Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][CH:8]1[NH2:19].[CH2:24]([O:26][C:27](Cl)=[O:28])[CH3:25]>N1C=CC=CC=1>[Cl:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][CH:8]1[NH:19][C:27](=[O:28])[O:26][CH2:24][CH3:25]
Reactant: COc1ccc2c(c1)C(Cc1ccc(Cl)c(Cl)c1)C(N)CC2
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)NC1CCc2ccc(OC)cc2C1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
To 1-(3,4-dichlorobenzyl)-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-amine hydrochloride (1.95 g, 5.80 mmol) in pyridine 10 ml) the ethylchloroformate (1.00 g, 9.28 mmol) was added slowly under nitrogen. The mixture was stirred over night at RT. The solvent was reduced under vacuo and extracted with CH2Cl2 after addition of HCl (1N). The organic layer was washed with HCl (1N), NaHCO3 solution, and NaCl solution, then dried on MgSO4 and the solvent was removed. The product was obtained as an orange oil that precipitates after a few hours (2.10 g, 5.14 mmol, 89%).
Reaction SMILES: Cl[C:2]1[S:6](=[O:7])[N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4](=[O:15])[CH:3]=1.[CH2:16]([O:18][C:19]1[O:20][CH:21]=[CH:22][CH:23]=1)[CH3:17]>>[CH2:8]([N:5]1[C:4](=[O:15])[C:3]2[C:19]([O:18][CH2:16][CH3:17])=[CH:23][CH:22]=[C:21]([OH:20])[C:2]=2[S:6]1=[O:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOc1ccco1
Reactant: O=C1C=C(Cl)S(=O)N1Cc1ccccc1
Product: CCOc1ccc(O)c2c1C(=O)N(Cc1ccccc1)S2=O
Yield: 40 %

