Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH:6]2[O:8][CH:5]2[CH2:4]1)[CH3:2].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[OH:17].[OH-].[Na+].O>Cl.C(Cl)Cl>[ClH:9].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[O:17][C@@H:6]1[CH2:7][N:3]([CH2:1][CH3:2])[CH2:4][C@H:5]1[OH:8]
Reactant: CCN1CC2OC2C1
Reactant: Oc1c(Cl)cccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCN1C[C@@H](O)[C@H](Oc2c(Cl)cccc2Cl)C1

Procedure:
A mixture of 11.3 g. (0.10 mole) of 1-ethyl-3,4-epoxypyrrolidine, 18.0 g. (0.11 mole) of 2,6-dichlorophenol and 2 drops concentrated hydrochloric acid was heated on a steam bath overnight. The oil was dissolved in methylene chloride and wahed with three 50-ml. portions of 5% sodium hydroxide an one 50-ml. portion of water. The methylene chloride solution was dried over anhydrous sodium sulfate, concentrated and chromatogrpahed on silica gel to give 12.9 g. (47%) of and oil residue. The oil was converted to the hydrchloride and recrystallized from isopropyl alcohol-diethyl ether to yield 12.3 g. (39%), m.p. 160°-162° C.
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C[O:22][C:23](=[O:34])[C@H:24]([CH:26](C(C)(C)C)[C:27]([OH:29])=[O:28])[NH2:25].[Li+].[OH-]>C1COCC1.O>[C:2]([O:29][C:27](=[O:28])[CH2:26][C@@H:24]([C:23]([OH:22])=[O:34])[NH:25][C:13](=[O:15])[C@@H:12]1[CH2:16][CH2:17][CH2:18][N:11]1[S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:19])=[CH:7][CH:6]=1)(=[O:9])=[O:10])([CH3:19])([CH3:7])[CH3:3]
Reactant: COC(=O)[C@@H](N)C(C(=O)O)C(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)O)cc1

Procedure:
N-(Toluene4-sulfonyl)-L-proline hydrate was coupled to β-tert-butyl L-aspartic acid methyl ester hydrochloride using the procedure described in Method 3. The title compound was prepared, via hydrolysis of the methyl ester using LiOH in THF/water, as a solid, mp=153-155° C.
Reaction SMILES: Cl[CH2:2][C:3](=[CH2:16])[CH2:4][CH:5]1[O:9][C:8](=[O:10])[CH:7]=[C:6]1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.[Cl:17][C:18]1[N:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][CH:19]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[Cl:17][C:18]1[N:23]=[CH:22][C:21]([CH2:24][NH:25][CH2:2][C:3](=[CH2:16])[CH2:4][CH:5]2[O:9][C:8](=[O:10])[CH:7]=[C:6]2[N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:20][CH:19]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: C=C(CCl)CC1OC(=O)C=C1N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=C(CNCc1ccc(Cl)nc1)CC1OC(=O)C=C1N1CCCC1
Yield: 75.3 %

