Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:20](=[O:21])[CH2:19][CH:18]([C:22]([OH:24])=O)[CH2:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:25][NH2:26]>>[CH3:25][NH:26][C:22]([CH:18]1[CH2:19][C:20](=[O:21])[N:16]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[CH:11][CH:12]=2)[CH2:17]1)=[O:24]
Reactant: CN
Reactant: O=C(O)C1CC(=O)N(c2ccc(CCc3cccc(F)c3)cc2)C1
Product: CNC(=O)C1CC(=O)N(c2ccc(CCc3cccc(F)c3)cc2)C1

Procedure:
In an analogous manner to that described in Example 36d), the esterification of (RS)-1-{4-[2-(3-fluoro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid and reaction of the intermediate acid chloride with methylamine yields the (RS)-1-{4-[2-(3-fluoro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid methylamide as a light yellow solid; MS: m/e=341 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][N:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([N:27]=[C:28]=[S:29])=[O:26])=[CH:20][CH:19]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:28]([NH:27][C:25](=[O:26])[CH2:24][C:21]3[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=3)=[S:29])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)c(F)c1
Solvent: ClCCl
Product: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2ccnc(Cl)c2)c(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 64 %

Procedure:
4-Fluorophenylacetylchloride (Aldrich, 0.072 mL, 0.525 mmol, 2.5 eq) was added to a solution of sodium thiocyanate (0.056 g, 0.695 mmol, 3.3 eq) in ethyl acetate (2.0 mL) at room temperature and the reaction mixture was stirred for 1.5 h to afford a solution of 2-(4-fluorophenyl)ethanoyl isothiocyanate (0.263 M). A solution of 4-(2-chloropyridin-4-yloxy)-3-fluorobenzenamine (0.050 g, 0.21 mmol, 1.0 eq) in CH2Cl2 (1.0 mL) was added dropwise to the 2-(4-fluorophenyl)ethanoyl isothiocyanate solution and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated in vacuo and the resulting residue was purified by silica gel flash chromatography (Merck, 40-63 μM, 230-240 mesh, eluting 3/1 hexane/ethyl acetate) to afford the title compound (0.058 g, 64%) as a solid. 1H NMR (DMSO-d6) δ 12.46 (s, 1H), 11.84 (s, 1H), 8.35-8.33 (m, 1H), 8.02-8.33 (m, 1H), 6.99-7.52 (m, 8H), 3.84 (s, 2H); MS (ESI+) m/z 434 (M+H)+; HRMS (ESI+) calcd.: 434.0542. found: 434.0547.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=O.[C:10](Cl)(=O)[C:11](Cl)=[O:12].[N:16]1[CH:21]=CC=C[CH:17]=1>C1(C)C=CC=CC=1>[CH3:17][N:16]([CH3:21])[C:7]([C:6]1([CH3:10])[CH:5]=[CH:4][S:3][CH2:2]1)=[O:9].[CH3:1][C:2]1[S:3][C:4]([CH2:11][OH:12])=[CH:5][C:6]=1[CH2:7][N:16]([CH3:21])[CH3:17]
Reactant: Cc1sccc1C(=O)O
Reactant: c1ccncc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: CN(C)C(=O)C1(C)C=CSC1
Product: Cc1sc(CO)cc1CN(C)C

Procedure:
A mixture of 2-methyl-3-thiophene carboxylic acid (2 g) and oxalyl chloride (2 ml) in dry toluene (20 ml) was heated under reflux and was treated with pyridine (0.05 ml). The reaction mixture was heated at reflux for 1 h, cooled and partially evaporated. The residue was added to a solution of dimethylamine in toluene at 0° to 5° C. After 2 hours water and diethyl ether were added. The organic phase was washed with dilute hydrochloric acid, sodium hydroxide and water, dried and evaporated to an oil which was distilled to give the title compound (1.4 g) as a colourless oil b.p. 100°/0.1 mm.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH:19]([C:22]1[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[C:25]2[O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:24]=2[C:23]=1[NH2:38])([CH3:21])[CH3:20]>C1(C)C=CC=C(C)C=1>[CH:19]([C:22]1[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[C:25]2[O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:24]=2[C:23]=1[N:38]1[CH2:2][CH2:3][N:4]=[C:5]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:21])[CH3:20]
Reactant: CC(C)c1cc(C(C)C)c2oc3ccccc3c2c1N
Reactant: O=C(NCCCl)c1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1cccc(C)c1
Product: CC(C)c1cc(C(C)C)c2oc3ccccc3c2c1N1CCN=C1c1ccccc1
Temperature: 25 °C
Yield: 90.1 %

