]=[N:33][N:32]=3)[CH3:29])[CH2:26][S:27][C@H:22]12.C[Si](CC(N)=O)(C)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O.CN(C)C=O>[NH2:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13](=[N:17][O:18][CH3:19])[C:14]([NH:20][CH:21]2[C:39](=[O:40])[N:23]3[C:24]([C:36]([OH:38])=[O:37])=[C:25]([CH:28]([S:30][C:31]4[NH:32][N:33]=[N:34][N:35]=4)[CH3:29])[CH2:26][S:27][C@H:22]23)=[O:16])[N:8]=1
Reactant: CON=C(C(=O)O)c1nccc(N)n1
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)CC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(C)Sc3nnn[nH]3)CS[C@H]12)c1nccc(N)n1
Temperature: -20 °C
Reaction time: 0.75 h
Yield: 19.5 %

Procedure:
Phosphoryl chloride (500 mg.) was added dropwise to a suspension of 2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetic acid (syn isomer) (250 mg.) in ethyl acetate (5 ml.) at 0° to 6° C. with stirring and the stirring was continued at the same temperature for 45 minutes. To this solution was added dropwise N,N-dimethylformamide (0.7 ml.) over a period of 6 minutes at 0° to 6° C. with stirring, and the stirring was continued at the same temperature for 40 minutes. To the resultant solution was added all at once a solution of 7-amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (365 mg.) and trimethylsilylacetamide (1.5 g.) in ethyl acetate (7 ml.) under cooling at -20° C., and the mixture was stirred at 0° to 6° C. for an hour. The reaction mixture was poured into water (20 ml.) and adjusted to pH 4 with an aqueous solution of sodium bicarbonate. The aqueous layer was separated out and the remaining organic layer was extracted with water. The aqueous layers were combined together and the ethyl acetate remained in the aqueous solution was removed therefrom under reduced pressure. The aqueous solution was subjected to column chromatography on a non-ionic adsorption resin, "Diaion HP-20" (Trade Mark, manufactured by Mitsubishi Chemical Industry Ltd.) (20 ml.). After the column was washed with water, elution was carried out with 5-10% aqueous methanol (100 ml.), 20% aqueous methanol (150 ml.) and 20 to 30% aqueous methanol (150 ml.) in turn, and the fractions containing the desired compound were collected and evaporated to dryness under reduced pressure. The resultant residue was lyophilized to give 7-[ 2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer) (110 mg.), mp. 155° to 158° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=3)[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:19][CH2:20][C:21]1([OH:29])[CH2:26][CH2:25][CH2:24][C:23]([CH3:28])([CH3:27])[CH2:22]1.C(#N)C.C(=O)(O)[O-].[Na+]>>[CH3:27][C:23]1([CH3:28])[CH2:24][CH2:25][CH2:26][C:21]([CH2:20][NH:19][C:2]2[C:3]3[CH2:11][N:10]([C:12]4[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=4)[CH2:9][CH2:8][C:4]=3[N:5]=[CH:6][N:7]=2)([OH:29])[CH2:22]1
Reactant: CC1(C)CCCC(O)(CN)C1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(N2CCc3ncnc(NCC4(O)CCCC(C)(C)C4)c3C2)nc1
Temperature: 25 °C

Procedure:
4-chloro-5,6,7,8-tetrahydro-6-(5-methylpyridin-2-yl)pyrido[4,3-d]pyrimidine (0.030 g, 0.00012 mol) and 1-aminomethyl-3,3-dimethyl-cyclohexanol (0.022 g, 0.00014 mol) in acetonitrile (3 mL, 0.06 mol) was heated via microwave in a sealed tube at 180° C. for a total of 2 hours and five minutes. The reaction mixture was cooled to room temperature and poured into saturated sodium bicarbonate. The mixture was extracted with equal amounts of ethyl acetate and the organic layer was dried over magnesium sulfate. The residue was purified by flash chromatography over silica gel methanol/dichloromethane (0-10%) to yield the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)(=O)[CH3:2].C([O-])(=O)C([O-])=O.[OH-].[K+].O.NN.C(O)COCCOCCO>>[CH2:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc(OC2CCNCC2)cc1
Agent: NN
Agent: O=C([O-])C(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: OCCOCCOCCO
Product: CCc1ccc(OC2CCNCC2)cc1
Temperature: 25 °C
Yield: 38.6 %