Procedure:
At 60° C., 600 mg (2.48 mmol) of 5-[2-(chloromethyl)prop-2-en-1-yl]-4-pyrrolidin-1-ylfuran-2(5H)-one (V-1a), 354 mg (2.48 mmol) of 1-(6-chloropyridin-3-yl)methanamine and 0.43 ml (2.48 mmol) of N-ethyl-N-isopropylpropan-2-amine in 10 ml of acetonitrile are stirred for 21 hours. Concentration under reduced pressure and purification of the residue by column chromatography on silica gel (silica gel 60, Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture dichloromethane:methanol (98:2 to 90:10) gives 650 mg (73% of theory) of 5-[2-({[(6-chloropyridin-3-yl)methyl]amino}methyl)prop-2-en-1-yl]-4-pyrrolidin-1-ylfuran-2(5H)-one.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[N:15]=[C:16]([C:31]#[N:32])[C:17]2[C:22]([C:23]=1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)C>[F:30][C:26]1[CH:25]=[C:24]([C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([C:31]#[N:32])=[N:15][C:14]=2[CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[CH:29]=[CH:28][CH:27]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: CC(N)c1nc(C#N)c2ccccc2c1-c1cccc(F)c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1nc(C#N)c2ccccc2c1-c1cccc(F)c1
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (5.48 mg, 0.0275 mmol), 3-(1-aminoethyl)-4-(3-fluorophenyl)isoquinoline-1-carbonitrile (4 mg, 0.01 mmol), and N,N-diisopropylethylamine (0.00480 mL, 0.0276 mmol) in ethanol (0.05 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on a RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at a flow rate of 30 mL/min) to give the desired product. LCMS calculated for C23H17FN7 (M+H)+: m/z=410.2; Found: 410.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:11][C@H:12]1[CH2:17][N:16]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][CH3:26])=[CH:21][CH:20]=2)[CH2:15][CH2:14][N:13]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([N:25]([CH3:26])[C:22]2[CH:21]=[CH:20][C:19]([CH2:18][N:16]3[CH2:15][CH2:14][N:13]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[C@@H:12]([CH3:11])[CH2:17]3)=[CH:24][CH:23]=2)=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cccc(Cl)n1
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3cccc(Cl)n3)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The acid chloride from step 1 was dissolved in DCM (15 mL) and added to a mixture of 1,1-dimethylethyl (2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate (D3) (0.500 g, 1.57 mmol) and triethylamine (0.284 mL, 2.04 mmol) in DCM (15 mL). The reaction mixture was stirred at room temperature overnight and then washed with water (×2) and brine. The organic layer was dried and concentrated to give the crude product, which was purified by column chromatography. Elution with 20-60% EtOAc/pentane yielded the title compound as a yellow oil/solid (0.658 g). δH (CDCl3, 400 MHz) 7.56 (1H, m), 7.46 (1H, m), 7.17 (2H, m), 6.99 (2H, m), 4.16 (1H, br.s), 3.79 (1H, d), 3.50 (3H, s), 3.46 (1H, d), 3.32 (1H, d), 3.07 (1H, m), 2.69 (1H, d), 2.50 (1H, d), 2.08 (1H, m), 1.97 (1H, m), 1.46 (9H, s), 1.19 (3H, d). MS (ES): MH+ 459/461.
Reaction SMILES: [F:1][CH2:2][CH2:3][S:4][C:5]1[S:6][C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([N:20](C)[C:21](=O)OC(C)(C)C)=[CH:16][CH:15]=3)[CH:11]=[CH:10][C:8]=2[N:9]=1.O1CCOCC1.Cl>>[F:1][CH2:2][CH2:3][S:4][C:5]1[S:6][C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][CH3:21])=[CH:16][CH:15]=3)[CH:11]=[CH:10][C:8]=2[N:9]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(-c2ccc3nc(SCCF)sc3c2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CNc1ccc(-c2ccc3nc(SCCF)sc3c2)cc1

Procedure:
Tert-butyl 4-(2-(2-fluoroethylthio)benzo[d]thiazol-6-yl)phenyl(methyl)carbamate (15 mg, 0.036 mmol) was treated with 3 mL of 4 M HCl dioxane solution for 2 h and concentrated. The crude product was purified with RP-HPLC (20% to 80% TFA buffered MeCN in water) to afford 4-(2-(2-fluoroethylthio)benzo[d]thiazol-6-yl)-N-methylaniline as a yellow wax (4 mg, 25%). 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J=8.4 Hz, 1 H), 7.81 (d, J=1.6 Hz, 1 H), 7.58-7.56 (m, 2 H), 7.53 (dd, J=8.8, 2.0 Hz, 1 H), 7.34-7.32 (m, 2 H), 4.86 (t, J=6.4 Hz, 11 H), 4.74 (t, J=6.4 Hz, 1 H), 3.73 (t, J=6.4 Hz, 1 H), 3.68 (t, J=6.4 Hz, 1 H), 3.02 (s, 3 H); MS (ESI) m/z 319 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([OH:15])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[H-].[Na+].[CH2:18](Br)[C:19]#[CH:20]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:14]([O:15][CH2:20][C:19]#[CH:18])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4]
Reactant: C#CCBr
Reactant: COC(=O)c1cc2ccccc2cc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCOc1cc2ccccc2cc1C(=O)OC
Reaction time: 0.5 h
Yield: 35 %

