Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.[C:9]1(B(O)O)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:17]1[C:18]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: Brc1ccccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccccc1-c1cccc2ccccc12
Yield: 82.9 %

Procedure:
Under an atmosphere of argon, 2-bromoiodobenzene (7.0 g, 25 mmole), naphthaleneboronic acid (4.0 g, 23 mmole) and tetrakis(triphenylphosphine)palladium(0) (0.5 g, 0.43 mmole, 1.7% Pd) were dissolved into toluene (50 ml). To the obtained solution, an aqueous solution of sodium carbonate (7.3 g, 69 mmole, 3 eq/35 ml) was added. The resultant solution was heated under refluxing for 10 hours and left standing for one night. The formed organic layer was separated, washed with a saturated aqueous solution of sodium chloride (50 ml) and dried with anhydrous magnesium sulfate. Then, the solvent was removed by distillation and a yellow oil was obtained. The obtained oil was purified by the column chromatography (silica gel/hexane, hexane+3% dichloromethane and hexane+10% dichloromethane, successively) and white needle crystals (5.4 g, 83%) were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].CCCCCC.C(OCC)(=O)C>C(OCC)(=O)C>[CH2:28]([O:27][C:25](=[O:26])[NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([F:18])[CH:11]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OCc2ccccc2)c(F)c1)OCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 34.9 g 1-benzyloxy-2-fluoro-4-nitro-benzene (WO03064413) (MW: 247.28, 141 mmol) and 340 mg platinium 5% on activated carbon in 350 ml ethyl acetate was stirred under hydrogen at rt and normal pressure. The reaction was monitored by HPLC and was complete after twenty hours. The catalyst was filtered over a glass fiber filter, and the filtrate evaporated under reduced pressure to dryness. The oily residue was dissolved in 500 ml acetone and treated with 250 ml of a saturated solution of sodium bicarbonate and 17.5 g of sodium bicarbonate (MW: 84.01, 208 mmol). The mixture was cooled to 5° C. and treated drop wise with 26.08 g of benzyl chloroformate (MW: 170.59, 152 mmol). The reaction was allowed to stirred at room temperature for two hours and monitored by TLC (hexane/ethyl acetate 3:1). The acetone was evaporated, the residue diluted with 500 ml water, and the solid filtered off. The crystals were washed with 500 ml water and dried. Yield: 48.05 g, 95.8%. MS: 352.5 (M+H)+, 350.8, (M−H)−. Method ESI+, ESI−.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[F:14][C:15]1[C:20]([F:21])=[C:19](F)[N:18]=[CH:17][N:16]=1>O1CCCC1>[O:7]([C:19]1[C:20]([F:21])=[C:15]([F:14])[N:16]=[CH:17][N:18]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: Fc1ncnc(F)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Fc1ncnc(Oc2ccccc2)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
At 0° C., a solution of 42.4 g (0.45 mol) of phenol and 50.4 g (0.45 mol) of potassium tert-butoxide in 400 ml of tetrahydrofuran is added dropwise to a solution of 80 g (0.6 mol) of 4,5,6-trifluoropyrimidine in 1 l of tetrahydrofuran. After the addition, the reaction mixture is stirred at 0° C. for 30 minutes and then poured onto water and extracted with ethyl acetate. The organic phase is dried over sodium sulphate and concentrated under reduced pressure and the residue is stirred with low-boiling petroleum ether. 63.8 g (68.1% of theory) of 4-phenoxy-5,6-difluoropyrimidine of melting point 65-66° C. are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[C:3]=1[F:12].S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[C:3]([F:12])[C:4]=1[F:11]
Reactant: O=C(O)c1ccc(O)c(F)c1F
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)c(F)c1F

