Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][OH:8])[C:5](=[O:9])[CH:4]([CH3:10])[N:3]1[CH2:11][C:12]#[CH:13].[Cl:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[NH:25][C@H:26]([C:30](O)=[O:31])[CH:27]([CH3:29])[CH3:28].CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C=O>[Cl:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[NH:25][CH:26]([CH:27]([CH3:29])[CH3:28])[C:30]([O:8][CH2:7][N:6]1[C:5](=[O:9])[CH:4]([CH3:10])[N:3]([CH2:11][C:12]#[CH:13])[C:2]1=[O:1])=[O:31]
Reactant: CC(C)[C@H](Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O
Reactant: C#CCN1C(=O)N(CO)C(=O)C1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C#CCN1C(=O)N(COC(=O)C(Nc2ccc(C(F)(F)F)cc2Cl)C(C)C)C(=O)C1C
Reaction time: 2 h

Procedure:
To a stirred solution of (2,4-dioxo-5-methyl-1-propargyl-3-imidazolidinyl)methanol (1.8 mmol), N-(2-chloro-4-trifluoromethylphenyl)valine (2.0 mmol) and dimethylaminopyridine (0.65 mmol) in 20 ml of methylene chloride and 2 ml of dimethylformamide is added N,N'-dicyclohexylcarbodiimide (2.0 mmol). The reaction mixture is stirred, under nitrogen, for two hours and then filtered and extracted with water. The aqueous phase is extracted with ether. The combined organic phases are washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over calcium sulfate and solvent evaporated. The crude product is chromatographed on a rotary chromatograph, eluting with 25% ether/hexane, to yield (2,4-dioxo-5-methyl-1-propargyl-3-imidazolidinyl)methyl 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][N:17]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH2:14])=O)=[CH:8]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][N:17]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:35])[NH2:14])=[CH:8]2
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C(N)=O)[nH]c12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: COc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C(N)=S)[nH]c12
Temperature: 60 °C
Reaction time: 0.83 h
Yield: 96 %

Procedure:
To a solution of 7-methoxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxamide (2.1 g) in tetrahydrofuran (400 mL) was added Lawesson's reagent (2.3 g) and the mixture was stirred at 60° C. for 50 min. The mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The mixture was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was solidified with ethyl acetate and the resulting solid was washed with diethyl ether to give the title compound (2.06 g, 94%) as a pale yellow solid. MS 378 (MH+).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:6])#[N:2].C(S)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23][CH2:24][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:6])#[N:2]
Reactant: CSc1ccc(S(=O)(=O)C[C@@H]2CCCC[C@H]2C(=O)NCC#N)cc1
Reactant: SCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CCNC(=O)[C@@H]1CCCC[C@H]1CS(=O)(=O)c1ccc(SCCc2ccccc2)cc1
Temperature: 100 °C

Procedure:
A mixture of trans-N-cyanomethyl-2-(4-methylsulfanylbenzenesulfonylmethyl)-cyclohexanecarboxamide (0.1 g, 0.298 mmol), phenethyl mercaptan (0.103 mL, 0.764 mmol) and cesium carbonate (0.25 g, 0.764 mmol) was dissolved in dimethylformamide (1.5 mL) and heated at 100° C. for 4 h. The reaction mixture was diluted with ethyl acetate (30 mL), filtered through Celite, evaporated to dryness, and purified on a short plug of silica gel (2040% ethyl acetate/CHCl3), yielding the desired product. NMR (DMSO-d6): 1.1 (3H, m); 1.3 (1H, m) 1.6-1.7 (3H, m); 2.03 (2H, m); 2.16 (1H, d): 2.92 (3H, m); 3.15 (1H, dd); 3.36 (2H, m); 4.03 (2H, d); 7.1 (1H, d); 7.25 (4H, m); 7.47 (2H, d); 7.68 (2H, d); 8.56 (1H, t). MS [ESI, (M+Na)+] m/z=479 amu.
Reaction SMILES: [OH:1][N:2]1[CH:5]([CH2:6][OH:7])[CH:4]([N:8]2[CH:23]=[CH:22][C:12]([NH:13][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:11][C:9]2=[O:10])[C:3]1=[O:24].[CH3:25][O:26][C:27]1[CH:48]=[CH:47][C:30]([C:31](Cl)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)=[CH:29][CH:28]=1>N1C=CC=CC=1>[OH:1][N:2]1[CH:5]([CH2:6][O:7][C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[C:30]2[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[CH:48][CH:47]=2)[CH:4]([N:8]2[CH:23]=[CH:22][C:12]([NH:13][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:11][C:9]2=[O:10])[C:3]1=[O:24]
Reactant: O=C(Nc1ccn(C2C(=O)N(O)C2CO)c(=O)n1)c1ccccc1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(OCC2C(n3ccc(NC(=O)c4ccccc4)nc3=O)C(=O)N2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 8 h