Procedure:
Methyl-3-hydroxy-2-naphthoate (2.63 g, 0.013 mol) was dissolved in dry THF (80 ml) and treated with sodium hydride (80%) ((0.398 g, 0.013 mol), with stirring under N2. After 0.5 h, propargyl bromide (80% in toluene) (2.57 ml 0.017 mol) was added and the mixture heated to reflux. After 20 h, the reaction mixture was allowed to cool and then evaporated under reduced pressure. The residue was then evaporated under reduced pressure. The residue was then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (1×), and the combined organic layers were dried (Na2SO4) and evaporated to given an orange oil. Crystallisation of the oil from petrol (60/80) diethyl ether provided the title compound as a pale yellow solid (1.0 gg, 35%).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:11]1.O>CS(C)=O>[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C@@H:19]2[CH2:4][C@H:20]2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:11]1
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)/C=C/c1cn(C)c2ccccc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)[C@@H]1C[C@H]1c1cn(C)c2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 21.5 %

Procedure:
To a suspension of sodium hydride (ca 60%, 21 mg, 0.52 mmol) in DMSO (1 mL) was added trimethylsulfoxonium iodide (115 mg, 0.52 mmol), and the mixture was stirred at room temperature for 20 minutes. Then, ethyl (E)-3-(1-methyl-1H-indol-3-yl)acrylate (Synlett, (9), 1319-1322 (2006)) (100 mg, 0.44 mmol) was added to the mixture, and the mixture was stirred at room temperature for 1 hour and at 60° C. for 20 hours. After cooling to room temperature, the mixture was poured into water (30 mL), and the aqueous phase was extracted with ethyl acetate (twice). The combined organic layers were dried over Magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (7:1) to give 23 mg (21% yield) of the title compound as a pale yellow oil:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][NH:11][C:12]([C:14]2[NH:23][C:22](=[O:24])[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:25]#[N:26])[CH:20]=3)[N:15]=2)=[O:13])[CH:7]=[CH:8][CH:9]=1.[NH:27]1[CH:31]=[N:30][C:29]([CH2:32][C:33](O)=[O:34])=[N:28]1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[C:25]([C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([C:12]([NH:11][CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][NH:2][C:33](=[O:34])[CH2:32][C:29]3[N:30]=[CH:31][NH:27][N:28]=3)[CH:5]=1)=[O:13])[NH:23][C:22]2=[O:24])#[N:26]
Reactant: O=C(O)Cc1nc[nH]n1
Reactant: N#Cc1ccc2nc(C(=O)NCc3cccc(CN)c3)[nH]c(=O)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc2nc(C(=O)NCc3cccc(CNC(=O)Cc4nc[nH]n4)c3)[nH]c(=O)c2c1
Temperature: 40 °C
Reaction time: 15 h
Yield: 24 %

Procedure:
A solution of N-{[3-(aminomethyl)phenyl]methyl}-6-cyano-4-oxo-3,4-dihydroquinazoline-2-carboxamide hydrochloride obtained in Reference Example 47 (170 mg, 0.460 mmol), 1H-1,2,4-triazol-3-ylacetic acid obtained in Reference Example 15 (70.0 mg, 0.551 mmol), diisopropylethylamine (0.079 mL, 0.460 mmol), 1-[3-(dimethylamino)propyl]-3-ethyl-carbodiimide hydrochloride (106 mg, 0.550 mmol) and 1-hydroxybenzotriazole (74.0 mg, 0.550 mmol) in DMF (10 mL) was stirred at 40° C. for 15 hr. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. The resulting solid was collected by filtration, washed with water and IPE, and dried. The obtained crude crystals were recrystallized from ethyl acetate-IPE to give the title compound as a white powder (49.4 mg, 24%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[C:10]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)(=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O.C(O)C>[N:21]1[CH:22]=[CH:23][C:18]([C:10](=[N:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:9])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:19][CH:20]=1
Reactant: O=C(c1ccccc1)c1ccncc1
Reactant: CC(C)(C)OC(=O)NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NN=C(c1ccccc1)c1ccncc1
Yield: 11.9 %

