Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[NH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[CH2:6][NH3+:7].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>CC(N(C)C)=O>[NH2:2][C:3]1[CH:4]=[C:5]([CH2:6][NH:7][S:23]([CH3:22])(=[O:25])=[O:24])[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(C[NH3+])cc1N
Agent: [Cl-]
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CNS(C)(=O)=O)cc1N
Reaction time: 1 h

Procedure:
3 g of 3-amino4-methoxycarbonylbenzylammonium chloride (18.8 mmol) are dissolved in 50 ml of dimethylacetamide, triethylamine (2.8 g, 27.7 mmol) is added, and the mixture is subsequently reacted at 0-10° C. with a solution of methanesulfonyl chloride (1.6 g, 13.8 mmol) in 20 ml of dimethylacetamide. After 1 h, the solvent is removed in vacuo and the residue is worked up by extraction with water/dichloromethane. The combined organic extracts are washed with water and dried (Na2SO4) and then evaporated on a rotary evaporator. The residue obtained is crystallized from water, whereupon 3 g (84%) of methyl 2-amino-4-methanesulfonylaminomethylbenzoate of melting point 120-121° C. are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7](N)=[C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=1)([O-:3])=[O:2].N([O-])=O.[Na+].[ClH:22]>CN(C)C=O>[C:12]1([O:11][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[CH:9][C:7]=2[Cl:22])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1Oc1ccccc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Cl)c(Oc2ccccc2)c1
Yield: 60 %

Procedure:
4-Nitro-2-phenoxyaniline was dissolved in N,N-dimethylformamide and hydrochloric acid and diazotized with sodium nitrite. The resulting slurry was added to a solution of cuprous chloride in hydrochloric acid to give a 60-70% yield of 2-chloro-5-nitrophenyl phenyl ether, b2-3 180°-90°, m. 73°-5°. This was converted to N-(4-nitro-2-phenoxyphenyl)-pyrrolidine, m. ca. 90°, by refluxing with excess pyrrolidine in 94-97% yield. Catalytic reduction followed by treatment with hydrochloric acid then gave N-(4-amino-2-phenoxyphenyl)pyrrolidine hydrochloride, which was slurried with water and diazotized conventionally with sodium nitrite. The clarified diazonium chloride solution was finally treated with hexafluoroarsenic acid to precipitate the desired 3-phenoxy-4-(1-pyrrolidinyl)benzenediazonium hexafluoroarsenate, m. 138°-140° (dec.), E395 36,3000) in 96% of the yield calculated from the amount of N-(4-nitro-2-phenoxyphenyl)pyrrolidine charged to the catalytic reduction preceding the diazotization.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][NH:5][C:6]1[C:11]([Cl:12])=[C:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH:23]([CH3:25])[CH3:24])[CH:17]=2)(=[O:15])=[O:14])[C:9]([Cl:26])=[C:8]([F:27])[N:7]=1.[Li+].[OH-].Cl>C1COCC1>[Cl:12][C:11]1[C:6]([NH:5][CH2:4][C:3]([OH:28])=[O:2])=[N:7][C:8]([F:27])=[C:9]([Cl:26])[C:10]=1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH:23]([CH3:25])[CH3:24])[CH:17]=1)(=[O:14])=[O:15]
Reactant: COC(=O)CNc1nc(F)c(Cl)c(S(=O)(=O)c2ccc(O)c(C(C)C)c2)c1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)c1cc(S(=O)(=O)c2c(Cl)c(F)nc(NCC(=O)O)c2Cl)ccc1O
Yield: 88.5 %

