Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]([NH:18][C:19]([C@@H:21]([NH:35]C(OC(C)(C)C)=O)[CH2:22][C:23]1[N:24]=[CH:25][N:26](C(OC(C)(C)C)=O)[CH:27]=1)=[O:20])[C@@H:9]([OH:17])[CH2:10][C@@H:11]([CH:14]([CH3:16])[CH3:15])[CH:12]=[CH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl.O1CCOCC1>[NH2:35][C@@H:21]([CH2:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1)[C:19]([NH:18][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]([OH:17])[CH2:10][C@@H:11]([CH:14]([CH3:15])[CH3:16])[CH:12]=[CH2:13])=[O:20]
Reactant: C=C[C@@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1cn(C(=O)OC(C)(C)C)cn1)NC(=O)OC(C)(C)C)C(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=C[C@@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)Cc1c[nH]cn1)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
1 g (1.7 mmol) of t-butyl 4-[(S)-2-[[(1S,2S,4S)-1-benzyl-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-(1-t-butoxyformamido)ethyl]imidazole-1-carboxylate were dissolved in 7 ml of 5N hydrogen chloride in dioxane and subsequently stirred at room temperature for 2 hours. Thereafter, the reaction mixture was poured into sodium carbonate solution and extracted with ethyl acetate. The organic extract was dried and evaporated and the residue was chromatographed on silica gel with a 3:1 mixture of methylene chloride and methanol, to obtain 340 mg (52%) of (S)-α-amino-N-[(1S,2S,4S)-1-benzyl-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propion-amide as a foam, MS; 385 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C([O:19][CH:20]=[C:21]([C:27](OCC)=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])C>>[C:4]([C:3]1[CH:12]=[C:13]([Cl:16])[CH:14]=[C:15]2[C:2]=1[NH:1][CH:27]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:20]2=[O:19])(=[O:5])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1c[nH]c2c(C(=O)c3ccccc3)cc(Cl)cc2c1=O
Yield: 45.6 %

Procedure:
2-Amino-5-chlorobenzophenone (3.0 g) and diethyl ethoxymethylenemalonate (3.3 g) were reacted in the same manner as in Experimental Example 1 to give 8-benzoyl-6-chloro-3-ethoxycarbonyl-4(1H)-quinolone (2.1 g). The compound (1.4 g) was dissolved in methanol (24 ml). A 10% aqueous solution of NaOH (16 ml) was added to the solution, and the mixture was heated under reflux for 1 hour. After acidification of the mixture with a 10% aqueous solution of HCl, the precipitate was collected by filtration, washed with water and dried to give a carboxylic acid (1.2 g). The carboxylic acid (1.2 g) was suspended in diphenyl ether (30 ml), and the suspension was heated under reflux under a stream of argon at 280° C. for 3 hours. After the reaction mixture was left to cool, a mixed solvent of ether (50 parts) and n-hexane (50 parts) was added, and the crude crystal thus obtained was collected by filtration and recrystallized from chloroform-methanol-n-hexane to give 8-benzoyl-6-chloro-4(1H)-quinolone (compound 18, 0.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:17][CH:18]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19]2)[C:10]([NH:12][C:13]([NH:15][CH3:16])=[O:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:17][CH:18]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19]2)[C:10]([NH:12][C:13]([NH:15][CH3:16])=[O:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC(=O)NC(=O)C(CC1CCC(O)C1)c1ccc(Cl)c(Cl)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CNC(=O)NC(=O)C(CC1CCC(=O)C1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.4 %

