Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([O:13]CC)=[O:12])=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:16]1([S:26](Cl)(=[O:28])=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1.[Li+].[OH-]>C(Cl)Cl>[C:16]1([S:26]([NH:1][C:2]2[C:10]([C:11]([OH:13])=[O:12])=[C:9]3[C:5]([CH:6]=[CH:7][NH:8]3)=[CH:4][CH:3]=2)(=[O:28])=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1c(N)ccc2cc[nH]c12
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(O)c1c(NS(=O)(=O)c2cccc3ccccc23)ccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of ethyl 6-amino-1H-indole-7-carboxylate (prepared as described in Showalter, H. D. et al., J. Org. Chem., 1996, 61, 1155-1158, 0.05 g, 0.25 mmol) in CH2Cl2 (5 mL) was treated with 1-naphthalenesulfonyl chloride (0.066 g, 0.29 mmol) and pyridine (0.040 mL, 0.50 mmol), shaken for 16 hours at ambient temperature, filtered, and concentrated. The concentrate was dissolved in 9:1 methanol/water (1 mL), treated with LiOH (25 mg, 0.6 mmol), and heated to 60° C. for 16 hours. The mixture was concentrated and the concentrate was purified by C18 reverse-phase HPLC using acetonitrile/water/0.1% TFA to provide the desired product. MS (DCI) m/e 384 (M+NH4)+; 1H NMR (500 MHz, DMSO-d6) δ 12.43 (br s, 1H), 10.77 (s, 1H), 8.62 (d, 1H), 8.30 (dd, 1H), 8.18 (d, 1H), 8.03 (d, 1H), 7.69 (m, 1H), 7.64-7.60 (m, 3H), 7.20 (d, 1H), 7.17 (t, 1H), 6.35 (dd, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[C:6]([N:8]2[CH2:12][CH2:11][O:10][C:9]2=[O:13])[CH:7]=1.[O:30]1[CH2:34][CH2:33][NH:32][C:31]1=[O:35]>>[CH3:28][C:27]1[C:22]([N:19]2[CH2:20][CH2:21][N:16]([C:14]([C:5]3[CH:4]=[CH:3][C:2]([N:32]4[CH2:33][CH2:34][O:30][C:31]4=[O:35])=[CH:7][C:6]=3[N:8]3[CH2:12][CH2:11][O:10][C:9]3=[O:13])=[O:15])[CH2:17][CH2:18]2)=[N:23][CH:24]=[C:25]([CH3:29])[CH:26]=1
Reactant: O=C1NCCO1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3N3CCOC3=O)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3N3CCOC3=O)CC2)c(C)c1
Yield: 17.3 %

Procedure:
By reaction and treatment in the same manner as in Example 201 and using 3-{5-chloro-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}oxazolidin-2-one (207 mg) described in Preparation Example 120 and oxazolidin-2-one (43.5 mg), the title compound (40.1 mg) was obtained.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([OH:37])=[C:13]2[C:18](=[CH:19][N:20]=1)[N:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16](=[O:28])[C:15]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[CH:14]2)=[O:10])C.[OH-].[Na+].CO.C1COCC1>C([O-])(O)=O.[Na+]>[CH2:21]([N:17]1[C:18]2[C:13](=[C:12]([OH:37])[C:11]([C:9]([NH:8][CH2:7][CH2:6][CH2:5][C:4]([OH:38])=[O:3])=[O:10])=[N:20][CH:19]=2)[CH:14]=[C:15]([C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)[C:16]1=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)CCCNC(=O)c1ncc2c(cc(-c3ccc(OC)cc3)c(=O)n2Cc2ccccc2)c1O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2cc3c(O)c(C(=O)NCCCC(=O)O)ncc3n(Cc3ccccc3)c2=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 18.4 %

Procedure:
A mixture of 4-{[1-benzyl-5-hydroxy-3-(4-methoxy-phenyl)-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carbonyl]-amino}-butyric acid ethyl ester (20 mg, 0.039 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred at r.t. for 16 h, then concentrated to approximately one-third of its original volume. 1 M HCl was added to acidify the mixture, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washes several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration. The crude solid was purified by silica gel chromatography (5-80% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 3.5 mg of the title compound. MS: (+) m/z 488.34 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([C@@H:13]([CH3:15])[OH:14])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].CC1C=CC=C(C)N=1.FC(F)(F)S(O[Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])(=O)=O.Cl>C(Cl)Cl>[C:9]([O:8][C:6]([NH:5][C@@H:4]([C@H:13]([O:14][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH3:15])[C:3]([O:2][CH3:1])=[O:16])=[O:7])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O[Si](C)(C)C(C)(C)C
Reaction time: 16 h
Yield: 100.3 %