Procedure:
To 6.61 gm (0.05 mole) of t-butylcarbazate dissolved in 100 ml of warm water is added 9.16 gm (0.05 mole) of 4-benzoylpyridine in 30 ml of ethanol. The mixture is refluxed 7 hr. Cooling several weeks yields 1.77 gm (12%) of the title compound having a melting point of 134.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc(Br)cnc1N1CCCCC1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
To a 100 mL round bottom flask containing 5-bromo-2-chloro-3-nitropyridine (5.05 g, 21.3 mmol) in DMSO (20 mL) was added piperidine (4.2 mL, 42.6 mmol) dropwise. The reaction was heated to 60° C. and monitored with TLC and LC-MS. After 2.5 h, LC-MS showed that the reaction was complete. The mixture was cooled to rt then diluted with water. After extracting three times with EtOAc, the organic layers were combined then washed with brine and dried over anhydrous magnesium sulfate. After filtration, the mixture was concentrated under reduced pressure to afford an orange oil 5-bromo-3-nitro-2-(piperidin-1-yl)pyridine. 1H NMR (400 MHz, CDCl3) δ ppm 8.30 (1H, d, J=2.3 Hz), 8.22 (1H, d, J=2.2 Hz), 3.39 (4H, d, J=5.7 Hz), 1.75 (6H, m).
Reaction SMILES: [N:1]1([C:8]([C:10]2[CH:14]=[C:13]([C:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH:20]=3)[S:12][CH:11]=2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29]>C(Cl)Cl>[N:1]1([C:8]([C:10]2[CH:14]=[C:13]([C:15]3[CH2:16][CH2:17][N:18]([C:28](=[O:30])[CH3:29])[CH2:19][CH:20]=3)[S:12][CH:11]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C(c1csc(C2=CCNCC2)c1)N1CCCCCC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CC=C(c2cc(C(=O)N3CCCCCC3)cs2)CC1
Reaction time: 1 h
Yield: 33.8 %

Procedure:
To a solution of azepan-1-yl-[5-(1,2,3,6-tetrahydro-pyridin-4-yl)-thiophen-3-yl]-methanone (0.023 g, 0.08 mmol) in DCM (1 mL) was added triethylamine (0.27 mmol) and acetyl chloride (0.11 mmol). The reaction mixture was stirred for 1 hour, and then the solvent evaporated. The product was purified by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound as a colourless oil (0.009 g). LCMS m/z 333.11 [M+H]+ RT=8.18 min (Analytical Method 2).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:17]=3[C:18]#[N:19])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[S:25]1(=[O:31])(=[O:30])[CH2:29][CH2:28][CH2:27][NH:26]1>>[O:30]=[S:25]1(=[O:31])[CH2:29][CH2:28][CH2:27][N:26]1[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:17]=3[C:18]#[N:19])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C#N)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)nc3)CC2)c(C#N)c1
Yield: 68.8 %

Procedure:
Using 2-[4-(6-bromopyridine-3-carbonyl)piperazin-1-yl]-5-methylnicotinonitrile (150 mg) described in Preparation Example 184 and isothiazolidine 1,1-dioxide (71 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (114 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3[CH:18]=[C:17]([OH:19])[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[H-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3[CH:18]=[C:17]([O:19][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: BrCc1ccccc1
Reactant: CCN1c2ncc(O)cc2C(=O)N(C)c2ccc(Cl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1c2ncc(OCc3ccccc3)cc2C(=O)N(C)c2ccc(Cl)nc21
Temperature: 0 °C
Reaction time: 24 h
Yield: 52.1 %

