Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([CH3:20])[C@@H:3]([CH2:7][CH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:4]([OH:6])=O.[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:27][NH2:28].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:27][NH:28][C:4](=[O:6])[C@H:3]([CH2:7][CH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C@H:2]([OH:1])[CH3:20]
Reactant: C[C@@H](O)[C@@H](CC1CCC(c2ccccc2)CC1)C(=O)O
Reactant: NOC1CCCCO1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@@H](CC1CCC(c2ccccc2)CC1)C(=O)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 133.6 %

Procedure:
A mixture of (2R,3R)-3-hydroxy-2-(4-phenylcyclohexylmethyl)butanoic acid (3.43 g, 0.012 mol), 2-tetrahydropyranyloxyamine (1.64 g, 0.014 mol), BOP (5.75 g, 0.013 mol), HOBt (1.76 g, 0.13 mol) and NMM (2.63 g, 0.026 mol) in DMF (30 mL) is stirred at 25° C. for 18 h. The mixture is concentrated in vacuo and the residue is taken up in EtOAc. The mixture is washed with ice-cold 0.1 M HCl, saturated aqueous sodium bicarbonate, and saturated aquesous sodium chloride. The organic phase is dried over sodium sulfate and concentrated in vacuo to give 6.02 g of a white solid. Chromatography on silica gel using EtOAc as eluent gives 4.05 g (90%) of (2R,3R)-3-hydroxy-2-(4-phenylcyclohe,(ylmethyl)butanoic acid 2-tetrahydropyranyloxyamide as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[C:22]([Cl:28])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.Cl.[NH2:61][CH:62]([C:64]1[CH:65]=[CH:66][C:67]2[C:71]([CH3:73])([CH3:72])[O:70][B:69]([OH:74])[C:68]=2[CH:75]=1)[CH3:63]>CN(C=O)C.CC(=O)OCC>[OH:74][B:69]1[C:68]2[CH:75]=[C:64]([CH:62]([NH:61][C:4](=[O:5])[C:3]3[CH:7]=[CH:8][C:9]([C:11]4[CH2:15][C:14]([C:20]5[CH:21]=[C:22]([Cl:28])[C:23]([Cl:27])=[C:24]([Cl:26])[CH:25]=5)([C:16]([F:18])([F:19])[F:17])[O:13][N:12]=4)=[CH:10][C:2]=3[CH3:1])[CH3:63])[CH:65]=[CH:66][C:67]=2[C:71]([CH3:72])([CH3:73])[O:70]1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Reactant: CC(N)c1ccc2c(c1)B(O)OC2(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC(C)c1ccc2c(c1)B(O)OC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.8 %

Procedure:
To a solution of 2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)benzoic acid (150 mg, 0.33 mmol), HATU (188 mg, 0.495 mmol) and Et3N (0.15 mL, 0.99 mmol) in DMF (10 mL) was added 6-(1-aminoethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (0.93 mmol). The mixture was stirred at rt overnight and EA (50 mL) was added. The mixture was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound N-(1-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)ethyl)-2-methyl-4-(5-(3,4,5-tri-chlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzamide (103 mg; yield 18% over 5 steps) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.00 (s, 1H), 8.82 (d, J=7.6 Hz, 1H), 7.84 (s, 2H), 7.37-7.67 (m, 6H), 5.16 (m, 1H), 4.40 (d, J=18.0 Hz, 1H), 4.33 (d, J=18.0 Hz, 1H), 2.33 (s, 3H), 1.47-1.44 (m, 9H) ppm; HPLC purity: 99.88% at 220 nm and 99.77% at 254 nm; MS: m/z=639.8 (M+1, ESI+).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=O)=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:4]=1.[CH3:15][O:16][C:17](=[O:38])[CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O.O>[CH3:15][O:16][C:17](=[O:38])[CH:18]=[CH:9][C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:11]([F:14])([F:13])[F:12]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc(C(F)(F)F)c(C=O)cn1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C=Cc1cnc(OC)cc1C(F)(F)F
Temperature: 110 °C
Yield: 73.4 %

