Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]([CH3:11])[CH3:10])[CH:5]=[C:4]([CH3:12])[C:3]=1[OH:13].[C:14]([N:17]1[CH2:22]CNC[CH2:18]1)(=[O:16])[CH3:15]>C1(C)C(C)=CC=CC=1>[C:14]([N:17]1[CH2:22][CH2:11][N:9]([CH2:8][C:6]2[CH:7]=[C:2]([CH3:1])[C:3]([OH:13])=[C:4]([CH3:12])[CH:5]=2)[CH2:10][CH2:18]1)(=[O:16])[CH3:15]
Reactant: Cc1cc(CN(C)C)cc(C)c1O
Reactant: CC(=O)N1CCNCC1
Solvent: Cc1ccccc1C
Product: CC(=O)N1CCN(Cc2cc(C)c(O)c(C)c2)CC1

Procedure:
A solution of 35.8 g=0.2 mole of 2,6-dimethyl-4-(N,N-dimethylaminomethyl)-phenol and 25.6 g=0.2 mole of acetylpiperazine in 100 ml of xylene is boiled under reflux for 5 hours, in the course of which nitrogen is passed through the solution. After cooling, the precipitate is filtered off, washed with ethyl acetate and dried over phosphorus pentoxide in vacuo. This gives 46.1 g (88% of theory), melting point: 150°-151° C.
Reaction SMILES: Br[C:2]1[C:3]([CH3:17])=[N:4][C:5]([N:8]2[CH2:13][C@@H:12]3[C@@H:10]([CH2:11]3)[CH:9]2[C:14]([OH:16])=[O:15])=[N:6][CH:7]=1.[F:18][C:19]([F:33])([F:32])[C:20]1[CH:28]=[C:27]2[C:23]([CH:24]=[N:25][NH:26]2)=[C:22](B(O)O)[CH:21]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:17][C:3]1[C:2]([C:22]2[CH:21]=[C:20]([C:19]([F:33])([F:32])[F:18])[CH:28]=[C:27]3[C:23]=2[CH:24]=[N:25][NH:26]3)=[CH:7][N:6]=[C:5]([N:8]2[CH2:13][C@@H:12]3[C@@H:10]([CH2:11]3)[CH:9]2[C:14]([OH:16])=[O:15])[N:4]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc2[nH]ncc12
Reactant: Cc1nc(N2C[C@H]3C[C@H]3C2C(=O)O)ncc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: Cc1nc(N2C[C@H]3C[C@H]3C2C(=O)O)ncc1-c1cc(C(F)(F)F)cc2[nH]ncc12
Temperature: 140 °C
Reaction time: 0.75 h

Procedure:
In a 10 mL microwave vial were mixed (1R,5S)-3-(5-bromo-4-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (200 mg, 0.671 mmol), (6-(trifluoromethyl)-1H-indazol-4-yl)boronic acid (201 mg, 0.872 mmol), PdCl2(dppf) (49.1 mg, 0.067 mmol), and aqueous NaHCO3 (1.435 mL, 2.68 mmol) in dioxane (10 mL) to give an orange suspension. The vial was sealed and heated in a microwave reactor to 140° C. for 40 minutes. Additional (6-(trifluoromethyl)-1H-indazol-4-yl)boronic acid (201 mg, 0.872 mmol) and PdCl2(dppf) (49.1 mg, 0.067 mmol) were added and heating was continued for 45 minutes. The reaction mixture was subsequently partitioned between water (50 mL) and EtOAc (50 mL). The phases were separated. The organic layer was discarded and the aqueous layer was acidified with 1N HCl and extracted with EtOAc (2×75 mL). The organic layers were combined, washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to give the title compound as a tan glass, which was used without further purification (170 mg, 62.8%).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[CH2:32][CH2:33][C:34](O)=[O:35])=[CH:27][CH:26]=1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:34](=[O:35])[CH2:33][CH2:32][CH:31]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[C:28]3[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=3)[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: O=C(O)CCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Product: O=C(CCC(c1ccc(F)cc1)c1ccc(F)cc1)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1