Procedure:
A solution of 1-[2-(3,4-dichloro-phenyl)-3-(3-hydroxy-cyclopentyl)-propionyl]-3-methyl-urea (prepared as in Example 35, 60.5 mg, 0.17 mmol) in methylene chloride (1.68 mL) was treated with pyridinium chlorochromate (20 wt. % on basic alumina, 218 mg, 0.20 mmol). The reaction mixture was stirred at 25° C. for 4 h. At this time, the reaction was filtered through a plug of celite (ethyl acetate as eluent). The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 90/10 methylene chloride/methanol) afforded 1-[2-(3,4-dichloro-phenyl)-3-(3-oxo-cyclopentyl)-propionyl]-3-methyl-urea (45.8 mg, 76.1%) as a white solid: mp 70–74° C.; FAB-HRMS m/e calcd for C16H18Cl2N2O3 (M+H)+ 357.0773, found 357.0768.
Reaction SMILES: [Mg+2].[Cl-].[Cl-].[C:4]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2([C:29](O)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:19]=[CH:20][C:21]=1[F:22].S(Cl)(Cl)=O>C(#N)C>[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2([C:29]([CH:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:4]([O:12][CH2:13][CH3:14])=[O:11])=[O:30])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(O)C1(c2ccc(F)c(Cl)c2)CCOCC1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: CCOC(=O)C(C(=O)OCC)C(=O)C1(c2ccc(F)c(Cl)c2)CCOCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
MgCl2 (2.39 g, 25.1 mmol) was added to diethyl malonate (3.45 mL, 22.8 mmol) in ACN (45.7 mL) after cooling the reaction mixture to 0° C. TEA (6.36 mL, 45.7 mmol) was then added dropwise, and the reaction mixture was warmed to ambient temperature and stirred for 2 hours. 4-(3-Chloro-4-fluorophenyl)-tetrahydro-pyran-4-carboxylic acid (5.61 g, 21.7 mmol) was converted to the acid chloride by reaction with thionyl chloride at 70° C. for 1 hour. The acid chloride reaction mixture was concentrated, dissolved in ACN, and added dropwise to the initial reaction mixture. The resulting mixture was stirred at ambient temperature for 2 hours and then quenched with water, acidified with 5N HCl, diluted with 100 mL of diethyl ether, added to a separatory funnel, partitioned with water, washed 2 times with 50 mL of water, separated, dried over Na2SO4, and concentrated in vacuo to give the title (3.87 g) after flash chromatography. MS m/e=401 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[CH3:9][C:10]([CH3:15])([CH3:14])[C:11](Cl)=[O:12]>C(Cl)Cl>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:11](=[O:12])[C:10]([CH3:15])([CH3:14])[CH3:9])=[N:3][CH:4]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(Cl)cn1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 102.8 %

Procedure:
TEA (6.78 mL, 48.6 mmol) was added to a suspension of 2-amino-5-chloropyridine (5.00 g, 38.9 mmol) in DCM (75 mL). The resulting solution was cooled to 0° C. and a solution of 2,2-dimethylpropanoyl chloride (5.74 mL, 46.7 mmol) in DCM (10.0 mL) was added dropwise over a 5 min period. The resulting mixture was allowed to stir at rt for 1 h. The reaction mixture was then transferred to a separatory funnel and washed with a saturated aqueous solution of NaHCO3. The organic solution was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give N-(5-chloropyridin-2-yl)-2,2-dimethylpropanamide (8.0 g, 40 mmol, 99%). LCMS (FA): m/z=215.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([SH:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C:3]=1[F:21].[CH3:22]C1C=CC(S(O)(=O)=O)=CC=1.O>C(OC)(OC)OC>[F:21][C:3]1[C:2]2[N:1]=[CH:22][S:12][C:11]=2[CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[C:4]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(=O)c1cc(S)c(N)c(F)c1Nc1ccccc1F
Solvent: COC(OC)OC
Solvent: O
Product: COC(=O)c1cc2scnc2c(F)c1Nc1ccccc1F
Reaction time: 1 h
Yield: 85.1 %

