Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].Cl[CH2:19][CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>O>[CH3:3][N:2]([CH3:1])[CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:13][CH:12]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: ClCCN1CCCC1
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CC1(c2ccc(OCCN3CCCC3)cc2)CCOCC1
Temperature: 25 °C
Yield: 28.7 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (389 mg, 1.65 mmol), 1-(2-chloro-ethyl)-pyrrolidine (210 mg, 1.57 mmol), DMF (4.5 ml) and K2CO3 (885 g, 6.40 mmol) was heated to 130° C. for 30 minutes. The mixture was cooled to ambient temperature; water (9 ml) was added and the mixture was extracted with EtOAc (3×4.5 ml). The organic phase was washed with brine (10 ml), NaOH solution (2M, 10 ml) and water (10 ml). The organic layer was dried over MgSO4, filtered and concentrated in vacuo at 35° C. and the residue subjected to chromatography on silica eluting with DCM:MeOH:NH3 (98:1:1) to give the title compound as a white solid (150 mg, 27%). 1H NMR (400 MHz, CDCl3) δ7.21 (d, 2H), 6.89 (d, 2H), 4.10 (t, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 2.89 (t, 2H), 2.67-2.58 (m, 4H), 2.40 (s, 2H), 2.13-2.05 (m, 2H), 1.97 (s, 6H), 1.88 (ddd, 2H), 1.84-1.77 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]=1.[Cl:10][CH2:11][C:12]([CH2:14]Cl)=O>C(COC)OC>[Cl:10][CH2:11][C:12]1[N:1]=[C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]2[CH:14]=1
Reactant: O=C(CCl)CCl
Reactant: COc1ccc(N)nc1
Solvent: COCCOC
Product: COc1ccc2nc(CCl)cn2c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-amino-5-methoxypyridine (0.5036 g; prepared by the method of Lombardino, J. Med. Chem. 1981, 24, 39-42), 1,3-dichloroacetone (Aldrich; 0.3935 g), and dimethoxyethane (2.5 mL) is stirred overnight at room temperature. The mixture is concentrated under reduced pressure and ethanol (7.9 mL) is added. After the mixture has stirred for 30 min at 80° C., it is cooled and concentrated under reduced pressure. The residue is partitioned between dichloromethane and saturated aq. sodium bicarbonate and the combined organic layers are dried with MgSO4 and concentrated under reduced pressure. The residue is chromatographed on silica gel using methanol/dichloromethane (4/96) to give 0.1392 g of 2-(chloromethyl)-6-methoxyimidazo[1,2-α]pyridine; 1H NMR (CDCl3) δ3.82, 4.75, 6.99, 7.48, 7.56, 7.59.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[C:44]1([CH2:54][C:55](O)=[O:56])[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46][CH:45]=1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:55](=[O:56])[CH2:54][C:44]3[C:53]4[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=4)[CH:47]=[CH:46][CH:45]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(O)Cc1cccc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(Cc1cccc2ccccc12)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 69.9 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 1-naphthylacetic acid (0.4 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight then was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL), washed with water (40 mL), 1NHCl (2×30 mL), water (40 mL), and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: EtOAc: CH2Cl2 3:7) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-naphthalen-1-yl-acetamide (0.7 g, 74%) as a white solid: mp 187-189° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=4.70 min. (98%); 1H NMR (DMSO-d6) δ 1.98-2.06 (m, 1H), 2.54-2.63 (m, 2H), 2.83-2.96 (m, 1H), 4.03 (s, 2H), 4.74 (d, J=5.8 Hz, 2H), 5.11-5.17 (dd, J=5.2 and 12.8 Hz, 1H), 7.43-8.11 (m, 10H), 8.71 (t, J=4.6 Hz, 1H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ 21.95, 30.90, 37.89, 48.82, 121.86, 124.17, 125.52, 125.64, 125.95, 127.11, 127.15, 127.92, 128.37, 131.48, 131.90, 132.47, 133.23, 133.33, 134.56, 139.23, 166.89, 167.42, 169.77, 170.60, 172.72; Anal. Calcd. for C26H21N3O5: C, 68.56; H, 4.65; N, 9.23. Found: C, 68.24; H, 4.54; N, 9.19.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)(OC(C)(C)C)=O.S(=O)(=O)(O)O>C(O)(=O)C.C(OCC)C>[Br:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[NH:1][C:22]1([CH2:23][CH2:24][NH:19][CH2:20][CH2:21]1)[NH:6][C:4]2=[O:5]
Reactant: NC(=O)c1cc(Br)ccc1N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C1NC2(CCNCC2)Nc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 33 mg (0.15 mmol) of 2-amino-5-bromobenzamide and 30 mg (0.15 mmol) of 1-Boc-4-piperidone in 400 μL of acetic acid containing 10 μL of sulfuric acid is stirred overnight at room temperature. The reaction mixture is diluted with diethyl ether. The yellow precipitate is collected by filtration, washed with excess ether, and dried under vacuum to give 55 mg (0.15 mmol) of the acetic acid salt of 6′-bromospiro-[piperidine-4,2′(1′H)-quinazolin]-4′-(3′H)-one. MS m/z: 297.0 (M+H)+, 319.0 (M+Na)+.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]3[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=3[CH:34]=2)=[O:23])[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[NH:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]3[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=3[CH:34]=2)=[O:23])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc3c(c2)NC(=O)CS3)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CSc2ccc(C(=O)NC3CCNCC3)cc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.6 %