Procedure:
N-(2-chloroethyl)benzamide (2.1 g, 11.2 mmol), PCl5 (3.5 g, 16.8 mmol) were dissolved in m-Xylene (100 mL) and refluxed for 2 h. After cooling down the reaction flask to room temperature, 2,4-diisopropyldibenzo[b,d]furan-1-amine (3.3 g, 12.3 mmol) was added to it and the reaction mixture was refluxed overnight. From the cooled reaction mixture white precipitate was filtered out. Precipitate was dissolved in ethylacetate and partitioned between ethylacetate and aqueous Na2CO3. Organic phase was extracted out and dried under vacuum. Target compound (4 g, 90% yield) was used in next step without further purification.
Reaction SMILES: [CH2:1]([S-:3])[CH3:2].[Na+].[Cl:5][C:6]1[CH:11]=[C:10](I)[CH:9]=[CH:8][C:7]=1[NH:13][C:14](=[O:22])[C@:15]([OH:21])([CH3:20])[C:16]([F:19])([F:18])[F:17]>N1C2C(=CC=CC=2)C=CC=1.N1C=CC=CC=1.C(OCC)(=O)C.[Cu]Cl>[Cl:5][C:6]1[CH:11]=[C:10]([S:3][CH2:1][CH3:2])[CH:9]=[CH:8][C:7]=1[NH:13][C:14](=[O:22])[C@:15]([OH:21])([CH3:20])[C:16]([F:19])([F:18])[F:17]
Reactant: CC[S-]
Reactant: C[C@@](O)(C(=O)Nc1ccc(I)cc1Cl)C(F)(F)F
Agent: Cl[Cu]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Solvent: c1ccncc1
Product: CCSc1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1
Temperature: 200 °C
Yield: 84 %

Procedure:
Copper (I) chloride (0.5 g) and sodium ethanethiolate (0.54 g) were added sequentially to a deoxygenated solution of (R)-N-(2-chloro-4-iodophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 197) (2.0 g) in quinoline (6 ml) and pyridine (1.5 ml). The mixture was heated to 200° C. under argon for 18 hours, cooled dissolved in ethyl acetate (200 ml), washed with dilute aqueous hydrochloric acid (2×100 ml) and brine (2×50 ml) and then dried. Volatile material was removed by evaporation and the residue was purified by chromatography on silica gel eluting with 10-40% ethyl acetate/iso-hexane to give the title compound as a gum (1.4 g). NMR (CDCl3): 1.29 (t, 3H), 1.57 (s, 3H), 2.91 (q, 2H), 3.69 (s, 1H), 7.24 (d, 1H), 7.35 (s, 1H), 8.24 (d, 1H), 8.77 (s, 1H); MS (ESP−): 326.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([C:21](=[O:37])[N:22]([C@@H:24]([C:32](=[O:36])[N:33]([CH3:35])[CH3:34])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:23])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)C)(C)(C)C.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O.ClCCl>[CH3:35][N:33]([CH3:34])[C:32]([C@H:24]([N:22]([CH3:23])[C:21](=[O:37])[C@H:9]([NH:7][CH3:6])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:36]
Reactant: CN(C)C(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)N(C)C
Yield: 78.6 %

Procedure:
A solution of N-((1R)-1-(N-((1R)-1-(dimethylcarbamoyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butylester (6.6 g, 12.8 mmol) in 50% trifluoroacetic acid/dichloromethane (15 ml) was stirred for 10 min. Then saturated sodium bicarbonate was added until pH 8 and the organic phase was separated. The aqueous phase was extracted with dichloromethane (2 ×20 ml) and the combined organic phases were washed with brine (10 ml), dried over magnesium sulfate and concentrated in vacuo to give 4.2 g of (2R)-N-((1R)-1-dimethylcarbamoyl-2- phenylethyl)-N-methyl-2-methylamino-3-(2-naphthyl) propionamide.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[F:16][C:17]([F:30])([F:29])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26].[CH:31]([O:34][C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1)([CH3:33])[CH3:32]>>[CH:31]([O:34][C:35]1[CH:41]=[CH:40][C:38]([N:39]2[CH2:13][CH2:12][C:6]3([CH2:7][CH2:8][N:9]([S:25]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[O:18][C:17]([F:30])([F:29])[F:16])(=[O:27])=[O:26])[CH2:10][CH2:11]3)[C:4]2=[O:5])=[CH:37][CH:36]=1)([CH3:33])[CH3:32]
Reactant: CC(C)Oc1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Product: CC(C)Oc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4OC(F)(F)F)CC3)C2=O)cc1