Procedure:
To a solution of methyl 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-mercaptobenzoate in trimethyl orthoformate (50 mL) was added p-TsOH (0.61 g, 3.17 mmol). The reaction mixture was stirred for 1 h and treated with water (100 mL). The precipitate was filtered off and the filter cake was washed with water to afford the desired product (pale yellow solid, 8.64 g, 85.1% yield for two steps). 1H NMR (400 MHz, CDCl3): δ 9.13 (s, 1H), 8.68 (s, 1H), 8.46 (s, 1H), 7.10 (m, 1H), 7.01 (m, 1H), 6.92 (s, 2H), 3.97 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:29][N:30](C)[C:31](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([NH:25][CH2:26][CH2:27][OH:28])=[O:24])[CH:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:45]>C(OCC)(=O)C.CC(O)C>[ClH:45].[F:1][C:2]1[C:3]([CH2:29][NH:30][CH3:31])=[CH:4][N:5]([S:14]([C:17]2[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=2)[C:23]([NH:25][CH2:26][CH2:27][OH:28])=[O:24])(=[O:15])=[O:16])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2cccc(C(=O)NCCO)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2cccc(C(=O)NCCO)c2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To a solution of tert-butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(3-{[(2-hydroxyethyl)amino]carbonyl}phenyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (226 mg) in ethyl acetate (3 mL) and 2-propanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (6 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 99 mg, 50%).
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[CH2:15][CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:21])[CH2:5][CH2:4]2.[BH4-].[K+].O.C(O)(=[O:27])C>C(O)C>[OH:27][C@H:15]1[CH2:14][CH2:13][C@H:12]2[C@H:11]3[C@H:20]([CH2:19][CH2:18][C@:16]12[CH3:17])[C@:3]1([CH2:2][OH:1])[C:8](=[CH:7][C:6](=[O:21])[CH2:5][CH2:4]1)[CH2:9][CH2:10]3
Reactant: C[C@@]12CCC[C@H]1[C@@H]1CCC3=CC(=O)CC[C@]3(CO)[C@H]1CC2
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CC[C@@H]2O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 150 g of 19-hydroxyandrost-4-en-3-one in 6 liters of ethanol is cooled in an ice bath. To this cold solution is added 13.5 g of potassium borohydride, and the reaction mixture is stirred for two hours at about 0° C after which a second 13.5 g or potassium borohydride is added. Two hours later a third 13.5 g portion of potassium borohydride is added to the reaction mixture which is stirred for an additional 1 hour then poured into 11 liters of water to which 70 ml of acetic acid is added. The ethanol is distilled off under reduced pressure and the aqueous residue cooled to 0° C. The solid which separates is filtered off, dried and dissolved in 25 liters of hot chloroform after which the temperature is adjusted to 25° C. To the chloroform solution is added 250 g of manganese dioxide, and the mixture is stirred for 2 hours then filtered and the solvents removed under reduced pressure. The solid residue is recrystallized from acetonitrile to give 17β,19-dihydroxyandrost-4-en-3-one. M.P. 205°-207° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]([NH2:27])[CH3:26])=[CH:21][CH:20]=1>CC#N>[Cl:11][C:4]1[N:3]=[C:2]([NH:27][C@H:25]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)[CH3:26])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: C[C@H](N)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H](Nc1nc(Cl)ccc1[N+](=O)[O-])c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 81.8 %

Procedure:
To a mixture of 2,6-dichloro-3-nitropyridine (2.26 g, 10.8 mmol) and potassium carbonate (1.29 g, 9.34 mmol) in anhydrous CH3CN (20 ml), was added (5)-1-(4-fluoro-phenyl)-ethylamine (1.00 g, 7.19 mmol) dropwise at 0° C. The reaction mixture was stirred at 25° C. for 17 hrs. The solid was removed by filtration and the resulted cake was washed with EtOAc (20 ml). The combined filtrate was concentrated and purified by column chromatography (hexane-EtOAc=10:1) to give the title compound as a yellow solid (1.74 g, 82%). 1H NMR (400 MHz) δ 8.65 (d, J=7.6 Hz, 1H), 8.43 (d, J=8.4 Hz, 1H), 7.51 (m, 2H), 7.16 (m, 2H), 6.81 (d, J=8.8 Hz, 1H), 5.37 (m, 1H), 1.59 (d, J=6.8 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1)#[CH:2].I[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19]>>[C:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]2[O:19][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:2]=2)=[CH:4][CH:5]=1)(=[O:11])[CH3:10]
Reactant: Oc1ccccc1I
Reactant: C#Cc1ccc(C(C)=O)cc1
Product: CC(=O)c1ccc(-c2cc3ccccc3o2)cc1

