Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[CH:8]=[C:9]1[CH2:13][CH2:12][NH:11][C:10]1=[O:14])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].C(=O)(OC1C=CC=C[C:29]=1[N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)N.CN(C=[O:45])C>>[O:37]1[CH2:38][CH2:39][N:34]([C:29]([N:11]2[CH2:12][CH2:13][C:9](=[CH:8][C:7]3[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:17]([OH:18])=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=3)[C:10]2=[O:14])=[O:45])[CH2:35][CH2:36]1
Reactant: CN(C)C=O
Reactant: NC(=O)Oc1ccccc1N1CCOCC1
Reactant: CC(C)(C)c1cc(C=C2CCNC2=O)cc(C(C)(C)C)c1O
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)c1cc(C=C2CCN(C(=O)N3CCOCC3)C2=O)cc(C(C)(C)C)c1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of 3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2-one (241 mg, 0.8 mmole) dissolved into DMF (2.4 ml), sodium hydride (60% in mineral oil, 96 mg, 2.4 mmole) was added under ice-cooling under nitrogen atmosphere with stirring for 30 min. Morpholinophenyl carbamate (249 mg, 1.2 mmole) was added thereto and the mixture was allowed to stand at room temperature for 4 hours. The reactant was poured into ice-water, and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and evaporated. The obtained residue was recrystallized from dichloromethane/ether, whereby 300 mg of the objective compound (Ia-15) was obtained in 90% yield.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.[Cl:20][CH2:21][CH2:22]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O>[Cl:20][CH2:21][CH2:22][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][C:9]2[CH:8]=[CH:7][C:6]([C:2]3[O:1][CH:5]=[CH:4][N:3]=3)=[CH:11][CH:10]=2)=[CH:14][CH:15]=1
Reactant: ClCCBr
Reactant: Oc1ccc(Cc2ccc(-c3ncco3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: ClCCOc1ccc(Cc2ccc(-c3ncco3)cc2)cc1
Yield: 98.3 %

Procedure:
A solution of 4-[[4-(2-oxazol yl)phenyl]methyl]phenol (2.2 g, 8.75 mmol) and 2-chloroethylbromide (10 g, 70 mmol) in acetonitrile as stirred as cesium carbonate (22.8 g, 70 mmol) was added. The reaction was heated at reflux for 3 days. The reaction was diluted with water. The product, 2-[4-[[4-(2-chloroethoxy)phenyl]methyl]phenyl]oxazole (2.7 g), was isolated by filtration, 1H NMR (400 MHz, CDCl3) δ 7.97 (d, 2H), 7.68 (s, 1H), 7.35 (m, 2H), 7.21 (s, 1H), 7.13 (d, 2H), 6.82 (d, 2H), 4.22 (t, 2H), 3.96 (s, 2H), 3.79 (t, 2H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](=O)[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH2:20]([O:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([N+:32]([O-:34])=[O:33])[C:30]=1[OH:31])[CH:26]=O)[CH3:21].[NH2:35][C:36]([NH2:38])=[O:37].Cl>C(O)C>[CH2:20]([O:22][C:23]1[CH:24]=[C:25]([CH:26]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:11]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[CH:1]=[N:2][CH:3]=[CH:4]4)[NH:38][C:36](=[O:37])[NH:35]2)[CH:28]=[C:29]([N+:32]([O-:34])=[O:33])[C:30]=1[OH:31])[CH3:21]
Reactant: NC(N)=O
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: O=C(Cc1ccccc1)c1ccc2cnccc2c1
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccc4cnccc4c3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 34.7 %