Procedure:
4-hydroxy-2,3-difluoro-benzoic acid (2.0 g, 11.5 mmol) was dissolved in MeOH (20 mL) and catalytic quantity of sulfuric acid was added. The mixture was refluxed overnight, after that the solvent was evaporated under reduced pressure; the crude was dissolved in DCM and washed with saturated NaHCO3. The organic phase was dried and evaporated under reduced pressure, and the product was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([OH:19])=O.C(Cl)(=O)C(Cl)=O.C[N:27](C)C=O.[NH4+].[OH-]>ClCCl.O1CCCC1>[CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([NH2:27])=[O:19]
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(C(F)(F)F)cn1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1c(C(N)=O)cnn1-c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxylic acid (2.07 g) described in Reference Example 8 in dichloromethane (50 ml) were added oxalyl chloride (2.62 ml) and N,N-dimethylformamide (catalytic amount) at room temperature, stirred at room temperature for 2 hours, and then the solvent and an excess amount of oxalyl chloride were evaporated. To the obtained reaction mixture was added tetrahydrofuran (50 ml), then 28% ammonia aqueous solution (30 ml) was added thereto under ice-cooling, and stirred at room temperature overnight. After completion of the reaction, the organic solvent was evaporated in vacuo, then 1 N aqueous solution of sodium hydroxide was added thereto, the precipitated solid was collected by filtration, and dried at 60° C. under air blow to give the titled compound (1.8 g) as a pale yellow solid. MS (ESI) m/z: 271 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[CH:6]=[CH:7][C:8](O)=[O:9])([O-])=O>C(O)C.[Pd]>[NH:1]1[C:4]2[C:5](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:7][C:8]1=[O:9]
Reactant: O=C(O)C=Cc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: O=C1CCc2ccccc2N1

Procedure:
A solution of 25 g of o-nitrocinnamic acid in 250 ml of ethanol was shaken with 2.5 g of 10% palladium on carbon under hydrogen at a pressure of 3 atmospheres. When the theoretical amount of hydrogen had been absorbed the catalyst was filtered off, washed with hot ethanol and the filtrate evaporated under reduced pressure to give 3,4-dihydrocarbosytril, m.p. 168°-169° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1.[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]([CH2:14][Br:15])=[CH:12][CH:13]=1
Reactant: Cc1ccc(-c2ccccc2F)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccccc1-c1ccc(CBr)cc1

Procedure:
A mixture of 2-fluoro-4′-methylbiphenyl (8.70 g), N-bromosuccinimide (8.32 g), 2,2′-azobisisobutyronitrile (0.10 g) and carbon tetrachloride (150 ml) is refluxed by heating for five hours. The reaction solution is washed with water. The residue, which is obtained by concentrating the organic layer, is purified using silica gel column chromatography (eluate: hexane/ethyl acetate=9/1) and thus, preliminarily purified 2-fluoro-4′-bromomethylbiphenyl is obtained. Furthermore, crystallization using hexane produced 2-fluoro-4′-bromomethylbiphenyl (4.93 g). 1H-NMR (CDCl3, δ): 4.55 (2H, s), 7.13-7.23 (2H, m), 7.33 (1H, m), 7.43 (1H, m), 7.47 (2H, d, J=8.1 Hz), 7.54 (2H, d, J=8.1 Hz).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[N+:8]([CH3:11])([O-:10])=[O:9].C(N)C1C=CC=CC=1.C(O)(=O)C>CC(O)C>[N+:8]([CH:11]=[CH:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)([O-:10])=[O:9]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccsc1
Solvent: CC(C)O
Solvent: NCc1ccccc1
Solvent: CC(=O)O
Product: O=[N+]([O-])C=Cc1ccsc1
Yield: 56 %

Procedure:
When R2 is H the thiophene-3-carboxaldehyde (1 eq) was dissolved in 2-propanol and treated with nitromethane (1 eq), benzylamine (0.065 eq) and glacial acetic acid (0.13 eq). After 60 minutes of refluxing, the mixture was cooled, the solid was collected and washed with ice-cold ether to afford the product (56%); mp 94.5°-96.5° C.
Reaction SMILES: C1(C)C(C([O-])=S)=CC=CC=1O.[Na+].CN(C)P(N(C)C)(N(C)C)=O.[CH:24]([C:26]1[C:41]([OH:42])=[CH:40][CH:39]=[CH:38][C:27]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:25].[OH-].[Na+]>C1C=CC=CC=1>[CH:24]([C:26]1[C:41]([OH:42])=[CH:40][CH:39]=[CH:38][C:27]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:25]
Reactant: CCOC(=O)CCCCOc1cccc(O)c1C=O
Agent: Cc1c(O)cccc1C([O-])=S
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=Cc1c(O)cccc1OCCCCC(=O)O