Procedure:
Trifluoroacetic acid (1.73 mL, 22.20 mmol, 15.0 eq) is added at 0° C. to a stirred solution of 4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (610 mg, 1.48 mmol, 1.0 eq) in dichloromethane (20 mL). After 2 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×20 mL) and water (20 mL) and the pH is adjusted to 12 by the addition of a 1N sodium hydroxide aqueous solution. The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid piperidin-4-ylamide as a light brown solid (244 mg, 51% yield).
Reaction SMILES: C(OCCO)C.[BH4-].[Na+].[O:9](C)[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=O.S(=O)(=O)(O)O>C1(C)C(C)=CC=CC=1>[CH2:10]([OH:9])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCC(=O)OC
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCCO
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCO
Temperature: 25 °C
Yield: 90 %

Procedure:
7.5 g (0.083 mole) of ethylene glycol monoethyl ether was added dropwise to a mixture consisting of 1.6 g (0.042 mole) of sodium borohydride, 10 ml of xylene and 5 g (0.027 mole) of methyl caprate at 90° C. over two hours while agitating the mixture. Subsequently, the mixture was agitated at the same temperature for 2.5 hours. After cooling to room temperature, the mixture was neutralized with dilute sulfuric acid. As a result, n-decanol was obtained in 90% yield.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:13]([O:14]C)=[N:12][C:11]2[C:6]1=[N:7][C:8]([O:17][C@@H:18]([CH3:22])[CH2:19][CH2:20][CH3:21])=[N:9][C:10]=2[NH2:16].[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[NH2:16][C:10]1[N:9]=[C:8]([O:17][C@@H:18]([CH3:22])[CH2:19][CH2:20][CH3:21])[N:7]=[C:6]2[C:11]=1[NH:12][C:13](=[O:14])[N:5]2[CH2:4][CH2:3][CH2:2][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C1CCNCC1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCl)c2n1
Product: CCC[C@H](C)Oc1nc(N)c2[nH]c(=O)n(CCCN3CCCCC3)c2n1

Procedure:
Prepared similarly to Example 29 from 9-(3-chloropropyl)-2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9H-purin-6-amine and piperidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]=O)=[CH:4][CH:3]=1.[Cl:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][N:18]2[CH3:21])=C(Cl)[N:13]=1>>[Cl:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][N:18]2[CH3:21])=[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: O=CNc1ccc(F)cc1
Reactant: Cn1cnc2c(Cl)nc(Cl)nc21
Product: Cn1cnc2c(Nc3ccc(F)cc3)nc(Cl)nc21

Procedure:
Was prepared according to Example 3 from N-(4-fluoro-phenyl)-formamide and 2,6-dichloro-9-methyl-9H-purine.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15]C)[C:9]=3[C:8]([NH:17][C:18]3[CH:19]=[C:20]([S:24]([NH2:27])(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([NH:17][C:18]3[CH:19]=[C:20]([S:24]([NH2:27])(=[O:25])=[O:26])[CH:21]=[CH:22][CH:23]=3)=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1nccc2c1c(Nc1cccc(S(N)(=O)=O)c1)nn2C1CCCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: NS(=O)(=O)c1cccc(Nc2nn(C3CCCC3)c3cc[nH]c(=O)c23)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
To a solution of 3-((1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)benzenesulfonamide (14.4 mg) in acetonitrile (5 mL) were added sodium iodide (11.1 mg) and chloro(trimethyl)silane (0.038 mL), and the mixture was stirred at 60° C. for 1 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was washed with ethyl acetate/diisopropyl ether to give the title compound (10.4 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].CCCCCC>CC(=O)CC>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1ccc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1
Reaction time: 18 h
Yield: 56.4 %

