Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[O:16][C:17]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:25]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[O:16][C:17]3[CH:23]=[CH:22][C:21]([NH:24][C:29]([CH:25]4[CH2:28][CH2:27][CH2:26]4)=[O:30])=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3cc(N)ccc3o2)CC1
Reactant: O=C(Cl)C1CCC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc3cc(NC(=O)C4CCC4)ccc3o2)CC1
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of 4-(5-amino-benzooxazol-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.40 g, 4.21 mmol, 1.0 equiv) in anhydrous DMF (5 mL) was added cyclobutanecarbonyl chloride (0.55 g, 4.63 mmol, 1.1 equiv; commercially available) and diisopropylethylamine (1.03 mL, 1.14 g, 8.84 mmol, 2.1 equiv) and the reaction mixture stirred at rt. After 1 h, water was added (50 mL) and the water phase extracted with dichloromethane (3×50 mL). The combined organic phases were dried over MgSO4, the organic solvent removed under reduced pressure and the crude oil purified with column chromatography on silica eluting with ethyl acetate/heptane (2:1) to afford 1.1 g (64%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.46-1.50 (m, 2H), 1.47 (s, 9H), 1.94-2.02 (m, 2H), 2.10-2.13 (m, 2H), 2.20-2.26 (m, 2H), 2.34-2.47 (m, 2H), 2.95-2.97 (m, 2H), 3.10-3.22 (m, 1H), 3.90 (br s, 1H), 4.05 (br s, 2H), 5.24 (brs, 1H), 7.14 (d, J=8.6 Hz, 1H), 7.28 (brs, 1H), 7.33 (d, J=8.6 Hz, 1H), 7.41 (brs, 1H). 13C NMR (75 MHz, CDCl3): δ 18.05, 25.33, 28.41, 32.30, 40.85, 42.49, 50.45, 79.76, 108.41, 108.54, 113.47, 134.57, 143.38, 145.21, 154.70, 161.76, 173.04. MS (ISP): 413.1 [M−H]−.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Br:19][C:20]1[C:21]([CH:27]=[O:28])=[N:22][CH:23]=[CH:24][C:25]=1[CH3:26].[F:29][C:30]([Si](C)(C)C)([F:32])[F:31]>C1COCC1.C(OCC)(=O)C>[Br:19][C:20]1[C:21]([CH:27]([OH:28])[C:30]([F:32])([F:31])[F:29])=[N:22][CH:23]=[CH:24][C:25]=1[CH3:26]
Reactant: Cc1ccnc(C=O)c1Br
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccnc(C(O)C(F)(F)F)c1Br
Temperature: -15 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
Tetrabutylammonium fluoride (1.0 mol/L) in THF (1.2 mL, 1.20 mmol) was added dropwise to a solution of 3-bromo-4-methyl-pyridine-2-carbaldehyde (150 mg, 0.75 mmol), and (trifluoromethyl)trimethylsilane (2.0 mol/L) in THF (0.49 mL, 0.975 mmol) in THF (10 mL) cooled at −15° C. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (25 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue that was purified by flash chromatography (12 g, Silica, 0-30% ethyl acetate in heptane). Desired fractions were combined and evaporated in vacuo to afford the title compound as a white solid (90 mg, 44%), which was used in the next step without further purification.
Reaction SMILES: CN(P(N(C)C)N(C)C)C.Br[C:12](Br)([F:14])[F:13].[CH3:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)=O.O>COCCOCCOCCOC>[F:13][C:12]([F:14])=[C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH3:16]
Reactant: COc1ccc(C(C)=O)cc1
Reactant: FC(F)(Br)Br
Agent: CN(C)P(N(C)C)N(C)C
Solvent: O
Solvent: COCCOCCOCCOC
Product: COc1ccc(C(C)=C(F)F)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
At between 0° C. and −10° C., 181 g of tris(dimethylamino)phosphine in 75 ml of triglyme were added dropwise to 84 g of dibromodifluoromethane in 50 ml of triglyme. At 0° C., 30 g of 4-methoxyacetophenone dissolved in 125 ml of triglyme were subsequently added dropwise and the mixture was stirred for ½ h at room temperature and for 24 h at 80° C. The mixture was cooled to room temperature, mixed with 200 ml of water and extracted with petroleum ether. The combined organic phases were dried and concentrated. For purification, the crude product was chromatographed over silica gel (petroleum ether/ethyl acetate 5:1), to give the title product as a colourless oil.