Procedure:
The general procedure was used to convert 1-(4-Ethynyl-phenyl)-ethanone and 2-iodophenol to the title product. Purification by flash chromatography (10% ethyl acetate in hexanes as the eluent) gave the analytically pure product as a white solid (326 mg, 69% yield). 1H NMR (300 MHz, CDCl3) δ 8.02 (d, J=8.67, 2H), 7.92 (d, J=8.67, 2H), 7.60 (d, J=7.72, 1H), 7.52 (d, J=7.35, 1H), 7.35-7.22 (m, 2H), 7.14 (s, 1H), 2.62 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 197.33, 155.18, 154.50, 136.48, 134.55, 128.91, 128.87, 125.14, 124.75, 123.24, 121.32, 111.35, 103.65, 26.62. HRMS El calcd for C16H12O2—236.0837, Found—236.0835. mp.—168-170° C. (lit., 3168-170° C.).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH3:15].[CH3:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH:19]([CH3:23])[NH:18]1>ClCCl.CO>[CH3:15][O:14][C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:18]1[CH:19]([CH3:23])[CH2:20][CH2:21][CH2:22][CH:17]1[CH3:16]
Reactant: COc1cc([N+](=O)[O-])ccc1OCCBr
Reactant: CC1CCCC(C)N1
Solvent: ClCCl
Solvent: CO
Product: COc1cc([N+](=O)[O-])ccc1OCCN1C(C)CCCC1C

Procedure:
Prepared analogously to Example 1.1.c. from 1 g (3.622 mmol) of 1-(2-bromoethoxy)-2-methoxy-4-nitrobenzene and 1.5 mL (10.87 mmol) of 2,6-dimethylpiperidine. Yield: 0.85 g (76% of theory); C16H24N2O4 (M=308.37); calc.: molecular ion peak (M+H)+: 309; found: molecular ion peak (M+H)+: 309; Rf value: 0.55 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]=[C:10]3[CH:27]=[C:26](/[CH:28]=[CH:29]/[C:30]4[S:31][CH:32]=[C:33]([CH:35]([CH3:37])[CH3:36])[N:34]=4)[CH:25]=[CH:24][N:11]3[C:12](=[O:23])[C:13]=2/[CH:14]=[CH:15]/[C:16]([O:18]C(C)(C)C)=[O:17])[CH2:3]1.Cl>O1CCOCC1>[OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]=[C:10]3[CH:27]=[C:26](/[CH:28]=[CH:29]/[C:30]4[S:31][CH:32]=[C:33]([CH:35]([CH3:37])[CH3:36])[N:34]=4)[CH:25]=[CH:24][N:11]3[C:12](=[O:23])[C:13]=2/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])[CH2:3]1
Reactant: CC(C)c1csc(/C=C/c2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(N4CCCC(O)C4)nc3c2)n1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)c1csc(/C=C/c2ccn3c(=O)c(/C=C/C(=O)O)c(N4CCCC(O)C4)nc3c2)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 48.8 %

Procedure:
The tert-Butyl (E)-3-{2-(3-hydroxypiperidino)-8-[(E)-2-(4-isopropyl-1,3-thiazol-2-yl)-1-ethenyl]-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl}-2-propenoate (43.4 mg, 0.0830 mmol) obtained in (H) was dissolved in 1,4-dioxane (200 μl), added with 4 N hydrochloric acid solution in 1,4-dioxane, and stirred at room temperature for 3.5 hours. The reaction solution was concentrated, and the residue was purified by thin layer chromatography (chloroform:methanol:water=10:1:0→8:3:0.1→7:3:1, v/v) to obtain the title compound (18.9 mg, 49%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.[Br:14][C:15]1[CH:26]=[CH:25][C:18]2[C:19](Cl)=[N:20][S:21](=[O:23])(=[O:22])[C:17]=2[CH:16]=1>C(#N)C>[Br:14][C:15]1[CH:26]=[CH:25][C:18]2[C:19]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][C:5]3[C:4]([CH3:13])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=3)=[N:20][S:21](=[O:23])(=[O:22])[C:17]=2[CH:16]=1
Reactant: Cc1cc(Br)cnc1CCCCN
Reactant: O=S1(=O)N=C(Cl)c2ccc(Br)cc21
Solvent: CC#N
Product: Cc1cc(Br)cnc1CCCCNC1=NS(=O)(=O)c2cc(Br)ccc21