Procedure:
The 2-chloro-5,11-dihydro-11-ethyl-8-hydroxy-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.052 g, 0.17 mmol) was dissolved in tetrahydrofuran and treated with excess sodium hydride (60% wt.) followed by benzyl bromide (0.04 mL, 0.34 mmol). After 24 hours stirring the mixture was cooled to 0° C. and the excess sodium hydride was quenched by the dropwise addition of water and the resulting solution was extracted with dichloromethane (3×20 mL) The combined organics were dried over magnesium sulfate, concentrated and the residue was purified by chromatography (hexanes to 1:1 hexanes/ethyl acetate gradient) followed by crystallization from hexanes to give the title compound (0.035 g, 52%), m.p. 159°-160° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)=[O:8])[CH2:2]1.C1(C)C=CC(S(O[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])(=O)=O)=CC=1>>[F:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][CH2:29][N:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)=[O:8])[CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccccc2F)cc1
Reactant: O=C(N[C@H]1CCNC1)C12CC3CC(CC(C3)C1)C2
Product: O=C(N[C@H]1CCN(CCc2ccccc2F)C1)C12CC3CC(CC(C3)C1)C2
Yield: 29.6 %

Procedure:
(S)-N-(Pyrrolidin-3-yl)-1-adamantanecarboxamide (0.5 g) and 2-(2-fluorophenyl)ethyl p-toluenesulfonate (0.59 g) were reacted under the same conditions as in Example 6 to give (S)-N-(1-(2-(2-fluorophenyl)ethyl)pyrrolidin-3-yl)-1-adamantanecarboxamide (0.22 g), melting point 106-108° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:18](Cl)(=O)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>ClCCl>[CH3:15][C:14]([OH:16])([CH3:17])[CH2:13][N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[C:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCC(=O)Cl
Reactant: CC(C)(O)CNc1c(N)cnc2ccccc12
Solvent: ClCCl
Product: CCCCCc1nc2cnc3ccccc3c2n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 59.1 %

Procedure:
To a solution of 1-(3-aminoquinolin-4-ylamino)-2-methylpropan-2-ol (CAN 129655-59-0, 0.94 g, 4.06 mmol) in dichloromethane (9.5 mL) in an inert atmosphere was added dropwise with stirring at room temperature over a period of 6 min a solution of hexanoyl chloride (422 μl, 4.47 mmol) in dichloromethane (6.4 mL). After 3 h additional hexanoyl chloride (192 μl, 2.03 mmol) was added and stirring continued for another hour and finally the mixture was concentrated in vacuo. The residue was re-dissolved in ethanol (13.5 mL) and, after addition of sodiumhydroxide solution (1 M, 10.8 mL) the mixture was heated with stirring in argon to 90° C. After 75 min the mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was stirred with ethyl acetate (30 mL) and water (5 mL) dried by filtration over ChemElut® and ethyl acetate was removed in vacuo. The residue was purified by flash chromatography (silica gel-NH2, 0% to 100% ethyl acetate in heptane) to give the title compound (747 mg, 89%) as yellow oil; LC-MS (UV peak area, ESI) 95%, 312.2 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH2:24][CH2:25][C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].I[C:35]1([S:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:37][CH2:36]1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[C:39]1([S:38][C:35]2([O:22][C:19]3[CH:20]=[CH:21][C:16]([C:15]([NH:14][C:5]4([C:3]([OH:2])=[O:4])[CH2:13][C:12]5[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=5)[CH2:6]4)=[O:33])=[CH:17][C:18]=3[O:23][CH2:24][CH2:25][C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)[CH2:37][CH2:36]2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: COC(=O)C1(NC(=O)c2ccc(O)c(OCCc3cccc(C)c3)c2)Cc2ccccc2C1
Reactant: IC1(Sc2ccccc2)CC1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1cccc(CCOc2cc(C(=O)NC3(C(=O)O)Cc4ccccc4C3)ccc2OC2(Sc3ccccc3)CC2)c1
Yield: 65.4 %