Procedure:
To a solution of 1-(isoquinolin-6-yl)-2-phenylethanone (Intermediate 68) (100 mg, 0.4 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (85 mg, 0.4 mmol) and urea (72 mg, 1.2 mmol) in 2 mL of ethanol was added 0.5 mL of conc. HCl and the mixture was refluxed overnight. The reaction was evaporated and purified by preparative HPLC (20-50% acetonitrile+0.15% trifluoroacetic acid in water, over 15 min.), followed by column chromatography (PE: EtOAc=3:1˜EtOAc:MeOH=10:1) to give Compound 133 (67 mg, yield 34.3%). 1H NMR (CD3OD 400 MHz): δ 9.18 (s, 1H), 8.42 (d, J=5.6 Hz, 1H), 7.95 (d, J=8.8 Hz, 1H), 7.94 (s, 1H), 7.76 (d, J=6.0 Hz, 1H), 7.65 (d, J=2.0 Hz, 1H), 7.48 (dd, J=2.0 Hz, 8.8 Hz, 1H), 7.17 (d, J=1.6 Hz, 1H), 7.07-7.06 (m, 3H), 6.95-6.93 (m, 2H), 5.45 (s, 1H), 4.13-4.02 (m, 2H), 1.41 (t, J=6.8 Hz, 3H); MS (ESI): m/z 483.3 [M+1]+.
Reaction SMILES: [OH-].[Na+].C(OC([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)C.C(=O)(O)N>O.C(O)C>[C:15]1([C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)N1CCC(=C(c2ccccc2)c2ccccc2)CC1
Agent: NC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 75.3 %

Procedure:
Sodium hydroxide (15.85 g, 396 mmol) in water (30 mL) was added to the carbamate 1-ethoxycarbonyl 4-(diphenylmethylidene)piperidine 19 (11.47 g, 35.7 mmol) dissolved in ethanol (150 mL). The mixture was heated at reflux overnight. The reaction mixture was cooled to room temperature was then partitioned between water (100 mL) and ethyl acetate (150 mL). The mixture was stirred to dissolve the solid and the layers were separated. The organic layer was washed with brine (100 mL) and the separate aqueous layers were extracted with ethyl acetate (100 mL). The combined organic layers were dried with Na2SO4, filtered, and concentrated. The yellow oil was dried by high vacuum to give 6.7 g (75%) of 20 as a yellow-white waxy solid. 1H NMR was used to confirm the structure of the product. (Amine 22 was similarly prepared.)
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:29]1([C:35]2[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[C:29]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:34]=[CH:33][C:32]([O:1][C@H:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[CH:31][CH:30]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](Oc3ccc(-c4ccccc4)cc3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 41.1 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 4-phenylphenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (3.00 mg, 41.2% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.48 (m, 2H), 7.40-7.30 (m, 8H), 7.30-7.25 (m, 4H), 6.97 (apparent d, 1H, J=7.6 Hz), 6.91 (apparent d, 2H, J=8.7 Hz), 5.34 (apparent dd, 1H, J=4.4, 8.0 Hz), 3.40 (m, 2H), 2.98 (m, 2H), 2.53 (apparent sept, partially hidden, 1H, J=8.1 Hz), 2.44 (m, 1H), 2.30-2.10 (m, 6H), 1.93 (d, 2H), 1.26 (d, 6H, J=6.9 Hz); ESMS m/e: 533.4 (M+H)+.
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([O:21][CH3:22])[C:16]=1[O:17][CH2:18][C:19]#[CH:20])[C:11](Cl)=[O:12].[CH3:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[NH2:30].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[NH:30][C:11](=[O:12])[C:10]1[CH:9]=[C:8]([O:7][CH3:6])[C:16]([O:17][CH2:18][C:19]#[CH:20])=[C:15]([O:21][CH3:22])[CH:14]=1
Reactant: CC1CCCCC1N
Reactant: C#CCOc1c(OC)cc(C(=O)Cl)cc1OC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCOc1c(OC)cc(C(=O)NC2CCCCC2C)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.7 %

Procedure:
To a mixture of 15 ml of THF and 0.45 g of 3,5-dimethoxy-4-(2-propynyloxy)benzoyl chloride were added 0.24 g of 2-methylcyclohexylamine and 0.27 g of triethylamine in order at room temperature. The mixture obtained was stirred at room temperature for 4 hours. Then, ethyl acetate was added to the reaction mixture and the mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue obtained was washed with methyl tert-butyl ether and hexane to obtain 0.49 g of N-(2-methylcyclohexyl)-3,5-dimethoxy-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 19 of the present invention) represented by the formula:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1.Cl.N>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][NH:20]4)=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)cn1
Agent: Cl
Agent: N
Product: COc1ccc(Nc2ncccc2-c2ncnc3[nH]cnc23)cn1
Reaction time: 8 h
Yield: 80.1 %

