Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:13][OH:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[C:15]1(=O)[CH2:19][CH2:18][C:17](=[O:20])[CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([CH2:13][O:14][C:15]3[CH2:19][CH2:18][C:17](=[O:20])[CH:16]=3)=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)C1
Reactant: OCc1cnc(-c2ccc(Cl)cc2)s1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1C=C(OCc2cnc(-c3ccc(Cl)cc3)s2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
To a solution of [2-(4-Chloro-phenyl)-thiazol-5-yl]-methanol (2 g, 8.8 mmol) in anhydrous THF (50 ml), at 0° C., under an atmosphere of nitrogen was added cyclopentane-1,3-dione (1.12 g, 11.4 mmol), followed by triphenylphosphine (2.99 g, 11.4 mmol). Diisopropylazodicarboxylate (2.2 ml, 11.4 mmol) was then added dropwise over a period of 5 minutes and the reaction allowed to warm to room temperature and stirred for 2 hours. The crude reaction mixture was dry loaded onto silica and purified by flash chromatography to give 3-[2-(4-Chloro-phenyl)-thiazol-5-ylmethoxy]-cyclopent-2-enone (2.12 g).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:7])[C:3]([CH3:6])([OH:5])[CH3:4].[Cl:8][C:9]([Cl:14])([Cl:13])[C:10](Cl)=[O:11]>N1C=CC=CC=1>[OH:5][C:3]([CH3:6])([CH3:4])[C@@H:2]([NH:1][C:10](=[O:11])[C:9]([Cl:14])([Cl:13])[Cl:8])[CH3:7]
Reactant: C[C@H](N)C(C)(C)O
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: C[C@H](NC(=O)C(Cl)(Cl)Cl)C(C)(C)O
Reaction time: 0.17 h
Yield: 93.6 %

Procedure:
To a solution of (3) (1.193 g, 8.56 mmol) at 0° C. in pyridine (24 ml) was added trichloroacetyl chloride (1.05 ml, 9.41 mmol). After stirring at this temperature for 10 minutes, the reaction mixture was stirred overnight at room temperature. The reaction was quenched by the addition of saturated aqueous sodium chloride solution, after which the product was extracted with dichloromethane and the combined organic extracts were washed with hydrochloric acid (1M). Concentration in vacuo and purification by flash column chromatography using 30% ethyl acetate/40-60 petroleum ether as eluant furnished the title compound (4) (1.992 g, 94%) as an oil; νmax (CH2Cl2) 1713 cm-1 ; [α]D24 (c 1.2 in CHCl3)=+6.3; (Found: C, 33.71; H, 5.12; N, 5.72. C7H12Cl3NO2 requires C, 33.83; H, 4.87; N, 5.64%); δH (200 MHz; CDCl3) 1.21 (3H, d, J=3.4, CH3CH), 1.25 (3H, s, C(CH3)2), 1.26 (3H, s, C(CH3)2), 2.31 (1H, s, OH), 3.82 (1H, dq, J=6.7 and 8.8, CHCH3NH), 7.1 (1H, s, NH); δC (125 MHz; CDCl3) 14.89 (CH3), 26.68 (CH3), 27.56 (CH3), 55.19 (CH), 72.01 (C), 92.82 (CCl3), 161.56 (CO); m/z (CI+, NH3) 248 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].N1C=CC=CC=1.[C:15]([O:30][CH3:31])(=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O-])=[O:27]>C(Cl)Cl>[C:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])=[O:27])([O:30][CH3:31])=[O:29]
Reactant: COC(=O)CCCCCCCCCCC(=O)[O-]
Reactant: Nc1ccccc1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CCCCCCCCCCC(=O)Nc1ccccc1O