Procedure:
A slurry of 4-(5-bromo-3-methyl-2-pyridinyl)butylamine (252 mg, 1.04 mmol) and 6-bromo-3-chlorobenzisothiazole 1,1-dioxide (U.S. Pat. No. 4,490,527) (292 mg, 1.04 mmol) in 15 ml acetonitrile was heated under dry nitrogen until nearly completely dissolved, when the above compound precipitated as the hydrochloride salt, yielding 360 mg (66%), m.p. 224°-232° C. IR(KBr) 1620, 1300, 1160, 650 cm-1.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:35])=[C:8]2[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])=[N:26][S:25][C:9]2=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[N:11]=1)=[O:5])C.[NH2:36][CH2:37][C:38]([OH:40])=[O:39]>>[F:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:27]1[C:8]2[C:9](=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:14][CH:13]=3)[N:11]=[C:6]([C:4]([NH:36][CH2:37][C:38]([OH:40])=[O:39])=[O:5])[C:7]=2[OH:35])[S:25][N:26]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(-c2ccc(Oc3ccccc3)cc2)c2snc(-c3ccccc3F)c2c1O
Product: O=C(O)CNC(=O)c1nc(-c2ccc(Oc3ccccc3)cc2)c2snc(-c3ccccc3F)c2c1O

Procedure:
The title compound was synthesized in analogy Example 1 from 3-(2-fluoro-phenyl)-4-hydroxy-7-(4-phenoxy-phenyl)-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and glycine: MS (m/z) 516.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@@H:13]([O:15][Si](C(C)(C)C)(C)C)[CH2:12][N:11]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@@H:13]([OH:15])[CH2:12][N:11]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN(C(=O)OCc2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](O)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of (3S,5R)-benzyl 3-(tert-butoxycarbonylamino)-5-(tert-butyldimethylsilyloxy)piperidine-1-carboxylate (1 eq) in 30 mL of THF was added 5.2 mL of TBAF (1.2 eq). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate, washed with brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (5% methanol in EtOAc:hexanes=1:1) to yield (3S,5R)-benzyl 3-(tert-butoxycarbonylamino)-5-hydroxypiperidine-1-carboxylate (100%). LC/MS (m/z): 251.2 (MH+), Rt:0.89. HPLC: Rt:3.26 min.
Reaction SMILES: I[C:2]1[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=1.C([Sn](CCCC)(CCCC)[C:13](=[CH2:24])[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])CCC>C1COCC1.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.[Cu]Cl>[CH3:7][N:4]1[CH:5]=[CH:6][C:2]([C:13](=[CH2:24])[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[N:3]1
Reactant: Cn1ccc(I)n1
Reactant: C=C(C(=O)OCc1ccccc1)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Cu]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C(C(=O)OCc1ccccc1)c1ccn(C)n1
Temperature: 55 °C
Yield: 67.8 %

Procedure:
To a solution of 0.30 g (1.4 mmol) of 3-iodo-1-methyl-1H-pyrazole in 3 mL of anhydrous THF was added a solution of 0.82 g (1.8 mmol) of benzyl 2-(tributylstannyl)acrylate from step B above in 1 mL of anhydrous THF, 0.18 g (0.15 mmol) of tetrakis(triphenylphosphine)palladium(0) and 0.14 g (1.4 mmol) of copper (I) chloride. The reaction mixture was heated to 55° C. for 12 h, cooled and evaporated to dryness under reduced pressure. The residue was dissolved in 10 mL of a 1:1 mixture of hexane and EtOAc then filtered through a pad of Celite®. The pad was washed with 15 mL of a 1:1 mixture of hexane and EtOAc and the combined filtrates were evaporated to dryness. The crude residue was purified by silica gel chromatography eluting with a 0-80% EtOAc in hexanes gradient to afford the title compound as a colorless oil (0.23 g, 66%). LC-MS: m/z (ES) 265 (M+Na)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)=[CH:12][CH:11]=3)[CH2:6][CH2:7]2)[CH2:3]1.[Cl:22][C:23]1[N:24]=[N:25][C:26](Cl)=[CH:27][CH:28]=1.C(N(CC)CC)C>C(#N)C>[Cl:22][C:23]1[N:24]=[N:25][C:26]([N:19]2[CH2:18][CH2:17][N:16]([C:13]3[CH:12]=[CH:11][C:10]([N:5]4[CH2:6][CH2:7][C@@H:8]5[CH2:9][N:2]([CH3:1])[CH2:3][C@H:4]45)=[CH:15][CH:14]=3)[CH2:21][CH2:20]2)=[CH:27][CH:28]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CN1C[C@H]2CCN(c3ccc(N4CCNCC4)cc3)[C@H]2C1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN1C[C@H]2CCN(c3ccc(N4CCN(c5ccc(Cl)nn5)CC4)cc3)[C@H]2C1
Temperature: 60 °C