Procedure:
Reaction of 5.8 g (0.024 mol) of 5-chloro-2-benzyl-2H-isothiazol-3-one-1-oxide with 3.76 g (0. 0335 mol) of 2-ethoxyfuran afforded 3.05 g (40%) of 2-benzyl-4-ethoxy-7-hydroxybenzisothiazol-3-one-1-oxide, 5.7 g of which was reacted with 3.6 g (0.0197 mol) of 2-[2-methoxyethoxy]ethyl bromide in the presence of 4.95 g (0.0358 mol) of potassium carbonate in 125 ml of methyl ethyl ketone and 25 ml of DMF to give 7.0 g (93%) of 2-benzyl-4-ethoxy-7-[2-(2-methoxy-ethoxy]-ethoxy]benzisothiazol-3-one-1-oxide, which was oxidized as before with 3-chloroperbenzoic acid in MDC to give 2-benzyl-4-ethoxy-7-[2-(2-methoxyethoxy)ethoxy]-saccharin. Debenzylation of 6.6 g (0.015 mol) of the latter with 3.34 g (0.053 mol) of ammonium formate in the presence of 6.4 g of 10% palladium-on-charcoal catalyst in methanol afforded the ammonium salt of 4-ethoxy-7-[2-(2-methoxyethoxy)ethoxy]saccharin, which was reacted with 2.38 g (0.015 mol) of chloromethyl phenyl sulfide in 100 mL of DMF to give 1.46 g (21%) of 2-phenylthiomethyl-4-ethoxy-7-[2-(2-methoxyethoxy]-ethoxy]saccharin, mp 73°-75 ° C. (from isopropanol). Treatment of 1.4 g (0.0029 mol) of the product with 0.4 g (0.0029 mol) of sulfuryl chloride in MDC afforded 1.16 g (100%) of 2-chloromethyl-4-ethoxy-7-[2-(2-methoxyethoxy)ethoxy]-saccharin.
Reaction SMILES: C([O:3][C:4]([CH:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][N:8]([C:20](=[O:28])[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].CC(O)=O>O1CCOCC1.O>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:20]([N:8]2[CH2:9][CH2:10][C:11]3[C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[NH:13][C:12]=3[CH:6]([C:4]([OH:5])=[O:3])[CH2:7]2)=[O:28])=[CH:26][CH:25]=1
Reactant: CCOC(=O)C1CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: O=C(O)C1CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1ccccc21
Temperature: 20 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a solution of 3-(4-fluorobenzoyl)-1,2,3,4,5,6-hexahydro-azepino[4,5-b]indole-5-carboxylic acid ethyl ester (543 mg, 1.42 mmol) in 1,4-dioxane (8 mL) was added aqueous sodium hydroxide (114 mg in 2 mL of water). The mixture was stirred for 1 hour at 20° C. Solvent was then removed under high vacuum to give a crude product, which was redissolved in water and acidified with AcOH. Solid was collected by filtration and washed with water and dried under high vacuum to give 3-(4-fluorobenzoyl)-1,2,3,4,5,6-hexahydro-azepino[4,5-b]indole-5-carboxylic acid (421 mg, 84%); MS (ES): 353 (MH+).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[C:13]([CH:29]3[CH2:31][CH2:30]3)=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25]C(=O)[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(O)C.O.[OH-].[Li+].O>>[NH2:23][C@@:22]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:7][CH2:6][C@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:9]3)[C:13]=2[CH:29]2[CH2:31][CH2:30]2)[CH:18]=1)([CH3:28])[CH2:26][OH:25]
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2C2CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2C2CC2)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
(R)-4-[6-(4-tert-Butyl-cyclohexyloxy)-5-cyclopropyl-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (0.1093 g, 0.0002593 mol) was dissolved in ethanol (2.00 mL, 0.0342 mol) in a capped 40 mL vial equipped with a magnetic stir bar. 4.2 M lithium hydroxide, monohydrate in water (1.00 mL, 0.00420 mol) was added and the reaction was stirred overnight at 80° C. HPLC analysis showed that the reaction was complete. The solvent was removed under reduced pressure. Methylene chloride and water were added and the layers were separated. The combined organic layer was concentrated to dryness and purified by HPLC to give 41.0 mg of the title compound (40% yield). MS; m/z=379.33 [M-16]+. 1H NMR (MeOD) δ: 8.52 (d, J=9.0 Hz, 1H), 7.84 (d, J=2.0 Hz, 1H), 7.77 (d, J=9.0 Hz, 1H), 7.57 (dd, J=9.2, 2.1 Hz, 1H), 7.34 (d, J=9.3 Hz, 1H), 4.26-4.36 (m, 1H), 3.95 (d, J=11.5 Hz, 1H), 3.84 (d, J=11.5 Hz, 1H), 2.18-2.27 (m, 2H), 1.85-1.95 (m, 3H), 1.80 (s, 3H), 1.43-1.57 (m, 2H), 1.08-1.28 (m, 5H), 0.92 (s, 9H), 0.68-0.75 (m, 2H)
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][O:6][CH:5]([CH2:8][OH:9])[CH2:4][O:3]1.[CH3:11][S:12](Cl)(=[O:14])=[O:13].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:11][S:12]([O:9][CH2:8][CH:5]1[CH2:4][O:3][C:2]([CH3:10])([CH3:1])[CH2:7][O:6]1)(=[O:14])=[O:13]
Reactant: CC1(C)COC(CO)CO1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)COC(COS(C)(=O)=O)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
(5,5-Dimethyl-1,4-dioxan-2-yl)methanol (740 mg, 5.06 mmol) and TEA (0.988 mL, 7.09 mmol) were dissolved in DCM (20 mL). At 0° C. MsCl (0.473 mL, 6.07 mmol) was added dropwise. After the addition the solution was warmed to ambient temperature and stirred for 1 hr. Saturated NaHCO3 solution was added and the two layers were separated. The aqueous layer was extracted three times with DCM. The organic layers were combined, dried over Na2SO4 and concentrated. The resulting residue was purified on a silica gel column (heptane:EtOAc 4:1 to 1:1) to give the product as a colorless oil (805 mg, 71%). 1H NMR (400 MHz, CDCl3) δ ppm 4.18-4.19 (2H, m), 3.71-3.76 (1H, m), 3.66 (1H, t, J= 10.8 Hz), 3.52-3.57 (2H, m), 3.37 (1H, d, J= 11.6 Hz), 3.03 (3H, s), 1.28 (3H, s), 1.09 (3H, s).
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.FC(F)(F)C([N:19]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[C:20]1[CH:35]=[CH:34][C:23]([C:24](ON2C(=O)CCC2=O)=[O:25])=[CH:22][CH:21]=1)=O.[OH-].[Na+]>O.C(O)C>[CH2:36]([NH:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([NH:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4])=[O:25])=[CH:34][CH:35]=1)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51]
Reactant: CCCCCCCCCCCCCCCCN(C(=O)C(F)(F)F)c1ccc(C(=O)ON2C(=O)CCC2=O)cc1
Reactant: CC(C)(N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)NC(C)(C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a stirred solution of 103 mg. of 2-aminoisobutyric acid and 4.5 ml. of triethylamine in 1.5 ml. of water is added a solution of 550 mg. of N-[N-trifluoroacetyl-4-(hexadecylamino)benzoyloxy]succinimide in 4.5 ml. of ethanol. The mixture is stirred for 23 hours at room temperature, treated with 2 ml. of 2N sodium hydroxide solution, and then acidified. The mixture is diluted with water and then filtered. Recrystallization from ether-hexane affords the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[CH3:12][C:13]1[N:14]=[C:15]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[S:16][C:17]=1[CH2:18][CH2:19]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:19][CH2:18][C:17]3[S:16][C:15]([C:21]4[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=4)=[N:14][C:13]=3[CH3:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCO
Reactant: Cc1c[nH]c2cc(O)ccc12
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCOc1ccc2c(C)c[nH]c2c1