Procedure:
A solution of methyl indole-5-carboxylate, (21.7 g), p-toluenesulfonyl chloride (47.3 g), and K2CO3 (68.4 g) in 2-butanone (310 ml) was refluxed under a nitrogen atmosphere for 18 hr. Additional p-toluenesulfonyl chloride (12.0 g) and K2CO3 (17 g) was added to the reaction mixture and reflux was continued for 18 hr. The reaction mixture was filtered hot and the filtrate was evaporated to give an ivory solid that was tritrated with hexane to give methyl 1-(4-methylphenylsulfonyl)indole-5-carboxylate (23.0 g, 56%) as an ivory solid: NMR (80 MHz, CDCl3): 2.34 (s, 3H, ArCH3), 3.91 (s, 3H, OCH3), 6.7 (d, 1H, H2 -indole).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)=[C:21]([CH3:34])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[CH3:35][O:36][CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[F:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[CH2:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:40]4[CH2:41][CH2:42][CH:37]([O:36][CH3:35])[CH2:38][CH2:39]4)[C:17]=23)=[CH:20][C:21]=1[CH3:34]
Reactant: Cc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1cccc(F)c1
Reactant: COC1CCNCC1
Product: COC1CCN(CCOc2n[nH]c3ncnc(Nc4ccc(OCc5cccc(F)c5)c(C)c4)c23)CC1
Yield: 27 %

Procedure:
The procedure described in Example 55 was repeated using 2-{[4-({4-[(3-fluorobenzyl)oxy]-3-methylphenyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy}ethyl methanesulfonate (prepared as described in Example 21) and 4-methoxypiperidine to give the title compound in 27% yield; NMR Spectrum: 1.36-1.41 (m, 2H), 1.78-1.80 (m, 2H), 2.18-2.23 (m, 2H), 2.23 (s, 3H), 2.76-2.78 (m, 4H), 3.12-3.15 (m, 1H), 3.19 (s, 3H), 4.39 (t, 2H), 5.16 (s, 2H), 7.00 (d, 1H), 7.16 (td, 1H), 7.28-7.32 (m, 2H), 7.42-7.47 (m, 3H), 8.21 (s, 1H), 8.24 (s, 1H); Mass Spectrum: 507 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:12]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:11][C:10]=1[C:27]([CH3:29])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](=O)([O:34]CC)[O:31][CH2:32][CH3:33].[H-].[Na+]>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:12]([O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:11][C:10]=1[C:27]([CH2:29][C:30]([O:31][CH2:32][CH3:33])=[O:34])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1cc(Oc2ccccc2)c(NS(C)(=O)=O)cc1OCc1ccccc1
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(=O)c1cc(Oc2ccccc2)c(NS(C)(=O)=O)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
There were mixed 4.11 g of methyl 2-benzyloxy-4-methylsulfonylamino-5-phenoxyphenyl ketone, 20.6 ml of diethyl carbonate, 20.6 ml of N,N-dimethylformide and 1.6 g of sodium hydride (purity: 60%). The mixture was stirred for 30 minutes at 90°-100° C. The reaction mixture was introduced into 200 ml of ice water. The resulting mixture was washed with 50 ml of diethyl ether. The aqueous layer was separated, adjusted to pH 5 with 4N hydrochloric acid, and extracted with two 100-ml portions of ethyl acetate. The extracts were combined, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: a 3 : 1 mixture of toluene and ethyl acetate) to obtain 4.35 g (yield: 90%) of ethyl 2-(2-benzyloxy-4-methylsulfonylamino-5-phenoxybenzoyl)acetate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:12][CH2:13][CH2:14][CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: OCCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: O=[N+]([O-])c1ccc(SCCCCO)cc1

