Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([O:10][CH2:11][CH:12]=[CH2:13])[CH:6]([OH:9])C=C)[CH3:2]>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:5]1[CH:6]([OH:9])[CH:13]=[CH:12][CH2:11][O:10]1)=[O:14])[CH3:2]
Reactant: C=CCOC(C(=O)OCC)C(O)C=C
Solvent: ClCCl
Product: CCOC(=O)C1OCC=CC1O
Temperature: 25 °C

Procedure:
To a solution of 2-allyloxy-3-hydroxypent-4-enoic acid ethyl ester (200 mg, 1.0 mmol) in CH2Cl2 (10 ml) was added bis-(tricyclohexylphosphine)benzylidine ruthenium (IV) chloride (20 mg, 0.024 mmol) and the resulting mixture was stirred at ambient temperature for 4H. Bis-(tricyclohexylphosphine)benzylidine ruthenium (IV) chloride (20 mg, 0.024 mmol) was added again and the resulting mixture was stirred at ambient temperature for an additional 10 h. The solution was concentrated in vacuo. The crude product was purified by flash chromatography with 25 to 30% EtOAc-hexane
Reaction SMILES: O.Cl.[CH2:3]([O:5][C:6](=[O:21])[CH:7]([N+:18]([O-])=O)[CH2:8][C:9]1[C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[S:12][CH:13]=1)[CH3:4]>[Fe].C(O)C>[CH2:3]([O:5][C:6](=[O:21])[CH:7]([NH2:18])[CH2:8][C:9]1[C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[S:12][CH:13]=1)[CH3:4]
Reactant: CCOC(=O)C(Cc1csc2ccccc12)[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(N)Cc1csc2ccccc12
Reaction time: 1 h
Yield: 45.8 %

Procedure:
To a mixed solution of 7.5 ml of water, 7.5 ml of ethanol, and 10 ml of 12N hydrochloric acid were added 3.5 g of iron powder and 2.79 g of 3-(benzo[b]thiophen-3-yl)-2-nitropropionic acid ethyl ester and then the reaction was carried out for one hour at room temperature. After filtered away excess iron powder, 200 ml of water was added to the filtrate and after adjusting the pH thereof to from 9 to 10 with sodium hydrogencarbonate, the mixture was extracted thrice with 50 ml of chloroform. The chloroform layer was washed twice with 200 ml of water and then twice with 100 ml of a saturated aqueous sodium chloride solution and after drying with magnesium sulfate, chloroform was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, 10 ml of a solution composed of 1N hydrochloric acid and ethyl acetate, and crystals thus deposited were collected by filtration to provide 1.14 g (yield of 40%) of 2-amino-3-(benzo[b]thiophen-3-yl)propionic acid ethyl ester.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)([OH:8])[CH2:5][CH:6]=[CH2:7].[N:16]([C@@H:19]([CH3:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:17]=[O:18].C1CCN2C(=NCCC2)CC1>C1COCC1.CCOC(C)=O>[CH2:5]([C:4]1([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[O:8][C:17](=[O:18])[N:16]([C@H:19]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH3:24])[CH2:2][CH2:3]1)[CH:6]=[CH2:7]
Reactant: C=CCC(O)(CCCl)c1ccc(F)cc1
Reactant: C[C@H](N=C=O)C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: C=CCC1(c2ccc(F)cc2)CCN([C@@H](C)C(C)(C)C)C(=O)O1
Yield: 11.4 %

Procedure:
A mixture of 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (500 mg, 2.19 mmol), (S)-3-isocyanato-2,2-dimethyl-butane (845 mg, 5.58 mmol), and DBU (681 mg, 5.9 mmol) in THF (10 mL) was heated to reflux for 25 h. The mixture was diluted with EtOAc and washed with 1 N aq HCl. The aqueous phase was extracted with EtOAc (3×). The combined organic phase was dried over Na2SO4. After the solvents were evaporated, the crude product was purified by column to give 6-allyl-3-((2S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (80 mg, crude).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[C:18]([CH3:25])[CH:17]=1>ClCCl>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)=[O:21])=[C:18]([CH3:25])[CH:17]=1
Reactant: O=C1CNCCN1
Reactant: Cc1cc(Cl)ccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(Cl)ccc1C(=O)N1CCNC(=O)C1
Reaction time: 0.5 h