Procedure:
N-Cyclopropyl-N-{1-[4,4-bis(4-fluorophenyl)butanoyl]piperidin-4-yl}-3-trifluoromethylbenzenesulfonamide was prepared from N-cyclopropyl-N-(piperidin-4-yl)-3-trifluoromethylbenzenesulfonamide and 4,4-bis(4-fluorophenyl)butanoic acid. LC: 100%. MS: m/z=607 (M+H+). 1H NMR (CDCl3): δ 8.12 (1H, s), 8.04 (1H, d), 7.86 (1H, d), 7.69 (1H, t), 7.16 (4H, dd), 6.98 (4H, dd), 4.71 (1H, d), 3.98 (1H, d), 3.80 (1H, t), 3.68 (1H, d), 2.91 (1H, t), 2.50 (1H, t), 2.33 (2H, m), 2.21 (2H, m), 1.93 (1H, m), 1.75 (4H, m), 0.91 (4H, m);
Reaction SMILES: [Br-].[O:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:11][CH:10]=1.[CH2:37]([C@H:42]1[CH2:47][CH2:46][C@H:45]([CH:48]=O)[CH2:44][CH2:43]1)[CH2:38][CH2:39][CH2:40][CH3:41].O1CCCC1>O>[O:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH:17]=[CH:48][C@H:45]2[CH2:46][CH2:47][C@H:42]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:43][CH2:44]2)=[CH:13][CH:14]=1
Reactant: CCCCC[C@H]1CC[C@H](C=O)CC1
Reactant: c1ccc([P+](CCCc2ccc(OC3CCCCO3)cc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](C=CCCc2ccc(OC3CCCCO3)cc2)CC1
Reaction time: 2 h
Yield: 36.5 %

Procedure:
A mixture of 4.0 g of [3-(4-[tetrahydro-2-pyranyloxy]phenyl)-1-propyl]triphenylphosphonium bromide, 1.3 g of trans-4-pentylcyclohexanecarboxaldehyde and 50 ml of absolute tetrahydrofuran was treated portionwise with 0.8 g of solid potassium t-butylate. After completion of the addition the reaction mixture was stirred for a further two hours and then poured into 500 ml of water and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed twice with 500 ml of concentrated sodium chloride solution each time, dried over magnesium sulphate, filtered and subsequently concentrated. Chromatography of the residue on silica gel with toluene gave 1.0 g of 1-[tetrahydro-2-pyranyloxy]-4-[4-(trans-4-pentylcyclohexyl)-3-butenyl]benzene (cis/trans mixture).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][O:10][CH3:11])=[CH:4][CH:3]=1.CN(C)[CH:14]=[O:15]>>[CH3:11][O:10][CH:9]=[CH:8][C:5]1[CH:6]=[CH:7][C:2]([CH:14]=[O:15])=[CH:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: COC=Cc1ccc(Br)cc1
Product: COC=Cc1ccc(C=O)cc1

Procedure:
By the method of example 28, 1-bromo-4-(2-methoxyethenyl)benzene is prepared, lithiated, and reacted with dimethylformamide to provide 4-(2-methoxyethenyl) benzaldehyde as a yellow oil after chromatography. This material is converted to 1-(2-phenylethenyl)-4-(2-methoxyethenyl)benzene by Wittig reaction with benzyl triphenylphosphonium chloride, using the conditions described in example 1 (A). The material is obtained as a mixture of all four possible (E) and (Z) stereoisomers.
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11](NCC3C=CC=CN=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>>[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:32][CH2:31][C:30]3[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)[N:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Reactant: COc1ccc(CN)cc1
Agent: Cl
Product: COc1ccc(CNc2nc(C)c(C)c(NC3CCCCC3)n2)cc1

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using (4-methoxybenzyl)amine instead of (pyridin-2-ylmethyl)amine. The product was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.10-1.13 (m, 1H), 1.24-1.35 (m, 3H), 1.62 (d, J=13.16 Hz, 1H), 1.72 (d, J=9.94 Hz, 4H), 1.87 (s, 3H), 2.22 (s, 3H), 3.72 (s, 3H), 3.94 (s, 1H), 4.46 (d, J=5.37 Hz, 2H), 6.88 (s, 2H), 7.26 (s, 2H), 7.57 (s, 1H), 8.01 (s, 1H), 12.66 (bs, 1H); MS (ESI) m/z 341.7 (M+1)+.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:24]([CH:25]([F:27])[F:26])[C:23]4[CH:28]=[CH:29][CH:30]=[CH:31][C:22]=4[N:21]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])C>C(O)C.O>[F:27][CH:25]([F:26])[N:24]1[C:23]2[CH:28]=[CH:29][CH:30]=[CH:31][C:22]=2[N:21]=[C:20]1[C:16]1[CH:15]=[C:14]([N:11]2[CH2:12][CH2:13][CH:8]([C:6]([OH:7])=[O:5])[CH2:9][CH2:10]2)[CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)C1CCN(c2cccc(-c3nc4ccccc4n3C(F)F)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1CCN(c2cccc(-c3nc4ccccc4n3C(F)F)c2)CC1
Temperature: 80 °C
Yield: 71.6 %