Reaction SMILES: [CH:1]1([S:7]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9]([NH:11][S:12]([C:15]1[S:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1)(=[O:14])=[O:13])[CH3:10].C(N(CC)CC)C>CN(C)C=O.C(Cl)(Cl)Cl>[CH:1]1([S:7][N:11]([CH2:9][CH3:10])[S:12]([C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)(=[O:13])=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClSC1CCCCC1
Reactant: CCNS(=O)(=O)c1nc2ccccc2s1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCN(SC1CCCCC1)S(=O)(=O)c1nc2ccccc2s1
Temperature: 0 °C

Procedure:
7.8 grams (0.0517 mole) of cyclohexyl chlorosulfide prepared as in Example 1 is added over a 60-minute period to a stirred solution of 12 grams (0.0495 mole) of N-ethyl benzothiazole-2-sulfonamide, 5.5 grams of triethylamine (0.0495 mole) in 200 ml anhydrous dimethylformamide and 200 ml chloroform. The temperature is maintained between about 15° and 20° C. The reaction mixture is poured into 2 liters of ice water. The solvent layer is well washed, dehydrated with anhydrous sodium sulfate and any remaining solvent is removed by vacuum distillation.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[N:7](C(OC(C)(C)C)=O)[CH2:8][C@@H:9]([O:10][S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C@H:5]2[O:4][CH2:3]1.[H][H]>[Pd].C(O)C>[CH3:18][C:17]1[CH:19]=[CH:20][C:14]([S:11]([O:10][C@@H:9]2[CH2:8][NH:7][C@@H:6]3[C@@H:2]([OH:1])[CH2:3][O:4][C@H:5]23)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CN(C(=O)OC(C)(C)C)[C@H]3[C@@H]2OC[C@@H]3O)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CN[C@H]3[C@@H]2OC[C@@H]3O)cc1
Reaction time: 4.5 h

Procedure:
Preparation (3R,3aR,6R,6aS)— tert-Butyl 3-hydroxy-6-(tosyloxy)tetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate (35b). Ethanol (1.5 mL) was added dropwise to a mixture of 10% palladium on charcoal (20 mg) and anti-(33b) (100 mg, 0.25 mmol) under an atmosphere of argon. The argon was replaced by hydrogen then the suspension was stirred for 4.5 hours before filtering the mixture through celite in vacuo. The filter cake was washed with ethanol (10 mL) then the solvents removed in vacuo from the filtrate. The residue was azeotroped with toluene (2×3 mL) to obtain (3R,3aR,6R,6aS)-3-hydroxyhexahydro-2H-furo[3,2-b]pyrrol-6-yl 4-methylbenzenesulfonate which was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:38])[N:18]([CH:28]3[CH2:31][CH:30]([C:32]([O:34]CCC)=O)[CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[OH-].[Na+].Cl.[CH3:42][Mg]Br.[Cl-].[NH4+]>O1CCCC1.O.CO>[C:32]([C@@H:30]1[CH2:31][C@H:28]([N:18]2[C:17](=[O:38])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[CH:26][N:27]=[C:19]23)[CH2:29]1)(=[O:34])[CH3:42]
Reactant: C[Mg]Br
Reactant: CCCOC(=O)C1CC(n2c(=O)c(Cc3ccc(-c4ccccc4C#N)cc3)c(CCC)n3ncnc23)C1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2C[C@@H](C(C)=O)C2)c2ncnn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
A mixture of propyl 3-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclobutanecarboxylate (5 g), 1N aqueous sodium hydroxide solution (10 mL), methanol (10 mL) and tetrahydrofuran (10 mL) was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 4 with water and 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained extract was dissolved in N,N-dimethylformamide (50 mL), N-methoxymethanamine hydrochloride (1.4 g), 1-hydroxybenzotriazole (2.3 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.8 g) and triethylamine (2.1 mL) were added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by purification by silica gel column chromatography was dissolved in tetrahydrofuran (20 mL), and methylmagnesium bromide (1.0 M tetrahydrofuran solution, 6.1 mL) was added at room temperature. The reaction mixture was stirred for 3 hr, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (2.2 g, 49%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:13]2[C:18](=[O:19])[N:17]([CH3:20])[C:16]3[CH:21]=[CH:22][CH:23]=[CH:24][C:15]=3[S:14]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].[CH2:25]([O:27][CH:28]([O:32][CH2:33][CH3:34])[CH2:29][CH2:30]Cl)[CH3:26].C(OCC)(=O)C>CN(C)C=O.O>[CH2:25]([O:27][CH:28]([O:32][CH2:33][CH3:34])[CH2:29][CH2:30][C:13]1([C:7]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([O:4][CH3:3])[CH:6]=2)[C:18](=[O:19])[N:17]([CH3:20])[C:16]2[CH:21]=[CH:22][CH:23]=[CH:24][C:15]=2[S:14]1)[CH3:26]