Procedure:
A solution of 6-methoxy-N-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)pyridin-3-amine (190 mg, 471 μmol) in 2 N aqueous HCl (2.0 mL, 4 mmol) was heated briefly at 100° C. in an oil bath, and then the heater was turned off and the mixture allowed to slowly cool and stand overnight. An essentially clean conversion was observed. The solution was neutralized with aqueous ammonia, and the precipitated product was collected by filtration washing with a small volume of water and dried under vacuum. N-(6-methoxypyridin-3-yl)-3-(9H-purin-6-yl)pyridin-2-amine (120.4 mg, 80.1% yield) was obtained as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ 13.80 (br. s., 1H); 12.33 (br. s., 1H); 9.73 (br. s., 1H); 9.10 (s, 1H); 8.70 (s, 1H); 8.50-8.58 (m, 1H); 8.25-8.34 (m, 1H); 8.08-8.20 (m, 1H); 6.95-7.07 (m, 1H); 6.79-6.90 (m, 1H); 3.85 (s, 3H). m/z (ESI, +ve) 320.0 (M+H)+.
Reaction SMILES: [Na].[C:2]([O:5][CH2:6][C:7]1[CH2:14][S:13][CH:12]2[N:9]([C:10](=[O:29])[CH:11]2[NH:15][C:16](=[O:28])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]=[N+:26]=[N-:27])=[CH:20][CH:19]=2)[C:8]=1[C:30]([OH:32])=[O:31])(=[O:4])[CH3:3].Cl[CH2:34][N:35]([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37].[CH3:42]N(C)C=O>>[CH2:39]([O:38][C:36]([N:35]([CH2:34][CH2:42][O:31][C:30]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:7]=1[CH2:6][O:5][C:2](=[O:4])[CH3:3])[CH:11]([NH:15][C:16](=[O:28])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][N:25]=[N+:26]=[N-:27])=[CH:22][CH:23]=1)[C:10]2=[O:29])=[O:32])[CH3:41])=[O:37])[CH3:40]
Reactant: CCOC(=O)N(C)CCl
Reactant: CN(C)C=O
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccc(CN=[N+]=[N-])cc3)C2SC1
Agent: [Na]
Product: CCOC(=O)N(C)CCOC(=O)C1=C(COC(C)=O)CSC2C(NC(=O)Cc3ccc(CN=[N+]=[N-])cc3)C(=O)N12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1.2 g of the sodium salt of 3-[(acetyloxy)-methyl]-7-[[2-[4-(azidomethyl]phenyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and 0.5 g of N-chloromethyl-N-methylurethane in 40 ml of dimethylformamide is stirred at room temperature for 2 hours. The mixture is poured into ice-water and decanted. The oily residue is taken up in 75 ml of ethyl acetate and washed with 5 ml of dilute aqueous sodium bicarbonate and 15 ml of water then dried over magnesium sulfate, filtered and evaporated to give 3-[(acetyloxy)methyl]-7-[[2-[4-(azidomethyl)phenyl]-acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid N-ethoxycarbonyl-N-methylaminoethyl ester.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([SH:12])[CH:9]=[C:8]([CH3:13])[C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:21]([O:25][CH3:26])(=[O:24])[CH:22]=[CH2:23]>C1(C)C=CC=CC=1>[NH2:7][C:6]1[C:8]([CH3:13])=[CH:9][C:10]([S:12][CH2:23][CH2:22][C:21]([O:25][CH3:26])=[O:24])=[CH:11][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(=O)OC
Reactant: Cc1cc(S)cc(C(C)(C)C)c1N
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CCSc1cc(C)c(N)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.2 %