Procedure:
To a solution of 6-methoxy-4-trifluoromethyl-3-pyridinecarboxaldehyde (150 mg, 0.73 mmol) in toluene (8 mL) was added methyl(triphenylphosphoranylidene)acetate (270 mg, 0.81 mmol). The mixture was heated at 110° C. for overnight, cooled to room temperature, and diluted with EtOAc and water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc/hexanes=1/4) to give 3-(6-methoxy-4-trifluoromethylpyridin-3-yl)-acrylic acid methyl ester (140 mg, 73.3%) as a mixture of cis- and trans-isomers (cis-/trans-=1/10). The trans-isomer was then isolated by recrystallization from hexanes to give 60 mg as a solid.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:34]=[CH:35][CH:36]=1)[CH:23]=[C:24]1[C:29](=[O:30])[O:28][C:27]([CH3:32])([CH3:31])[O:26][C:25]1=[O:33])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:37]1([Mg]Br)[CH2:39][CH2:38]1.Cl.O>C1COCC1>[Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:23]([CH:37]2[CH2:39][CH2:38]2)[CH:24]2[C:25](=[O:33])[O:26][C:27]([CH3:31])([CH3:32])[O:28][C:29]2=[O:30])[CH:34]=[CH:35][CH:36]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC1(C)OC(=O)C(=Cc2cccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)C(=O)O1
Reactant: Br[Mg]C1CC1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OC(=O)C(C(c2cccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)C2CC2)C(=O)O1
Temperature: 0 °C
Reaction time: 5.5 h

Procedure:
Under an argon atmosphere, to a solution of 5-(3-(((tert-butyldiphenylsilyl)oxy)methyl)benzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (6.39 g) in THF (85 mL) was added dropwise a 0.70 M solution of cyclopropylmagnesium bromide in THF (54.7 mL) at 0° C. over 15 min, and the mixture was stirred at 0° C. for 5.5 hr. 0.50N Hydrochloric acid (300 mL) was added dropwise at 0° C., and water was further added. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.05 g) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:16]3[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:15]=3[CH2:14][C:13]([CH3:25])=[N:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O>CN(C)C=O.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:16]3[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:15]=3[CH2:14][C:13]([CH3:25])=[N:12][N:11]=2)=[CH:6][CH:5]=1
Reactant: COc1cc2c(cc1OC)C(c1ccc([N+](=O)[O-])cc1)=NN=C(C)C2
Agent: [Pd]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)C(c1ccc(N)cc1)=NN=C(C)C2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
26.6 g (0.078 mole) of 1-(4-nitrophenyl)-4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine are suspended in 540 ml of dimethylformamide, 2 g of 10% palladium on bone coal catalyst are suspended in 60 ml of dimethylformamide and added to the previous suspension. The reaction mixture is stirred vigorously at room temperature, under hydrogen. The reduction terminates in about 15 hours. Then the catalyst is filtered off, the filtrate is clarified with activated carbon and evaporated in vacuo. The crystalline residue is boiled with 250 ml of ethanol for one hour. Then it is cooled, the crystals are filtered off, washed twice with 30 ml of ethanol each and dried at 80° to 100° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([CH2:15][C:16](OCC)=[O:17])[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C>C1COCC1>[OH:17][CH2:16][CH2:15][C:13]1[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH:14]=1
Reactant: CCOC(=O)Cc1ccnc(NC(=O)OC(C)(C)C)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(CCO)ccn1
Temperature: -69 °C
Reaction time: 0.67 h
Yield: 70.5 %

Procedure:
To a solution of ethyl 2-(2-(tert-butoxycarbonylamino)pyridin-4-yl)acetate (WO 2007089512) (10.0 g, 35.7 mmol) under N2 in THF (100 mL), at −78° C., was added a solution of DIBAL in THF (1.0M, 71.0 mL, 71.0 mmol) over 1 hr. The reaction mixture was stirred at −78 to −60° C. for 40 min and was then warmed to −15° C. over 1 hr. The solution was re-cooled to −78° C. and was treated with a further aliquot of DIBAL solution (36.0 mL, 36.0 mmol) and was allowed to warm to −40° C. and stirred for 1 hr. The reaction was quenched by the cautious addition of water (10 mL), followed MgSO4. The solids were removed by filtration and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 330 g, EtOAc in hexanes, 65% v/v, isocratic elution) to give tert-butyl 4-(2-hydroxyethyl)pyridin-2-ylcarbamate, (6.0 g, 64%) as a yellow solid: m/z 239 (M+H)+ (ES+).
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]=[C:14]=[O:15])(=[O:12])=[O:11].[NH2:17][C:18]1[N:23]=[C:22]([CH:24]2[CH2:26][CH2:25]2)[N:21]=[C:20]([C:27]([Cl:30])([Cl:29])[Cl:28])[N:19]=1>CCCCCC>[CH:24]1([C:22]2[N:21]=[C:20]([C:27]([Cl:29])([Cl:28])[Cl:30])[N:19]=[C:18]([NH:17][C:14]([NH:13][S:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[O:3][CH:2]([F:1])[F:16])(=[O:12])=[O:11])=[O:15])[N:23]=2)[CH2:25][CH2:26]1
Reactant: Nc1nc(C2CC2)nc(C(Cl)(Cl)Cl)n1
Reactant: O=C=NS(=O)(=O)c1ccccc1OC(F)F
Solvent: CCCCCC
Product: O=C(Nc1nc(C2CC2)nc(C(Cl)(Cl)Cl)n1)NS(=O)(=O)c1ccccc1OC(F)F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2.7 g of 2-difluoromethoxybenzenesulfonylisocyanate are added to a solution of 2.54 g of 2-amino-4-cyclopropyl-6-trichloromethyl-1,3,5-triazine, and the whole is stirred at room temperature for 14 hours. Hexane is then added until the reaction product precipitates. Filtration is carried out and the filtration residue is dried to thus obtain 3 g of the above urea, which melts at 103°-105° C.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[CH2:10]([O:13][CH2:14][CH2:15]Cl)[CH2:11]Cl.[NH4+].[Br-].[OH-].[Na+]>CCOC(C)=O>[I:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH2:15][CH2:14][O:13][CH2:10][CH2:11]2)=[C:4]([CH3:9])[CH:3]=1
Reactant: ClCCOCCCl
Reactant: Cc1cc(I)ccc1N
Agent: [Br-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cc(I)ccc1N1CCOCC1
Temperature: 25 °C
Yield: 49.9 %