Procedure:
2-piperazinone (0.701 g, 7 mmol, commercially available from e.g. Sigma-Aldrich) was dissolved in dichloromethane (DCM) (30 mL), and to this was added triethylamine (1.171 mL, 8.40 mmol). The solution was then cooled to 0° C. before 4-chloro-2-methylbenzoyl chloride (I55) (1.456 g, 7.70 mmol) in Dichloromethane (DCM) (5 mL) was added dropwise. The solution was stirred, under argon, for 30 minutes before the solvent was evaporated in vacuo. The remaining residue was then dissolved in DCM (40 mL) and the solution was washed with water (20 mL), a saturated solution of sodium bicarbonate (20 mL) and brine (20 mL). The organic phase was then dried over anhydrous sodium sulphate, and the solid sodium sulphate was then filtered off. The solvent was then evaporated in vacuo, and the remaining solid was stirred in hexane, at 55° C., for 30 minutes. The solid was then filtered off and the remaining solid was further purified by flash chromatography (Biotage SP4, 40S cartridge) with a gradient of 0-10% MeOH in DCM. TLC confirmed product location and the solvent from the combined fractions was evaporated in vacuo to yield the product in 0.798 g.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH2:4][CH2:3]1.Cl.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[O:14]=[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][N:8]1[CH:5]1[CH2:6][CH2:7][CH:2]([N:16]2[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=3)=[O:22])[CH2:17]2)[CH2:3][CH2:4]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(n2ccccc2=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(n3ccccc3=O)CC2)C1

Procedure:
A solution of 1-(4-oxo-cyclohexyl)-1H-pyridin-2-one (as prepared in the previous step, 150 mg, 0.79 mmol) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide HCl salt (as prepared in Example 2 Step C, 400 mg, 1.18 mmol) in DCM (10 mL) was treated with TEA (340 μL, 2.40 mmol) for 10 min followed by NaBH(OAc)3 (Aldrich, 510 mg, 2.40 mmol) for another 4 hours at room temperature. The reaction was quenched with saturated sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted 3 times with a chloroform/IPA “cocktail” (˜3:1, v/v). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was then purified by a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford two title compounds as white solids: a less polar isomer, and a more polar isomer.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([F:16])[C:13]=1[O:14][CH3:15])[C:8]([OH:10])=O)(=O)C.Cl.[CH3:18][O:19][C:20]([C:22]1([NH2:31])[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1)=[O:21].C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:18][O:19][C:20]([C:22]1([NH:31][C:8](=[O:10])[C:7]2[CH:6]=[C:5]([OH:4])[C:13]([O:14][CH3:15])=[C:12]([F:16])[CH:11]=2)[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1)=[O:21]
Reactant: COc1c(F)cc(C(=O)O)cc1OC(C)=O
Reactant: COC(=O)C1(N)Cc2ccccc2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)C1(NC(=O)c2cc(O)c(OC)c(F)c2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound of step 3 (120 mg, 0.526 mmol) was reacted with 2-amino-indane-2-carboxylic acid methyl ester hydrochloride in analogy to step 1 of example 15. The obtained product was dissolved in methanol (0.77 ml), potassium carbonate (2 mg) was added, and the mixture was stirred at room temperature for 30 min. The solvent was evaporated, the residue was partitioned between EA and a saturated sodium chloride solution, and the aqueous phase extracted with EA. The combined organic extracts were dried over sodium sulfate, filtered and evaporated to dryness to give 60 mg of the title compound.
Reaction SMILES: COCC([NH:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@@H:16]2[O:36][C@H:35]([CH2:37][O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@@H:26]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@@H:17]2[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:9]([NH:46]C(=O)COC)[N:8]=1)=O.C[O-].[Na+]>CO>[NH2:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@@H:16]2[O:36][C@H:35]([CH2:37][O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@@H:26]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@@H:17]2[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:9]([NH2:46])[N:8]=1
Reactant: COCC(=O)Nc1nc(NC(=O)COC)c2ncn([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1nc(N)c2ncn([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2n1
Temperature: 61 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
The protected 2,6-di(methoxyacetamido)purine (IV) (1.55 kg, 2.20 mol) was dissolved in methanol (3.6 L) with stirring and warmed to 46°-48° C. A solution of sodium methoxide (30 g, 95%, 0.55 mol, in 250 mL methanol) was added and the solution was warmed to 61° C. The reaction was completed in about 1 hour (tlc) at which time the product started to precipitate. The mixture was allowed to cool to 30° C. and then refrigerated overnight. The product was collected, washed with ice-cold methanol (800 mL) and air-dried to give the title compound (V) 823 g (68%), mp 60°-62° C.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[C-:18]#[N:19].[K+]>C(O)C>[C:18]([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)#[N:19]
Reactant: [C-]#N
Reactant: COc1ccc(-c2ccc(CCCl)cc2)cc1
Agent: [K+]
Solvent: CCO
Product: COc1ccc(-c2ccc(CCC#N)cc2)cc1
Yield: 52 %