Procedure:
To a stirred near solution of 2-aminophenol (0.24 g, 2.2 mM) in anhydrous methylene chloride (25 mL) was added dry pyridine (0.66 mL) and the mixture cooled in an ice-water bath. A solution of (7) (0.525 g, 2.0 mM) in methylene chloride (2 mL) was added over 1 minute (2×1.5 mL methylene chloride rinses), and the mixture allowed to stir cold. After 30 minutes the bath was removed. After stirring overnight at ambient temperatures, the mixture was filtered, the solvents removed in vacuo, and the residue pumped to remove all traces of pyridine. The product, (44) was used as is in subsequent steps.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22]>>[OH:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:17][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[O:12][C:13]([F:16])([F:15])[F:14])(=[O:10])=[O:9]
Reactant: NCCCCO
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Product: O=S(=O)(NCCCCO)c1ccc(Br)cc1OC(F)(F)F

Procedure:
Using a method analogous to that described in Example 1, 4-bromo-2-trifluoromethoxyphenyl sulphonyl chloride was reacted with 4-aminobutanol, and the title compound obtained as a white solid after recrystallisation from ether/petrol. δC (CDCl3, 62.9 MHz): 26.5, 29.4, 43.3, 62.1, 127.3, 131.7, 131.7, 133.1, 135.4 and 137.9.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[N:17]1([CH2:23][CH2:24][CH2:25][Cl:26])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[ClH:26].[N:17]1([CH:23]([C:14]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:15]=2[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][NH:9]3)[CH2:24][CH3:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: ClCCCN1CCCCC1
Reactant: c1ccc(-c2n[nH]c3ccccc23)cc1
Agent: Cl
Product: CCC(c1cccc2[nH]nc(-c3ccccc3)c12)N1CCCCC1
Yield: 74.5 %

Procedure:
By the procedure similar to that described in Example 1, 3-phenylindazole (3.88 g) and piperidinopropyl chloride hydrochloride (5.94 g) were treated to obtain 5.3 g of 1-piperidinopropyl-3-phenylindazole hydrochloride (m.p. 201°-202° C).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH2:23][CH2:24][O:25][CH3:26])[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][CH:10]=1)#[N:2].C([Sn]([N:40]=[N+:41]=[N-:42])(CCCC)CCCC)CCC.[OH-].[Na+]>CC1C=CC=CC=1C.C1(C)C=CC=CC=1>[CH3:26][O:25][CH2:24][CH2:23][N:16]([C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]2[NH:42][N:41]=[N:40][N:2]=2)=[CH:10][CH:11]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CCCCC(=O)N(CCOC)Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: CCCCC(=O)N(CCOC)Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 2 h