Procedure:
To a stirred solution of 1.00 g (5.1 mmol) of 2-tert-butyl-4-mercapto-6-methylaniline and 0.05 g (0.5 mmol) of triethylamine in 5 mL of toluene at -5° C. is added dropwise a solution of 0.44 g (5.1 mmol) of methyl acrylate in 5 mL of toluene. The reaction mixture is stirred for 24 hrs at room temperature. The solvent is removed in vacuo and the crude product is purified by flash column chromatography (silica gel, 95:5, heptane:ethyl acetate eluent) to give 0.95 g (66%) of the title compound as a colorless liquid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:10].[C:20]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C:26]1=O)(OCC)=[O:21].P(Cl)(Cl)(Cl)=O>>[OH:1][C:2]1[C:3]([CH:9]([CH3:10])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:4][C:5]2[O:8][C:20](=[O:21])[C:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=3[C:6]=2[CH:7]=1
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: CC(CCCc1ccccc1)c1cc(O)ccc1O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(CCCc1ccccc1)c1cc2oc(=O)c3c(c2cc1O)CCCC3

Procedure:
A mixture of 5.0 g. (19.5 mmoles) of 2-(2',5'-dihydroxyphenyl)-5-phenylpentane, 3.4 g. (21.7 mmoles) 2-carboethoxycyclohexanone and 1.78 ml. (19.5 mmoles) of phosphorus oxychloride was stirred for five days under a nitrogen atmosphere. The solidified reaction mixture was dissolved in 175 ml. of chloroform, washed with 3×50 ml. of water and 50 ml. of saturated sodium bicarbonate solution, dried (MgSO4) and evaporated to dryness at reduced pressure to obtain 13.8 g. of a partially crystalline solid. Trituration with hexane and evaporation of the filtrate gave 6.0 g. of crude product, M.P. 184°-193° C. Recrystallization from chloroform-hexane provided 2.66 g. of the title compound as tan crystals; M.P. 201°-203° C. A second crop, 1.7 g. was obtained from the mother liquor. 1H-NMR(CDCl3)ppm, (δ): 7.4-7.1 (m,5,phenyl), 7.1 and 7.05 (s,1,aromatic), 3.6-3.0 (m,1,CH), 2.9-2.3 (m,6,benzylic and allylic CH2), 1.9-1.4 (m,8,CH2), 1.2 (d,3,J=7), α-CH3); IR(KBr) 6.0μ; Mass spectrum (m/e): 362(M+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:13][CH2:12][O:11][C:10]2=[O:14])=[N:6][C:7]=1[CH3:8].N1C=CC=CC=1.[CH3:21][C:22]1[C:26]([CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=2)=[C:25]([CH3:39])[O:24][N:23]=1>ClCCl>[CH3:21][C:22]1[C:26]([CH2:27][O:28][C:29]2[CH:30]=[CH:31][C:32]([S:35]([NH:1][C:2]3[C:7]([CH3:8])=[N:6][C:5]([N:9]4[CH2:13][CH2:12][O:11][C:10]4=[O:14])=[CH:4][CH:3]=3)(=[O:37])=[O:36])=[CH:33][CH:34]=2)=[C:25]([CH3:39])[O:24][N:23]=1
Reactant: Cc1nc(N2CCOC2=O)ccc1N
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc(N2CCOC2=O)ccc1NS(=O)(=O)c1ccc(OCc2c(C)noc2C)cc1
Temperature: 65 °C
Yield: 72.2 %

Procedure:
To a solution of 3-(5-amino-6-methyl-2-pyridinyl)-1,3-oxazolidin-2-one (80 mg, 0.414 mmol) in dichloromethane (3 mL) and pyridine (0.033 mL, 0.414 mmol) was added 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}benzenesulfonyl chloride (125 mg, 0.414 mmol). The reaction vessel was sealed and heated at 65° C. for 6 hours. The reaction mixture was then allowed to cool and separated between dichloromethane (40 mL) and saturated sodium bicarbonate solution (30 mL). The organic phase was separated using a hydrophobic frit and evaporated in vacuo. The crude was then purified by flash silica (Si) chromatography (0-100% ethyl acetate-cyclohexane gradient). The appropriate fractions were combined and evaporated in vacuo to give the title compound (137 mg) as a colourless glassy solid. LCMS (2 min, formic) Rt 0.92 min, m/z (ES+) 459 (M+H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.[F:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][C:13]=1F.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][C:13]=1[N:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: OC1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCC(O)C2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.2 %