Reactant: COc1ccc(C2Sc3ccccc3N(C)C2=O)cc1OC
Reactant: CCOC(CCCl)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(CCC1(c2ccc(OC)c(OC)c2)Sc2ccccc2N(C)C1=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.8 %

Procedure:
To a stirred suspension of 60% sodium hydride (0.6 g) in dimethylformamide (5 ml), 3,4-dihydro-2-(3,4-dimethoxyphenyl)-4-methyl-3-oxo-2H-1,4-benzothiazine (4.4 g) dissolved in dimethylformamide (15 ml) is added under nitrogen atmosphere and ice-cooling, and the mixture is stirred for 15 minutes at room temperature. β-Chloropropionaldehyde diethyl acetal (2.8 g) is added to the reaction mixture, and the mixture is stirred for 2.5 hours at 60° C. The mixture is poured into a mixture of ethyl acetate and water. The organic layer is washed with 1N sodium hydroxide and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography to give 4.4 g (71.5 %) of 2-(3,3-diethoxypropyl)-3,4-dihydro-2-(3,4-dimethoxyphenyl)-4-methyl-3-oxo-2H-1,4-benzothiazine as an oily form (compound No. 36, (IR: neat, cm-1) 1660, 1588, 1444, 1325, 1238, 750).
Reaction SMILES: [C:1]1([CH2:9][OH:10])C=CC=C(CO)C=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:17](Cl)(=[O:27])[C:18]1[CH:26]=[CH:25][CH:24]=[C:20]([C:21](Cl)=[O:22])[CH:19]=1>O1CCCC1>[CH:17]([O:10][CH:9]=[CH2:1])=[CH2:18].[C:18]1([CH2:17][OH:27])[CH:26]=[CH:25][CH:24]=[C:20]([CH2:21][OH:22])[CH:19]=1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Agent: OCc1cccc(CO)c1
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: C=COC=C
Temperature: 0 °C
Reaction time: 4 h

Procedure:
1,3-benzenedimethyl divinyl ether (BDMDVE) was synthesized from 1,3-benzenedimethanol, which was prepared in a two-liter, 3-necked round-bottomed flask equipped with a 500-ml constant pressure addition funnel, an overhead stirrer, a thermocouple and a nitrogen inlet into which was added 27 g (0.74 mol) of lithium aluminum hydride (95%) and 1000 ml of anhydrous tetrahydrofuran (THF). The addition funnel was charged with a solution of 100 g (0.493 mol) of isophthaloyl dichloride in 400 ml of anhydrous THF. Diacylchloride was added slowly over a period of 2 hours with cooling in an ice bath. Once addition was complete the ice bath was removed and the suspension allowed to reach room temperature for four hours at which time it was re-cooled and 200 ml of ethyl acetate was slowly added to decompose the remaining hydride. The addition funnel was recharged with 200 ml of 2M NaOH, which was then added slowly with vigorous stirring until the ensuing suspension became granular in appearance. The suspension was filtered and well washed with ethyl acetate. The combined filtrate and washings were then washed with brine, dried over anhydrous magnesium sulfate and evaporated on a rotary evaporator to yield 64 g (94%) of 1,3-benzenedimethanol as a clear, colorless oil which solidified upon standing. The BDMDVE was then prepared in a two-liter round bottomed flask equipped with a positive-pressure nitrogen inlet and a magnetic stir bar was added 64 g (0.46 mol) of 1,3-benzenedimethanol, 10 g (0.03 mol) of mercuric acetate and 1 liter of ethyl vinyl ether. The solution was stirred at room temperature for four days at which time it was washed well with saturated sodium bicarbonate solution and brine. The solution was then stirred for three days over 20 g of anhydrous magnesium sulfate (the reaction is driven to completion by stirring over the acidic magnesium sulfate), filtered, and evaporated on a rotary evaporator. The resulting oil was distilled twice through an 8″ Vigreux to yield 53 g (60%) of BDMDVE, boiling point=84° C. at 1 mm Hg.