Procedure:
The compound of step 1 of example 254 (50 mg, 0.116 mmol), (1-iodo-cyclopropylsulfanyl)-benzene (G. J. Hollingworth et al., Tetrahedron Lett. 40 (1999), 2633-2636) (64 mg, 0.232 mmol) and silver carbonate (64 mg, 0.232 mmol) in toluene (1 ml) were stirred overnight at 50° C. The mixture was filtered, the filtrate evaporated to dryness and the residue purified by silica gel chromatography (HEP/EA gradient) to yield 44 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[C:6]=2[CH:19]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]=2[CH:19]=1
Reactant: CC(C)(C)OC(=O)Cn1c(=O)oc2ccc(Cl)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cn1c(=O)oc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a mixture of tert-butyl (5-chloro-2-oxo-1,3-benzoxazol-3(2H)-yl)acetate (50 g) and dichloromethane (250 mL) was added TFA (67.4 mL), followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and then to the residue was added water. The resulting solid was collected by filtration and then washed with water to obtain (5-chloro-2-oxo-1,3-benzoxazol-3(2H)-yl)acetic acid (38.5 g).
Reaction SMILES: [CH:1]12[NH:10][CH:5]([CH2:6][C:7](=[O:9])[CH2:8]1)[CH2:4][O:3][CH2:2]2.CCN(CC)CC.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>ClCCl>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:10]2[CH:5]3[CH2:6][C:7](=[O:9])[CH2:8][CH:1]2[CH2:2][O:3][CH2:4]3)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: O=C1CC2COCC(C1)N2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CC2COCC(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
To a stirring mixture of 3-oxa-9-aza-bicyclo[3.3.1]nonan-7-one (408 mg, 2.3 mmol) in dichloromethane (8 mL) was added Et3N (1.2 mL, 9.2 mmol) and 4-chlorobenzenesulfonyl chloride (582 mg, 2.76 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with dichloromethane (50 mL) and washed with a saturated aqueous NaHCO3 solution (15 mL). The aqueous phase was separated and extracted twice with EtOAc (2×25 mL). The combined organic phases were then dried (Na2SO4), filtered, concentrated under vacuum, and the residue was purified on a silica gel column (eluant hexane/EtOAc, 50/50 to 100) to give 510 mg (70%) of 9-(4-chloro-benzenesulfonyl)-3-oxa-9-aza-bicyclo[3.3.1]nonan-7-one as a white solid; Retention time (min)=1.687 min, Method [1], MS (ESI) 316.1 (M+H); 1H-NMR (300 MHz, CDCl3) δ 7.84-7.81 (m, 2H), 7.56-7.51 (m, 2H), 4.28-4.27 (m, 2H), 3.76 (d, J=12.1 Hz, 2H), 3.61 (d, J=11.5 Hz, 2H), 2.65 (dd, J=15.93, 5.49 Hz, 2H), 2.46 (d, J=15.93 Hz, 2H); 13C-NMR (75 MHz, CDCl3) δ 204.3, 140.1, 139.1, 130.1, 128.7, 71.7, 51.7, 44.4 ppm.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:21])=[C:4]([CH:10](C(OCC)=O)[C:11]([O:13]CC)=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[OH-].[Na+].CCOC(C)=O.Cl>CO>[Cl:1][C:2]1[C:3]([CH3:21])=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(C#N)c(Cl)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1c(CC(=O)O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.8 %

Procedure:
To compound 1F (2.3 g, 7.4 mmol) in 20 mL of MeOH was added 1N NaOH solution (30 mL, 30 mmol), and stirred at RT for 5 hr. It was concentracted, EtOAc was added, then acidified with conc. HCl. The biphase solution was heated at 60° C. for 2 hr, and cooled to RT. The organic layer was separated, dried over Na2SO4, filtered and concentrated to give the title compound (1.44 g). MS (ES) m/z 164 [M-CO2H]−.