Procedure:
To a solution of the title compound of example 53 (90 mg, 0.20 mmol) in THF (2 mL) was added 1N LiOH aqueous solution (0.6 mL). After an hour, the mixture was acidified with 1N HCl and the product was extracted with EtOAc (50 mL). The organic extract was washed with brine (20 mL), dried (Na2SO4), filtered and concentrated and dried in vacuo to afford 77.4 mg (89%) of the title compound as a white solid.
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[CH2:6][CH2:7][NH2:8].C(O[CH:16](OCC)[CH2:17][O:18][C:19]1[CH:23]=[N:22][S:21][N:20]=1)C.O>Cl.C(O)CCC>[ClH:1].[S:21]1[N:22]=[CH:23][C:19]([O:18][CH2:17][CH:16]2[C:9]3[C:5](=[CH:4][C:3]([OH:2])=[C:11]([OH:12])[CH:10]=3)[CH2:6][CH2:7][NH:8]2)=[N:20]1
Reactant: CCOC(COc1cnsn1)OCC
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: Oc1cc2c(cc1O)C(COc1cnsn1)NCC2

Procedure:
A mixture of 3,4-dihydroxyphenethylamine hydrochloride (1.62 g), (1,2,5-thiadiazol-3-yl)oxyacetaldehyde diethyl acetal (2.6 g), n-butanol (50 ml), water (25 ml) and 10% hydrochloric acid (3 drops) was refluxed for 15 hours. After the reaction, n-butanol was distilled off from the reaction mixture under reduced pressure. The residue was dissolved in water, and the solution was washed twice with chloroform and once with ether and then the aqueous layer was concentrated to give colourless crystals of 1-(1,2,5-thiadiazol-3-yl)oxymethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (2g). The product was recrystallized from aqueous methanol to give colourless crystals like cotton, mp 252°C (dec.).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([O:23][C:24]2[N:32]=[CH:31][N:30]=[C:29]3[C:25]=2[N:26]=[C:27](I)[N:28]3[CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].COCCOC.[Cl:46][C:47]1[CH:56]=[C:55]2[C:50]([C:51](B3OC(C)(C)C(C)(C)O3)=[CH:52][CH:53]=[N:54]2)=[CH:49][CH:48]=1.[OH-].[Ba+2].[OH-].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([O:23][C:24]2[N:32]=[CH:31][N:30]=[C:29]3[C:25]=2[N:26]=[C:27]([C:51]2[C:50]4[C:55](=[CH:56][C:47]([Cl:46])=[CH:48][CH:49]=4)[N:54]=[CH:53][CH:52]=2)[N:28]3[CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ncnc3c2nc(I)n3C2CCCCO2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CC1(C)OB(c2ccnc3cc(Cl)ccc23)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ncnc3c2nc(-c2ccnc4cc(Cl)ccc24)n3C2CCCCO2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 90 °C

Procedure:
To a solution of 6-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-8-iodo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (258.4 mg, 0.0003752 mol) in 1,2-Dimethoxyethane (3.0 mL, 0.029 mol) was added 7-chloroquinoline-4-boronic acid pinacol ester (0.158 g, 0.000546 mol), barium hydroxide (0.228 g, 0.00133 mol), water (0.5 mL, 0.03 mol) and Tetrakis(triphenylphosphine)palladium(0) (0.02 g, 0.00002 mol), and the mixture was heated at 90° C. overnight. The reaction was cooled, quenched by addition of water and the mixture was extracted with DCM (3×), washed with water, brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (0 to 30% EtOAc/hexanes) to obtain 180 mg (66.2%) mg. Reference: Cammidge, A. N.; Crepy, K. V. L. Tetrahedron, 2004, 60, 4377-4386.
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:22][Si:23]([CH3:33])([CH3:32])[C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]O>C(#N)C.C(OCC)C>[CH3:22][Si:23]([CH3:33])([CH3:32])[C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][Br:1]
Reactant: BrBr
Reactant: C[Si](C)(C)c1ccccc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Product: C[Si](C)(C)c1ccccc1CBr
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Bromine (1.07 g, 6.7 mmol) was slowly added to a cooled solution of triphenylphosphine (1.83 g, 7.0 mmol) in acetonitrile to maintain a temperature less than or equal to 5° C. A solution of 2-(trimethylsilyl)benzyl alcohol in acetonitrile (10 mL) was slowly introduced and the resulting mixture was allowed to warm to room temperature and stir. Thin layer chromatography after 20 min indicated no starting material remained. The mixture was diluted with diethyl ether (50 mL) and washed with H2O (two-times with 20 mL), dried (MgSO4) and concentrated under vacuum to yield an opaque oil, 2.5 g. Purification by column chromatography (100 g SiO2 eluting with hexanes) provided the product of Step C as a clear, colorless oil, 1.12 g; (69%); IR (neat): 2954, 1250, 1216, 1110 cm-1 ; 1H NMR (CDCl3); δ7.5-7.3 (m,4H), 4.6 (s,2H), 0.4 (s,9H).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:20]1[CH2:23][CH2:22][CH2:21]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.C(N(CC)CC)C.CN(C)C=O>[N:20]1([C:16](=[O:18])[CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:14][CH2:13]2)[CH2:23][CH2:22][CH2:21]1
Reactant: C1CNC1
Reactant: O=C(O)CN1CCN(C(=O)c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CN1CCN(C(=O)c2ccccc2)CC1)N1CCC1
Temperature: 25 °C
Reaction time: 66 h
Yield: 31.6 %