Procedure:
In analogy to the procedure described in example 3 c], 3-methyl-1H-indol-6-ol was reacted with 2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol (example 5 c]) in the presence of triphenylphosphine and di-tert-butyl azodicarboxylate to yield 3-methyl-6-{2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-1H-indole as yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:38]=[CH:39][C:40]=1[F:41])[CH2:5][O:6][C:7]1([C:30]([NH:32][CH2:33][C:34]([F:37])([F:36])[F:35])=[O:31])[CH2:12][CH2:11][CH2:10][N:9]2[C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[O:26][C:25]([CH3:27])=[N:24][CH:23]=4)=[C:18]([O:28][CH3:29])[CH:17]=3)=[N:14][N:15]=[C:8]12.[C:42](=O)([O-])[O-].[Cs+].[Cs+].CI.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:38]=[CH:39][C:40]=1[F:41])[CH2:5][O:6][C:7]1([C:30]([N:32]([CH3:42])[CH2:33][C:34]([F:37])([F:35])[F:36])=[O:31])[CH2:12][CH2:11][CH2:10][N:9]2[C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[O:26][C:25]([CH3:27])=[N:24][CH:23]=4)=[C:18]([O:28][CH3:29])[CH:17]=3)=[N:14][N:15]=[C:8]12
Reactant: COc1cc(-c2nnc3n2CCCC3(OCc2ccc(F)c(F)c2)C(=O)NCC(F)(F)F)ccc1-c1cnc(C)o1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(-c2nnc3n2CCCC3(OCc2ccc(F)c(F)c2)C(=O)N(C)CC(F)(F)F)ccc1-c1cnc(C)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.6 %

Procedure:
To a mixture of 8-[(3,4-difluorobenzyl)oxy]-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-N-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide (200 mg) in DMF (5 mL) were added cesium carbonate (169 mg) and methyl iodide (0.026 mL) at room temperature. After stirring at room temperature for 2 hr, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate/THF (2/1). The extract was washed with brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (75 mg).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[C:6]([CH2:9][P:10](=[O:15])([O:13]C)[O:11]C)(O)=[O:7].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:1]([NH:5][C:6]([CH2:9][P:10](=[O:11])([OH:15])[OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: COP(=O)(CC(=O)O)OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)NC(=O)CP(=O)(O)O