Procedure:
1-N-Hydroxy-3-(N-benzoylcytosin-1-yl)-4-hydroxymethyl-2-azetidinone (10 mmole) is dissolved in pyridine (20 ml) and 4,4'-dimethoxytrityl chloride (12 mmole) is added and stirred under argon for 8 hours. The reaction mixture is concentrated under reduced pressure. The crude product is purified by flash chromatorgraphy using silica gel and ethyl acetate/dichloromethane/1% triethylamine as eluants to give the title compound.
Reaction SMILES: [OH2:1].O.Cl.O.O.Cl.NC1N=CN=C2C=1N=CN2[C@@H]1O[C@H](C(O)=O)[C@@H](N[C:27](=[O:39])[C@H:28]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[NH2:29])[C@H]1O.[OH-].[Na+]>O>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][C@@H:28]([C:27]([OH:39])=[O:1])[NH2:29])=[CH:36][CH:35]=1
Reactant: O
Reactant: COc1ccc(C[C@H](N)C(=O)N[C@H]2[C@@H](O)[C@H](n3cnc4c(N)ncnc43)O[C@@H]2C(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C[C@H](N)C(=O)O)cc1

Procedure:
A solution of hydrochloride dihydrate of FR-48736 substance [1-(6-amino-9H-purin-9-yl)-1,3-dideoxy-3-(O-methyl-L-tyrosylamino)-β-D-ribofuranuronic acid hydrochloride dihydrate] (100 mg) prepared by Example 98 in 1N-methanolic sodium hydroxide (10 ml) was refluxed for 20 hours. To the cooled solution was added water (50 ml) and the methanol in the solution was evaporated under reduced pressure. The resulting aqueous solution was adjusted to pH 7 with 1N-hydrochloric acid and applied to a column of activated charcoal (20 ml). The column was washed with water (40 ml) and eluted with a mixture of methanol and water (1:1) (60 ml). The solvent was evaporated under reduced pressure. The residue was chromatographed on a cellulose column and eluted with a mixture of acetonitrile and water (8:2). The first ninhydrin positive and weak UV absorbing fraction was evaporated under reduced pressure to give a powder of O-methyltyrosine (21 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22](Cl)(=[O:24])=[O:23])[CH:17]=1>N1C=CC=CC=1.C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([S:22]([C:18]3[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=3)(=[O:24])=[O:23])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(N2CCN(S(=O)(=O)c3cccnc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.7 %