Procedure:
Methanol (300 ml) and water (50 ml) were added to (4-benzoylpiperazin-1-yl)acetic acid ethyl ester (8.19 g), and lithium hydroxide (1.34 g) was added thereto with cooling in an ice water bath, followed by stirring for 10 minutes. The reaction mixture was brought to room temperature, followed by stirring for 24 hours. After adding 1N hydrochloric acid (55.9 ml), the reaction mixture was concentrated under reduced pressure, and ethanol (200 ml) was added to the resultant residue. The precipitated insoluble matter was removed by filtration through celite. The filtrate was concentrated under reduced pressure to give a crude product of (4-benzoylpiperazin-1-yl)acetic acid (8.6 g) as a white solid. N,N-Dimethylformamide (80 ml) was added to (4-benzoylpiperazin-1-yl)acetic acid (2 g) at room temperature under a nitrogen atmosphere, and azetidine hydrochloride (1.51 g), triethylamine (4.49 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.09 g) and 1-hydroxybenzotriazole (2.18 g) were added in this order, followed by stirring at room temperature for 66 hours. Ethyl acetate (100 ml) and a saturated aqueous solution of sodium hydrogencarbonate (50 ml) were added to the reaction mixture, which was partitioned. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 ml), water (50 ml) and brine (50 ml) in this order, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate). The residue obtained by concentrating the fractions containing the target compound under reduced pressure was suspended by the addition of diethyl ether (10 ml). The solid was collected by filtration, and dried under aeration to give the title compound (731.5 mg) as white powder.
Reaction SMILES: B.O1CCCC1.[Br:7][C:8]1[S:12][C:11]2[CH:13]=[C:14]([C:17](O)=[O:18])[CH:15]=[CH:16][C:10]=2[C:9]=1[CH3:20].B.CO>O1CCCC1>[Br:7][C:8]1[S:12][C:11]2[CH:13]=[C:14]([CH2:17][OH:18])[CH:15]=[CH:16][C:10]=2[C:9]=1[CH3:20]
Reactant: Cc1c(Br)sc2cc(C(=O)O)ccc12
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(Br)sc2cc(CO)ccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.1 %

Procedure:
A solution of borane-tetrahydrofuran complex (150 ml. of 1 M solution in THF) was added dropwise with stirring to a solution of 2-bromo-3-methylbenzo[b]-thiophene-6-carboxylic acid (7.32 g.) in dry tetrahydrofuran (120 ml.) at 0° C. under an atmosphere of dry nitrogen. The solution was stirred at room temperature for 4 hours and then the excess borane was decomposed by the cautious addition of methanol. The solution was evaporated and the residue was dissolved in ether. The solution was washed with water, dried (Na2SO4) and evaporated to give a solid which was crystallized from ether/petrol (b.p. 40°-60°) to give 2-bromo-6-hydroxymethyl-3-methylbenzo[b]thiophene (5.70 g.), m.p. 91° C.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3](=[O:9])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH2:5].[Cl:11][C:12]1[CH:13]=[C:14]([NH:19][CH:20]([C:22](O)=[O:23])[CH3:21])[CH:15]=[CH:16][C:17]=1[Cl:18]>>[CH3:1][N:2]([CH3:10])[C:3](=[O:9])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH:5][C:22](=[O:23])[CH:20]([CH3:21])[NH:19][C:14]1[CH:15]=[CH:16][C:17]([Cl:18])=[C:12]([Cl:11])[CH:13]=1
Reactant: CC(C)[C@H](N)C(=O)N(C)C
Reactant: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Product: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)N[C@H](C(=O)N(C)C)C(C)C