Procedure:
A solution of 4-(4-acetylphenoxy)piperidine (liberated from 15.0 g, 48.5 mmol, of the oxalate), 7.45 g of potassium hydroxide, 5.39 ml of 85% hydrazine hydrate and 54 ml of triethyleneglycol was stirred at reflux for 1 hour. The mixture was then cooled to room temperature and the flask fitted with a distillation apparatus. The temperature was then raised to 190°-195° and water removed by distillation. The mixture was stirred at 190°-195° for 3 hours and the mixture allowed to cool to room temperature. The mixture was diluted with water, extracted twice with ether and with 1N HCl, made basic with saturated sodium carbonate, extracted with ether and dried over potassium carbonate. Filtration followed by evaporation of the solvent provided an oil. Kugelrohr distillation at 114°-116°/1 mm provided 3.84 g (18.7 mmol, 38.6%) of 4-(4-ethylphenoxy)piperidine, m.p. 37-41.
Reaction SMILES: [S:1]1[N:5]=[CH:4][C:3]([C:6](=O)[C:7]([OH:9])=[O:8])=[N:2]1.Cl.[NH2:12][OH:13].[OH-].[Mg+2].[OH-]>>[OH:13][N:12]=[C:6]([C:3]1[CH:4]=[N:5][S:1][N:2]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)C(=O)c1cnsn1
Reactant: NO
Agent: Cl
Agent: [Mg+2]
Agent: [OH-]
Product: O=C(O)C(=NO)c1cnsn1
Yield: 97.1 %

Procedure:
2-(1,2,5-Thiadiazol-3-yl)glyoxylic acid (7.4 g.) and hydroxylamine hydrochloride (3.1 g.) were reacted in the presence of magnesium hydroxide (4.7 g.) according to a similar manner to that of Example 6(a)(3) to give 2-hydroxyimino-2-(1,2,5-thiadiazol-3-yl)acetic acid (syn isomer) (7.5 g.).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:16])([CH3:15])[CH3:14])C1C=CC=CC=1.CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C.CC([O-])=O>CO>[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:16])([CH3:15])[CH3:14]
Reactant: CC(C)(O)[C@@H]1CCCN1Cc1ccccc1
Agent: CC(=O)[O-]
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Solvent: CO
Product: CC(C)(O)[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (S)-2-(1-benzylpyrrolidin-2-yl)propan-2-ol (1.38 g, 6.29 mmol) in MeOH (50 mL) was added palladium hydroxide, 20 wt % pd (dry basis) on carbon, wet, degussa type e101 ne/w (230 mg, 1.64 mmol) and acetic acid glacial (690 μl, 12.0 mmol). The reaction mixture was stirred at RT under 1 atm of H2 for 24 h. The reaction mixture was filtered through a pad of celite and washed with MeOH. The solvent was evaporated and the residue was partitioned between 2 N NaOH and EtOAc. The aqueous layer was extracted with EtOAc (2×) and the combined organic layer was dried (Na2SO4) and concentrated. The crude product was chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 50% to 100% MeOH in EtOAc, to provide (S)-2-(pyrrolidin-2-yl)propan-2-ol as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]([CH2:10][CH3:11])[C:5]([F:9])=[C:6]([Cl:8])[N:7]=1.[Mn]([O-])(=O)(=O)=O.[K+].Cl.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>O>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([F:9])=[C:4]([CH2:10][CH3:11])[N:3]=1
Reactant: CCC1NC(Cl)=NC(Cl)=C1F
Agent: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: O=S([O-])S(=O)(=O)[O-]
Solvent: O
Product: CCc1nc(Cl)nc(Cl)c1F

Procedure:
To the solution obtained as the product of part (ii) was added a solution of potassium permanganate (23 g) in water (260 ml) over 2 hours, keeping the temperature of the reaction below 20° C. 5N hydrochloric acid (30 ml) was then added followed by a solution of sodium metabisulphite (14 g) in water (42 ml). After decolourisation of the mixture the product was extracted into ethyl acetate (250 ml). The organic layer was then concentrated to give an oil. The oil was partitioned between dichloromethane (50 ml) and 2N sodium hydroxide (105 ml) and the organic layer was washed with 5% brine (100 ml). The organic layer was concentrated to give a solution of the title compound which was used directly in the next step.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:29])[N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][OH:28])[CH:22]=2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)#[N:2].[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:29])[N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][O:28][C:30](=[O:32])[CH3:31])[CH:22]=2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)#[N:2]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(-c2cccc(CO)c2)c1=O
Solvent: c1ccncc1
Product: CC(=O)OCc1cccc(-n2cc(-c3ccccn3)cc(-c3ccccc3C#N)c2=O)c1
Temperature: 25 °C

