Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].Cl.[C:14]([O:18][C:19](=[O:22])[CH2:20][NH2:21])([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C>C(O)C>[C:14]([O:18][C:19](=[O:22])[CH2:20][NH:21][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)CN
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)CNc1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 74.7 %

Procedure:
To a solution of 4-chloro-3-nitrobenzonitrile (33.87 g) and glycine tert-butyl ester hydrochloride (55.98 g) in ethanol (400 ml) was added triethylamine (77.6 ml), and the mixture was stirred at room temperature for 15 hours and then at 50° C. for 3 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was extracted with ethyl acetate. The extract was washed with 10% aqueous citric acid solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The obtained residue was washed with diisopropyl ether and collected by filtration to give the title compound (38.419 g).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][NH:6][C:7](=[O:11])[O:8][CH2:9][CH3:10])C.Cl.O>C1COCC1>[O:3]=[CH:4][CH2:5][NH:6][C:7](=[O:11])[O:8][CH2:9][CH3:10]
Reactant: CCOC(=O)NCC(OCC)OCC
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)NCC=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 28.3 %

Procedure:
A solution of ethyl (2,2-diethoxyethyl)carbamate (2.0 g, 0.0097 mol.)) in 5 mL of THF at 0° C. was added HCl (10 mL, 2.0 eq) and then H2O (0.17 mL). The solution was then stirred for 4 h at 0° C. the solvent was evaporated at room temperature and solid NaHCO3 was added, filtration and concentration to give after silica gel chromatography ethyl (2-oxoethyl)carbamate as a colorless oil (0.36 g, 28%). 1HNMR (400 MHz), CDCl3: δ 1.19 (t, J=7.2 Hz, 3H); 4.05-4.10 (m, 4H); 5.44 (sbr, 1H); 9.60 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[CH:22]1([C:25]2[O:26][CH:27]=[C:28]([CH2:30][NH2:31])[N:29]=2)[CH2:24][CH2:23]1>>[CH:22]1([C:25]2[O:26][CH:27]=[C:28]([CH2:30][NH:31][C:14]([C:12]3[CH:11]=[CH:10][C:9]([O:17][CH2:18][CH:19]4[CH2:21][CH2:20]4)=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[N:13]=3)=[O:16])[N:29]=2)[CH2:24][CH2:23]1
Reactant: NCc1coc(C2CC2)n1
Reactant: O=C(O)c1ccc(OCC2CC2)c(-c2ccc(Cl)cc2)n1
Product: O=C(NCc1coc(C2CC2)n1)c1ccc(OCC2CC2)c(-c2ccc(Cl)cc2)n1

Procedure:
The title compound was synthesized in analogy to Example 41, using 6-(4-Chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid (example AW) and 2-cyclopropyl-4-oxazolmethanamine (example BH) as starting materials, LC-MS (UV peak area/ESI) 97.6%, 424.0 (M+H)+.
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][N:6]=1.Br[CH2:13][CH2:14][CH2:15][Cl:16].O>CS(C)=O>[NH2:4][C:5]1[C:10]([O:11][CH2:13][CH2:14][CH2:15][Cl:16])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: ClCCCBr
Reactant: Nc1ncccc1O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ncccc1OCCCCl
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 48.7 ml (200 mmol) of a 4.1M sodium methoxide solution in 100 ml of dimethyl sulfoxide, 22.03 g (200 mmol) of 2-amino-3-hydroxypyridine was added at room temperature, followed by stirring at 80° C. for 10 minutes to dissolve the latter. After the reaction mixture was cooled, the methanol was distilled off. To this mixture, 19.8 ml (200 mmol) of 1-bromo-3-chloropropane was added at 0° C., followed by stirring for 30 minutes. The reaction mixture was poured into water (400 ml), extracted with chloroform, washed with2N aqueous sodium hydroxide and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4→ethyl acetate). The obtained crude crystal was washed with diethyl ether-n-hexane to yield 20.48 g (54.8%, white powder) of the desired product.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[S:4]1[CH:8]=[CH:7][N:6]=[C:5]1[CH:9]=O>>[CH2:1]([NH:3][CH2:9][C:5]1[S:4][CH:8]=[CH:7][N:6]=1)[CH3:2]
Reactant: O=Cc1nccs1
Reactant: CCN
Product: CCNCc1nccs1