Procedure:
A solution of 1.6 g (4.5 mmol) of crude N-[(2'-cyanobiphenyl-4-yl)methyl]-N-(2methoxyethyl)valeramide and 1.8 g (5.5 mmol) of tri-n-butyltin azide in 15 ml of o-xylene is heated under reflux for 20-24 hours while passing a gentle stream of nitrogen through. After cooling, the solution is diluted with about 30 ml of toluene, treated with 15 ml of 1N aqueous sodium hydroxide solution and intensively stirred for 2 hours. The aqueous phase is separated off and rendered acidic with 16 ml of 1N aqueous hydrochloric acid. The precipitated product is isolated by extraction with ethyl acetate. The crude title compound is thus obtained as an oil which crystallizes from a little ethyl acetate, m.p. 120°-122°.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12]2[C:7](=[C:8]([C:32]([NH:34][CH2:35][C:36]3[C:37](=[O:46])[NH:38][C:39]([CH3:45])=[CH:40][C:41]=3[CH2:42][CH2:43][CH3:44])=[O:33])[CH:9]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]([N:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)=[N:17][CH:18]=3)[CH:11]=2)[CH:6]=[CH:5]1)[CH3:3].C(O)(C(F)(F)F)=O>ClCCl>[CH:2]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[CH:18]=[N:17][C:16]([N:19]4[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]4)=[CH:15][CH:14]=3)[CH:9]=[C:8]([C:32]([NH:34][CH2:35][C:36]3[C:37](=[O:46])[NH:38][C:39]([CH3:45])=[CH:40][C:41]=3[CH2:42][CH2:43][CH3:44])=[O:33])[C:7]=2[CH:6]=[CH:5]1)([CH3:1])[CH3:3]
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)cc2c1ccn2C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N3CCNCC3)nc2)cc2c1ccn2C(C)C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
To a suspension of 1,1-dimethylethyl 4-{5-[1-(1-methylethyl)-4-({[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]amino}carbonyl)-1H-indol-6-yl]-2-pyridinyl}-1-piperazinecarboxylate (70 mg, 0.112 mmol) in dichloromethane (2 mL) was added TFA (0.5 ml, 6.49 mmol), and the mixture was stirred for 1 h. The mixture was concentrated and the residue was treated with saturated aqueous NaHCO3 solution and filtered. The solid was purified using column chromatography (silica gel, 0 to 15% (9:1 MeOH/NH4OH)/CH2Cl2) to give 1-isopropyl-N-((6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl)-6-(6-(piperazin-1-yl)pyridin-3-yl)-1H-indole-4-carboxamide (51 mg, 84%) as off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.91 (m, 3 H), 1.47 (d, J=4.00 Hz, 6H), 1.53-1.60 (m, 2 H), 2.14 (s, 3 H), 2.89-2.98 (m, 4 H), 3.51-3.59 (m, 4 H), 4.40 (d, J=5.05 Hz, 2 H), 4.93 (quin, J=6.63 Hz, 1 H), 5.92 (s, 1 H), 6.87 (d, J=3.03 Hz, 1 H), 6.94 (d, J=8.84 Hz, 1 H), 7.60 (d, J=3.03 Hz, 1 H), 7.66 (d, J=1.26 Hz, 1 H), 7.88 (s, 1 H), 8.00 (dd, J=8.84, 2.53 Hz, 1 H), 8.28 (t, J=5.05 Hz, 1 H), 8.58 (d, J=2.27 Hz, 1 H). MS: (M+H)+=527.2.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]=[C:11]=[O:12])[CH3:9].[F:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([F:24])[C:15]=1[O:25][C:26]1[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=1.Cl>C(OCC)(=O)C>[CH2:8]([NH:10][C:11]([N:28]1[C:29]([CH3:31])=[CH:30][C:26]([O:25][C:15]2[C:16]([F:24])=[CH:17][C:18]([C:20]([F:23])([F:21])[F:22])=[CH:19][C:14]=2[F:13])=[N:27]1)=[O:12])[CH3:9]
Reactant: CCN=C=O
Reactant: Cc1cc(Oc2c(F)cc(C(F)(F)F)cc2F)n[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCNC(=O)n1nc(Oc2c(F)cc(C(F)(F)F)cc2F)cc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 21 %

Procedure:
Triethylamine (0.20 g, 2.0 mmol) and ethyl isocyanate (0.14 g, 2.0 mmol) were added to a solution of 3-(2,6-difluoro-4-trifluoromethylphenyloxy)-5-methylpyrazole (0.42 g, 1.5 mmol) in ethyl acetate (10 ml), and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (chloroform), to give a white solid of N-ethyl-3-(2,6-difluoro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.11 g, yield: 21.0%). mp: 102-104° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.21 (t, J=7.3 Hz, 3H), 2.19 (s, 3H), 3.32 (dq, J=6.0 and 7.3 Hz, 2H), 5.00-5.25 (m, 1H), 6.25 (s, 1H), 7.36 (d, JHF=7.0 Hz, 2H).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=O.[CH:10]([OH:13])(C)C>>[CH:10]([NH:1][C@@H:2]1[C:7](=[O:8])[O:9][C:4](=[O:6])[CH2:3]1)=[O:13]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: CC(C)O
Product: O=CN[C@H]1CC(=O)OC1=O

Procedure:
formylating L-aspartic acid in a first reaction mixture of formic acid, acetic anhydride and isopropyl alcohol to yield N-formyl aspartic anhydride;
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:33][CH2:34]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1)(=[O:38])[CH3:37]
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ccnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ccnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f2) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])([O-])=O.[K+].[K+].[CH2:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][NH:16][CH2:15]1.O(CC)CC.[ClH:29]>C(#N)C.CCOCC>[ClH:29].[CH:17]1([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:15][NH:16]1
Reactant: CCOC(=O)CBr
Reactant: c1ccc2c(c1)CCNC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: CCOC(=O)CC1NCCc2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 77 %