Procedure:
To 56 mg of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-(3-hydroxymethylphenyl)-1,2-dihydropyridin-2-one were added 1 ml of acetic anhydride and 1 ml of pyridine and the mixture was stirred at room temperature for one night. The reaction solution was concentrated in vacuo and purified by an NH silica gel chromatography (hexane-ethyl acetate system) to give 30 mg of the title compound.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.C(O)(=O)C>C1COCC1>[C:1]1([N:7]2[C:11]([B:17]([OH:22])[OH:18])=[CH:10][CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-n2cccn2)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: OB(O)c1ccnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
To a solution of 1-phenyl-1H-pyrazole (20.0 g) in THF (700 mL) was added dropwise n-butyllithium (2.5 M hexane solution, 58.3 mL) at −78° C. under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 30 min. To the reaction mixture was added triisopropyl borate (52.2 g) at −78° C., and the mixture was stirred at the same temperature for 1 hr, gradually warmed to room temperature, and stirred at room temperature for 20 hr. The reaction mixture was adjusted to pH 5 with acetic acid (20 mL) and concentrated to give the title compound (25.0 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15](O)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CC[N:36]([CH:40]([CH3:42])[CH3:41])[CH:37]([CH3:39])[CH3:38].C(NC(C)C)(C)C>O1CCCC1.CN(C1C=CN=CC=1)C.CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15](=[O:16])[N:36]([CH:40]([CH3:42])[CH3:41])[CH:37]([CH3:39])[CH3:38])[CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)N(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C(C)C