Procedure:
prepared by reaction of ethylamine with thiazole-2-carbaldehyde
Reaction SMILES: [CH3:1][C:2]1[O:7][C:6]([C:8]([O:10]CC)=[O:9])=[CH:5][C:4](=[O:13])[CH:3]=1.[O-]CC.[Na+].[Na].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C.O>[O:13]=[C:4]1[CH:3]=[C:2]([CH:1]=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5]1
Reactant: CCOC(=O)c1cc(=O)cc(C)o1
Reactant: O=Cc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(=O)cc(C=Cc2ccccc2)o1

Procedure:
A solution of this ester (3.6 g) in ethanol (100 ml) was added to a solution of sodium ethoxide prepared by dissolving sodium (1.0 g) in ethanol (100 ml). Benzaldehyde (2.45 ml) was added and the stirred mixture was heated at 80°-90° C. for an hour, cooled, diluted with water (800 ml) and washed with ether. The aqueous phase was acidified with 2 M hydrochloric acid and extracted with ethyl acetate. The extract was dried and evaporated and the solid residue was recrystallised from dimethylformamide-water to give the title product (mp 227°-228° C. with decomposition).
Reaction SMILES: [N:1]([C:4]1[CH:20]=[CH:19][C:7]([C:8]([NH:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].O=[C:22]([CH2:29][CH2:30][CH3:31])[CH2:23][C:24]([O:26]CC)=[O:25].[O-]CC.[Na+].O>C(O)C>[N:13]1([CH2:12][CH2:11][NH:10][C:8]([C:7]2[CH:6]=[CH:5][C:4]([N:1]3[C:22]([CH2:29][CH2:30][CH3:31])=[C:23]([C:24]([OH:26])=[O:25])[N:3]=[N:2]3)=[CH:20][CH:19]=2)=[O:9])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: [N-]=[N+]=Nc1ccc(C(=O)NCCN2CCCCC2)cc1
Reactant: CCCC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCc1c(C(=O)O)nnn1-c1ccc(C(=O)NCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
4-Azido-N-(2-piperidin-1-ylethyl)benzamide obtained in Example 62a) and ethyl 3-oxohexanoate (1.08 ml, 6.44 mmol, 1.25 eq.) were dissolved in ethanol (20 ml), sodium ethoxide (487 mg, 6.44 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 30 min, and then at 60° C. for 13 hr. Water (40 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was washed twice with ethyl acetate-hexane (2:1, 50 ml). The aqueous layer was neutralized (pH 6-7) with 6N hydrochloric acid and concentrated. The residue was dissolved in isobutanol, THF and ethyl acetate, dried over anhydrous sodium sulfate and concentrated, and ethyl acetate and THF were added to the residue. The precipitate was collected by filtration, washed with ethyl acetate and dried to give the title compound as a pale-brown powder (purity 90%, 2.05 g, 4.78 mmol, 92.9%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:23]([CH3:33])=[C:22]([C:34](O)=[O:35])[C:17]=3[N:18]=[C:19]([CH3:21])[N:20]=2)[CH2:3][CH2:2]1.[NH2:37][CH:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:23]([CH3:33])=[C:22]([C:34]([NH:37][CH:38]4[CH2:39][CH2:40][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:42][CH2:43]4)=[O:35])[C:17]=3[N:18]=[C:19]([CH3:21])[N:20]=2)[CH2:2][CH2:3]1
Reactant: COc1cc(OCC2CC2)c(-c2nc(C)nc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: COc1cc(OCC2CC2)c(-c2nc(C)nc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2,6-dimethyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c17) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as colorless foam.
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:22])[NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[S:23]1[CH2:29][C:27](=[O:28])[N:26]([CH2:30][C:31]([OH:33])=[O:32])[C:24]1=[S:25].[Cl-].[NH4+].N>C(O)C>[CH:1]1([NH:7][C:8](=[O:22])[NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15](=[C:29]3[S:23][C:24](=[S:25])[N:26]([CH2:30][C:31]([OH:33])=[O:32])[C:27]3=[O:28])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)NC2CCCCC2)n1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=O)NC2CCCCC2)n1