Procedure:
A solution of N-(tert-butoxycarbonyl)-L-threonine methyl ester (Aldrich) (717 mg, 3.07 mmol) in DCM (10 mL) was cooled in an ice-water bath and treated with 2,6-dimethylpyridine (Aldrich) (1.07 mL, 9.22 mmol) followed by tert-butyldimethylsilyl trifluoromethanesulfonate (Fluka) (0.85 mL, 3.69 mmol). The solution was stirred for 16 h, poured into 1 M aq. HCl (100 mL), and extracted with DCM (2×50 mL). The organic extracts were washed with saturated aq. NaHCO3 (100 mL), dried (MgSO4), filtered, and concentrated to give (2S,3R)-methyl 2-((tert-butoxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)butanoate (614a) (1.07 g, 3.08 mmol, 100% yield) as a colorless oil.
Reaction SMILES: Br.Br[C:3]1[O:7][C:6]([C:8]2[C:9]([NH2:14])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:4]=1.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([C:3]2[O:7][C:6]([C:8]3[C:9]([NH2:14])=[N:10][CH:11]=[CH:12][CH:13]=3)=[CH:5][CH:4]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ncccc1-c1ccc(Br)o1
Reactant: OB(O)c1ccccc1
Agent: Br
Product: Nc1ncccc1-c1ccc(-c2ccccc2)o1

Procedure:
In the same manner as in Example 14, step A, the title compound (1.19 g) was obtained as a yellow solid from 3-(5-bromofuran-2-yl)pyridin-2-amine hydrobromide and phenylboronic acid.
Reaction SMILES: [CH3:1][NH:2][C:3](=S)[NH:4][C:5]1[CH:9]=[N:8][N:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])[N:6]=1.[NH3:17]>>[CH3:1][N:2]=[C:3]([NH2:17])[NH:4][C:5]1[CH:9]=[N:8][N:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])[N:6]=1
Reactant: CNC(=S)Nc1cnn(CCCCC#N)n1
Reactant: N
Product: CN=C(N)Nc1cnn(CCCCC#N)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5-[4-(3-methylthioureido)1,2,3-triazol-2-yl]valeronitrile in methanolic ammonia (6M; 15 ml.) was treated with mercuric oxide (1.1 g.) and tne mLxture stirred for 3 hours at room temperature. The resulting suspension was filtered through diatomaceous earth and the filtrate evaporated to give 5-[4-(2-methylguanidino)-1,2,3-triazol-2-yl]valeronitrile as a yellow oil.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH:11]2[C:20]3[N:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1.[ClH:21]>CN(C)C=O.CCOCC>[ClH:21].[CH2:9]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH:11]2[C:20]3[N:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1)[CH2:4][CH2:5][CH3:6]
Reactant: Oc1ccc(SC2CCCc3cccnc32)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCOc1ccc(SC2CCCc3cccnc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.72 g (24 mmol) of sodium hydride were added to a solution of 5.15 g (20 mmol) of 8-(4-hydroxyphenylthio)-5,6,7,8-tetrahydroquinoline in 26 ml of dimethylformamide under nitrogen. When effervescence had ceased, 3.29 g (24 mmol) of n-bromobutane were added dropwise with ice-cooling. After stirring at room temperature overnight, the mixture was poured into ice-cold water and extracted with ether to obtain a brown oil. A solution of the oil in ether was treated with ethereal hydrogen chloride to precipitate 4.89 g (70%) of 8-(4-n-butoxyphhenylthio)-5,6,7,8-tetrahydroquinoline hydrochloride as pale yellow crystals (from ethanol-ether).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:25]#[N:26])=[C:11]([O:17]C(C1OC=CC=1)=O)[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1.[OH-].[K+].O.Cl>C(O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=[C:11]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)[OH:17])[C:25]#[N:26]
Reactant: N#CC(=C(OC(=O)c1ccco1)c1ccco1)c1nc2ccccc2s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#CC(=C(O)c1ccco1)c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
A mixture of furan-2-carboxylic acid 2-benzothiazol-2-yl-2-cyano-1-furan-2-yl-vinyl ester (660 mg, 1.82 mmol) and KOH (108 mg, 1.93 mmol) in ethanol (20 mL) was stirred first at room temperature overnight and then at 50° C. for 2 hours. The resulting suspension was poured into water (200 mL), and the solution was adjusted to pH 7 using 5% HCl solution. The solids were isolated by filtration, washed with water, and air-dried to yield 474 mg (97%) of crude 2-benzothiazol-2-yl-3-furan-2-yl-3-hydroxy acrylonitrile which was used in the next step: without further purification. MS (m/z, ES+): 268.98 (M+1, 100%).
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[C:7]([O:13][CH3:14])(=[O:12])[CH2:8][C:9]([CH3:11])=[O:10]>CC(O)(C)C>[C:9]([CH:8]([C:7]([O:13][CH3:14])=[O:12])[CH:3]1[CH2:4][CH2:5][C:1](=[O:6])[CH2:2]1)(=[O:10])[CH3:11]
Reactant: O=C1C=CCC1
Reactant: COC(=O)CC(C)=O
Solvent: CC(C)(C)O
Product: COC(=O)C(C(C)=O)C1CCC(=O)C1
Temperature: 40 °C
Reaction time: 24 h
Yield: 98.9 %