Procedure:
To a solution of 3-pyrrolidinol (1.82 g) and 3,4-difluoronitrobenzene (3.0 g) in dimethylformamide (30 ml) was added potassium carbonate (3.94 g). The mixture was stirred at room temperature overnight and then filtered followed by washing with dichloromethane. The filtrate combined was concentrated under reduced pressure. The residue obtained was chromatographed over a silica gel column eluting with ethyl acetate/hexane with increasing in the content of ethyl acetate (50% to 60%). The appropriate fractions were pooled and concentrated under reduced pressure to give the title compound (4.83 g); 1H NMR (CD3OD, 270 MHz), δ 0.85 (2H, m), 2.25-2.57 (4H, m), 3.26 (1H, m), 5.47 (1H, t, J=8.6 Hz), 6.62 (1H, dd, J=2.4, 14.0 Hz), 6.69 (1H, dd, J=2.4, 8.6 Hz).
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]([OH:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.C(Cl)Cl>[C:1]([O:5][CH2:6][CH:7]([O:9][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(O)COC(C)(C)C
Reactant: COc1ccc2c(Cl)ccnc2c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc2c(OC(C)COC(C)(C)C)ccnc2c1
Temperature: 37 °C
Reaction time: 0.17 h

Procedure:
To a stirring solution of 1-tert-butoxypropan-2-ol (293 μl, 1937 μmol) in DMF (2.5 mL) under nitrogen was added NaH (93 mg, 3873 μmol) at 23° C. After 10 min, 4-chloro-7-methoxyquinoline (250 mg, 1291 μmol) was added. The mixture was heated to 37° C. for 18 h. The reaction was partioned between 5% NaHCO3 (10 mL) and CH2Cl2 (15%). The aqueous was extracted with CH2Cl2 (10 mL). The combined organics were dried with brine and MgSO4, concentrated under reduced pressure from toluene, and purified on silica (12 g) eluting with 0-30% of 5% (MeOH/CH2Cl2). MS (ESI pos. ion) m/z (MH+): 290. Calc'd exact mass for C17H23NO3: 291. 1H NMR (400 MHz, Chloroform-d) δ ppm 1.19 (s, 9H) 1.44 (d, J=6.26 Hz, 3H) 3.46-3.54 (m, 2H) 3.69 (dd, J=9.49, 5.77 Hz, 1H) 3.93 (s, 3H) 4.69-4.77 (m, 1H) 6.70 (d, J=5.28 Hz, 1H) 7.12 (dd, J=9.19, 2.54 Hz, 1H) 7.34 (d, J=2.54 Hz, 1H) 8.10 (d, J=9.19 Hz, 1H) 8.63 (d, J=5.48 Hz, 1H). 13C NMR (101 MHz, Chloroform-d) δ ppm 17.15, 27.45, 50.29, 55.40, 65.09, 73.31, 74.06, 100.45, 106.89, 116.62, 118.04, 123.38, 151.26, 151.58, 160.89, 161.07
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[CH:10][C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:4]2[N:3]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:5]2[N:9]=[CH:10][C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:4]2[N:3]=1
Reactant: Clc1cc(Cl)n2ncc(-c3ccccc3)c2n1
Reactant: C1COCCN1
Solvent: C1COCCO1
Product: Clc1cc(N2CCOCC2)n2ncc(-c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
There was dissolved, in 1,4-dioxane (2 mL), 5,7-dichloro-3-phenyl-pyrazolo-[1,5-a]pyrimidine (47.7 mg, 0.181 mM), then morpholine (31.6 μL, 0.362 mM) was added to the solution and the resulting mixture was stirred at room temperature for 30 minutes. The solvent was distilled off from this reaction mixture, the resulting residue was diluted with water and extracted with methylene chloride. The extracts thus obtained were combined, dried over anhydrous sodium sulfate, the solvent was then distilled off, and the resulting solid was washed with methanol to thus obtain the title compound (46.8 mg, yield: 82%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]([CH2:33][CH2:34][OH:35])[CH2:20][C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25][CH2:24]2)=[O:22])[CH:15]=[CH:16][C:17]=1[Cl:18].CCN(CC)CC>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]([CH2:33][CH:34]=[O:35])[CH2:20][C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25][CH2:24]2)=[O:22])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: O=C(CC(CCO)c1ccc(Cl)c(Cl)c1)N1CCCc2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=CCC(CC(=O)N1CCCc2ccccc21)c1ccc(Cl)c(Cl)c1
Reaction time: 0.25 h
Yield: 90.5 %