Procedure:
Light brown solid. MS (ESI): 513.16 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-trifluoromethoxy-benzenesulfonyl chloride and 4-isopropoxy-aniline.
Reaction SMILES: [C:1]([C:3](=[C:7](SC)[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[C:18]1([NH:28][NH2:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.[OH-].[Na+].C(OCC)(=O)C>CCCCCC>[NH2:2][C:1]1[N:28]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[N:29]=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CSC(=C(C#N)C(N)=O)c1ccc(C)cc1
Reactant: NNc1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc(-c2nn(-c3cccc4ccccc34)c(N)c2C(N)=O)cc1
Yield: 27 %

Procedure:
The title compound was prepared from 2-cyano-3-methylthio-3-(4-tolyl) acrylamide (464 mg, 2.0 mmol), 1-naphthyl hydrazine hydrochloride (389 mg, 2.0 mmol) and sodium hydroxide (88 mg, 2.2 mmol) following the procedure used for the compound of Example 12. The crude product was subjected to column chromatography (SiO2, 50-60% ethyl acetate in hexane) and was recrystallised from diethylether to give the title compound as pink crystals (185 mg) m.p. 195°. δH (CDCl3) 8.00 (1H, d, J 8.3 Hz), 7.95 (1 H., m), 7.73-7.55 (7H, m), 7.30 (2H, d, J 8.3 Hz), 5.52 (2H, br s), 5.16 (2H, br s) and 2.42 (3H, s).
Reaction SMILES: [C:1]1(=[O:7])[NH:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20](Cl)=[O:21]>C1COCC1>[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]([N:6]1[CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:7])=[O:21]
Reactant: O=C1CCCCN1
Reactant: O=C(Cl)c1ccco1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CCCCN1C(=O)c1ccco1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a subsequent reaction, 9.2 g (92 mmol) of valerolactam (Aldrich) and 14.1 mL (101 mmol) of triethylamine (Aldrich, d=0.726 g/mol) are added to 150 mL THF (Aldrich, HPLC grade) in a 3-neck round bottom flask equipped with a reflux condenser, addition funnel, and magnetic stirrer. Addition of a solution of 12.0 g (92 mmol) of the 2-furoyl chloride in 150 mL THF proceeds dropwise over a period of 30 min, and the resulting reaction mixture is heated to reflux and stirred for 16 h. Upon cooling to room temperature, the THF is removed by evaporation under reduced pressure. The solid residue is redissolved in methylene chloride, and extracted several times with 5% aqueous hydrochloric and then deionized water. The organic layer is dried over Na2SO4, filtered, concentrated by removal of solvent, and poured into hexane to precipitate the product. The precipitate is collected by suction filtration, rinsed with hexane, and dried under vacuum to yield N-(2-furoyl)valerolactam as a white, crystalline solid.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[CH2:29][C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[NH:22][C:21]4=[O:30])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)C=CC=CC=1.N>[OH-].[OH-].[Pd+2].ClCCl.CO.C1CCCCC1>[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:22][C:21]3=[O:30])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1
Reactant: O=C1Nc2ccccc2CN1C1CCN(C2CCN(Cc3ccccc3)CC2)CC1
Agent: [Pd+2]
Agent: N
Agent: [OH-]
Solvent: C1CCCCC1
Solvent: CO
Solvent: ClCCl
Product: O=C1Nc2ccccc2CN1C1CCN(C2CCNCC2)CC1
Yield: 92 %