Procedure:
Following General Procedure D and using valine N,N-dimethyl amide (from Example D above) and N-(3,4-dichlorophenyl)-D,L-alanine (from Example A above), the title compound was prepared as a solid (mp=145-160° C.).
Reaction SMILES: C[C:2]([C:15]1[CH:20]=[CH:19][C:18](OCC2OC2)=[CH:17][CH:16]=1)([C:4]1[CH:9]=[CH:8][C:7]([O:10]CC2OC2)=[CH:6]C=1)C.CCC.C(OCC1OC1)C1[O:32]C1>>[CH:17]1[CH:16]=[C:15]([C:2]2[CH:4]=[CH:9][CH:8]=[C:7]([OH:10])[CH:6]=2)[C:20]([OH:32])=[CH:19][CH:18]=1
Reactant: C(OCC1CO1)C1CO1
Reactant: CC(C)(c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1
Solvent: CCC
Product: Oc1cccc(-c2ccccc2O)c1
Temperature: 110 °C

Procedure:
To a suitable reactor were added 885 parts of the diglycidyl ether of Bisphenol A having an epoxide equivalent weight of 186 and 615 parts of 2,2'-bis(3,5-dibromo, 4-hydroxyphenyl) propane. Heat and agitation were applied raising the temperature to 230° F. When solution of the diphenol in the glycidyl ether was obtained, heating was discontinued and 30 parts of a nonionic surfactant, made by polymerizing ethylene oxide with a condensate of propylene oxide with propylene glycol (plutonic F98, obtained from Wyandotte Chemicals Corp.) were added. Deionized water, 1530 parts, was slowly added dropping the temperature to 120° F. Triphenyl phosphine, 4.15 parts, was added and heat was applied raising the temperature to 200° F. The temperature was held at 200° F., while the resinous reactants went from a taffy slurry to finely divided beads. After heating for 2 hours and 30 minutes at 200° F., the acid value of the reactants was reduced tp 0, indicating no free phenolic groups. Heating was discontinued and 2000 parts of cold water were added. The water was drawn off and the resin was washed with an additional 2000 parts of water. The resin produce was then placed on foil sheets and dried at 212° F. for 2 days. The produce had an epoxide equivalent weight of 606, a Durran's melting point of 86° C., and at 40% solids in diethylene glycol monobutyl ether, a Gardner color of 1-2 and a Gardner-Holdt viscosity at 25° C. of B-C.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:28]#[N:29])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:30][CH2:31][C:32]([OH:34])=[O:33].C[O-].[Na+]>>[C:28]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:7])[N:9]=1)#[N:29]
Reactant: CCCCOC(=O)c1nc(C#N)c2cc(Oc3ccc(OC)cc3)ccc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(Oc2ccc3c(O)c(C(=O)NCC(=O)O)nc(C#N)c3c2)cc1
Yield: 65.4 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-(4-methoxy-phenoxy)-isoquinoline-3-carboxylic acid butyl ester (110 mg, 0.28 mmol) and glycine (275 mg, 2.82 mmol) in a solution of sodium methoxide (0.5 M in methanol; 5.7 mL) was refluxed overnight. Reaction mixture was concentrated and dissolved in water (50 mL). It was washed with ethyl acetate (10 mL). Aqueous layer was acidified by 1 N HCl to pH=3-4 and extracted with ethyl acetate. Organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated. Crude product was triturated with methanol (3 mL) and solid was collected and dried to give the title compound (72 mg). MS-(+)-ion: M+1=394.32.
Reaction SMILES: [Na].[C:2]([O:10]CC)(=O)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:13][C:14]1[N:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17].Cl>O.C(O)C>[CH2:7]([O:6][C:4]([C:3]1[C:2](=[O:10])[NH:13][C:14]2[C:15]([C:16]=1[NH2:17])=[CH:18][CH:19]=[CH:20][N:21]=2)=[O:5])[CH3:8]
Reactant: N#Cc1cccnc1N
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(N)c2cccnc2[nH]c1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4.14 g. (0.18 g. atom) of sodium in 100 ml. of ethanol was added 28.8 g. (0.18 mole) of diethyl malonate. After stirring at room temperature for 5 minutes, 7.14 g. (0.06 mole) of 2-aminonicotinonitrile was added and the mixture was heated under reflux for 6 hours. The mixture was cooled and was diluted with 100 ml. of water and was acidified with conc. hydrochloric acid. On cooling, a precipitate was formed which was collected and was triturated with 1000 ml. of boiling ethanol. The mixture was filtered and the filtrate was cooled in ice to precipitate 2.9 g. of product, m.p. 264°-267° C. dec.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.Cl[CH2:23][C:24]([O:26][CH3:27])=[O:25]>CC(C)=O>[CH3:27][O:26][C:24]([CH2:23][O:11][C:10](=[O:12])[CH2:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=1)=[O:25]
Reactant: COC(=O)CCl
Reactant: O=C(O)COc1ccc([N+](=O)[O-])cc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)COC(=O)COc1ccc([N+](=O)[O-])cc1
Yield: 90.7 %