Procedure:
NaOH powder (0.24 g, 6.02 mmol) was added to a solution of 1-[3-(1-Difluoromethyl-1H-benzoimidazol-2-yl)-phenyl-]piperidine-4-carboxylic acid ethyl ester (1.20 g, 3.01 mmol) in ethanol:water 3:1 and the reaction was heated at 80° C. overnight. Reaction was cooled to room temperature and the organic solvent concentrated by evaporation under reduced pressure. The resulting solution was neutralized by dropwise addition of 6N HCl. A pale brown precipitated and it was filtered off and dried to afford 0.80 g of the title compound (72%).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:18])[CH2:9]P(OCC)(OCC)=O)([CH3:6])([CH3:5])[CH3:4].[CH2:19]([O:26][C:27]([C:29]1[S:30][C:31]([CH:34]=O)=[CH:32][CH:33]=1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1.C(OCC)(=O)C>[CH2:19]([O:26][C:27]([C:29]1[S:30][C:31]([CH:34]=[CH:9][C:8]([O:7][C:3]([CH3:4])([CH3:5])[CH3:6])=[O:18])=[CH:32][CH:33]=1)=[O:28])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=Cc1ccc(C(=O)OCc2ccccc2)s1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C=Cc1ccc(C(=O)OCc2ccccc2)s1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.7 %

Procedure:
To a suspension of 60% sodium hydride (1.64 g, 41 mmol) in tetrahydrofuran (50 ml) was added dropwise diethylphosphonoacetic acid tert-butyl ester (12.0 g, 47.6 mmol) at 0° C. After stirring at room temperature for 20 minutes, a solution of 5-formyl-2-thiophenecarboxylic acid benzyl ester (8.75 g, 35.5 mmol) in tetrahydrofuran (10 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, and washed successively with 1N hydrochloric acid and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated and the residue was purified by column chromatography (10 to 30% ethyl acetate/hexane mixed solvent) to give the title compound (10.6 g).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.C([Mg]Cl)(C)C.[Cl:26][C:27]1[CH:44]=[CH:43][C:30]([CH2:31][O:32][C:33]2[C:34]([O:41][CH3:42])=[CH:35][C:36]([CH:39]=[O:40])=[N:37][CH:38]=2)=[CH:29][CH:28]=1>O1CCCC1>[Cl:26][C:27]1[CH:44]=[CH:43][C:30]([CH2:31][O:32][C:33]2[C:34]([O:41][CH3:42])=[CH:35][C:36]([CH:39]([C:2]3[C:10]4[C:5](=[N:6][CH:7]=[CH:8][CH:9]=4)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=3)[OH:40])=[N:37][CH:38]=2)=[CH:29][CH:28]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cccnc21
Reactant: COc1cc(C=O)ncc1OCc1ccc(Cl)cc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1cc(C(O)c2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncccc23)ncc1OCc1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
3-Iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (68, 180 mg, 0.450 mmol, prepared as described in Example 22) was dissolved in tetrahydrofuran (2.5 mL) and the reaction was cooled to −20° C. under an atmosphere of nitrogen. Isopropylmagnesium chloride in tetrahydrofuran (2.00 M, 0.243 mL) was added. The reaction was stirred for 1 hour, during which the temperature rose to 0° C. The reaction was cooled to −20° C. and 5-(4-chloro-benzyloxy)-4-methoxy-pyridine-2-carbaldehyde (74, 80.0 mg, 0.288 mmol) in tetrahydrofuran (0.75 mL) was added. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with methanol and adsorbed onto silica, then purified by silica gel chromatography, methanol:dichloromethane, to provide the desired compound (75, 94 mg, 59%). 1H-NMR was consistent with the desired compound. MS (ESI) [M+H+]+=552.4, 554.4, 555.4.
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:34])=[C:12]([C:29](OCC)=[O:30])[C:13](=[O:28])[N:14]3[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:37][O:38][CH2:39][CH2:40][NH2:41]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:34])=[C:12]([C:29]([NH:41][CH2:40][CH2:39][O:38][CH3:37])=[O:30])[C:13](=[O:28])[N:14]3[CH2:17][C:18]3[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=3)=[N:9][CH:8]=2)=[CH:35][CH:36]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(Cc2ccc(S(C)(=O)=O)cc2)c1=O
Reactant: COCCN
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(Cc2ccc(S(C)(=O)=O)cc2)c1=O