Procedure:
4-[2-Cyanoethyl]-4'-methoxy-biphenyl was prepared from 4-[2-chloroethyl]-4'-methoxy-biphenyl (see Example A) by boiling with potassium cyanide in aqueous ethanol for 78 hours. Yield: 52% of theory; m.p. 105°-107° C.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=[O:4].[BH4-].[Na+].[CH3:10][OH:11]>>[OH:4][CH:3]1[O:5][C@H:2]([CH2:10][OH:11])[C@@H:3]([OH:4])[C@H:10]([OH:11])[C@H:2]1[OH:5]
Reactant: O=C(O)C(F)(F)F
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 2 h

Procedure:
The solution was diluted with MeOH (2.7 mL, total volume: 3.2 mL) and the pH value was adjusted to 1 by addition of trifluoroacetic acid. An aqueous solution of HAuCl4 (314 μL, 0.025M) was added. Then, 1N aqueous solution of NaBH4 (157 μL) was added in several portions with rapid shaking. The black suspension formed was shaken for an additional 2 h and the methanolic layer was separated by decantation[2]. The black solid was dissolved in water (700 μL) and purified by centrifugal filtering (AMICON MW 10000, 30 min, 14000 rpm). The process was repeated twice, until the nanoparticles were free of salts and starting materials. The residue in the AMICON filter was dissolved in 500 μL of water and lyophilised to afford 1.0 mg of BMIX I nanoparticles. TEM: average diameter 1.80 nm, 201 gold atoms, 71 chains, MW=63300.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH:9]2[C:12]([OH:14])=O)=[CH:4][CH:3]=1.[CH2:15]([N:17]1[CH:21]=[C:20]([CH2:22][NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[CH:19]=[N:18]1)[CH3:16]>>[CH2:15]([N:17]1[CH:21]=[C:20]([CH2:22][N:23]([C:24]2[CH:25]=[CH:26][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:29]=2)[C:12]([CH:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([CH3:1])[CH:11]=3)[CH2:6][CH2:7][CH2:8]2)=[O:14])[CH:19]=[N:18]1)[CH3:16]
Reactant: CCn1cc(CNc2ccc(C(C)C)cc2)cn1
Reactant: Cc1ccc2c(c1)C(C(=O)O)CCC2
Product: CCn1cc(CN(C(=O)C2CCCc3ccc(C)cc32)c2ccc(C(C)C)cc2)cn1
Yield: 64.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 4 using 7-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.29 g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) as starting materials, N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-7-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.41 g) was obtained. melting point: 110-112° C.
Reaction SMILES: FC1C=C([N+]([O-])=O)C=CC=1OC1[C:6]2[S:13][C:12]([S:14]([CH3:16])=[O:15])=[CH:11][C:7]=2N=CN=1.[F:24][C:25]1[CH:26]=[C:27]([NH:43][C:44]([NH:46][C:47](=[O:55])[CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[S:45])[CH:28]=[CH:29][C:30]=1[O:31][C:32]1C2SC(SC)=CC=2[N:35]=[CH:36][N:37]=1>>[F:24][C:25]1[CH:26]=[C:27]([NH:43][C:44]([NH:46][C:47](=[O:55])[CH2:48][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)=[S:45])[CH:28]=[CH:29][C:30]=1[O:31][C:32]1[C:7]2[CH:11]=[C:12]([S:14]([CH3:16])=[O:15])[S:13][C:6]=2[N:35]=[CH:36][N:37]=1
Reactant: CSc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Reactant: CS(=O)c1cc2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Product: CS(=O)c1cc2c(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)ncnc2s1
Yield: 36 %