Procedure:
To a suspension of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.10 g) in tetrahydrofuran (5 ml) was added DMF (0.005 ml) and oxalyl chloride (0.175 ml). After 0.5 h DIPEA (0.13 ml), diisopropylamine (0.20 ml) and DMAP (0.002 g) were added. After 18 h the mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The combined organic phases were washed with brine and dried over magnesium sulphate. Filtration and evaporation gave the crude product which was purified by flash column chromatography on silica eluting with cyclohexane/ethyl acetate (1:3). This afforded the title compound as a colourless gum (0.078 g).
Reaction SMILES: COC1C=CC(CN(CC2C=CC(OC)=CC=2)C2N=CC(C3C4CCNC=4N=C(N4CCOCC4)N=3)=CN=2)=CC=1.N1C=CC=CC=1.ClC(Cl)(O[C:51](=O)[O:52][C:53](Cl)(Cl)Cl)Cl.NC1C(F)=CC(C(N2CCN(CC)CC2)=O)=CC=1F.[CH2:78]([N:80]1[CH2:85][CH2:84][N:83]([C:86]([C:88]2[CH:93]=[C:92]([F:94])[C:91]([NH:95][C:96]([N:98]3[C:102]4[N:103]=[C:104]([N:132]5[CH2:137]COC[CH2:133]5)[N:105]=[C:106]([C:107]5[CH:108]=[N:109][C:110]([N:113](CC6C=CC(OC)=CC=6)CC6C=CC(OC)=CC=6)=[N:111][CH:112]=5)[C:101]=4[CH2:100][CH2:99]3)=[O:97])=[C:90]([F:138])[CH:89]=2)=[O:87])[CH2:82][CH2:81]1)[CH3:79].C(N[C@H](C(O)=O)CS)(=O)C>ClCCl.C(O)(C(F)(F)F)=O>[CH2:78]([N:80]1[CH2:85][CH2:84][N:83]([C:86]([C:88]2[CH:89]=[C:90]([F:138])[C:91]([NH:95][C:96]([N:98]3[C:102]4[N:103]=[C:104]([N:132]5[CH2:137][CH2:51][O:52][CH2:53][CH2:133]5)[N:105]=[C:106]([C:107]5[CH:112]=[N:111][C:110]([NH2:113])=[N:109][CH:108]=5)[C:101]=4[CH2:100][CH2:99]3)=[O:97])=[C:92]([F:94])[CH:93]=2)=[O:87])[CH2:82][CH2:81]1)[CH3:79]
Reactant: CCN1CCN(C(=O)c2cc(F)c(NC(=O)N3CCc4c(-c5cnc(N(Cc6ccc(OC)cc6)Cc6ccc(OC)cc6)nc5)nc(N5CCOCC5)nc43)c(F)c2)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: CC(=O)N[C@@H](CS)C(=O)O
Agent: CCN1CCN(C(=O)c2cc(F)c(N)c(F)c2)CC1
Agent: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN1CCN(C(=O)c2cc(F)c(NC(=O)N3CCc4c(-c5cnc(N)nc5)nc(N5CCOCC5)nc43)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (2.50 g, 4.63 mmol) in dichloromethane (50 ml), pyridine (749 ml, 9.27 mmol) was added, and triphosgene (2.75 g, 9.27 mmol) was added under ice cooling. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure. To this, dichloroethane (100 ml) was added, and (4-amino-3,5-difluoro-phenyl)-(4-ethyl-piperazin-1-yl)-methanone (4.99 g, 18.5 mmol) obtained in Step D was added, followed by refluxing for 14 hours. The solvent was distilled off under reduced pressure, followed by purification by silica gel column chromatography (dichloromethane/methanol=50/1 to 10/1), to obtain a mixture of 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid [4-(4-ethyl-piperazine-1-carbonyl)-2,6-difluoro-phenyl]-amide and (4-amino-3,5-difluoro-phenyl)-(4-ethyl-piperazin-1-yl)-methanone. This was dissolved in TFA (40 ml), and N-acetylcysteine (1.13 g, 6.95 mmol) was added, followed by refluxing for 14 hours. The solvent was distilled off under reduced pressure. 5M-NaOH aqueous solution was added to adjust the pH to 8, and 500 ml of water was added, followed by extraction with dichloromethane (1 l×3). The solvent was distilled off under reduced pressure. This was purified by silica gel column chromatography (dichloromethane/methanol=40/1 to 10/1), followed by further washing with methanol (100 ml), to obtain the desired compound as a yellow solid (1.31 g, 51%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][S:17]([CH2:20][CH3:21])(=[O:19])=[O:18])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.[CH3:29]C(S(Cl)(=O)=O)C.C(S(Cl)(=O)=O)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][S:17]([CH:20]([CH3:29])[CH3:21])(=[O:19])=[O:18])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: CCS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Reactant: CC(C)S(=O)(=O)Cl
Agent: CCS(=O)(=O)Cl
Product: CC(C)S(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(isopropylsulfonylmethyl)benzamide was prepared using the same procedure as N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(ethylsulfonylmethyl)benzamide except propane-2-sulfonyl chloride was substituted for ethanesulfonyl chloride. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(isopropylsulfonylmethyl)benzamide. MS (Q1) 429 (M)+.
Reaction SMILES: [OH-].[K+].[CH2:3]([C:5]([S:26]([CH3:29])(=[O:28])=[O:27])([CH2:11][CH2:12][N:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][C:14]1=[O:25])[C:6]([O:8]CC)=[O:7])[CH3:4].O1CCCC1CO.O.Cl>O>[CH2:3]([C:5]([S:26]([CH3:29])(=[O:28])=[O:27])([CH2:11][CH2:12][N:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][C:14]1=[O:25])[C:6]([OH:8])=[O:7])[CH3:4]
Reactant: CCOC(=O)C(CC)(CCn1ccc(-c2ccccc2)cc1=O)S(C)(=O)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: OCC1CCCO1
Solvent: O
Product: CCC(CCn1ccc(-c2ccccc2)cc1=O)(C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
Potassium hydroxide (37 mg, 0.66 mmol, 6.0 equiv) was added to a solution of ethyl 2-ethyl-2-(methylsulfonyl)-4-(2-oxo-4-phenylpyridin-1(2H)-yl)butanoate (43 mg, 0.11 mmol, 1.0 equiv) in 2:2:1 tetrahydrofuran-methanol-water (2.5 mL) at 0° C. The reaction was allowed to warm to room temperature and stir overnight. The reaction was concentrated under reduced pressure to provide a wet residue that was diluted with water (5 mL) and acidified (to pH=2) with 1.0 hydrochloric acid. The resulting white precipitate was filtered, washed with water, and dried under reduced pressure to provide the title compound (34 mg, 85%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.09 (t, J=7.52 Hz, 3H) 1.42 (s, 3H) 1.93-2.07 (m, 1H) 2.23-2.37 (m, 2H) 2.55 (d, J=5.66 Hz, 1H) 3.25 (s, 3H) 4.10-4.24 (m, 2H) 4.47-4.59 (m, 2H) 6.63-6.67 (m, 1H) 6.90 (d, J=1.95 Hz, 1H) 7.44-7.50 (m, 4H) 7.54-7.62 (m, 2H).
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([S:16]C(=O)N(C)C)=[C:11]([Cl:22])[CH:10]=1)(C)(C)C.[OH-].[K+].Cl>C(O)C>[Cl:15][C:13]1[CH:14]=[C:9]([CH2:8][CH2:7][OH:6])[CH:10]=[C:11]([Cl:22])[C:12]=1[SH:16]
Reactant: CN(C)C(=O)Sc1c(Cl)cc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: OCCc1cc(Cl)c(S)c(Cl)c1
Temperature: 95 °C
Yield: 76.2 %