Procedure:
A solution of ethyl bromoacetate (20.9 g) in acetonitrile (30 mL) was added to a mixture of K2CO3 (27.6 g, 0.2 mol) and 1,2,3,4-tetrahydro-2-isoquinoline (13.3 g, 0.1 mol) in acetonitrile (220 mL). The reaction mixture was stirred at room temperature for about 2 days, and then was refluxed for 4 hours. The reaction mixture was filtered, the filtrate was concentrated in vacuo and the residue was partitoned between ether and water. The ether layer was separated, dried over MgSO4 and concentrated in vacuo to afford a liquid which was dissolved in ether (200 mL), cooled and treated with Et2O·HCl to afford 12,5 g (77%) of ethyl 1,2,3,4-tetrahydro-2-isoquinolinylacetate hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([C:18]3[NH:22][C:21]([C:23]([OH:25])=O)=[CH:20][N:19]=3)=[O:17])=[CH:8]2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([C:18]3[NH:22][C:21]([C:23]([N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)=[O:25])=[CH:20][N:19]=3)=[O:17])=[CH:8]2)=[CH:26][CH:27]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1cnc(C(=O)c2cn(Cc3ccc(Cl)cc3)c3ccccc23)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(c1ncc(C(=O)N2CCOCC2)[nH]1)c1cn(Cc2ccc(Cl)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
A mixture of 2-[1-(4-chloro-benzyl)-1H-indole-3-carbonyl]-3H-imidazole-4-carboxylic acid (10 mg, 0.026 mmol), 4-(dimethylamino)pyridine (DMAP) (30 mg, 0.25 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (30 mg, 0.16 mmol) in CH2Cl2 (2 mL) was stirred at room temperature under N2 for 1 hour. Then morpholine (0.1 mL) in CH2Cl2 (2 mL) was added followed by stirring overnight at room temperature. After removal of solvent, product {2-[1-(4-Chloro-benzyl)-1H-indole-3-carbonyl]-3H-imidazol-4-yl}-morpholin-4-yl-methanone (8 mg, yield 68%) was purified by column chromatography (ethyl acetate:methanol=10:1). 1H NMR (CD3OD) δ 3.7 (m, 8H), 5.58 (s, 2H), 7.3–7.45 (m, 7 H), 7.80 (s, 1H), 8.42 (m, 1H), 9.05 (s, 1H) ppm; ESMS calcd (C24H21ClN4O3): 448.13; found: 449.1 (M+H)+.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH2:7][CH2:6][NH:5]1.[CH3:17][Si:18]([CH3:25])([CH3:24])[CH2:19][CH2:20][O:21][CH2:22]Cl>>[CH3:17][Si:18]([CH3:25])([CH3:24])[CH2:19][CH2:20][O:21][CH2:22][N:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2[CH2:7][CH2:6][NH:5][C:4](=[O:3])[C:16]1=2
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=C1NCCc2c1[nH]c1ccccc21
Agent: [H-]
Agent: [Na+]
Product: C[Si](C)(C)CCOCn1c2c(c3ccccc31)CCNC2=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 57 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with anhydrous DMF (4 mL) and a 60% dispersion of sodium hydride in mineral oil (181 mg, 4.52 mmol) and the reaction mixture was cooled to 0° C. 1,2,3,4-tetrahydro-1-oxo-beta-carboline (841 mg, 4.52 mmol) was added, and the reaction was stirred at 0° C. for 15 min. After this time, 2-(trimethylsilyl)ethoxymethyl chloride (829 mg, 4.97 mmol) was added, and the reaction was stirred at 0° C. for 1 h. The reaction mixture was then partitioned between water (10 mL) and ethyl acetate (20 mL). The layers were separated, and the aqueous phase was extracted with ethyl acetate (2×10 mL). The organic extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford 117a in 57% yield (818 mg) as a colorless oil: 1H NMR (500 MHz, CDCl3) d 7.67 (d, 1H, J=8.0 Hz), 7.65 (d, 1H, J=8.0 Hz), 7.46 (t, 1H, J=8.0 Hz), 7.27 (t, 1H, J=8.0 Hz), 6.14 (s, 2H), 5.72 (br s, 1H), 3.75 (t, 2H, J=7.0 Hz), 3.66 (t, 2H, J=8.0 Hz), 3.14 (t, 2H, J=7.0 Hz), 0.96 (t, 2H, J=8.0 Hz), −0.25 (s, 9H).
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH:22][C:23](=[O:48])[CH:24]=[CH:25][CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34]COCCOC)=[C:30]([O:41]COCCOC)[CH:29]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH:1]([N:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][NH:22][C:23](=[O:48])[CH:24]=[CH:25][CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([OH:41])[CH:29]=2)[CH2:18][CH2:19]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COCCOCOc1ccc(C=CC=CC(=O)NCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1OCOCCOC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(C=CC=Cc1ccc(O)c(O)c1)NCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Yield: 47.7 %