Procedure:
To a mixture of (4-nitrophenoxy) acetic acid 22 (150 g, 761.4 mmol) and triethylamine (85 g, 840 mmol) in acetone (750 ml) was added methyl chloroacetate (91.6 g, 844 mmol) drop wise and stirred under reflux for 8 hours. Solids were filtered off and poured onto cold 5% sodium bicarbonate solution (4 L). Crude 44 was filtered, dried and recrystallised from chloroform:hexane (1:6) to get pure 44 (186 g, 90.8%) as a white powder with an m.p. between 88-90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([OH:14])[CH3:13])[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1-c1ccccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1cc(Cl)c2cccnc2c1-c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 1-[5-chloro-8-(2-fluorophenyl)quinolin-7-yl]ethanone (0.032 g, 0.11 mmol) in methanol (0.3 mL) was added sodium tetrahydroborate (0.0040 g, 0.11 mmol). The reaction was stirred at room temperature for 1 hour, quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and then concentrated to dryness under reduced pressure. The resulting residue was used in next step (33 mg, 100%). LCMS calculated for C17H14ClFNO(M+H)+: m/z=302.1; found: 302.0.
Reaction SMILES: ClC1C=CC(C2OC3C=CC=CC=3C=2)=CC=1.C(Cl)(=O)C1C=CC(OC)=CC=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[O:36][C:37]3[CH:53]=[CH:52][CH:51]=[CH:50][C:38]=3[C:39]=2[C:40](=[O:49])[C:41]2[CH:46]=[CH:45][C:44]([O:47]C)=[CH:43][CH:42]=2)=[CH:31][CH:30]=1.Cl.N1C=CC=CC=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[O:36][C:37]3[CH:53]=[CH:52][CH:51]=[CH:50][C:38]=3[C:39]=2[C:40](=[O:49])[C:41]2[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=2)=[CH:31][CH:30]=1
Reactant: COc1ccc(C(=O)c2c(-c3ccc(Cl)cc3)oc3ccccc23)cc1
Agent: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: Clc1ccc(-c2cc3ccccc3o2)cc1
Solvent: c1ccncc1
Product: O=C(c1ccc(O)cc1)c1c(-c2ccc(Cl)cc2)oc2ccccc12