Procedure:
A solution of dimethyl-thiocarbamic acid S-{4-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-2,6-dichloro-phenyl}ester (72) (2.0 g, 3.76 mmol) in ethanol (6.0 mL) was treated with a 3N aqueous potassium hydroxide solution (4.4 mL, 13.2 mmol). The reaction was then heated to 95° C. for 18 h. At this time, the reaction was poured onto water (200 mL), acidified to pH=2 with a 3N aqueous hydrochloric acid solution, and then extracted into methylene chloride (3×100 mL). The organics were washed with water (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried with magnesium sulfate, filtered, and concentrated under vacuum. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80:20 petroleum ether/ethyl acetate) afforded 2-(3,5-dichloro-4-mercapto-phenyl)-ethanol (73) (639 mg, 76%) as a white solid; EI(+)-HRMS m/e calcd for C8H8Cl2OS (M+) 221.9673, found 221.9672. Exact Mass=221.9673; Molecular Weight=223.12
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=[O:4].Br[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:38])[CH:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>CN(C=O)C>[C:26]1([CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:24]([NH:23][CH2:22][CH2:21][CH2:20][N:15]2[CH2:16][CH2:17][CH:12]([C:9]3[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH:2]([CH3:18])[CH3:1])=[CH:7][CH:8]=3)[CH2:13][CH2:14]2)=[O:38])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)C(=O)Nc1ccc(C2CCNCC2)cc1
Reactant: O=C(NCCCBr)C(c1ccccc1)c1ccccc1
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)C(=O)Nc1ccc(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15.8 %

Procedure:
A mixture of 2-methyl-N-[4-(4-piperidinyl)phenyl]propanamide (50.0 mg, 2.0 mmol), N-(3-bromopropyl)-2,2-diphenylacetamide (64.2 mg, 0.2 mmol), K2CO3 (55.0 mg, 4.0 mmol), and Nal (45.0 mg, 0.3 mmol) in 2 mL of DMF was stirred at room temperature for 10 minutes followed by heating to 80–90° C. for 12 h. The reaction mixture was cooled to room temperature and purified by preparative TLC (silica gel, EtOAc/NH3 (2 M in MeOH); 95:5) to afford N-[4-(1-{3-[(diphenylacetyl)amino]propyl}-4-piperidinyl)phenyl]-2-methylpropanamide as a colorless oil (15.7 mg, 32%): ESMS m/e: 498.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([NH:17]C(=O)OC(C)(C)C)[CH2:12]1)(=[O:10])=[O:9].[ClH:25].CCOCC>C(Cl)Cl>[ClH:25].[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([NH2:17])[CH2:12]1)(=[O:10])=[O:9]
Reactant: CC(C)(C)OC(=O)NC1CCCN(S(=O)(=O)c2ccccc2Br)C1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: NC1CCCN(S(=O)(=O)c2ccccc2Br)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of racemic tert-butyl (1-((2-bromophenyl)sulfonyl)piperidin-3-yl)carbamate (82 mg, 0.20 mmol) in CH2Cl2 (5 mL) was treated with 2 N HCl/Et2O (1 mL, 2 mmol) and stirred 16 hours at rt. The reaction mixture was then concentrated to dryness to give the title compound in quantitative yield. The product was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:16]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=2)=[N:17][C:18]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([O:27][CH3:28])[CH:26]=2)=[N:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:37](Cl)(=[O:39])[CH3:38].C(N(CC)CC)C>O1CCCC1.CCOC(C)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:16]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37](=[O:39])[CH3:38])[CH:31]=2)=[N:17][C:18]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([O:27][CH3:28])[CH:26]=2)=[N:19][CH:20]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cncc(-c2ncc(NC[C@@H]3CCCN3C(=O)OC(C)(C)C)c(Oc3cccc(O)c3)n2)c1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cncc(-c2ncc(NC[C@@H]3CCCN3C(=O)OC(C)(C)C)c(Oc3cccc(OC(C)=O)c3)n2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To a solution of Compound 10a (50 mg; 0.1 mmol) in tetrahydrofuran (5 mL), cooled to −78° C., was added acetyl chloride (0.009 mL; 0.12 mmol) and triethylamine (0.035 mL; 0.25 mmol). The mixture was stirred at −78° C. for 1 hour. Diluted the resulted mixture with EtOAc and H2O. The organic phase was washed sequentially with H2O, and then dried over Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a EtOAc-heptane gradient to afford Compound 10b (43 mg; 80% yield). MS: m/z 536.0 (M+H)+.