Procedure:
Under an atmosphere of argon, 12.6 mg (0.02 mmol, S/C=50) of Ru[(S,S)-Tsdpen] (hexamethylbenzene), 84 μL (1.0 mmol) of 2-cyclopentenone, 108 μL (1.0 mmol) of methyl acetoacetate, and 1 mL of 2-methyl-2-propanol were placed in a 20 mL Schlenk tube and stirred at 40° C. for 24 hours. This solution was purified by flash column chromatography (hexane/acetone=90/10, SiO2) to give 196 mg (99% yield) of the title compound. The percentage diastereomeric excess and the percentage enantiomeric excess were measured by 1H NMR and HPLC (CHIRALPAK AS manufactured by Daicel Chemical Industries, Ltd., hexane:2-propanol=80:20, flow rate 1.0 mL/min, detection at 210 nm), it was found that the product was a 1:1 diastereomeric mixture and each diastereomer was present in 70% ee.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][NH:22][CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[CH2:24]2)[O:12]1.[BH3-]C#N.[Na+].[CH3:43][C:44](O)=O.CC=O>CO.O>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:19])([CH3:20])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH2:43][CH3:44])[CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:30])[CH2:24]2)[O:12]1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CNC1CC(CCC(=O)OCc3ccccc3)C1)O[C@H]2n1cnc2c(N)ncnc21
Reactant: CC(=O)O
Agent: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)OCc2ccccc2)C1
Temperature: 30 °C
Reaction time: 1.5 h
Yield: 66 %

Procedure:
To a mixture of benzyl 3-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)amino)cyclobutyl)propanoate (3.76 g, 7.2 mmol) and NaBH3CN (5.9 g, 93.6 mmol) in MeOH (40 mL) was added AcOH to adjust to pH=6. Then, 40% MeCHO (8.7 mL, 122.5 mmol) was added and the mixture was stirred at 30° C. for 1.5 h. Water (15 mL) was added and the mixture was concentrated in vacuo. Then, the mixture was extracted with DCM (30 mL×3). The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The crude was purified by SGC (DCM: MeOH=100:1-20:1) to obtain the target (2.6 g, yield: 66%) as a white solid. 1H NMR (500 MHz, MeOD): δH 8.26 (s, 1H), 8.23 (m, 1H), 7.37-7.28 (m, 5H), 6.24 (s, 1H), 5.52-5.49 (m, 1H), 5.10-5.06 (m, 3H), 4.41-4.40 (m, 1H), 3.20-2.90 (m, 2H), 2.80-2.60 (m, 2H), 2.12-1.77 (m, 4H), 1.74-1.60 (m, 3H), 1.39 (s, 3H), 1.26-1.22 (m, 3H), 0.94-0.89 (m, 3H) ppm; ESI-MS (m/z): 551.3 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5](O)=[O:6].[BH4-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[CH2:5][OH:6]
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Product: OCc1cc(Cl)cc(Cl)c1
Yield: 74.1 %

Procedure:
Prepared according to the method described in Example X(i) above from 3,5-dichlorobenzoic acid (15.3 g; 80 mmol), TEA (8.9 g; 88 mmol), i-Bu chloroformate (12 g; 88 mmol) and NaBH4 (9.0 g; 240 mmol), yielding 10.5 g (74%) of sub-title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH3:14]>>[CH2:13]([O:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)[CH3:14]
Reactant: CCOCCCCl
Reactant: O=C1CCNCC1
Product: CCOCCCN1CCC(=O)CC1