Procedure:
To a solution of 1-(4-nitrophenyl)-piperazine (2.50 g, 12.1 mmol) in pyridine (15 mL) was added a solution of pyridine-3-sulfonyl chloride (2.78 g, 15.7 mmol) in THF (30 mL) under an argon atmosphere at 0° C. The reaction was warmed to r.t. and stirred for 2 h, before the mixture was evaporated to dryness. The residue was partitioned between water and dichloromethane, the organic layer separated and washed successively with sat. sodium bicarbonate solution, water and brine. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was subjected to column chromatography over neutral alumina using 5% to 70% ethyl acetate in petroleum ether as eluent to afford 1-(4-nitrophenyl)-4-(pyridine-3-sulfonyl)-piperazine (1.63 g, 39%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[F:12][C:13]1[N:18]=[CH:17][C:16]([N:19]2[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20]2)=[CH:15][CH:14]=1.C(N(CC)CC)C.[BH4-].[Na+]>CO>[F:12][C:13]1[N:18]=[CH:17][C:16]([N:19]2[CH2:23][CH2:22][C@H:21]([NH:24][CH2:4][C:3]3[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:2]=3[Br:1])[CH2:20]2)=[CH:15][CH:14]=1
Reactant: N[C@H]1CCN(c2ccc(F)nc2)C1
Reactant: O=Cc1ccc(Cl)cc1Br
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: Fc1ccc(N2CC[C@H](NCc3ccc(Cl)cc3Br)C2)cn1
Reaction time: 18 h

Procedure:
Add 2-bromo-4-chlorobenzaldehyde (159 mg, 0.73 mmol) to a solution of (S)-1-(6-fluoropyridin-3-yl)-pyrrolidin-3-ylamine hydrochloride (144 mg, 0.66 mmol) and triethylamine (292 μL, 2.1 mmol) in methanol (5 mL). Stir the resulting mixture for 18 h. Add sodium borohydride (80 mg, 2.1 mmol). Stir for 1 h. Dilute the reaction mixture with methanol (10 mL) and pour onto a column of Dowex® 50Wx2 (H+ form). Rinse the column with methanol then elute the product with 5% triethylamine in methanol. Concentrate and dissolve the residue in methanol. Dilute with acetonitrile and concentrate to give the title compound as a oil. Dissolve the oil in methanol and add excess 1 N HCl in methanol. Concentrate to dryness and crystallize from methanol/acetonitrile to give the title compound as its hydrochloride salt, an off white solid (84 mg, 30%). Elemental analysis calculated for C16H17BrCl2FN3: C, 45.63; H, 4.07; N, 9.98. Found: C, 45.39; H, 4.02; N, 9.85. MS (ES): m/z=386 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[CH:11][N:12]=[C:13]([NH:16][C:17](=O)[CH3:18])[CH:14]=3)[CH:9]([CH3:20])[O:8][C:6]=2[CH:7]=1.[H-].[Na+].[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[CH:11][N:12]=[C:13]([N:16]([CH2:29][C:28]4[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=4)[CH2:17][C:18]4[CH:2]=[CH:7][C:6]([O:8][CH3:9])=[CH:5][CH:4]=4)[CH:14]=3)[CH:9]([CH3:20])[O:8][C:6]=2[CH:7]=1
Reactant: CC(=O)Nc1cc2c(cn1)C(C)Oc1cc(Cl)ccc1-2
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc3c(cn2)C(C)Oc2cc(Cl)ccc2-3)cc1
Reaction time: 0.17 h
Yield: 46.2 %