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared using 1 g of ethyl 2-(3-cyclohexylureido)thiazol-4-ylglyoxylate, 0.58 g of rhodanine-3-acetic acid, 0.3 g of ammonium chloride, 0.3 ml of 28% v/v aqueous ammonia and 10 ml of ethanol. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([C:25]2[NH:26][CH:27]=[CH:28][CH:29]=2)[C:14]2[C:15](=[O:24])[NH:16][C:17]3[C:22]=2[C:21]=1[C:20]([F:23])=[CH:19][CH:18]=3)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([C:25]2[NH:26][CH:27]=[CH:28][CH:29]=2)[C:14]2[C:15](=[O:24])[NH:16][C:17]3[C:22]=2[C:21]=1[C:20]([F:23])=[CH:19][CH:18]=3
Reactant: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc[nH]2)c2c3c(ccc(F)c13)NC2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCOc1cc(-c2ccc[nH]2)c2c3c(ccc(F)c13)NC2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of [2-[6-fluoro-2-oxo-3-(1H-pyrrol-2-yl)-1,2-dihydro-benzo[cd]indol-5-yloxy]-ethyl]-carbamic acid tert-butyl ester (from Example 18 above) (16.5 mg, 0.2 mmol) in CH2Cl2 (1 mL) was added trifluoroacetic acid (0.5 mL) at room temperature. After stirring at room temperature for 30 minutes, the reaction mixture was quenched with 1.0 N NaOH (2.0 mL) and extracted with ethyl acetate (3×30 mL). The combined organic extracts were successively washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 5-(2-amino-ethoxy)-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 11.2 mg, 89.7%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14][N:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:11][N:10]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:9][CH2:8]1)=[O:5])[CH3:2].[CH2:31]([N:35]([CH2:40][CH:41]1[CH2:43][O:42]1)[S:36]([CH3:39])(=[O:38])=[O:37])[CH2:32][CH2:33][CH3:34]>C(O)C>[CH2:31]([N:35]([S:36]([CH3:39])(=[O:38])=[O:37])[CH2:40][CH:41]([OH:42])[CH2:43][N:16]1[CH2:15][CH2:14][N:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:11][N:10]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:9][CH2:8][N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:18][CH2:17]1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCCN(CC1CO1)S(C)(=O)=O
Reactant: CCOC(=O)CN1CCNCCN(CC(=O)OCC)CCN(CC(=O)OCC)CC1
Solvent: CCO
Product: CCCCN(CC(O)CN1CCN(CC(=O)OCC)CCN(CC(=O)OCC)CCN(CC(=O)OCC)CC1)S(C)(=O)=O

Procedure:
200 ml of absolute ethanol is poured over 8.61 g (20 mmol) of N,N',N"-tris-(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (produced according to DE 36 25 417 A1) in a bomb tube. After 4.15 g (20 mmol) of N-butyl-N-[(2-oxiranyl)-methyl]-methanesulfonic acid amide is added (Example 2a), the bomb tube is closed, flushed with nitrogen, and the resulting reaction mixture is heated for 16 hours to 90° C. After the reaction (TLC control) is completed, the solvent is evaporated in a vacuum and the yellowish, oily residue is chromatographed on silica gel (eluent: chloroform/methanol; methanol: 0-80%).
Reaction SMILES: [P:1]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.II.[O:25]=O>[Fe](Cl)(Cl)Cl>[P:1]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[O:25]
Reactant: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Reactant: O=O
Agent: Cl[Fe](Cl)Cl
Agent: II
Product: O=P(Oc1ccccc1)(Oc1ccccc1)Oc1ccccc1
Reaction time: 2.5 h

Procedure:
To a one-liter, stainless steel Parr autoclave vessel equipped for agitation, heating/cooling, and gas pressurization were charged 710 grams (2.29 moles) of triphenyl phosphite, 1.78 grams (0.0070 mole; 0.31 mole %) of iodine, and 2.34 grams (0.0144 mole; 0.63 mole %) of anhydrous iron (III) chloride. The mixture was heated to 115°-120° C. with efficient agitation and pressurized with oxygen at 55 psig. These conditions were maintained by applying sufficient cooling to control the accompanying exotherm which subsided after about 2.5 hours. The oxygenation was continued until no oxygen pressure drop was observed when the reaction vessel was isolated from the outside pressure line. The total reaction time was 5 hours. When the reaction vessel was vented, there was obtained 747 grams of triphenyl phosphate, an amber liquid that solidified upon cooling to room temperature. Gas chromatography showed the absence of triphenyl phosphite, thus demonstrating that the conversion of the phosphite to the phosphate was quantitative.
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.[C:6]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1Br)([CH3:9])([CH3:8])[CH3:7].C(I)C>C1COCC1>[C:6]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[CH2:1][CH3:2])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1Br
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCI
Product: CCc1cc(C(=O)O)ccc1C(C)(C)C
Reaction time: 0.67 h