Procedure:
1-(3-Ethoxypropyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-3-ethoxypropane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([Cl:11])[CH:5]=1.Cl[C:13]([O:15][CH3:16])=[O:14].Cl>O>[Cl:11][C:6]1[CH:5]=[C:4]([NH:3][C:13](=[O:14])[O:15][CH3:16])[CH:9]=[CH:8][C:7]=1[OH:10]
Reactant: COC(=O)Cl
Reactant: Nc1ccc(O)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)Nc1ccc(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
5 ml of water and 2.5 ml of 10% aqueous sodium hydroxide solution were carefully added to 1.70 g of 4-amino-2-chlorophenol cooled in an ice-water bath and 2 ml of methyl chloroformate were added dropwise to the resulting mixture. The reaction mixture was then stirred for 3 hours at room temperature, at the end of which it was acidified with 4 ml of 2N hydrochloric acid, and the resulting mixture was extracted with methylene; chloride. The resulting extract was washed with water and then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure to give a crude crystalline solid which was purified by column chromatography through silica gel using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent to give 2.08 g (yield 87%) of the title compound as a pale brown crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[CH2:33]([S:37](Cl)(=[O:39])=[O:38])[CH:34]([CH3:36])[CH3:35]>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([S:37]([CH2:33][CH:34]([CH3:36])[CH3:35])(=[O:39])=[O:38])[CH2:17][CH2:18]1)=[N:7]2
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Reactant: CC(C)CS(=O)(=O)Cl
Product: Cc1c(N2CCN(S(=O)(=O)CC(C)C)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure M using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (50.0 mg, 0.11 mmol) and isobutylsulfonyl chloride to give 5,7-difluoro-2-(4-(isobutylsulfonyl)piperazin-1-yl)-3-methyl-N-(5-morpholinopyridin-3-yl)quinolin-4-amine. 1H NMR (DMSO-d6) δ ppm 1.05 (d, J=6.8 Hz, 6H), 2.11 (br s, 3H), 2.12-2.16 (m, 1H) 2.96 (d, J=6.8 Hz, 2H), 3.06 (br s, 4H), 3.33-3.37 (m, 8H), 3.69 (t, J=9.2 Hz, 4H), 6.53 (s, 1H), 7.16-7.20 (m, 1H), 7.29-7.32 (m, 1H), 7.52 (s, 1H), 7.79 (s, 1H,), 8.41 (s, 1H). Mass Spectrum (ESI) m/e=561.4 (M+1).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:14])[CH2:6][CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]1>>[O:13]=[C:10]1[CH2:11][CH2:12][CH:7]([CH2:6][C:5]([OH:14])=[O:4])[CH2:8][CH2:9]1
Reactant: COC(=O)CC1CCC(=O)CC1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)CC1CCC(=O)CC1

Procedure:
Prepared from LiOH hydrolysis of (4-Oxo-Cyclohexyl)-acetic acid methyl ester (commercial available).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7]([S:9][C:10]3[CH:15]=[C:14]([N:16]([CH3:18])[CH3:17])[CH:13]=[CH:12][C:11]=3[N:19]([CH3:21])[CH3:20])=[N:8][C:4]=2[CH:3]=1.ClC1C=CC=C(C(OO)=[O:32])C=1.CCOCC>C(OCC)(=O)C>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7]([S:9]([C:10]3[CH:15]=[C:14]([N:16]([CH3:17])[CH3:18])[CH:13]=[CH:12][C:11]=3[N:19]([CH3:21])[CH3:20])=[O:32])=[N:8][C:4]=2[CH:3]=1
Reactant: CN(C)c1ccc(N(C)C)c(Sc2nc3cc(Cl)ccc3[nH]2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CN(C)c1ccc(N(C)C)c(S(=O)c2nc3cc(Cl)ccc3[nH]2)c1
Reaction time: 3 h

Procedure:
The product of step (a) above (550 mg) was dissolved in ethyl acetate (20 ml) and cooled to -10°. A solution of m-chloroperbenzoic acid (320 mg of 85%) in ethyl acetate (5 ml) was cooled to 0° and added to the above solution. After stirring at below 0° for 3 hours the solution was washed with sodium bicarbonate solution, sodium metabisulphite solution, water and brine, and then dried and concentrated in vacuo. The residue was flash chromatographed to produce a yellow gum. Trituration with ether and petroleum ether produced the title compound as a pale yellow solid (125 mg), mp 161°-3°.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([O-:3])=[O:2].[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][O:13][C:10]1[CH:9]=[CH:8][C:7]([O:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=1
Reactant: Fc1ccccc1CBr
Reactant: O=[N+]([O-])c1ccccc1Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccccc1Oc1ccc(OCc2ccccc2F)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 95.8 %