Procedure:
This compound was prepared from ethyl 7-(4-fluorobenzyl)-4-hydroxy-1-[4-(methylsulfonyl)benzyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-methoxyethylamine employing methods similar to those described in Example 5 and was obtained as a white solid; 1H NMR (CDCl3) δ 10.22 (1H, br t, J=5 Hz), 8.58 (1H, d, J=1.2 Hz), 7.85 (2H, d, J=8.3 Hz), 7.21 (2H, d, J=8.3 Hz), 7.01-6.98 (5H, m), 5.44 (2H, br), 4.02 (2H, s), 3.68 (2H, q, J=5.2 Hz), 3.60 (2H, t, J=5.2 Hz); 3.41 (3H, s), 3.03 (3H, s); ES+ MS: 540 (M+H+, 100).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:5]=1[O:12][C:13]1[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[N:14]=1.O.Cl>C(O)(=O)C>[Cl:11][C:6]1[C:5]([O:12][C:13]2[N:14]=[C:15]([O:21][CH3:22])[CH:16]=[C:17]([O:19][CH3:20])[N:18]=2)=[C:4]([CH:9]=[C:8]([Cl:10])[CH:7]=1)[CH:3]=[O:2]
Reactant: COc1cc(OC)nc(Oc2c(Cl)cc(Cl)cc2C(OC)OC)n1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(OC)nc(Oc2c(Cl)cc(Cl)cc2C=O)n1

Procedure:
3,5-Dichloro-2-(4,6-dimethoxypyrimidin-2-yl)oxy benzaldehyde dimethylacetal (2.1 g) was dissolved in acetic acid (50 ml), and then water (10 ml) and 35% hydrochloric acid (1 ml) were added thereto The mixture was reacted at room temperature for 6 hours. The reaction mixture was poured into water, and extracted with toluene. The extract was washed with a 2% sodium hydroxide aqueous solution, and further washed 3 times with water. The toluene phase was dried, and concentrated under reduced pressure The crystal thus obtained was recrystallized from a mixture of carbontetrachloride and hexane to obtain the above identified compound as a white crystal (1.0 g). (Melting point: 132°-133° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([B:9]([OH:11])[OH:10])[C:5]([F:8])=[N:6][CH:7]=1.[CH3:12][N:13]([CH2:18][C:19](O)=[O:20])[CH2:14][C:15](O)=[O:16].CS(C)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([B:9]2[O:11][C:19](=[O:20])[CH2:18][N:13]([CH3:12])[CH2:14][C:15](=[O:16])[O:10]2)[C:5]([F:8])=[N:6][CH:7]=1
Reactant: OB(O)c1cc(Br)cnc1F
Reactant: CN(CC(=O)O)CC(=O)O
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CN1CC(=O)OB(c2cc(Br)cnc2F)OC(=O)C1
Yield: 82 %