Procedure:
The product of Example 49B (30 mg, 0.105 mmole), 3,6-dichloropyridazine (18.8 mg, 0.126 mmole), and triethylamine (45 ml, 0.036 mmole) were dissolved in 1 ml of acetonitrile and heated at 60° C. under N2 for 24 hours. The mixture was cooled to room temperature, quenched with water and extracted with dichloromethane (5×). The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure and purified by chromatography (eluting with a mixture of 0.5% ammonium hydroxide and 5% methanol in dichloromethane) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.24 (s, 1H) 7.21 (s, 1H) 6.91-6.96 (m, 2H) 6.53-6.58 (m, 2H) 4.13-4.21 (m, 1H) 3.72-3.83 (m, 4H) 3.50-3.61 (m, 1H) 3.36-3.45 (m, 1H) 3.11-3.19 (m, 4H) 2.99-3.08 (m, 1H) 2.60-2.80 (m, 4H) 2.46 (s, 3H) 2.13-2.23 (m, 1H) 1.89-2.04 (m, 1H); MS: (M+H)+=399.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl>CCO.[Pt](=O)=O>[CH2:1]([O:3][C:4]([C:6]1([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccccc2)CCNCC1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1(C2CCCCC2)CCNCC1
Reaction time: 18 h

Procedure:
To a solution of 4-phenylpiperidine-4-carboxylic acid ethyl ester (56 g, 248 mmol) in EtOH (700 mL) is added platinum (IV) oxide (10.2 g, 45 mmol) and concentrated hydrochloric acid. The Flask is purged with nitrogen and shaken on a Parr hydrogenation apparatus at 40 psig for 18 hours. The flask is removed and additional PtO2 (2 g, 8.8 mmol) is added and hydrogenation is continued at 40 psig an additional 6 hours. The reaction solution is filtered to remove the catalyst and the filtrated is concentrated in vacuo to afford a residue which is partitioned between saturated NaHCO3 and methylene chloride. The organic phase is removed and the aqueous phase washed several times with methylene chloride. The organic layers are combined, dried and concentrated under in vacuo to afford the desired product in nearly quantitative yield as a waxy solid. 1H NMR (300 MHz, CDCl3) δ 0.90–1.45 (m, 6H), 1.25–1.32 (t, 3H), 1.55–1.85 (m, 7H), 2.15–2.28 (m, 2H), 2.98–2.80 (m, 2H), 3.18–3.27 (m, 2H), 4.10–4.25 (m, 2H), 7.10 (broad s, 1H); MS (ESI) m/z 240, (M+H+).
Reaction SMILES: [Na+].[Br-:2].[Br:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11](=[O:15])[CH:12](Cl)[CH3:13])[CH:7]=[CH:8][CH:9]=1>CC(C)=O.CCCCCC>[Br:2][CH:12]([CH3:13])[C:11](=[O:15])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Br:3])[CH:5]=1
Reactant: CC(Cl)C(=O)Cc1cccc(Br)c1
Reactant: [Br-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: CC(Br)C(=O)Cc1cccc(Br)c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of NaBr (197 mg, 1.9 mmol) and 1-(3-bromophenyl)-3-chlorobutan-2-one (100 mg, 0.38 mmol) in acetone (2 ml) was stirred at 70° C. for 3 h. The mixture was diluted with hexane and filtered to remove the solid. The solvent was removed under reduced pressure and the residue was used for the next step without further purification. MS (ES+) C10H10Br2O requires: 303, 305 found: 304, 306 [M+H]+(1:1).