Procedure:
To a solution of 4-(2-nitrophenoxy)phenol (462 mg, 2.0 mmol) in N,N-dimethylformamide (20 ml) were added 2-fluorobenzyl bromide (400 mg, 2.1 mmol), potassium iodide (40 mg, 0.24 mmol) and potassium carbonate (300 mg, 2.2 mmol), followed by stirring at 50° C. for 4 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution and dried. The solvent was evaporated under reduced pressure to give 1-[4-(2-fluorobenzyloxy)phenoxy]-2-nitrobenzene (0.65 g).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][O:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH:15]1[OH:28].[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C>C1COCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][O:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH:15]1[O:28][S:30]([CH3:29])(=[O:32])=[O:31]
Reactant: O=C(c1ccccc1)N1CCC(OCc2ccc3ccccc3c2Br)C(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(C(=O)c2ccccc2)CCC1OCc1ccc2ccccc2c1Br
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A solution of the alcohol 67 (1 mmole) in THF is cooled to 0° C. Methanesulfonyl chloride (1 mmole) and triethylamine (1 mmole) are added and the solution is stirred at 0° C. for 6 hr. Standard work-up and flash chromatography affords 68.
Reaction SMILES: CN(C=O)C.[N:6]([C:9]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13]([CH3:20])=[N:14]2)=[N+:7]=[N-:8].N1C=CN=C1.[Si:26](Cl)([C:39]([CH3:42])([CH3:41])[CH3:40])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(OCC)(=O)C>[N:6]([C:9]1[CH:18]=[CH:17][C:16]([O:19][Si:26]([C:39]([CH3:42])([CH3:41])[CH3:40])([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13]([CH3:20])=[N:14]2)=[N+:7]=[N-:8]
Reactant: Cc1ccc2c(N=[N+]=[N-])ccc(O)c2n1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc2c(N=[N+]=[N-])ccc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 10 h
Yield: 1917.5 %

Procedure:
A 100-mL flask was successively loaded with dry DMF (10 mL), 13 (200 mg, 1 mmol), imidazole (68.08 mg, 1 mmol), and tert-butyldiphenylsilyl chloride (302 mg, 1.1 mmol). The solution was stirred at room temperature for 10 h, diluted with ethyl acetate (500 mL), washed with aqueous HCl (0.1 M, 50 mL), brine (100 mL), water (100 mL), dried over Na2SO4 and evaporated under reduced pressure to afford 8.41 g (96%) of protected product as a colorless oil (428 mg, 98%). 1H NMR (500 MHz, CDCl3) δ ppm: 1.19 (s, 9H), 2.33 (s, 3H), 6.98 (d, J=8.5 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 7.38-7.26 (m, 6H), 7.81-7.79 (m, 4H), 8.11 (d, J=8.5 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ ppm: 20.1, 24.3, 26.8, 113.5, 116.7, 120.6, 121.8, 127.3, 128.4, 129.2, 130.6, 134.3, 135.1, 140.9, 148.9, 157.9. HRMS (ESI): calc'd for C26H26N4OSi [M+H]+: 438.1876, found: 438.1879.
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[C:16][C:17]2([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:10]=1)=O.C([O-])([O-])=O.[K+].[K+]>CO>[NH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15]#[C:16][C:17]2([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:12]=[CH:13][CH:14]=1
Reactant: O=C(NCCOc1cccc(C#CC2(O)CCCCCC2)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: NCCOc1cccc(C#CC2(O)CCCCCC2)c1
Temperature: 50 °C

Procedure:
To a solution of 2,2,2-trifluoro-N-(2-(3-((1-hydroxycycloheptyl)ethynyl)phenoxy)ethyl)acetamide (1.07 g, 2.9 mmol) in MeOH (20 mL) was added saturated aqueous K2CO3 (ca. 10 mL). The reaction mixture was stirred vigorously and heated at 50° C. for 2 h. After removal of the volatiles by concentration under reduced pressure, the mixture was partitioned into EtOAc and water. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (10% 7M NH3 in MeOH-EtOAc) gave 1-((3-(2-aminoethoxy)phenyl)ethynyl)cycloheptanol as a pale yellow solid. (Yield 0.70 g, 88%): 1H NMR (400 MHz, CDCl3) δ 7.19 (t, J=8.0 Hz, 1H), 7.01 (dt, J=8.0, 0.8 Hz, 1H), 6.95 (dd, J=2.8, 1.6 Hz, 1H), 6.85 (ddd, J=−8.4, 2.4, 1.2 Hz, 1H), 3.97 (t, J=4.8 Hz, 2H), 3.07 (br s, 2H), 2.08-2.13 (n4, 2H), 1.87-1.94 (m, 2H), 1.59-1.74 (m, 1H).