Procedure:
A solution of n-butyl lithium (1.6M in hexane, 2.67 mL, 4.27 mmol) was added dropwise to a solution of 4-tert-butyl-3-bromobenzoic acid (500 mg, 1.94 mmol) in THF at −78° C. whilst maintaining the temperature below −70° C. After 40 minutes, ethyl iodide (1.55 mL, 19.4 mmol) was added dropwise whilst maintaining the temperature below −65° C. After one hour at −70° C., the mixture was allowed to attain room temperature and stirred overnight The mixture was quenched by the addition of saturated ammonium chloride solution (30 mL) and extracted with ether (30 mL). The organic fraction was dried over magnesium sulphate and evaporated. Purification was achieved by reverse phase HPLC on a C18 column using a two-solvent gradient elution with (A) water containing formic acid (0.1%) and (B) acetonitrile-water (95:5 v/v) containing formic acid (0.05%) as the eluents, and analysis of the fractions by electrospray mass spectroscopy. This afforded the title compound as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([O:25]CC)=[O:24]>CC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:22][C:23]([OH:25])=[O:24])=[CH:6][C:5]=1[C:11]([F:12])([F:13])[F:14])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1C(F)(F)F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)COc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.6 %

Procedure:
The mixture of 4-nitro-3-trifluoromethylphenol (414 mg, 2.0 mmol), potassium carbonate (910 mg, 6.6 mmol), ethyl bromoacetate (500 mg, 3.0 mmol) and acetone (25 ml) was refluxed for 8 h. After cooling, the mixture was filtered to remove potassium carbonate. The filtrate was concentrated under reduced pressure. To this residue, 10 ml of dioxane and 14 ml 5% sodium hydroxide solution were added. After the mixture was stirred at room temperature overnight, it was acidified with concentrated hydrochloric acid to pH 2, and then extracted three times with ethyl acetate (20 ml each). Organic phases were combined, washed with water and brine, dried over magnesium sulfate, filtered, and then evaporated in vacuo. The residue was separated by column chromatography (eluent: ethyl acetate: EtOH 9:1) to give 35 mg 4-nitro-3-trifluoromethylphenoxyacetic acid as white solid, mp 92-95° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O>C1C=CC=CC=1>[Cl:1][C:2]1[C:11]([CH2:12][Br:13])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(Cl)ccc2cccnc12
Reactant: O=C1CCC(=O)N1Br
Solvent: c1ccccc1
Product: Clc1ccc2cccnc2c1CBr

Procedure:
7-Chloro-8-methylquinoline (1 g.) [Bradford et al., J. Chem. Soc., p. 437 (1947)] is dissolved in 20 ml. of benzene and brominated with one equivalent of N-bromosuccinimide in the presence of catalytic amounts of peroxide. The product, 7-chloro-8-(bromomethyl)quinoline is isolated by evaporation.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([Cl:9])[CH:3]=1.[CH3:10][O-:11].[Na+].Cl>CO.[Cu](I)I>[Cl:9][C:4]1[CH:3]=[C:2]([O:11][CH3:10])[CH:8]=[CH:7][C:5]=1[NH2:6]
Reactant: Nc1ccc(Br)cc1Cl
Reactant: C[O-]
Agent: I[Cu]I
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(N)c(Cl)c1
Yield: 41 %

Procedure:
A mixture of 4-bromo-2-chloro-aniline (25.0 g, 121 mmol), copper iodide (23.1 g, 121 mmol), and a solution of sodium methoxide in methanol (28%, 125 mL) was stirred for 1 h at 100° C. The reaction mixture was poured into a mixture of hydrochloric acid (6 M, 100 mL) and ice, and washed with ethyl acetate. The aqueous phase was basified with aqueous sodium hydroxide (8 M) and extracted with ethyl acetate. The extracts was washed with brine, dried over sodium sulfate, filtrated, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a 30% ethyl acetate/n-hexane gradient mixture to give the title compound as a pale yellow oil (7.90 g, 50.1 mmol, 41%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([N+:15]([O-])=O)[CH:7]=1.[CH3:18][O:19][CH2:20][CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([NH:31][C:32]([C:34]3[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=3)=[O:33])=[CH:28][CH:29]=2)[CH:24]=[C:23]1[CH3:42]>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[N:12]=[C:38]([C:37]3[CH:36]=[CH:35][C:34]([C:32]([NH:31][C:27]4[CH:26]=[C:25]5[C:30](=[CH:29][CH:28]=4)[N:22]([CH2:21][CH2:20][O:19][CH3:18])[C:23]([CH3:42])=[CH:24]5)=[O:33])=[CH:41][CH:40]=3)[NH:15][C:8]=2[CH:7]=1
Reactant: COCCOc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: COCCn1c(C)cc2cc(NC(=O)c3ccc(C=O)cc3)ccc21
Product: COCCOc1ccc2nc(-c3ccc(C(=O)Nc4ccc5c(c4)cc(C)n5CCOC)cc3)[nH]c2c1