Procedure:
When 2-(4'-chlorophenyl)benzofuran was acylated with anisoyl chloride was described in the procedure of Example 10 and the resulting 2-(4'-chlorophenyl)-3-(4'-methoxybenzoyl)benzofuran was demethylated with pyridine hydrochloride as previously described, 2-(4'-chlorophenyl)-3-(4'-hydroxybenzoyl)benzofuran was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24]C)[CH:5]=[CH:6][C:7]=1[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9].B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:17]2[C:18]([OH:24])=[CH:19][CH:20]=[C:21]([F:23])[CH:22]=2)[CH:5]=[CH:6][C:7]=1[S:8]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)(=[O:10])=[O:9]
Reactant: COc1ccc(F)cc1-c1ccc(S(=O)(=O)c2ccccc2)c(F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)c1ccc(-c2cc(F)ccc2O)cc1F
Temperature: 0 °C
Reaction time: 18 h

Procedure:
The product from step ii) (0.44 g) was treated with 1.0M boron tribromide in DCM (3.7 ml) in DCM (10 ml) and stirred at 0° C. for 18 h. The mixture was quenched in ice water and extracted with EtOAc; dried (MgSO4) and concentrated in vacuo to give the sub-title compound, yield 0.39 g.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.C([NH:20][C:21]1[C:26]([NH2:27])=[C:25]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:24]=[C:23]([C:36]2[N:37]([CH3:41])[CH:38]=[CH:39][N:40]=2)[N:22]=1)C1C=CC=CC=1>CN(C=O)C>[NH2:20][C:21]1[C:26]2[NH:27][C:6](=[O:7])[N:28]([CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:25]=2[CH:24]=[C:23]([C:36]2[N:37]([CH3:41])[CH:38]=[CH:39][N:40]=2)[N:22]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cn1ccnc1-c1cc(NCc2ccccc2)c(N)c(NCc2ccccc2)n1
Solvent: CN(C)C=O
Product: Cn1ccnc1-c1cc2c([nH]c(=O)n2Cc2ccccc2)c(N)n1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
CDI (184 mg, 1.13 mmol) was added to a solution of the N*2*,N*4*-Dibenzyl-6-(1-methyl-1H-imidazol-2-yl)-pyridine-2,3,4-triamine (218 mg, 0.567 mmol) in DMF (3 ml) in a ReactiVial. The vial was flushed with nitrogen then sealed and heated in an aluminium block at 60° C. (block temperature). The dark brown solution was left to stir at this temperature for 16 hrs. The solution was concentrated under high-vacuum then dissolved in concentrated sulphuric acid (5 ml). The brown solution was left to stir at room temperature for 30 minutes then poured onto crushed ice (˜20 ml). A saturated aqueous solution of potassium carbonate was added drop-wise until pH˜8. The aqueous solution was decanted from the solid that had precipitated out during neutralisation, then extracted with EtOAc (2×50 ml). The combined organics were dried (MgSO4) and evaporated to a yellow solid (106 mg).
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([CH3:11])[N+:7]([O-:10])=[CH:8][CH:9]=1)([O-])=O.C([Cl:15])(=O)C>C(OCC)(=O)C.C(Cl)(Cl)Cl>[Cl:15][C:4]1[CH:9]=[CH:8][N+:7]([O-:10])=[C:6]([CH3:11])[CH:5]=1
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1cc(Cl)cc[n+]1[O-]
Temperature: -12.5 °C
Reaction time: 0.25 h
Yield: 16.8 %

Procedure:
4-nitro-2-picoline N-oxide (20 g, 130 mmol) was added to acetyl chloride (120 ml, 1688 mmol) in a nitrogen atmosphere at −25° C. The mixture was stirred at −30 to 5° C. for 4 hours and 15 minutes. After the reaction mixture was diluted with ethyl acetate (about 150 ml) and chloroform (about 100 ml), the mixture was concentrated. The residue was purified by silica gel column chromatography (NH silica gel: 200 g, elution solvent: heptane, heptane/ethyl acetate=75/25, 50/50, 25/75, ethyl acetate, ethyl acetate/methanol=20/1) to obtain the title compound (3.14 g) as brown oil. Simultaneously, a crude product (about 17 g) was obtained. The crude product thus obtained was further purified by silica gel column chromatography (NH silica gel: 300 g, elution solvent: heptane, heptane/ethyl acetate=75/25, 40/60, 25/75, ethyl acetate) to obtain the title compound (5.39 g) separately as brown oil.