Procedure:
Ethyl 5-(2-formyl-3-methoxphenoxy)pentanoate (Example 4) (2.0 g, 0.00704 M), sodium thiocresolate (2.06 g, 0.014 M), hexamethylphosphoramide (2.48 ml, 0.014 M) and benzene (10 ml) were placed in a round bottom flask and refluxed for 18 hours. The reaction mixture, containing ethyl 5-(2-formyl-3-hydroxyphenoxy)pentanoate, was then cooled and poured into 2 N sodium hydroxide solution (20 ml). The organic layer was removed, diluted with ether (20 ml), then extracted with 2 N sodium hydroxide solution (2×20 ml). The aqueous layers were combined and extracted with dichloromethane (2×20 ml). The organic layer was discarded and the aqueous layer acidified with concentrated hydrochloric acid. The resulting precipitate was filtered, washed with water and dried in a desiccator over phosphorus pentoxide to give 5-(2-formyl-3-hydroxyphenoxy)pentanoic acid, m.p. 98°-99° C. from ethyl acetate/petrol.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]([C:13]2[CH:14]=[CH:15][C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=2)[CH2:5][CH2:4]1.ClC1C=C([C@H]2C3C(=CC=CC=3)C(=O)CC2)C=CC=1Cl>>[CH3:1][NH:2][C@H:3]1[C:8]2[C:7](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:6]([C:13]2[CH:14]=[CH:15][C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=2)[CH2:5][CH2:4]1
Reactant: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: O=C1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Product: CN[C@@H]1CC[C@H](c2ccc(Cl)c(Cl)c2)c2ccccc21

Procedure:
The (4S)-4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone final product afforded by the process of this invention is a valuable intermediate that can be used to synthesize the antidepressant agent known as sertraline or cis-(1S)(4S)-N-methyl4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine by methods disclosed in the previously discussed prior art. More specifically, (4S)-4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone is first converted to (4S)-N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidine]methanamine and then finally to the desired cis-(1S)(4S)-N-methyl4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine by the known methods of the prior art process, as earlier described in U.S. Pat. No. 4,536,518 (Aug. 20, 1985). In the present instance, the optically-active ketone, viz., (4S)-4-(3,4-dichlorophenyl)-1(2H)-naphthalenone, is first reductively aminated to give chiral cis-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine and the latter product is then separated by chromatographic means to ultimately yield the desired final medicinal product which is sertraline.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH:7]([C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)=[O:8].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.O.C(O)C>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[C:12]1[CH:13]=[CH:14][C:9]([CH:7]=[O:8])=[CH:10][CH:11]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Brc1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=Cc1ccc(-c2nccs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
A mixture of 2-bromothiazole (0.9 ml, 10 mmols), 4-formylphenylboronic acid (1.65 g, 11 mmols), sodium carbonate (2.65 g, 25 mmols), toluene (150 ml), ethanol (30 ml) and water (30 ml) was stirred in an argon atmosphere at room temperature for 30 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.58 mg, 0.5 mmols) was added thereto and heated under reflux for 15 hours. The reaction-mixture was cooled, poured into water, and extracted with ethyl acetate. The extract was washed with water and brine, then dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography, and then recrystallized from ethyl acetate/hexane to give 4-(2-thiazolyl)benzaldehyde (1.4 g, 74%).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH:7]([C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)=[O:8].C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>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.CCOC(C)=O.O.CCCCCC.C(O)C>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[C:12]1[CH:13]=[CH:14][C:9]([CH:7]=[O:8])=[CH:10][CH:11]=1
Reactant: Brc1nccs1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CCO
Product: O=Cc1ccc(-c2nccs2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.9 %

Procedure:
2-Bromothiazole (0.538 ml, 6.06 mmol), 4-formylphenylboronic acid (1.0 g, 6.67 mmol), and Na2CO3 (1.61 g) were suspended in the mixed solution of toluene (25 ml), ethanol (5 ml), and H2O (5 ml). The mixture was stirred at room temperature for 15 minutes under an argon gas atmosphere. After reducing the pressure inside of the reaction container by using a vacuum line, the mixture was degassed by introducing Ar gas and this procedure was repeated twice. After that, tetrakis(triphenylphosphine)palladium (0.701 g, 0.606 mmol) was added, and the mixture was stirred for 15 hours by heating under reflux. The end point of the reaction was confirmed on TLC (EtOAc:n-hexane=1:4), and the mixture was cooled to room temperature. H2O (50 ml) and EtOAc (50 ml) were added and the mixture was stirred for 15 minutes. Black insoluble matter was removed by filtration with Celite and the filtrate was separated by the step of extraction/separation. The organic layer was washed with saturated brine (50 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified on silica gel column chromatography (EtOAc:hexane=1:3) to obtain the title compound (985 mg) as an opaque white solid.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].P(=O)([O-])[O-].C([Li])CCC.[C:17]1([CH2:23][C:24](OC)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1.CCCCCC.C(O)(=O)C>[O:25]=[C:24]([CH2:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COC(=O)Cc1ccccc1
Reactant: COP(C)(=O)OC
Agent: O=[PH]([O-])[O-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COP(=O)(CC(=O)Cc1ccccc1)OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 29 %