Procedure:
To a solution of 289 mg (0.438 mmol) of the amide compound prepared above in methanol (10 ml) was added 127 mg (0.668 mmol) of p-toluenesulfonic acid hydrate. The mixture was refluxed in an argon atmosphere for 7 hours. Water was added to the reaction mixture, and the mixture was adjusted with an aqueous solution of sodium carbonate to a pH of 9, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure, a the residue obtained was recrystallized from dichloromethane to give 101 mg (0.209 mmol) of N-benzhydryl-N'-[2-{5-(3,4-dihydroxyphenyl)-2,4-pentadienoyl}aminoethyl]piperazine. Spectrophotometric data of the product support the structure shown below. ##STR39##
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([NH:11][C:12](=[O:31])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]34[CH2:30]C5CC(CC(C5)[CH2:22]3)[CH2:28]4)=[CH:17][CH:16]=2)[CH:5]=1.[OH-].[K+].Cl>O1CCOCC1.O>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:12]([NH:11][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=2[OH:10])[C:3]([OH:32])=[O:2])=[O:31])=[CH:16][CH:17]=1)([CH3:30])([CH3:22])[CH3:28]
Reactant: COC(=O)c1ccc(O)c(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)c1ccc(OCC(=O)Nc2cc(C(=O)O)ccc2O)cc1
Yield: 91.9 %

Procedure:
A 3-[2-(4-Adamantan-1-yl-phenoxy)-acetylamino]-4-hydroxy-benzoic acid methyl ester (151.8 mg, 0.35 mmol) in 1,4-dioxane/H2O (10 ml) was treated with KOH (290.7 mg, 5.18 mmol) at 60° C. for 3 h. The reaction mixture was then acidified with 10% HCl to PH 2, and then partitioned between ethyl acetate and brine. The organic phase was washed with water, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (CH2CH2:MeOH=4:1) to give 3-[2-(4-tert-butyl-phenoxy)acetylamino]-4-hydroxy-benzoic acid as a white solid (110.4 mg, 75.10% yield).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.[Br:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42]Br)=[CH:38][C:37]=1[N+:44]([O-:46])=[O:45]>>[Br:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][O:1][CH:2]2[CH:7]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[CH:10][CH:9]=3)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]2)=[CH:38][C:37]=1[N+:44]([O-:46])=[O:45]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: O=[N+]([O-])c1cc(CBr)ccc1Br
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(Br)c([N+](=O)[O-])c2)cc1

Procedure:
Analogously to Method D, 12.60 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 1-bromo-4-bromomethyl-2-nitrobenzene are reacted. The title compound is obtained as a yellow oil. Rf=0.21 (1:2 EtOAc-heptane); Rt=27.96 (II).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][S:10][C:11]#[N:12])=[CH:4][C:3]=1[F:14].[BrH:15]>>[Br:15][C:11]1[S:10][CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:14])[CH:4]=2)[N:12]=1
Reactant: Br
Reactant: N#CSCC(=O)c1ccc(Cl)c(F)c1
Product: Fc1cc(-c2csc(Br)n2)ccc1Cl
Yield: 68 %