Procedure:
Prepared analogously to Example A3f) from 3,4-dihydro-3-[1-[1-(phenylmethyl)-4-piperidinyl]-4-piperidinyl]-2(1H)-quinazolinone by hydrogenolysis, but using Pearlman's catalyst, in a yield of 92% of theory. Colourless crystals, Rf=0.48 (Macherey-Nagel, POLYGRAM® SIL G/UV254ready-made films for TLC; eluant: dichloromethane/methanol/cyclohexane/conc. ammonia 68/20/10/5 v/v/v/v).
Reaction SMILES: CO[C:3]1[C:7](OC)=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1.[CH3:12][C:13]1[C:14]([CH2:18][S:19][CH2:20][CH2:21][NH2:22])=[N:15][O:16][N:17]=1.[CH3:23][N:24]([CH2:26][C:27]1[O:31][C:30]([CH2:32][S:33][CH2:34][CH2:35][NH2:36])=[CH:29][CH:28]=1)[CH3:25]>>[CH3:25][N:24]([CH2:26][C:27]1[O:31][C:30]([CH2:32][S:33][CH2:34][CH2:35][NH:36][C:7]2[C:3]([NH:22][CH2:21][CH2:20][S:19][CH2:18][C:14]3[C:13]([CH3:12])=[N:17][O:16][N:15]=3)=[N:4][S:5](=[O:10])(=[O:11])[N:6]=2)=[CH:29][CH:28]=1)[CH3:23]
Reactant: COC1=NS(=O)(=O)N=C1OC
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: Cc1nonc1CSCCN
Product: Cc1nonc1CSCCNC1=NS(=O)(=O)N=C1NCCSCc1ccc(CN(C)C)o1

Procedure:
When a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide is treated with 2-[(4-methyl-1,2,5-oxadiazol-3-yl)methylthio]ethylamine [prepared in Example 58, Step B] and 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine, the title compound is thereby produced.
Reaction SMILES: [C:1]1([CH2:7][C@H:8]([N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](C)(C)[O:25][CH:26]=C(O[Si](C)(C)C)O[Si](C)(C)C.Cl.[Cl-].[Na+]>O1CCOCC1>[CH2:7]([C@H:8]([N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])[C:9](=[O:10])[CH2:26][OH:25])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Reactant: C[Si](C)(C)OC=C(O[Si](C)(C)C)O[Si](C)(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(CO)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 95 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
A mixture of 134 g of 3-phenyl-2(S)-phthalimido-propionyl chloride and 269.7 g of tris(trimethylsilyloxy)-ethylene was stirred at 95° C. for 5 hours. A further 54 g of tris(trimethylsilyloxy)ethylene were added and the mixture was stirred at 95° C. for a further 1.5 hours. The cooled reaction mixture was then treated with 435 ml of dioxan and 174 ml of 0.6N hydrochloric acid and the resulting mixture was heated to 85° C. for 30 minutes. The cooled mixture was saturated with sodium chloride and then extracted with diethyl ether. The ethereal solution was washed with aqueous sodium bicarbonate solution and evaporated. The resulting pale yellow solid was crystallized from ethyl acetate/n-hexane to give 103 g of N-[1(S)-benzyl-3-hydroxy-2-oxopropyl]phthalimide as a white solid, MS: m/e 310 [M+H]+.
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:30]1([CH2:36][CH:37]=O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)(Cl)Cl>[C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH:24]4[CH2:29][CH2:28][N:27]([CH2:37][CH2:36][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH2:26][CH2:25]4)[CH:21]=3)[NH:16][N:15]=2)(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=CCc1ccccc1
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OC3CCNCC3)cc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OC3CCN(CCc4ccccc4)CC3)cc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.8 %