Procedure:
5-Bromo-2-fluoropyridin-3-ylboronic acid (14.87 g, 67.7 mmol) (Frontier Scientific) and 2,2′-(methylazanediyl)diacetic acid (10.95 g, 74.4 mmol) (Aldrich) were dissolved in toluene (242 mL) and DMSO (97 mL) and the resulting mixture was heated at reflux under a Dean Stark trap for 2 h. After water (>2.5 mL) was collected in the trap, the reaction mixture was concentrated in vacuo to remove toluene, and water was slowly added to the resulting solution until the desired product precipitated as a white solid. This solid was collected by vacuum filtration, washed with water, and dried in a vacuum oven to give the title compound (82% yield) as a fluffy white solid. m/z (ESI, +ve ion) 330.8/332.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:45]=[CH:44][CH:43]=[CH:42][C:4]=2[S:5][C:6]=1[C:7]([N:9]([CH2:25][C:26]1[CH:27]=[C:28]([C:34]2[CH:39]=[CH:38][C:37]([CH2:40]O)=[CH:36][CH:35]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH:10]1[CH2:15][CH2:14][CH:13]([N:16](C)[C:17](=O)OC(C)(C)C)[CH2:12][CH2:11]1)=[O:8].[ClH:46]>>[ClH:1].[Cl:46][CH2:40][C:37]1[CH:36]=[CH:35][C:34]([C:28]2[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:26]([CH2:25][N:9]([CH:10]3[CH2:11][CH2:12][CH:13]([NH:16][CH3:17])[CH2:14][CH2:15]3)[C:7]([C:6]3[S:5][C:4]4[CH:42]=[CH:43][CH:44]=[CH:45][C:3]=4[C:2]=3[Cl:1])=[O:8])[CH:27]=2)=[CH:39][CH:38]=1
Reactant: COc1ccc(-c2ccc(CO)cc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Agent: Cl
Product: CNC1CCC(N(Cc2cc(-c3ccc(CCl)cc3)ccc2OC)C(=O)c2sc3ccccc3c2Cl)CC1

Procedure:
tert-Butyl carbamate 84 (10 mg, 15 μmol) is treated with HCl using Method F to afford the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([CH2:11][C:12]3(O)[CH:19]4[CH2:20][CH:15]5[CH2:16][CH:17]([CH2:21][CH:13]3[CH2:14]5)[CH2:18]4)=[N:8][C:7]=2[CH:23]=1.Cl.N1C=CC=CC=1>C(OCC)(=O)C>[CH:13]12[CH2:21][CH:17]3[CH2:16][CH:15]([CH2:20][CH:19]([CH2:18]3)[C:12]1=[CH:11][C:9]1[S:10][C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[CH:23][C:7]=3[N:8]=1)[CH2:14]2
Reactant: COc1ccc2sc(CC3(O)C4CC5CC(C4)CC3C5)nc2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Oc1ccc2sc(C=C3C4CC5CC(C4)CC3C5)nc2c1

Procedure:
300 mg 2-(5-methoxy-benzothiazol-2-ylmethyl)adamantan-2-ol (formula IX) and 527 mg pyridine hydrochloride are heated at about 200° for about 30 minutes. The melt obtained is dissolved in 100 ml of ethyl acetate, the mixture is extracted with water, 2.5 M sodium acetate solution and brine, the organic phase dried and the solvent evaporated off. The evaporation residue obtained is subjected to chromatography. The title compound is obtained (m.p. 156-158°).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>N1C=CC=CC=1>[N:12]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[CH2:6][CH2:5]3)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C1CCc2cc(F)ccc21
Reactant: C1CCNCC1
Solvent: c1ccncc1
Product: O=C1CCc2cc(N3CCCCC3)ccc21