Procedure:
Compound 675 was prepared according to the procedure similar to that described in Scheme III from 1-(2-methoxyethoxy-3,4-dinitrobenzene and 4-(1-(2-methoxyethyl)-2-methyl-5-indolylaminocarbonyl)benzaldehyde. [M+H]+ calcd for C29H30N4O4: 499.24; found: 499.06.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH:11]([CH2:13]Cl)[OH:12].[OH-].[Na+].O(C(C)C)C(C)C>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH:11]1[CH2:13][O:12]1
Reactant: OC(CCl)CCc1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Product: Clc1ccc(CCC2CO2)c(Cl)c1

Procedure:
A solution of 87 parts of 2,4-dichloro-α-(chloromethyl)-benzenepropanol in 144 parts of concentrated sodium hydroxide solution and 350 parts of 2,2'-oxybispropane is stirred overnight at room temperature. The product is extracted with 2,2'-oxybispropane. The extract is washed with water, dried, filtered and evaporated. The oily residue is distilled, yielding [2-(2,4-dichlorophenyl)ethyl]oxirane; bp. 90°-98° C. at 0.01 mm. pressure.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C)C=O.[N+:26]([O-:34])([O:28][CH2:29][CH2:30][CH2:31][CH2:32]Br)=[O:27]>ClCCl>[C:4]([O:3][C:1]([NH:8][CH:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[C:18]([O:20][CH2:32][CH2:31][CH2:30][CH2:29][O:28][N+:26]([O-:34])=[O:27])=[O:19])=[O:2])([CH3:5])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: O=[N+]([O-])OCCCCBr
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(Cc1ccc(O)cc1)C(=O)OCCCCO[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of Boc-(L)-tyrosine 5.0 g, 17.77 mmol) in N,N-dimethylformamide (40 ml) cesium carbonate (5.79 g, 17.77 mmol) was added. The reaction was cooled at 0° C. and a solution or 4-bromobutyl nitrate (17.77 mmol) in dichloromethane (20% w/w, 17.06 g) was added drop wise. The reaction was stirred at 0° C. for 20 minutes and then at room temperature for 22 hours. The mixture was poured into a 5% aqueous NaH2PO4 solution and extracted with diethyl ether (40×4 ml), the organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (n-hexane/EtOAc from 9:1 to 1:1 as eluent affording the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:10]=1)[C:5]([OH:7])=[O:6].[C:17](Cl)(=O)C>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[CH:10]=1)[C:5]([O:7][CH3:17])=[O:6]
Reactant: CC(=O)Cl
Reactant: O=C(O)c1cc(Br)cc(SC2CCCC2)c1
Solvent: CO
Product: COC(=O)c1cc(Br)cc(SC2CCCC2)c1

Procedure:
A solution of 3-bromo-5-(cyclopentylthio)benzoic acid (1.49 g, 4.95 mmol) in methanol (40 mL) was treated with acetyl chloride (3.87 mL, 54.4 mmol) at 0° C. The reaction mixture was heated to reflux overnight, and then concentrated under reduced pressure. The residue was purified by flash chromatography (0-20% EtOAc/hexane) to afford the title compound as a colorless oil.
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([OH:6])=O)[CH3:3].[NH:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:6])[CH3:3]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
To 25 ml of a solution of 0.68 g of Boc-Ala-OH in methylene chloride the H-Pro-resin described above was added and 5 ml of a solution of 0.74 g of DCC in methylene chloride was then added to the resulting mixture. The mixture was reacted at room temperature for 2 hours. After washing the resin 6 times with 30 ml of methylene chloride, the resin was added to 25 ml of a methylene chloride solution of 0.68 g of Boc-Ala-OH and 0.55 g of 1-hydroxybenzotriazole. Then, 5 ml of a methylene chloride solution of 0.74 g of DCC was added thereto and the resulting mixture was again reacted in a similar manner (double coupling). The resin was thoroughly washed with methylene chloride to obtain Boc-Ala-Pro-resin.