Procedure:
Starting from the compound 285 and following the procedure described above for the synthesis of compound 283 (scheme 64, step 4, example 225), title compound 286 was obtained in 36% yield as an off-white solid. 1H NMR (DMSO-d6) δ (ppm): 12.45(s, 1H), 11.83(s, 1H), 8.80(s, 1H), 8.13(s, 1H), 7.93(dd, 1H, J1=2.3 Hz, J2=10.9 Hz), 7.55 (t, 1H, J=8.6 Hz), 7.48 (m, 1H), 7.34-7.31(m, 4H), 7.28-7.25(m, 1H), 3.81(s, 2H), 3.08(s, 3H). MS (m/z): 501.0(M+H) (found).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH:6]2[CH2:5][NH:4][CH2:3]1.C(N(CC)CC)C.[CH:24]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>ClCCl>[CH:24]1([C:30]([N:4]2[CH2:3][C:2](=[O:1])[N:7]3[CH2:8][CH2:9][O:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[CH:6]3[CH2:5]2)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C1CNCC2c3ccccc3OCCN12
Reactant: O=C(Cl)C1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CCCCC1)N1CC(=O)N2CCOc3ccccc3C2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Oxo-1,2,3,6,7,12b-hexahydropyrazino[1,2-d][1,4]benzoxazepine (0.9 g) and triethylamine (1 g) were dissolved in dichloromethane (20 ml), cooled in ice and cyclohexanoyl chloride (0.7 g, 1.1 equiv.) added. The mixture was stirred at room temperature for 3 h, then washed with dilute aqueous hydrochloric acid, followed by dilute aqueous ammonia solution. Evaporation of the dichloromethane gave an oil which was purified by column chromatography (SiO2 /chloroform) and crystallised from ether/40°-60° petroleum ether to give white crystals of the title compound m.p. 92°-3°;
Reaction SMILES: [CH2:1]([CH:8]([C:12](=[O:19])C1CNCCO1)[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC(=O)C(CC1C=CC=CC=1)C(O)=O.[CH2:35]([O:42][NH2:43])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[OH-].[Na+]>O.CO>[CH2:35]([O:42][NH:43][C:12]([CH:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([OH:11])=[O:10])=[O:19])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(O)C(Cc1ccccc1)C(=O)C1CNCCO1
Reactant: NOCc1ccccc1
Agent: COC(=O)C(Cc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(Cc1ccccc1)C(=O)NOCc1ccccc1

Procedure:
In a manner analogous to that described for α-benzyltetrahydro-β-oxo-4H-1,4-oxazinepropionic acid, benzylmalonic acid monomethyl ester was amidated with O-benzylhydroxylamine and the resulting product [MS: 314 (M+H)+ ] was saponified with 1N sodium hydroxide solution in a 9:1 mixture of methanol and water to the corresponding acid. Recrystallization of the crude product from methanol/methylene chloride/ether yielded α-[(benzyloxy)carbamoyl]hydrocinnamic acid of melting point 147°.
Reaction SMILES: O1CCOCC1.Cl.[NH2:8][OH:9].[OH-].[Na+].C[O:13][C:14](=O)[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[CH:19][CH:18]=1>O.CO>[C:27]1([S:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([CH:16]=[CH:15][C:14]([NH:8][OH:9])=[O:13])=[CH:18][CH:19]=2)(=[O:26])=[O:25])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)C=Cc1ccc(NS(=O)(=O)c2ccccc2)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: O=C(C=Cc1ccc(NS(=O)(=O)c2ccccc2)cc1)NO
Temperature: 25 °C
Reaction time: 24 h
Yield: 31 %