Procedure:
In the same manner as described in step 5 of Example 78, using 1-(4-chloro-3-fluoro-phenyl)-2-thiocyanato-ethanone (2.45 g, 10.7 mmol), prepared in the previous step, and hydrogen bromide (30% in acetic acid, 16 mL), the solid was collected by suction filtration to give 2-bromo-4-(4-chloro-3-fluorophenyl)-1,3-thiazole (2.1 g, 68%). The material was used without further purification, MS (ES) m/z 293[M+H+].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1
Reactant: CO
Reactant: O=C(O)Cc1cccc(O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cccc(O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96 %

Procedure:
To a solution of 3-hydroxyphenyl acetic acid, (5.0 g, 0.033 mol) in methanol (100 mL) was added concentrated sulfuric acid (1 mL) and the reaction mixture stirred at room temperature for 12 hours. After concentration to remove methanol, the crude oil was dissolved in ethyl acetate (75 mL), washed with water (50 ml), saturated aqueous NaHCO3 (50 mL), and brine (50 ml). The organic layer was dried over Na2SO4, and concentrated to give the methyl ester (1) as an oil (5.28 g) in 96% yield, which was used without further purification. 1H NMR (CDCl3) δ 7.17 (t, 1H), 6.81 (m, 3H), 6.48 (s, 1H), 3.69 (s, 3H), 3.57 (s, 2H). 13C NMR (CDCl3) δ 169.9, 153.3, 132.3, 126.9, 118.4, 111.5, 57.8, 38.4.
Reaction SMILES: [CH3:1][S:2]([C:5]1[C:13]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][C:8]([C:9](Cl)=[O:10])=[C:7]([CH3:18])[CH:6]=1)(=[O:4])=[O:3].[NH2:19][C:20]([NH2:22])=[NH:21].O>CN(C=O)C>[CH3:1][S:2]([C:5]1[C:13]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][C:8]([C:9]([NH:21][C:20]([NH2:22])=[NH:19])=[O:10])=[C:7]([CH3:18])[CH:6]=1)(=[O:4])=[O:3]
Reactant: N=C(N)N
Reactant: Cc1cc(S(C)(=O)=O)c(S(C)(=O)=O)cc1C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(S(C)(=O)=O)c(S(C)(=O)=O)cc1C(=O)NC(=N)N
Reaction time: 5 h
Yield: 64.8 %

Procedure:
A solution of 4,5-bismethanesulfonyl-2-methylbenzoyl chloride, prepared as described in 2.1., in 5 l of DMF is added dropwise at 12° to the guanidine solution prepared as described in 2.2. The reaction mixture is stirred at 20° for 5 hours, and 45 l of cold water (0-50) are added slowly. The deposited crystals are filtered off and rinsed with ice-water, acetonitrile and diethyl ether. The crude crystals are dissolved in 315 l of hot acetonitrile/water (20:1). The solution is treated with 200 g of activated carbon, filtered and cooled to 0°, giving N-(4,5-bismethanesulfonyl-2-methylbenzoyl)guanidine as the acetonitrile adduct in a yield of 64.8%; m.p. 233-2340 °.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH2:9][S:10][CH3:11])[CH:6]=[CH:5][C:3]=1[NH2:4].O[CH2:13][CH:14]([CH2:16]O)O>>[CH3:11][S:10][CH2:9][C:7]1[CH:6]=[C:5]2[C:3](=[C:2]([Br:1])[CH:8]=1)[N:4]=[CH:16][CH:14]=[CH:13]2
Reactant: CSCc1ccc(N)c(Br)c1
Reactant: OCC(O)CO
Product: CSCc1cc(Br)c2ncccc2c1

Procedure:
2-bromo-4-(methylthiomethyl)aniline and glycerol can be combined to form 6-(methylthiomethyl)-8-bromoquinoline, and