Procedure:
A solution of 6.2 g (50 mmoles) dimethyl methylphosphonate (Aldrich) in 125 ml dry tetrahydrofuran was cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution was added 21 ml of 2.37 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 18 minutes at such a rate that the reaction temperature never rose above -65°. After an additional 5 minutes stirring at -78°, 7.5 g (50.0 mmole) methyl phenylacetate was added dropwise at a rate that kept the reaction temperature less than -70° (20 minutes). After 3.5 hours at -78°, the reaction mixture was allowed to warm to ambient temperature, neutralized with 6 ml acetic acid and rotary evaporated (water aspirator) to a white gel. The gelatinous material was taken up in 75 ml water, the aqueous phase extracted with 100 ml portions of chloroform (3×), the combined organic extracts were backwashed (50 cc H2O), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled, b.p. 134°-5° (<0.1 mm) to give 3.5 g (29% dimethyl 2-oxo-3-phenylpropyl-phosphonate (2a).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[O:5][C:6]2=[O:11].[CH3:13]I>CN(C)C=O>[CH3:13][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[O:5][C:6]2=[O:11]
Reactant: CI
Reactant: O=C1OC(=O)c2c(O)cccc21
Solvent: CN(C)C=O
Product: COc1cccc2c1C(=O)OC2=O
Reaction time: 48 h
Yield: 46.8 %

Procedure:
To a solution of 4-hydroxy-isobenzofuran-1,3-dione (195 mg, 1.2 mmol) in anhydrous N,N-dimethylformamide (4 ml) under nitrogen was added minutes and then methyl iodide (0.37 ml, 6.0 mmol) was added. The reaction was stirred for 48 h. and then quenched with saturated ammonium chloride. The mixture was concentrated in vacuo, diluted in ethyl acetate (20 ml) and the organic phase washed with 1N hydrochloric acid (5 ml) and brine (3×5 ml). The organic layer was dried (MgSO4) and concentrated in vacuo. To the crude solid was added methanol causing a precipitate to form. The flask was cooled in an ice bath for 2 h. and the solid filtered off, washed with methanol and dried in vacuo which afforded 0.1 g (47%) of 4-methoxy-isobenzofuran-1,3-dione as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH3:11])[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC.O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(Br)ccc1CO
Reaction time: 4 h
Yield: 80.4 %

Procedure:
To a solution of 4-bromo-2-methylbenzoic acid (1.0 g, 4.65 mmol) in Et2O (15 mL) was added lithium aluminiumhydride (370 mg, 10.23 mmol) and the mixture was stirred for 4 hours. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (4×100 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (silica, petrol ether/EtOAc) to give the title compound as a colorless gum (752 mg, 80%). 1H NMR (CDCl3, 400 MHz) δ 7.35-7.30 (2H, m), 7.24 (1H, m), 4.65 (2H, s), 2.32 (3H, s).
Reaction SMILES: [S:1]([Cl:5])(=O)(=[O:3])[OH:2].[CH3:6][C:7]1[CH:8]=[C:9]([O:14][CH3:15])[CH:10]=[C:11]([CH3:13])[CH:12]=1.O>ClCCl>[CH3:15][O:14][C:9]1[CH:10]=[C:11]([CH3:13])[C:12]([S:1]([Cl:5])(=[O:3])=[O:2])=[C:7]([CH3:6])[CH:8]=1
Reactant: O=S(=O)(O)Cl
Reactant: COc1cc(C)cc(C)c1
Solvent: O
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
Chlorosulfuric acid (2.3 eq) in dichloromethane (0.5 ml/mmol) was slowly added dropwise over 10 min to a solution of 3,5-dimethylanisol (1 eq) in dichloromethane (1 ml/mmol) cooled to 0° C. The reaction mixture was stirred for a further 10 min and then slowly dropped into iced water (5 eq relative to chlorosulfuric acid). The phases were separated and the aqueous phase extracted with dichloromethane (repeatedly, UV analysis). The combined organic phases were dried (Na2SO4) and concentrated to small volume under vacuum. Yield: 82%
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:11](OCC)(=[O:18])[CH2:12][C:13](OCC)=[O:14].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:3]1([C:2]2[N:10]=[C:13]([OH:14])[CH:12]=[C:11]([OH:18])[N:9]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N=C(N)c1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Oc1cc(O)nc(-c2ccccc2)n1
Temperature: 25 °C
Yield: 73.1 %