Procedure:
A mixture of 4-nitrothiophenol (0.11 mol), 4-chloro-1-butanol (0.09 mol), and potassium carbonate (0.1 mol) in dimethoxyethane (100 mL) is heated at reflux temperature for 18 hrs. The mixture is filtered and the filtrate is concentrated to dryness. The residue is dissolved in methylene chloride and washed with 10% sodium hydroxide. The chloroform solution is dried and concentrated to obtain the title compound.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:30]=[CH:29][CH:28]=[CH:27][C:10]=2[C:11]([NH:13][C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19]([C:24](O)=[O:25])[CH:20]=[N:21]3)=[CH:16][CH:15]=2)=[O:12])=[N:7][CH:8]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C@H:39]([NH2:42])[CH2:40][CH3:41].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C@H:39]([NH:42][C:24]([C:19]1[CH:20]=[N:21][C:22]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([NH:13][C:11](=[O:12])[C:10]1[CH:27]=[CH:28][CH:29]=[CH:30][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:31])[F:32])=[CH:8][N:7]=1)[CH:23]=2)=[O:25])[CH2:40][CH3:41]
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cn3)ccc2c1
Reactant: CC[C@@H](N)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@@H](NC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cn3)ccc2c1)c1ccccn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
7-[2-(5-Trifluoromethyl-pyridin-2-yl)-benzoylamino]-quinoline-3-carboxylic acid (25 mg, 0.06 mmol), [R]-1-pyridin-2-yl-propylamine (23 mg, 0.17 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (33 mg, 0.17 mmol), 1-hydroxybenzotriazole (23 mg, 0.17 mmol), and triethylamine (69 mg, 0.69 mmol) were combined in 5 ml of dichloromethane. After stirring 5 h at room temperature, the mixture was diluted with dichloromethane and washed with 10 ml of 1N HCl, the organic layer was dried (magnesium sulfate), filtered and concentrated under vacuum. Purification of the residue by silica gel chromatography eluting with 5% methanol in ethyl acetate afforded the title compound.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:41])[CH2:7][CH2:8][CH:9]([N:23]([C:25](=[O:40])[C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=1)[CH3:24])[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C>O1CCCC1.CO>[F:33][C:32]([F:34])([F:35])[C:30]1[CH:31]=[C:26]([CH:27]=[C:28]([C:36]([F:38])([F:37])[F:39])[CH:29]=1)[C:25]([N:23]([CH:9]([CH:10]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:8][CH2:7][C:6]([OH:41])=[O:5])[CH3:24])=[O:40]
Reactant: CCOC(=O)CCC(C(c1ccccc1)c1ccccc1)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CCC(=O)O)C(c1ccccc1)c1ccccc1

Procedure:
45 ml of 1N sodium hydroxide are added to a solution of 15.2 g (27.6 mmol) of 4-[N-(3,5-bistrifluoromethyl-benzoyl)-N-methyl-amino]-5,5-diphenyl-pentanoic acid ethyl ester in 160 ml of tetrahydrofuran/methanol (2:1). After 2 hours the reaction mixture is concentrated by evaporation, diluted with water and rendered acidic with cold 2N hydrochloric acid. The white precipitate is filtered off, then washed with water and dried under a high vacuum at 50° C. The title compound is obtained in the form of a white solid. TLC: methylene chloride/methanol (95:5) Rf =0.21; Rt (HPLC)=18.5 min; 1H-NMR (400 MHz, d6 -DMSO, 120° C.) d 7.96 (br, 1H), 7.48-7.18 (m, 12H), 5.43 (br, 1H), 4.31 (d, 1H), 2.55 (br s, 3H). 2.36-2.19 (m, 2H), 1.91 (m, 1H), 1.73 (m, 1H); FAB-MS (M+H)+ =524.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([OH:10])=[N:3][CH:2]=1.[CH2:11]([O:18][C:19](=[O:31])[NH:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([CH:28]=[O:29])[C:22]=1[F:30])C1C=CC=CC=1.[OH-].[K+].CO>Cl>[CH3:11][O:18][C:19](=[O:31])[NH:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([CH:28]([OH:29])[C:9]2[C:5]3[C:4]([OH:10])=[N:3][CH:2]=[N:1][C:6]=3[NH:7][CH:8]=2)[C:22]=1[F:30]
Reactant: O=Cc1c(F)ccc(NC(=O)OCc2ccccc2)c1F
Reactant: Oc1ncnc2[nH]ccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncnc(O)c23)c1F
Temperature: 50 °C
Reaction time: 48 h
Yield: 92.5 %