Procedure:
To a stirred solution of N-(8-chloro-5-methyl-5H-chromeno[3,4-c]pyridin-2-yl)acetamide (250 mg, 0.866 mmol) in DMF (25 mL) was added NaH (62.3 mg, 2.60 mmol) at room temperature and stirred for 10 min. 4-Methoxybenzyl chloride (0.236 mL, 1.732 mmol) was added dropwise and stirred at room temperature overnight. The reaction was quenched with ice and extracted with ethyl acetate (25 mL). The organic layer was separated, washed with water (25 mL), brine (25 mL), dried over sodium sulphate and concentrated under reduced pressure to afford 8-chloro-N,N-bis(4-methoxybenzyl)-5-methyl-5H-chromeno[3,4-c]pyridin-2-amine (200 mg, 0.20 mmol, 24% yield) as a yellow oil. This was taken to the next step without purification. LCMS (ESI) m/e 487.2 [(M±H)+, calcd for C29H28ClN2O3 487.2]; LC/MS retention time (Method C): tR=2.52 min.
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].F[C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>CN(C)C=O>[CH3:1][O:2][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2)c(F)c1
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1N1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
A solution of methanol (0.178 ml, 10.0 mmol) in N,N-dimethylformamide (1 ml) was added dropwise to a suspension of 60% sodium hydride (0.176 g, 4.40 mmol) in N,N-dimethylformamide (5 ml) under ice cooling, and the mixture was stirred at room temperature for 1 hour. 1-(2-Fluoro-4-nitrophenyl)piperidine (compound of Reference Example 3; 0.448 g, 2.00 mmol) was added to the reaction mixture under ice cooling, and the mixture was refluxed for 20 hours. Ice water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=5:1) to give the title compound (0.395 g, 84%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[CH:5]2.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:10][CH:9]=3)=[CH:12][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ccc(-c2cc3cc(Br)ccc3[nH]2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: Clc1ccc(-c2cc3cc(-c4ccccc4)ccc3[nH]2)cc1
Temperature: 160 °C
Yield: 10.6 %

Procedure:
To a suspension of 5-bromo-2-(4-chlorophenyl)-1H-indole (200 mg, 0.65 mmol) in dioxane/water 4:1 v/v (5 mL) was added phenylboronic acid (87 mg, 0.72 mmol) and a few milligrams of tetrakis(triphenylphosphine)palladium(0). The resulting suspension was heated in the microwave at 160° C. for 15 min. After cooling, the reaction was poured into water to give a precipitate, which was filtered off and washed with water. The resulting solid was purified by column chromatography eluting using a gradient (hexanes to ethyl acetate/hexanes 30:70 v/v), followed by a recrystallisation from hot ethyl acetate to afford 21 mg (11%) of the title compound (LCMS RT=8.54 min, MH+304.1)
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11](I)[N:10]=[CH:9]2)C=CC=CC=1.C([Mg]Br)C.[CH3:30][O:31][C:32]1[CH:40]=[C:39]2[C:35]([CH2:36][CH2:37][C:38]2=O)=[CH:34][C:33]=1[CH3:42].[Cl-].[NH4+]>C(Cl)Cl>[NH:8]1[C:12]([C:38]2[C:39]3[C:35](=[CH:34][C:33]([CH3:42])=[C:32]([O:31][CH3:30])[CH:40]=3)[CH2:36][CH:37]=2)=[CH:11][N:10]=[CH:9]1
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: COc1cc2c(cc1C)CCC2=O
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: COc1cc2c(cc1C)CC=C2c1cnc[nH]1
Temperature: 23 °C
Reaction time: 1 h
Yield: 18.4 %

Procedure:
A stirred solution of 5.0 grams (0.012 mole) of 1-(triphenylmethyl)-4-iodoimidazole (vii) in about 200 mL of anhydrous methylene chloride was cooled to about 21° C., and 3.84 mL (3.0M in diethyl ether: 0.012 mole) of ethylmagnesium bromide was added. Upon completion of addition, the reaction mixture was stirred for about one hour at 23° C., and then a solution of 2.0 grams (0.012 mole) of 6-methoxy-5-methylindan-1-one (ii) (prepared in a manner analogous to Step D of Example 1) in 50 mL of methylene chloride was added in one portion. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 18 hours. After this time, the reaction mixture was poured into a separatory funnel containing an aqueous saturated solution of ammonium chloride. The organic layer was separated and the aqueous layer was extracted with two portions of methylene chloride. The combined extracts and organic layer were dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was dissolved in methanol and aqueous 4N hydrochloric acid was then added to the solution. Upon completion of addition, the mixture was stirred at ambient temperature for about 18 hours. After this time, the methanol was removed from the mixture under reduced pressure, leaving an aqueous residue. The residue was washed with three portions of diethyl ether, then the pH of the residue was adjusted to about 8-9 by the addition of solid sodium carbonate. The mixture was then extracted with methylene chloride, and the extract was dried with sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure to a residue. The residue was again treated with aqueous 4N hydrochloric acid, and the mixture was washed with diethyl ether. The pH of the aqueous layer was adjusted to about 8-9 by the addition of solid sodium carbonate. The mixture was then extracted with methylene chloride, and the extract was dried with sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure, yielding about 0.5 gram of subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.N1CCCC1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23](O)[CH:22]=1>CO>[F:20][C:21]1[CH:26]=[C:25]2[C:24]([C:27](=[O:29])[CH2:28][C:2]3([O:1]2)[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]3)=[CH:23][CH:22]=1
Reactant: CC(=O)c1ccc(F)cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: C1CCNC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1ccc(F)cc1O2
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 21.4 %