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)(=[O:3])[CH3:2].[H-].[Na+].[CH3:24]I>CN(C)C=O.O>[Cl:21][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]=[CH:6][C:5]([N:4]([CH3:24])[C:1](=[O:3])[CH3:2])=[C:14]2[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)Nc1cnc2ccc(Cl)cc2c1-c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1cnc2ccc(Cl)cc2c1-c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 3-acetamido-6-chloro-4-phenylquinoline (1 g) in N,N-dimethylformamide (10 ml) was added 60% sodium hydride in oil (0.15 g). After stirring for 30 mins. at room temperature, to the mixture was added dropwise methyl iodide(0.25 ml) under stirring and then followed by stirring for 1 hr. at room temperature. After the mixture was diluted with water, the resultant precipitate was collected by filtration, and recrystallized from a mixture of methanol and chloroform to give 6-chloro-3-(N-methylacetamido)-4-phenylquinoline as colorless crystals. Yield 0.96 g (91.4%). m.p. 268°-270° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][OH:13])[CH:3]=1.[C:14]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:15][CH2:16][C:17]([CH3:19])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>C1C=CC=CC=1>[CH2:22]([O:21][C:14](=[O:20])[CH2:15][CH2:16][C:17]1([CH3:19])[C:3]2=[C:2]([CH3:1])[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]2[CH2:11][CH2:12][O:13]1)[CH3:23]
Reactant: CCOC(=O)CCC(C)=O
Reactant: Cc1cn(CCO)c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCOC(=O)CCC1(C)OCCn2c1c(C)c1ccccc12
Reaction time: 12 h

Procedure:
A mixture of the intermediate of formula III, 3-methylindole-1-ethanol (29.7 g., 0.17 mole), described in Example 1, ethyl levulinate (26.96 g., 0.187 mole) and p-toluenesulfonic acid (2.25 g.) in dry benzene (650 ml.) is refluxed with stirring for 12 hr. with hydrated alkali-aluminum silicate (Molecular Sieves No. 4). The benzene solution is washed with 5% aqueous NaHCO3, followed by water. Concentrations of the solution gave a residue, which is passed through a silica gel column using 15% ethyl acetate in benzene to afford the ester, 3,4-dihydro-1,10-dimethyl-1H-1,4-oxazino[4,3-a]indole-1-propionic acid ethyl ester, as an oil, γmaxCHCl3 1730 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([CH2:8][CH2:9][CH2:10][CH2:11][C:12](Cl)=[O:13])=[O:7])=[CH:4][CH:3]=1.[CH-:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1.[CH-:22]1[CH:26]=[CH:25][CH:24]=[CH:23]1.[Fe+2:27].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl.O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([C-:17]2[CH:21]=[CH:20][CH:19]=[CH:18]2)=[O:13])=[O:7])=[CH:4][CH:3]=1.[CH-:22]1[CH:26]=[CH:25][CH:24]=[CH:23]1.[Fe+2:27]
Reactant: O=C(Cl)CCCCC(=O)c1ccc(Cl)cc1
Agent: [Fe+2]
Agent: Cl
Agent: [Al+3]
Solvent: ClCCl
Solvent: O
Product: O=C(CCCCC(=O)[c-]1cccc1)c1ccc(Cl)cc1
Temperature: -20 °C
Yield: 39.5 %

Procedure:
5-(4-Chlorobenzoyl)pentanoyl chloride (5.2g -- 0.02 mole) -- prepared as described above -- and ferrocene (3.75g -- 0.02 mole) were dissolved in dry dichloromethane (100 ml) and cooled to -20°C. Aluminium chloride (2.70g -- 0.02 mole) was added, with stirring, over a period of one-half hour and stirring was continued at -20°C for 11/2 hours. The reaction mixture was poured into water (300 ml) acidified with 2N hydrochloric acid (20 ml). The dichloromethane layer was separated and the aqueous layer extracted with chloroform (3 × 100 ml). The combined organic extracts were washed with water (100 ml), saturated aqueous sodium bicarbonate solution (100 ml) and water (100 ml), dried (MgSO4) and concentrated affording the crude product (9.8g) as a brown solid. Recrystallisation from petroleum ether (bp 60°-80°) afforded the title compound (3.23g -- 40%) mp 103°-6°.