Procedure:
5-Fluoroindan-1-one (5 g, 33.3 mmol) and piperidine (8.52 g, 100 mmol, 10 ml) were dissolved in pyridine (20 ml) and heated to reflux for 3 hours. The reaction mixture was cooled, the solvent removed under vacuum, and the residue taken in diethyl ether. The ether solution was washed with 1N aqueous sodium hydroxide and with water, dried with magnesium sulfate, filtered, and the filtrate was removed under vacuum to provide the title compound which was used without further purification. 1H NMR (CDCl3) δ 1.67 (m, 6H), 2.63 (m, 2H), 3.02 (m, 2H), 3.40 (m, 4H), 6.78 (d, 1H), 6.86 (dd, 1H), 7.62 (d, 1H); MS (DCI) 216 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)=[CH:10][CH:9]=1)[CH3:2].[CH2:20]([O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)[CH2:21][CH:22]=[CH2:23].C(N(CC)CC)C>O1CCOCC1.O>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][N:6]([S:31]([C:28]1[CH:27]=[CH:26][C:25]([O:24][CH2:20][CH2:21][CH:22]=[CH2:23])=[CH:30][CH:29]=1)(=[O:33])=[O:32])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: C=CCCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)CNCc1ccc(-n2cncn2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: C=CCCOc1ccc(S(=O)(=O)N(CC(=O)OCC)Cc2ccc(-n3cncn3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2 g (7.683 mmol) of (4-[1,2,4]triazol-1-yl-benzylamino)-acetic acid ethyl ester in 15 ml of dioxane and 15 ml of H2O, 2.3 g (9.22 mmol) of 4-but-3-enyloxy-benzenesulfonyl chloride and 1.3 ml (9.22 mmol) of triethyl amine are successively added at 0-5° C. After being stirred for 18 h at r.t., the reaction mixture is diluted with H2O and extracted with AcOEt. The combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give the title compound. 1H-NMR (400 MHz, CDCl3): 1.17 (t, 3H, J=7.04 Hz), 2.55-2.65 (m, 2H), 3.95 (s, 2H), 4.07 (t, 2H, J=7.04 Hz), 4.09 (t, 2H, J=6.56 Hz), 4.53 (s, 2H), 5.10-5.25 (m, 2H), 5.85-5.95 (m, 1H), 6.99 (d, 2H, J=8.04 Hz), 7.44 (d, 2H, J=7.56 Hz), 7.64 (d, 2H, J=8.04 Hz), 7.82 (d, 2H, J=7.56 Hz), 8.11 (s, 1H), 8.55 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:8]([CH:9]=[O:10])[C:7]([OH:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:13][CH2:14]/[CH:15]=[CH:16]/[CH2:17]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:13][CH2:14]/[CH:15]=[CH:16]/[CH2:17][O:12][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][C:8]=1[CH:9]=[O:10]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Reactant: ClC/C=C/CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc([N+](=O)[O-])ccc1OC/C=C/CCl
Reaction time: 2 h
Yield: 43.3 %

Procedure:
A solution of 8 g of 5-nitrosalicylaldehyde, 30.8 g of trans-1,4-dichloro-2-butene and 13.2 g of potassium carbonate in 35 ml of dimethylformamide was stirred at room temperature for 19 hours, and further stirred at 80°-87° C. (outside temperature) for 2 hours. The mixture was allowed to cool, poured into 80 ml of water, and extracted with chloroform. The extract (organic layer separated) was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel. The product was eluted with benzene to give 5.3 g of 2-[(E)-4-chloro-2-butenyloxy]-5-nitrobenzaldehyde. (mp. 65°-66° C.).
Reaction SMILES: [CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23]([OH:25])=[O:24].C([O-])(O)=O.[Na+].[C:31]([O:35][C:36](=[O:39])[CH2:37]Br)([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]([N:10]2[C:9]3[C:4](=[CH:5][C:6]([O:20][CH3:21])=[CH:7][CH:8]=3)[C:3]([CH2:22][C:23]([O:25][CH2:37][C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:39])=[O:24])=[C:2]2[CH3:1])=[O:12])=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CC(=O)OCC(=O)OC(C)(C)C)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.7 %

Procedure:
To a solution of indomethacin (6.388 g, 18 mmol) in anhydrous DMF (45 mL) were successively added NaHCO3 (1.4 g, 16.7 mmol) and tert-butylbromoacetate (2.95 g, 15 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was then poured over ice-cold water, stirred, and the white solid obtained was filtered off, washed with water and dried. The product was recrystallized from EtOAc:hexane (1:4) to give the title compound (7.06 g, 88% yield) as a white solid. Mp 96-97° C. 1H NMR (300 MHz, CDCl3) δ 7.66 (d, J=8.5 Hz, 2H), 7.45 (d, J=8.5 Hz, 2H), 7.0 (d, J=2.4 Hz, 1H), 6.88 (d, J=9.0 Hz, 1H), 6.6 (dd, J=9.0 and 2.4 Hz, 1H), 4.52 (s, 2H), 3.83 (s, 3H), 3.77 (s, 2H), 2.37 (s, 3H), 1.44 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 170.1, 168.2, 166.6, 156.2, 139.2, 136.0, 133.8, 131.1 (2×C), 130.7, 130.5, 129.0 (2×C), 114.9, 112.1, 111.9, 101.1, 82.4, 61.5, 55.6, 29.7, 27.9, 13.4; LRMS (APIMS) m/z 472 (MH+)