Procedure:
A suspension of 3-(1-naphthylsulfonyl)-5-(piperidin-4-yloxy)-1H-indazole (53.9 mg, 0.132 mmol) in 1,2-dichloroethane was treated sequentially with phenylacetaldehyde (0.17 mL, 1.5 mmol) and acetic acid (1.7 mL, 3.0 mmol), stirred at ambient temperature for 1.5 hours, treated with sodium triacetoxyborohydride (66.9 mg, 0.316 mmol), stirred at ambient temperature for 3-19 hours, diluted with chloroform and washed with 1.0 N sodium hydroxide and brine. (Methanol was added to the organic phase to aid in solubility.) The organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash chromatography using 0.1-0.5% ammonium hydroxide/1.0-5.0% methanol in chloroform to yield 3-(1-naphthylsulfonyl)-5-{[1-(2-phenylethyl)piperidin-4-yl]oxy}-1H-indazole as an orange foam (45.8 mg, 67.8%). The foam was dissolved in methanol and chloroform, treated with isopropanolic HCl and concentrated in vacuo for 13 hours at 86° C. to give the title product as an orange foam (43.4 mg); Mass spectrum (+EI, [M+H]+) m/z 512. 1HNMR (500 MHz, DMSO-d6): δ14.16 (d, 1H, J=4.52 Hz), 10.19-10.30 (m*, 1H), 8.70-8.76 (m, 1H), 8.56 (dd, 1H, J=7.32 Hz and 1.10 Hz), 8.27 (d, 1H, J=8.18 Hz), 8.04 (d, 1H, J=7.68 Hz), 7.70-7.75 (m, 1H), 7.55-7.63 (m, 3H), 7.10-7.39 (m*, 7H), 4.60-4.82 (m*, 1H), 3.60-3.65 (m, 1H), 3.38-3.45 (m, 1H), 3.30-3.36 (m*, 1H), 3.15-3.24 (m, 2H), 3.01-3.07 (m, 2H), 2.01-2.28 (m*, 3H), 1.80-1.95 ppm (m*, 1H). *Conformational isomers due to protonation of tertiary amine.
Reaction SMILES: [H][H].[C:3]([C:7]1[CH:30]=[CH:29][C:10]2[CH2:11][CH2:12][C:13]3[CH:21]=[C:20]([CH:22]([N:24]([OH:28])[C:25]([NH2:27])=[O:26])[CH3:23])[CH:19]=[CH:18][C:14]=3[S:15](=[O:17])(=[O:16])[C:9]=2[CH:8]=1)([O:5]C)=[O:4].[OH-].[Na+]>C(O)C>[C:3]([C:7]1[CH:30]=[CH:29][C:10]2[CH2:11][CH2:12][C:13]3[CH:21]=[C:20]([CH:22]([N:24]([OH:28])[C:25]([NH2:27])=[O:26])[CH3:23])[CH:19]=[CH:18][C:14]=3[S:15](=[O:16])(=[O:17])[C:9]=2[CH:8]=1)([OH:5])=[O:4]
Reactant: [H][H]
Reactant: COC(=O)c1ccc2c(c1)S(=O)(=O)c1ccc(C(C)N(O)C(N)=O)cc1CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(c1ccc2c(c1)CCc1ccc(C(=O)O)cc1S2(=O)=O)N(O)C(N)=O

Procedure:
Where R1 is hydrogen and R2 is carbomethoxy, a compound of formula I, such as N-[1-(7-carbomethoxy-5,5-dioxo-10,11-dihydro dibenzo [b,f] thiepin-2-yl) ethyl]-N-hydroxy urea, may be hydrolyzed by base, such as aqueous sodium hydroxide, in an alcoholic solvent, such as ethanol to yield the N-[1-(7-carboxy-5,5-dioxo-10,11-dihydro dibenzo [b,f] thiepin-2-yl)ethyl]-N-hydroxy urea.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]CC)=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH:21]1[CH2:23][CH2:22]1>CN(C=O)C.C(OCC)(=O)C>[CH:21]1([CH2:20][O:1][C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([OH:7])=[O:6])[CH2:23][CH2:22]1
Reactant: BrCC1CC1
Reactant: CCOC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)c1cccc(OCC2CC2)c1
Temperature: 70 °C