Procedure:
Tertiary butyl amine (0.045 mole) and dimethyl (carboxymethyl)phosphonate (0.04 mole) were dissolved in 100 ml. of methylene chloride. As the solution was stirred, dicyclohexylcarbodiimide was added portionwise. The solution was stirred overnight and the mixture filtered. The filtrate was concentrated to a solid. It was recrystallized from an appropriate solvent such as methanol. m.p. 163°-5° C., yield, 61%.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:18])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:17])[C@H:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[NH2:12].C(N(CC)CC)C.Cl[C:27]1[S:31][N:30]=[C:29]([O:32][CH3:33])[N:28]=1>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:2][O:3][C:4](=[O:18])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:17])[C@H:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[NH:12][C:27]1[S:31][N:30]=[C:29]([O:32][CH3:33])[N:28]=1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC(C)C
Reactant: COc1nsc(Cl)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(C)C)Nc1nc(OC)ns1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.9 %

Procedure:
A solution of N-L-leucyl-L-proline methyl ester hydrochloride (5.6 g, 20 mmol, prepared according to the procedure by Jones, J. B. et al. in J. Med. Chem. 1995, 38, 3078) and triethylamine (5.6 mL, 40 mmol) in DMF (60 mL) was stirred at room temperature for 15 min. Then, a solution of 5-chloro-3-methoxy-[1,2,4]thiadiazole (1.51 g, 10 mmol) in DMF (10 mL) and tetrabutylammonium bromide (150 mg) were added and the resulting mixture was stirred at room temperature for 24 h. The reaction mixture was quenched with water and extracted into ethyl acetate. The organic layer was washed with a saturated solution of sodium bicarbonate, brine, dried (sodium sulfate), filtered and concentrated in vacuo. Purification by column chromatography on silica gel using a mixture of hexane and ethyl acetate (7/3 and 6/4) afforded N-(3-methoxy-[1,2,4]thiadiazol-5-yl)-L-leucyl-L-proline methyl ester (1.92 g, 53.9%) as as an off-white foam. 1H-NMR (CDCl3) δ7.10 (d, J=8.5 Hz, 1H, NHCH), 4.74 (m, 1H, NHCH), 4.57 (dd, J=8.6, 4.6 Hz, 1H, CHCO2), 3.92 (s, 3H, OMe), 3.85 (m, 1H), 3.69 (s, 3H, OMe), 3.62 (m, 1H), 2.17-2.23 (m, 1H), 1.95-2.07 (m, 4H), 1.77-1.82 (m, 1H), 1.59-1.66 (m,1H), 0.97 (d, J=6.5 Hz, 3H, Me), 0.94 (d, J=6.7 Hz, 3H, Me); MS (m/z) 357 (M+ +1), 228, 200, 130, 101, 70.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([Br:16])=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[Li]CCCC.CN([CH:25]=[O:26])C.C(Cl)Cl.CCCCCC>C1COCC1>[Br:16][C:9]1[C:10]2[C:15]([C:2]([CH:25]=[O:26])=[C:3]3[C:8]=1[CH:7]=[CH:6][CH:5]=[CH:4]3)=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: Brc1c2ccccc2c(Br)c2ccccc12
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1c2ccccc2c(Br)c2ccccc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 68 %