Procedure:
To a mixture, consisting of dioxane (25 ml), methanol (3 ml), and water (1 ml), hydroxylamine hydrochloride (0.834 g, 12 mmol) and NaOH (0.960 g, 24 mmol) followed by 3-(4-benzenesulfonylamino-phenyl)-acrylic acid methyl ester (74) (1.735 g, 4.1 mmol)) were added. The resulting mixture was vigorously stirred at ambient temperature for 24 hours and evaporated under reduced pressure. The residue was mixed with warm (50° C.) water and filtered. The aqueous solution was acidified with hydrochloric acid to pH 4 and filtered. The precipitate was washed with water (2×10 ml), ethyl acetate (10 ml), and crystallised from acetonitrile (15 ml) to give title compound as a yellow solid (0.405 g, 31%). M.p. 189–191° C. 1H NMR (DMSO-d6, HMDSO) δ: 6.30 (d, 1H, J=15.8 Hz); 7.12 (d, 2H, J=8.6 Hz); 7.32 (d, 1H, J=15.8 Hz); 7.45 (d, 2H, J=8.4 Hz); 7.48–7.86 (6H, m); 9.01 (s, 1H); 10.56 (s, 1H); 10.72 (s, 1H). HPLC analysis on Zorbax SB—C18 column: impurities 1.8% (column size 4.6×150 mm; mobile phase acetonitrile—0.1% H3PO4, gradient from 30:70 to 100:0; sample concentration 1.0 mg/ml; detector UV 220 nm). Anal. Calcd for C15H14N2O4S, %: C, 56.59; H, 4.43; N, 8.80; S, 10.07. Found, %: C, 56.03; H, 4.24; N, 8.66; S, 10.02.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][NH2:14].[C:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)(=[O:17])[CH3:16].Cl>ClCCl.C(N(CC)CC)C.O>[C:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:14][CH2:13][CH2:12][O:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[O:23])=[CH:20][CH:19]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: NCCOc1ccc2ccccc2c1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(C(=O)NCCOc2ccc3ccccc3c2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 53.9 %

Procedure:
A stirred mixture of 2-(2-naphthalenyloxy)ethanamine (4.9 g) in dichloromethane (25 mL) and triethylamine (5 mL) was chilled to 0° C. and treated with the acid chloride prepared from 4-acetyl benzoic acid (4.3 g) and then the mixture was stirred at room temperature for 10 minutes. The mixture was diluted with water and acidified with excess 2N hydrochloric acid, extracted with dichloromethane and the organic layer was washed in turn with sodium bicarbonate solution and saturated sodium chloride solution. The organic layer was dried (Na2SO4), filtered, and evaporated to give crude material which was purified by HPLC (ethyl acetate-dichloromethane; 1:9) and crystallized from ethyl acetate to provide 4.7 g of 4-acetyl-N-[2-(2-naphthalenyloxy)ethyl]benzamide as a colorless solid, mp 131°-132° C.
Reaction SMILES: ClC(OCC(C)C)=O.[CH2:9]([N:11]([CH2:18][CH3:19])[CH2:12][C:13]#[C:14][C:15]([OH:17])=O)[CH3:10].CN1CCOCC1.[NH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[CH:33][C:32]([C:38]#[N:39])=[C:31]2[NH:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([Br:47])[CH:42]=1>O1CCCC1.N1C=CC=CC=1>[Br:47][C:43]1[CH:42]=[C:41]([NH:40][C:31]2[C:30]3[C:35](=[CH:36][CH:37]=[C:28]([NH:27][C:15](=[O:17])[C:14]#[C:13][CH2:12][N:11]([CH2:9][CH3:10])[CH2:18][CH3:19])[CH:29]=3)[N:34]=[CH:33][C:32]=2[C:38]#[N:39])[CH:46]=[CH:45][CH:44]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: CCN(CC)CC#CC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: c1ccncc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCN(CC)CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.6 %