Reaction SMILES: [Na+].[I-:2].CN(C)CCN.Br[C:10]1[CH:11]=[CH:12][C:13]([O:18][CH2:19][CH2:20][OH:21])=[C:14]([CH:17]=1)[CH:15]=[O:16].CNCCNC.Cl>O1CCOCC1.[Cu]I>[OH:21][CH2:20][CH2:19][O:18][C:13]1[CH:12]=[CH:11][C:10]([I:2])=[CH:17][C:14]=1[CH:15]=[O:16]
Reactant: [I-]
Reactant: O=Cc1cc(Br)ccc1OCCO
Agent: [Cu]I
Agent: CN(C)CCN
Agent: CNCCNC
Solvent: C1COCCO1
Product: O=Cc1cc(I)ccc1OCCO
Temperature: 110 °C
Reaction time: 16 h

Procedure:
Under an argon atmosphere 0.91 g (4.80 mmol) of CuI, 14.37 g (95.89 mmol) of NaI, and 6.13 mL (57.53 mmol) of N,N-dimethylethane-1,2-diamine were added to a solution of 11.75 g (47.945 mmol) of 5-bromo-2-(2-hydroxyethoxy)benzaldehyde in 50 mL of 1,4-dioxane and the mixture was stirred for 16 hours at 110° C. Another 6.13 mL (57.53 mmol) of N,N′-dimethylethane-1,2-diamine was added and the mixture was stirred for 8 hours at 110° C. The reaction mixture was cooled to RT, acidified with 12% aqueous HCl, and stirred for 30 minutes. The aqueous phase was exhaustively extracted with EtOAc, and the organic phase was washed with dilute aqueous ammonia solution and water, dried over magnesium sulfate, and evaporated down in vacuo. Yield: 9.78 g (52% of theoretical); C9H9IO3 (M=292.070); calc.: molpeak (M+H)+: 292; found: molpeak (M+H)+: 292.