Procedure:
To the yellow suspension of 9,10-Dibromoanthracene (2 g, 5.95 mmol) in THF (20 mL) at −90° C., n-BuLi (2.88 mL, 7.18 mmol, 2.5 M in hexane) was added dropwise. Orange solution was observed after 45 min additional stirring. Anhydrous DMF (0.92 mL, 11.9 mmol) was added to the orange solution. The reaction mixture was slowly warmed to room temp and stirred overnight. The reaction mixture was quenched with H2O and extracted with CH2Cl2. The organic layer was washed with 10% aq. Na2CO3 solution (3×50 mL). The CH2Cl2 layer was separated, dried over anhydrous Na2SO4, filtered and removed in vacuo to give yellow solid. The crude product was purified by column chromatography using 30% CH2Cl2/hexane to give 6 in 68% yield. R1=0.3 (30% CH2Cl2/hexane; 1H NMR (CDCl3) δ 11.39 (s, 1H), 8.77-8.82 (d, 2H), 8.55-8.60 (d, 2H), 7.56-7.67 (m, 4H). (Ref. de Montigny, Frederic; Argouarch, Gilles; Lapinte, Claude. New route to unsymmetrical 9,10-disubstituted ethynylanthracene derivatives. Synthesis, 2006, 2, 293-298.)
Reaction SMILES: Cl.[NH2:2][CH:3]([CH3:20])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)=O.[CH:21]1([N:27]=[C:28]=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C.FC(F)(F)C(O)=O>CC(C)=O>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]2[N:27]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:28](=[O:29])[NH:2][C:3]=2[CH3:20])=[CH:7][CH:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(N)C(=O)c1ccc(OCc2ccccc2)cc1
Reactant: O=C=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1[nH]c(=O)n(C2CCCCC2)c1-c1ccc(OCc2ccccc2)cc1
Reaction time: 1 h

Procedure:
2-Amino-4'-benzyloxypropiophenone hydrochloride (349 mg, 1.20 mmol) was suspended in acetone (30 ml) under ice-cooling, and cyclohexyl isocyanate (204 mg, 1.62 mmol) was added thereto. Triethylamine (377 mg, 3.73 mmol) was then added, and the mixture was stirred for one hour under ice-cooling. After addition of trifluoroacetic acid (2 ml), the mixture was stirred for 6 days at room temperature. The solvent was removed by evaporation in vacuo, and the residue was extracted with dichloromethane. The extract was washed successively with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. Evaporation of the solvent provided a crude product, which was purified by column chromatography (chloroform/ ethanol=50/1 (v/v)) and recrystalization (ethanol-chloroform) to give the title compound. Yield: 240 mg (55%), m.p. 262° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1.C(OCC)(OCC)OCC.C([BH3-])#N.[Na+].[C:32]([C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33].[Cl-].[Na+]>CN(C=O)C.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:40][C:39]2[CH:41]=[CH:42][C:36]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:37][CH:38]=2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: COC(=O)CCNC(=O)c1ccc(CNc2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.8 %

Procedure:
The above 3-(4-formylbenzoylamino)propionic acid methyl ester (2.0 g, 8.5 mmol) was dissolved in DMF (20 mL). Triethyl orthoformate (10 mL), glacial acetic acid (1 mL), sodium cyanoborohydride (0.81 g, 12.8 mmol) and 4-tert-butylaniline 1.27 g, 8.5 mmol) were added and the resulting mixture was stirred at room temperature for 16 hours. The mixture was added saturated aqueous sodium chloride (100 mL) and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (3×100 mL). The organic phase was dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of ethyl acetate and heptane (1:1) to afford 0.87 g (30%) of 3-{4-[(4-tert-butylphenylamino)methyl]benzoylamino}propionic acid methyl ester as an oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]=[C:6]=[O:7].[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([NH:14][C:10]1[CH:9]=[N:8][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: Nc1cccnc1
Reactant: O=C=NCCCCl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(NCCCCl)Nc1cccnc1
Temperature: 25 °C
Yield: 92.9 %