Procedure:
A flask was charged with 4-iodo-2-methylaniline (2.0 g, 8.6 mmol), 2,2′-dichloroethyl ether (2.45 g, 17.2 mmol), NH4Br (8.28 g, 25 mmol), and an aqueous NaOH solution (42 wt %, 4.10 g, 42.9 mmol). The mixture was refluxed overnight. The reaction mixture was cooled to rt and diluted with EtOAc (20 mL). The organic layer was separated, and the aqueous layer extracted with EtOAc (20 mL). The combined organic layers were washed with water (20 mL), dried over MgSO4 and concentrated under reduced pressure. The material was purified on silica gel eluting with 10:1 hexane/EtOAc to give 4-(4-iodo-2-methylphenyl)morpholine (1.3 g, 50%): 1H NMR (CDCl3, 400 MHz): 7.48 (d, J=8.4 Hz, 2H), 6.76 (s, 2H), 3.84-3.82 (m, 4H), 2.88-2.85 (m, 4H), 2.26 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:22](=[O:24])=[O:23].O>O1CCCC1>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:22]([OH:24])=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=O
Reactant: c1ccc(Cn2cnc3ccccc32)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nc2ccccc2n1Cc1ccccc1
Temperature: 0 °C
Yield: 80 %

Procedure:
A solution of 2.08 g (10 mmol) of 1-benzylbenzimidazole in 200 ml of dry tetrahydrofuran was cooled under N2 atmosphere to -78° C. and treated with 8.0 ml (20 mmol) of n-butyllithium. The resulting solution was warmed to 0° C. for 0.5 h, recooled to -78° C., and poured into a mixture of excess dry ice in 200 ml of tetrahydrofuran. After being allowed to warm, the solution was treated with 200 ml of water, washed with ether, neutralized, and washed with ether. The aqueous layer was concentrated in vacuo, after which the residue was triturated with 2% methanol in chloroform and filtered. The filtrate was dried over MgSO4 and concentrated to give 2.01 g (80%) of the desired compound as a white powder. Mass spectrum: (M-OH)+ =235.
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].N1C=CC=CC=1.Cl[C:17]([C:19]1[C:31]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[C:32]([C:35]#[N:36])[C:33]#[N:34])[C:23]=2[CH:22]=[CH:21][CH:20]=1)=[O:18]>ClCCl>[C:35]([C:32]([C:33]#[N:34])=[C:24]1[C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([C:17]([O:2][C:1]3[CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=3)=[O:18])[C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)#[N:36]
Reactant: Oc1cc(O)cc(O)c1
Reactant: N#CC(C#N)=C1c2ccccc2-c2c(C(=O)Cl)cccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#CC(C#N)=C1c2ccccc2-c2c(C(=O)Oc3cc(O)cc(O)c3)cccc21
Reaction time: 1 h
Yield: 58.3 %