Reaction SMILES: B(Br)(Br)Br.ClCCl.C([O:15][C:16]1[C:25]([O:26][CH3:27])=[CH:24][C:23]2[N:22]=[CH:21][C:20]3[N:28]([CH3:39])[N:29]=[C:30]([C:31]4[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=4)[C:19]=3[C:18]=2[CH:17]=1)C1C=CC=CC=1.O>FC(F)(F)C(O)=O>[OH:15][C:16]1[C:25]([O:26][CH3:27])=[CH:24][C:23]2[N:22]=[CH:21][C:20]3[N:28]([CH3:39])[N:29]=[C:30]([C:31]4[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=4)[C:19]=3[C:18]=2[CH:17]=1
Reactant: COc1cc2ncc3c(c(-c4ccc(C#N)cc4)nn3C)c2cc1OCc1ccccc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2ncc3c(c(-c4ccc(C#N)cc4)nn3C)c2cc1O
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
A 1.0 M boron tribromide solution in dichloromethane (38.2 ml, 38.2 mmol) is slowly added dropwise to a solution of 4-(8-benzyloxy-7-methoxy-3-methyl-3H-pyrazolo[3,4-c]quinolin-1-yl)benzonitrile (3.82 g, 9.09 mmol) in trifluoroacetic acid (38 ml) under a dry nitrogen atmosphere with ice-bath cooling. When the addition is complete, the mixture is subsequently stirred for a further 30 min. When the reaction is complete (HPLC-MS check), the reaction mixture is carefully added to water (800 ml) and extracted twice with ethyl acetate (200 ml each time). The combined organic phases are washed with water (150 ml) and semi-saturated NaHCO3 solution (200 ml), subsequently dried using Na2SO4 and filtered with suction. The filtrate is evaporated in vacuo, suspended in a little ethanol, filtered off with suction and dried in a high vacuum, giving the title compound 4-(8-hydroxy-7-methoxy-3-methyl-3H-pyrazolo[3,4-c]quinolin-1-yl)benzonitrile (2.86 g, 8.66 mmol) as a solid having a melting point of 288.9° C. MS: 331.1 (M+H+), TLC (HPTLC): Rf=0.34 (ethyl acetate/ethanol 8:1, parts by volume).
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:2]([C:5]([O:7][CH3:8])=[O:6])[CH2:3][OH:4].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl.[Ag]=O>[CH2:16]([O:4][CH2:3][C@@H:2]([C:5]([O:7][CH3:8])=[O:6])[NH:1][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)C(CO)NC(=O)OC(C)(C)C
Agent: O=[Ag]
Solvent: ClCCl
Product: COC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 48 h

Procedure:
A mixture of BOC-DL-Ser-OMe (434 mg, 2.0 mmol), benzyl bromide (513 mg, 3.0 mmol), and silver oxide (695 mg, 3.0 mmol) in dichloromethane (10 mL) at room temperature was stirred for 2 days, filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 20% ethyl acetate/hexanes to provide the desired product. MS (ESI(−)) m/e 308 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-])=O)=[C:6]([N:8]([CH2:12][C:13](O)=[O:14])[CH:9]([CH3:11])[CH3:10])[CH:7]=1>C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:16][C:13](=[O:14])[CH2:12][N:8]2[CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)N(CC(=O)O)c1cc(Br)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: CC(C)N1CC(=O)Nc2ccc(Br)cc21
Reaction time: 2 h
Yield: 73.4 %

Procedure:
To a solution of [(5-bromo-2-nitro-phenyl)-isopropyl-amino] acetic acid (27 g, 85 mmol) in acetic acid (400 ml) was added iron powder (15 g, 0.27 mol) and the mixture was stirred for 2 hrs. at 90° C. The reaction mixture was cooled, filtered, and the acetic acid was evaporated. The remaining slurry was extracted with CH2CI2 (3×300 ml). The CH2Cl2 extracts were combined, dried (MgSO4) and evaporated to afford the subtitled compound (16.8 g, 73%): 1H-NMR (DMSO-d6) δ 1.13 (d, J=6.54 Hz, 6H), 3.57 (s, 2H), 3.99 (septet, J=6.54 Hz, 1H), 6.82 (dd, J=8.23, 1.88 Hz, 1H), 6.72 (d, J=8.17 Hz, 1H), 6.90 (d, J=1.59Hz, 1H), 10.50 (s, 1H): MS (EI) 267/269 (M)+ + 1 bromine.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[N:12]=[C:13](Cl)[C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[S:17][C:15]=2[N:16]=1>>[Cl:10][C:11]1[N:12]=[C:13]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:14]2[CH:19]=[C:18]([C:20]([F:22])([F:23])[F:21])[S:17][C:15]=2[N:16]=1
Reactant: FC(F)(F)c1cc2c(Cl)nc(Cl)nc2s1
Reactant: NCc1ccc(F)cc1
Product: Fc1ccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)cc1

Procedure:
Following the procedure of Example 1, the reaction of 4-fluorobenzylamine with 2,4-dichloro-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-trifluoromethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.