Procedure:
A solution of benzamidine hydrochloride (44.41 g; 0.284 mol), diethyl malonate (45.51 g; 0.284 mol) and DBU (86.40 g; 0.568 mol) in DMF (250 mL) was heated at 85° C. for 20 h. After cooling to room temperature, the flask was placed in a refrigerator overnight. The crystalline product was collected by filtration and washed with DMF (300 mL), then dissolved in water (ca. 110 mL) and acidified with 2 M HCl (110 mL) with water added, as necessary, to maintain a suspension. The product was collected by filtration, washed with water (100 mL) and dried to a constant weight under high vacuum giving 39.09 g (73%) of an off-white solid. LC (method B) tR=6.2 min; 1H NMR (200 MHz, DMSO-d6) δ 8.08 (m, 2H), 7.54 (m, 3H), 5.34 (s, 1H); ESIMS 189.0 ([M+H]+).
Reaction SMILES: [Na].Cl.[C:3]([NH2:11])(=[NH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12](OCC)(=[O:19])[CH2:13][C:14](OCC)=[O:15]>C(O)C>[C:4]1([C:3]2[N:11]=[C:14]([OH:15])[CH:13]=[C:12]([OH:19])[N:10]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N=C(N)c1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Oc1cc(O)nc(-c2ccccc2)n1
Yield: 44836.7 %

Procedure:
To ethanol (200 mL) was added sodium (7.9 g, 34 mmol). After dissolution, benzamidine hydrochloride (20.0 g, 0.128 mmol) and diethyl malonate (20 mL, 132 mmol) were added. The reaction was heated for 4 hours and the solvent was removed in vacuo. Hydrochloric acid was added and a precipitate formed. The solid was collected and dried in a vacuum oven to give 10.8 g (45%) of 2-phenyl-4,6-dihydroxypyrimidine.
Reaction SMILES: C(O)(=O)C.OO.[NH2:7][C:8]1[N:12]=[C:11]([SH:13])[NH:10][N:9]=1.[OH-].[Na+]>O>[NH2:7][C:8]1[N:12]=[C:11]([S:13][S:13][C:11]2[NH:10][N:9]=[C:8]([NH2:7])[N:12]=2)[NH:10][N:9]=1
Reactant: Nc1n[nH]c(S)n1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Nc1n[nH]c(SSc2nc(N)n[nH]2)n1
Reaction time: 1.25 h

Procedure:
Glacial acetic acid (2.60 g) was added to 4.89 g of a 15% aqueous hydrogen peroxide solution. The resulting solution was added over 20 minutes to a solution prepared from 5.01 g 3-amino-1,2,4-triazole-5-thiol, 65.2 g of water and 4.33 g 40% NaOH. The reaction mixture was kept between 18 C-22 C by use of an ice bath during the addition. After stirring for 75 min, the product was filtered, washed with water and then dried under vacuum at 70 C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[N:7]2)([O-])=O.O.NN>CO.[Ni]>[N:10]1[C:11]2[C:6](=[CH:5][C:4]([NH2:1])=[CH:13][CH:12]=2)[N:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc2nccnc2c1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1ccc2nccnc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a solution of 6-nitroquinoxaline (17.0 g, 0.097 mol) in MeOH (500 mL) was added hydrazine hydrate (19.4 g, 0.39 mol) and Raney Ni (2.0 g). The mixture was stirred at room temperature for 1 h. The mixture was then filtered, and the filtrate was concentrated under reduce pressure to give quinoxalin-6-amine as a yellow solid (14.0 g, yield 99%). ESI MS: m/z 146.1 [M+H]+.