Procedure:
In a reaction vessel, 7H-pyrrolo[2,3-d]pyrimidin-4-ol (37, 855 mg, 6.33 mmol) is combined with (2,4-difluoro-3-formyl-phenyl)-carbamic acid benzyl ester (33, 2.03 g, 6.96 mmol) and potassium hydroxide (1.06 g, 19.0 mmol) and 5 mL of methanol is added. The resulting solution is stirred at 50° C. for 2 days. The reaction is diluted with 1N hydrochloric acid and extracted with ethyl acetate, and the resulting solids collected by filtration and dried under vacuum. The organic layer is separated from the filtrate and the aqueous layer extracted twice more with ethyl acetate. The organic layers are combined and washed with water, brine, dried with magnesium sulfate and filtered. The filtrate is concentrated under vacuum and the resulting material is suspended in acetonitrile and sonicated for 1 hour. The solid is collected by filtration and dried under vacuum, then combined with the first solid collected to provide the desired compound (38, 2.05 g). MS (ESI) [M−H+]−=349.0.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:21][C:22]([CH2:24][C:25]2[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)=[O:23])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1.C(OP([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])(OCC)=O)C.[H-].[Na+]>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:21][C:22]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([CH:29]=[CH:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:31][CH:32]=2)=[O:23])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cc1ccc(C(NC(=O)Cc2ccc(C=O)cc2)c2ccccc2N2CCCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C=Cc1ccc(CC(=O)NC(c2ccc(C)cc2)c2ccccc2N2CCCCC2)cc1
Reaction time: 8 h

Procedure:
Four hundred twenty-seven milligrams (1 m mol) of 4-{N-[α-(4-methyl-phenyl)-2-piperidino-benzyl]-aminocarbonylmethyl}-benzaldehyde were added to an ethereal solution of 450 mg (2 m mol) of ethyl diethylphosphonoacetate and 100 mg (2 m mol) of 50% sodium hydride. After the mixture had been stirred overnight, water was added, and the resulting mixture was extracted with chloroform and purified by column chromatography on silica gel by use of toluene/ethyl acetate (5:1) as eluant.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[Cl:19][C:20]1[C:21]([N:27]=[C:28]=[S:29])=[N:22][CH:23]=[C:24]([Cl:26])[CH:25]=1>O1CCCC1>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[C:2]=1[NH:1][C:28](=[S:29])[NH:27][C:21]1[C:20]([Cl:19])=[CH:25][C:24]([Cl:26])=[CH:23][N:22]=1
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCCO
Reactant: S=C=Nc1ncc(Cl)cc1Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(NC(=S)Nc2ncc(Cl)cc2Cl)c1NCCCCO
Yield: 78.9 %

Procedure:
A solution of methyl 3-amino-4-chloro-2-[(4-hydroxybutyl)amino]benzoate (2.00 g, 7.33 mmol) and 3,5-dichloro-2-isothiocyanatopyridine (1.80 g, 8.80 mmol) in tetrahydrofuran (20 mL) was stirred for 12 h at room temperature. The reaction mixture was concentrated in vacuo and purified by flash column chromatography on NH-silica gel eluting with a 10-80% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (2.76 g, 5.78 mmol, 79%).
Reaction SMILES: [P:1]([O-:38])([O:34][CH2:35][CH2:36]Br)([O:3][CH2:4][CH:5]([O:28][C:29]1[CH:33]=[CH:32][O:31][N:30]=1)[CH2:6][O:7][C:8](=[O:27])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:2].[CH3:39][N:40]([CH3:42])[CH3:41]>>[P:1]([O-:38])([O:34][CH2:35][CH2:36][N+:40]([CH3:42])([CH3:41])[CH3:39])([O:3][CH2:4][CH:5]([O:28][C:29]1[CH:33]=[CH:32][O:31][N:30]=1)[CH2:6][O:7][C:8](=[O:27])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:2]
Reactant: CN(C)C
Reactant: CCCCCCCCCCCCCCCCCNC(=O)OCC(COP(=O)([O-])OCCBr)Oc1ccon1
Product: CCCCCCCCCCCCCCCCCNC(=O)OCC(COP(=O)([O-])OCC[N+](C)(C)C)Oc1ccon1

Procedure:
11(b) 0.800 g of (2RS)-3-(N-heptadecylcarbamoyloxy)-2-(3-isoxazolyloxy)propyl 2-bromoethyl phosphate [prepared as described in step (a) above] was reacted with trimethylamine in a similar manner to that described in Example 1(b), to give 0.640 g of the title compound as viscous oil.