Procedure:
1-Chloro-3-isocyanato-propane (1.897 g, 15.873 mmol) was added dropwise to a stirred solution of pyridin-3-ylamine (1 g, 10.582 mmol) in toluene (15 mL) over a period of 30 minutes at 0° C. The reaction temperature was maintained at room temperature for 6 hours. The reaction was monitored by TLC (100% ethyl acetate). The reaction mixture was filtered, washed with toluene and dried under reduced pressure to afford 2.1 g (95.45% yield) of 1-(3-chloro-propyl)-3-pyridin-3-yl-urea.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[NH:12][C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=3)=[C:14]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]=[CH:21][CH:20]=[N:19]4)[N:15]=2)=[CH:6][C:3]=1[C:4]#[N:5].[OH:33]S(O)(=O)=O.[NH4+].[OH-]>C(O)(=O)C.O>[F:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[NH:12][C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=3)=[C:14]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]=[CH:21][CH:20]=[N:19]4)[N:15]=2)=[CH:6][C:3]=1[C:4]([NH2:5])=[O:33]
Reactant: O=S(=O)(O)O
Reactant: Cc1cccc(-c2[nH]c(Cc3ccc(F)c(C#N)c3)nc2-c2ccc3nccnc3c2)n1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc(-c2[nH]c(Cc3ccc(F)c(C(N)=O)c3)nc2-c2ccc3nccnc3c2)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a stirred solution of 2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)benzonitrile (Example 78, prepared according to the method described in US 2008/0319012 A1) (130 mg, 0.31 mmol) in acetic acid (3 mL) was added conc. H2SO4 (0.7 mL) and the mixture was stirred at 100° C. After 2 hours, more conc. H2SO4 (0.2 mL) was added and the mixture was stirred at 100° C. for 1 hour. Then the reaction mixture was cooled to room temperature, diluted with H2O (10 mL) in the ice bath, and neutralized by addition of NH4OH solution to pH 7. The mixture was extracted with CH2Cl2 (3 times) and then the organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by MPLC (MeOH:CH2Cl2=1:20 (v/v) to 1:10 (v/v)) to afford the solid, which was recrystallized from CH2Cl2/MeOH/Et2O to give the title compound (131.6 mg, 68%). 1H NMR (300 MHz, CD3OD) δ 2.53 (3H, s), 4.23 (2H, s), 7.16-7.23 (3H, m), 7.54-7.59 (2H, m), 7.84 (1H, dd), 8.04 (2H, bs), 8.25 (1H, bs), 8.85 (2H, dd). MS (ESI) m/z 439 (MH+).
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[N:28]=[C:29]([N:34]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)[CH3:35])[S:30][C:31]=1[CH:32]=[O:33]>O1CCCC1>[Cl:26][C:27]1[N:28]=[C:29]([N:34]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)[CH3:35])[S:30][C:31]=1[CH:32]([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)[OH:33]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cccnc21
Reactant: CN(Cc1ccc(Cl)cc1)c1nc(Cl)c(C=O)s1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2sc(N(C)Cc3ccc(Cl)cc3)nc2Cl)c2cccnc21
Temperature: 0 °C
Yield: 62 %

Procedure:
To a solution of 3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (96, 0.82 g, 2.0 mmol) in tetrahydrofuran (5 mL) at −20° C., isopropylmagnesium chloride (2 M in tetrahydrofuran, 1.1 mL, 2.2 mmol) was added dropwise. The reaction mixture was allowed to warm to 0° C. in 10 minutes. The reaction mixture was then cooled to −40° C. To the reaction mixture was added a solution of 4-chloro-2-[(4-chloro-benzyl)-methyl-amino]-thiazole-5-carbaldehyde (551, 0.41 g, 1.4 mmol) in tetrahydrofuran (10 mL). The reaction mixture was allowed to warm to −10° C. in 30 minutes. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexanes to provide the desired compound as a yellow solid (552, 0.5 g, 60%). MS (ESI) [M+H+]+=575.29.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[I-:15].[Na+].CC(C)=O>O>[I:15][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)CCCCCCCCCCI

Procedure:
11-Iodo undecanoic acid was synthesized according to Bergbreiter, J. Org. Chem., 40 (6), (1975) 779-782. Briefly, 250 g 11-Bromo undecanoic acid, 325 g Sodium iodide and 2 liter acetone were refluxed under N2 atmosphere for 24 hours. The mixture was divided and added to 4 liter H2O each. The mixtures were fritted and the crude product recrystallized from methanol and finally characterized by the melting point.