Procedure:
A solution of oxalyl chloride (1.15 mL) in CH2Cl2 (30 mL) was cooled to -78° C. whereupon DMSO (1.87 mL) was added dropwise over 15 mins. This mixture was stirred for 15 minutes. Whereupon a CH2Cl2 (30 mL) solution of 1-[3-(3,4-dichlorophenyl)-5-hydroxy-1-oxopentyl]-1,2,3,4-tetrahydroquinoline (1.0 g) was added over 20 minutes. The mixture was stirred for 30 minutes and then treated with Et3N (7.4 mL) and stirred for an additional 30 minutes at -78° C., followed by 1.5 hours at room temperature. The reaction mixture was quenched with water and diluted with CH2Cl2 (100 mL). The organic fraction was separated, washed sequentially with 1N HCl (1×50 mL), sat. NaHCO3 (1×50 mL) and brine (1×50 mL), dried over MgSO4, filtered and concentrated under reduced pressure to yield an oil. Silica gel chromatography eluting with 5-15% EtOAc/Hex gave the title compound (900 mg).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH2:7][CH:8]([O:11][CH3:12])[O:9][CH3:10])[CH3:6])=[O:4].[NH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>C(OCCCC)(=O)C>[OH:20][C@H:17]1[CH2:18][CH2:19][C@H:14]([NH:13][CH2:2][C:3]([N:5]([CH2:7][CH:8]([O:11][CH3:12])[O:9][CH3:10])[CH3:6])=[O:4])[CH2:15][CH2:16]1
Reactant: COC(CN(C)C(=O)CCl)OC
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCOC(C)=O
Product: COC(CN(C)C(=O)CN[C@H]1CC[C@H](O)CC1)OC
Temperature: 65 °C

Procedure:
50 g 2-chloro-N-(2,2-dimethoxy-ethyl)-N-methyl-acetamide in 100 ml n-butyl acetate are added dropwise to a suspension of 35.3 g trans-4-aminocyclohexanol and 53 g potassium carbonate in 150 ml n-butyl acetate at 90-100° C. within 2.5 h. After 45 min the suspension is filtered at 65° C. and washed with 70 ml of n-butyl acetate warmed to 65° C. 100 ml solvent are distilled off from the filtrate and the solution evaporated down is inoculated with product at 40° C. After 16 h at ambient temperature the precipitate is filtered off and washed with 70 ml tert-butylmethylether. After drying, 50 g product is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[Br:24][CH2:25][CH2:26][CH2:27][CH2:28]Br>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:28][CH2:27][CH2:26][CH2:25][Br:24])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(O)ccc21
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)n1ccc2cc(OCCCCBr)ccc21
Temperature: 100 °C
Reaction time: 3 h
Yield: 75.2 %

Procedure:
6.07 g (26 mmol) 5-Hydroxy-indole-1-carboxylic acid tert-butyl ester in 10 ml acetone were treated with 13.8 g (100 mmol) powdered K2CO3 and 11.8 ml (100 mmol) 1,4-dibromobutane. The suspension was stirred at 100° C. for 3 h, cooled to RT, and acetone was added. The suspension was filtered and concentrated. The residue was redissolved in ether and 0.5 M HCl, the inorganic phase was extracted with ether and the combined organic phases were washed with water, and dried over Na2SO4. Column chromatography on silica gel with a gradient hexane to hexane/EtOAc 19:1 yielded 7.2 g (65%, 3 steps) 5-(4-Bromo-butoxy)-indole-1-carboxylic acid tert-butyl ester as colorless oil, MS: 367 (M, 1Br).