Procedure:
To a solution of ethyl 3-hydroxybenzoate (15.0 g) in DMF (150 mL) were added potassium carbonate (25.0 g) and (bromomethyl)cyclopropane (13.1 mL), and the mixture was stirred with heating at 70° C. for 3 hr. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, and washed with saturated brine. The obtained organic layer was subjected to silica gel column chromatography (NH, ethyl acetate), and the solvent was evaporated. To a solution of the obtained residue in a mixed solvent of THF (100 mL) and methanol (50 mL) was added 2 M aqueous sodium hydroxide solution (47 mL), and the mixture was stirred with heating at 60° C. for 40 min. The reaction mixture was allowed to cool to room temperature, and neutralized with 6 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid was washed with diethyl ether/hexane to give the title compound (13.4 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]1[C:17]([NH2:33])=[N:18][CH:19]=[C:20]([C:22]2[CH:23]=[N:24][N:25]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:26]=2)[CH:21]=1.C(N(C(C)C)C(C)C)C1C=CC=CC=1>ClCCl.C1COCC1>[NH2:33][C:17]1[N:18]=[CH:19][C:20]([C:22]2[CH:23]=[N:24][N:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH2:29][CH2:28]3)[CH:26]=2)=[CH:21][C:16]=1[C:8]1[O:7][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccccc2o1
Reactant: COCC(=O)Cl
Agent: CC(C)N(Cc1ccccc1)C(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: COCC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-methoxyacetyl chloride (0.033 ml) was added in one portion to a stirred ice-cooled suspension of 3-(1,3-benzoxazol-2-yl)-5-[1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (100 mg) and N-benzyl-N-isopropyl-propan-2-amine on polystyrene (185 mg, 3 mmol/g) in dichloromethane (5 ml) and THF (5 ml). The resulting suspension was stirred at room temperature for 2 hours. The resin was filtered, rinsed with dichloromethane/methanol. The filtrate was concentrated to dryness. The crude product was purified by flash chromatography on silica gel eluting with 0 to 4% methanol in dichloromethane. After evaporation of the solvants, the resulting solid was triturated in acetonitrile to give the title compound (79 mg). NMR Spectrum: (CDCl3): 1.97-2.11 (m, 2H), 2.22-2.35 (m, 2H), 2.80-2.91 (m, 1H), 3.17-3.29 (m, 1H), 3.46 (s, 3H), 4.06-4.23 (m, 3H), 4.38-4.47 (m, 1H), 4.69-4.80 (m, 1H), 7.08 (bs, 2H), 7.35-7.42 (m, 2H), 7.58-7.63 (m, 1H), 7.69 (s, 1H), 7.73-7.78 (m, 1H), 7.80 (s, 1H), 8.35 (d, 1H), 8.41 (d, 1H); Mass spectrum: M+H+ 433.
Reaction SMILES: Cl[C:2]1C(OC)=CC(NC2C3C(=CC4C=C(OCCCl)C(OC)=CC=4C=3)N=CC=2C#N)=C(C)C=1.[Cl:34][C:35]1[C:63]([O:64][CH3:65])=[CH:62][C:38]([NH:39][C:40]2[C:49]3[C:44](=[CH:45][C:46]4[CH:53]=[C:52]([O:54][CH3:55])[C:51]([O:56][CH2:57]CCl)=[CH:50][C:47]=4[CH:48]=3)[N:43]=[CH:42][C:41]=2[C:60]#[N:61])=[C:37]([CH3:66])[CH:36]=1.[CH3:67][N:68]1[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]1.[I-].[Na+]>COCCOC>[Cl:34][C:35]1[C:63]([O:64][CH3:65])=[CH:62][C:38]([NH:39][C:40]2[C:49]3[C:44](=[CH:45][C:46]4[CH:53]=[C:52]([O:54][CH2:55][CH2:67][N:68]5[CH2:73][CH2:72][N:71]([CH3:2])[CH2:70][CH2:69]5)[C:51]([O:56][CH3:57])=[CH:50][C:47]=4[CH:48]=3)[N:43]=[CH:42][C:41]=2[C:60]#[N:61])=[C:37]([CH3:66])[CH:36]=1
Reactant: COc1cc(Nc2c(C#N)cnc3cc4cc(OCCCl)c(OC)cc4cc23)c(C)cc1Cl
Reactant: CN1CCNCC1
Reactant: COc1cc(Nc2c(C#N)cnc3cc4cc(OC)c(OCCCl)cc4cc23)c(C)cc1Cl
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(Nc2c(C#N)cnc3cc4cc(OCCN5CCN(C)CC5)c(OC)cc4cc23)c(C)cc1Cl
Temperature: 90 °C

Procedure:
A mixture of 205 mg (0.425 mmol) of 4-(4-chloro-5-methoxy-2-methylanilino)-7-methoxy-8-(chloroethoxy)benzo[g]quinoline-3-carbonitrile and 4-(4-chloro-5-methoxy-2-methylanilino)-8-methoxy-7-(chloroethoxy)benzo[g]quinoline-3-carbonitrile (1:1 mixture), 0.15 mL (1.35 mmol) of 1-methyl piperazine and 0.05 g of sodium iodide in 5 mL of ethylene glycol dimethyl ether is heated at 90° C. for 4 days under nitrogen. The mixture is cooled, the solvent is removed in vacuo and the resulting residue is stirred with saturated solution of sodium bicarbonate. The crude solid is collected by filtration, washed with water, and dried in vacuo. Purification is carried out by silica gel chromatography, eluting with a gradient of 92:8 to 85:15 methylene chloride/methanol to yield 0.10 g of 4-(4-chloro-5-methoxy-2-methylamino)-8-methoxy-7-[2-(4-methyl-1-piperazinyl)ethoxy]benzo[g]quinoline-3-carbonitrile as a yellow solid, mp 121–135° C. and 0.068 g of 4-(4-chloro-5-methoxy-2-methylanilino)-7-methoxy-8-[2-(4-methyl-1-piperazinyl)ethoxy]benzo-[g]quinoline-3-carbonitrile as a yellow solid, mp 122–137° C.