Procedure:
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (7.5 g, 37.8 mmol) in pyrrolidine (4.5 mL, 54.1 mmol) and anhydrous methanol (10.2 mL) was added 1-(4-fluoro-2-hydroxy-phenyl)ethanone (5.8 g, 37.6 mmol). The reaction mixture was stirred at 80° C. for 2.5 hours. The methanol was removed under reduced pressure and the resulting residue was dissolved in ethyl acetate (150 mL), washed with 1N HCl (1×150 mL) and brine (2×100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to yield a yellow oil. The oil was diluted with hexanes (400 mL) and was heated at 60° C. until in solution. Once dissolved, the solution was allowed to cool to 25° C. The crystals were collected via vacuum filtration, rinsing with hexanes to remove tert-butyl 4-oxo-7-pyrrolidin-1-yl-spiro[chromane-2,4′-piperidine]-1′-carboxylate (8.6 g), which was collected as light yellow solid; ESI-MS m/z calc. 386.2. found 387.2 (M+1)+; Retention time: 2.59 minutes (3 min run). The filtrate was concentrated and the residue was subjected to column chromatography (0-100% ethyl acetate/hexanes) to give tert-butyl 7-fluoro-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (2.7 g, 21%) as a light yellow solid; ESI-MS m/z calc. 335.2. found 336.2 (M+1)+; Retention time: 2.49 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.89 (dd, J=8.6, 6.7 Hz, 1H), 6.80-6.62 (m, 2H), 3.88 (d, J=12.1 Hz, 2H), 3.21 (t, J=12.0 Hz, 2H), 2.71 (s, 2H), 2.02 (d, J=12.8 Hz, 2H), 1.62 (td, J=14.1, 4.8 Hz, 2H), 1.46 (s, 9H).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[CH:13][C:12]2=[O:25])=[CH:5][CH:4]=1.[NH:26]1[CH2:31][CH2:30][CH:29]([NH:32][C:33](=[O:35])[CH3:34])[CH2:28][CH2:27]1.C(N(CC)CC)C.CS(Cl)(=O)=O>>[O:25]=[C:12]1[CH:13]=[C:14]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)[CH:15]=[CH:16][N:11]1[CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:26]2[CH2:31][CH2:30][CH:29]([NH:32][C:33](=[O:35])[CH3:34])[CH2:28][CH2:27]2)=[CH:4][CH:5]=1
Reactant: CC(=O)NC1CCNCC1
Reactant: O=c1cc(OCc2ccncc2)ccn1CCc1ccc(CO)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)NC1CCN(Cc2ccc(CCn3ccc(OCc4ccncc4)cc3=O)cc2)CC1