Procedure:
Isobutyl chloroformate (0.261 g, 1.91 mmol) was dropwise added into an ice cold solution of 4-diethylamino-2-butynoic acid (0.456 g, 2.94 mmol) and N-methylmorpholine (0.294 g, 2.94 mmol) in 50 mL of tetrahydrofuran under N2. After stirring for 30 min, a solution of 0.5 g (1.47 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 3 mL of pyridine was added dropwise and the mixture was stirred at 0° C. for 2 hr. The reaction was quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer was concentrated and purified by thin-layer chromatography eluted with 15% methanol in ethyl acetate. The product was collected, and dried in vacuo to give 0.2 g (28.5%) of pale greenish yellow solid; ESMS m/z 476.2, 478.2 (M+H+); mp 133-135° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6](Cl)=[O:7])#[N:2].O[NH:17][C:18](=[NH:38])[C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][N:23]=[C:24]2[CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C(N(CC)CC)C>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:7][N:17]=[C:18]([C:19]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:20]=3[CH:21]=[CH:22][N:23]=[C:24]4[CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[N:38]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])#[N:2]
Reactant: CC(C)Oc1ccc(C(=O)Cl)cc1C#N
Reactant: CC(C)(C)OC(=O)CCc1nccc2c(C(=N)NO)cccc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)OC(C)(C)C)nccc34)no2)cc1C#N
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 3-cyano-4-[(1-methylethyl)oxy]benzoyl chloride (WO2008128951; 89 mg, 0.4 mmol) in dry DMF (1.5 ml) was added to a stirred solution of 1,1-dimethylethyl 3-{5-[(hydroxyamino)(imino)methyl]-1-isoquinolinyl}propanoate (D36; 114 mg, 0.360 mmol) and triethylamine (0.084 mL, 0.600 mmol) in dry DMF (1.5 ml) at 0° and the mixture was allowed to warm to room temperature and stirred for 45 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([CH:9]=1)[CH:7]=O.[NH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([CH:9]=1)[CH2:7][NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=Cc1cc(Br)ccc1CCc1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(NCc2cc(Br)ccc2CCc2ccccc2)cc1
Reaction time: 18 h
Yield: 89.1 %

Procedure:
5-Bromo-2-(phenethyl)benzaldehyde (1.27 g) and methyl 4-aminobenzoate (0.66 g) were heated together at 110° C. for 30 minutes and for a further 30 minutes under vacuum. The mixture was dissolved in toluene, evaporated to dryness, dissolved in ethanol (15 ml). Sodium borohydride (0.33 g) was added, the mixture stirred for 18 hours, the solvent evaporated and the residue mixed with acetic acid and partitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered and evaporated. The resulting residue was purified by MPLC, eluting with dichloromethane, to give methyl 4-[N-(5-bromo-2-(phenethyl)benzyl)amino]benzoate (1.65 g).
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)([CH3:9])[C:3]#[C:4][C:5]([O:7][CH3:8])=[O:6].C(C1(C2C=CC(OC)=C(C=2)[CH:28]=[O:29])CC1)#N>>[CH3:9][C:2]([C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[C:14]([CH:15]=1)[CH:28]=[O:29])([CH3:1])[C:3]#[C:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C#CC(C)(C)c1ccc(OC)cc1
Reactant: COc1ccc(C2(C#N)CC2)cc1C=O
Product: COC(=O)C#CC(C)(C)c1ccc(OC)c(C=O)c1

Procedure:
This compound was prepared from Compound 58 in the same manner of Compound 2.