Procedure:
N-[1-(4-{2-[2-Oxo-4-(pyridin-4-ylmethoxy)-2H-pyridin-1-yl]-ethyl}-benzyl)-piperidin-4-yl]-acetamide is prepared as example 10.1b from 80 mg (0.24 mmol) 1-[2-(4-hydroxymethylphenyl)-ethyl]-4-(pyridin-4-ylmethoxy)-1H-pyridin-2-one (example 10.1a), 101 mg (0.71 mmol) N-piperidin-4-yl-acetamide, 99 μL triethylamine (0.71 mmol) and subsequently 37 μL (0.48 mmol) methanesulfonyl chloride. The product is purified via reverse HPLC chromatography (Zorbax stable bond, C18; water (0.1% formic acid)/acetonitrile (0.1% formic acid) 95:5 to 10:90).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[OH-].[Na+]>ClCCl>[CH3:1][S:2]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)(=[O:4])=[O:3]
Reactant: C1CNCCN1
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CS(=O)(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of methanesulfonyl chloride (1.85 ml, 24 mmol) and piperazine (2.06 g, 24 mmol) in dichloromethane (60 ml) was stirred at room temperature for 14 hours. The mixture was basified with aqueous sodium hydroxide and filtered. The filtrate was washed with water, dried (magnesium sulfate) and evaporated down to give the title sulfonamide. 1HNMR(CDCl3) 1.75 (br s, 1H), 2.78 (s, 3H), 2.97 (t, 4H, J=5.1 Hz) and 3.19 (t, 4H, J=7.5 Hz). LRMS (m/e, % abundance) 165[(M+H)+, 7), 164(M+, 5), 8.5(100) and 56(68).
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[C:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]2[OH:23])[CH:10]=1)=O.N.CO>ClCCl>[NH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[C:11]([C:15]#[C:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]2[OH:23])[CH:12]=[CH:13][CH:14]=1
Reactant: O=C(NCCCc1cccc(C#CC2CCCCC2O)c1)C(F)(F)F
Agent: N
Solvent: CO
Solvent: ClCCl
Product: NCCCc1cccc(C#CC2CCCCC2O)c1

Procedure:
Deprotection of 2,2,2-trifluoro-N-(3-(3-((2-hydroxycyclohexyl)ethynyl)phenyl)propyl)acetamide followed by flash chromatography (10% (7N NH3/MeOH)/dichloromethane) gave 2-((3-(3-aminopropyl)phenyl)ethynyl)cyclohexanol as an orange oil. Yield (0.606 g, 69%): 1H NMR (400 MHz, CDCl3) δ 7.16-7.26 (m, 3H), 7.08-7.12 (m, 1H), 3.48-3.56 (m, 1H), 2.71 (t, J=7.2 Hz, 2H), 2.61 (t, J=7.2 Hz, 2H), 2.38-2.46 (m, 1H), 2.01-2.10 (m, 2H), 1.64-1.82 (m, 7H), 1.40-1.52 (m, 1H), 1.16-1.40 (m, 3H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[Br:25]Br>C(Cl)(Cl)(Cl)Cl>[Br:25][C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[CH:6][C:7]([O:11][S:12]([C:15]([F:18])([F:16])[F:17])(=[O:13])=[O:14])=[CH:8][CH:9]=2
Reactant: BrBr
Reactant: O=S(=O)(Oc1ccc2ncccc2c1)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=S(=O)(Oc1ccc2ncc(Br)cc2c1)C(F)(F)F
Temperature: 25 °C
Yield: 26.1 %

Procedure:
To a mixture of trifluoromethanesulfonic acid quinolin-6-yl ester (3.88 g, 14 mmol) and pyridine (2.26 mL, 28 mmol) in CCl4 (50 mL) was added bromine (0.86 mL, 16.8 mmol) dropwise. The mixture was heated to reflux for 2 hrs and cooled to room temperature. The liquid in the flask was decanted and washed with NaHCO3 and water. The dark solid on the bottom of the flask was treated with NaHCO3 and dichloromethane. The combined organic layers were washed with water again and dried before being evaporated to dryness. The crude product was purified by flash column chromatography eluting with petroleum ether/ethyl acetate (10/1˜1/1) to give 1.3 g of trifluoromethanesulfonic acid 3-bromo-quinolin-6-yl ester: 1H NMR (300 MHz, CDCl3) δ: 7.62 (m, 1H), 7.68 (d, 1H), 8.20 (d, 1H), 8.36 (m, 1H), 8.98 (d, 1H); MS (m/z) 356 [M+H]+.