Procedure:
A solution of 30.0 grams of phloroglucinol and 70 milliliters of pyridine in 300 milliliters of dichloromethane was stirred at room temperature under a nitrogen atmosphere. Thereafter, a solution of 8.0 grams of (4-chloroformyl-9-fluorenylidene)malononitrile in 400 milliliters of dichloromethane was added thereto over a period of 1 hour. After addition, the reaction mixture was further stirred for another hour. The mixture was washed three times with dilute aqueous HCl solution, twice with dilute aqueous NaHCO3 solution, and once with water. The solution was dried, filtered, and evaporated under reduced pressure to give the crude product. Recrystallization from methanol afforded 6.1 grams of (b), m.p., 255.5° to 257° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH:6]([CH3:14])[CH2:7][C:8]2=[O:13].[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=O.C1(S(O)(=O)=O)C=CC=CC=1.S([O-])([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1>[CH2:20]([O:19][C:15](=[O:18])[CH:16]=[C:7]1[CH:6]([CH3:14])[CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[C:8]1=[O:13])[CH3:21]
Reactant: COc1cccc2c1CC(C)CC2=O
Reactant: CCOC(=O)C=O
Agent: O=S(=O)(O)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C1C(=O)c2cccc(OC)c2CC1C
Temperature: 25 °C
Yield: 51 %

Procedure:
In a heavy walled sealed tube, 5-methoxy-3-methyl-3,4-dihydro-2H-naphthalen-1-one (1.3 g, 6.8 mmol), ethyl glyoxylate (3 mL, 50% solution in toluene), benzenesulfonic acid (100 mg), magnesium sulfate (5 g), and toluene (30 mL) were heated to 120° C. for 13 hours. The reaction was cooled to room temp, filtered, diluted with water, and extracted with ethyl acetate. The extracts were washed with brine, dried with sodium sulfate, and concentrated. The crude residue was purified by flash column chromatography to yield the desired product (960 mg, 51% yield). LCMS-ESI+ (m/z): [M+H]+ calcd for C16H19O4: 275.13. Found: 275.26.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][C:7]1[CH:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:8]=1>C(Cl)(Cl)Cl>[CH3:6][C:7]1[C:11]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:8]=1
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccn(-c2ccccn2)n1
Solvent: ClC(Cl)Cl
Product: Cc1nn(-c2ccccn2)cc1S(=O)(=O)Cl
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To 30 ml of chlorosulfonic acid contained in 60 ml of chloroform, 30 g of 3-methyl-1-(2-pyridyl)pyrazole was added dropwise under ice-cooling, followed by stirring at 60° C. for 3 hours. To a residue obtained by evaporating chloroform under reduced pressure, 30 ml of thionyl chloride was added dropwise at about 60° C. over a period of 1 hour. After the addition, the reaction mixture was stirred at 95° C. for 30 minutes while heating under reflux. After cooling, it was poured into ice water and extracted with chloroform, organic layer was washed with water and dried, and thereafter solvent was evaporated under reduced pressure to obtain 49 g of crude 3-methyl-1-(2-pyridyl)pyrazole-4-sulfonylchloride as an oily product. The sulfonylchloride obtained was dissolved in 50 ml of tetrahydrofuran, and then was added dropwise at 0° to 10° C. to 41.4 g of t-butylamine contained in 100 ml of tetrahydrofuran. After stirring at room temperature for 1.5 hour, filtration was carried out, and filtrate obtained was concentrated to give a residue, to which ethyl acetate was added, followed by washing with diluted hydrochloric acid and drying, and then solvent was evaporated to give crystals. Crystals obtained was washed with ether to obtain 48.6 g of the title compound. m.p.: 174° to 175° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[C:4]([Cl:11])[N:3]=1.[CH3:12][C:13]1[C:18]2[NH:19][C:20](=[O:22])[O:21][C:17]=2[CH:16]=[CH:15][CH:14]=1.[Cl-].[Cl-].[Cl-].[Al+3]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([C:15]2[CH:14]=[C:13]([CH3:12])[C:18]3[NH:19][C:20](=[O:22])[O:21][C:17]=3[CH:16]=2)=[O:9])[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: O=C(Cl)c1cc(Cl)nc(Cl)n1
Reactant: Cc1cccc2oc(=O)[nH]c12
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(C(=O)c2cc(Cl)nc(Cl)n2)cc2oc(=O)[nH]c12
Temperature: 0 °C

Procedure:
2.75 g (13.0 mmol) 2,6-dichloro-pyrimidine-4-carboxylic acid chloride, 1.94 g (13.0 mmol) 4-methyl-3H-benzoxazol-2-one and 6.93 g (52.0 mmol) aluminium trichloride were heated to 125° C. for 1.5 h with stirring. The mixture combined with ice water and the product precipitated as a solid was suction filtered, washed with water and dried i. vac.
Reaction SMILES: [Li]CCCC.CC1(C)CCCC(C)(C)N1.[Br:16][C:17]1[CH:18]=[C:19]([F:23])[CH:20]=[CH:21][CH:22]=1.CN([CH:27]=[O:28])C>C1COCC1>[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[CH:27]=[O:28]
Reactant: CN(C)C=O
Reactant: Fc1cccc(Br)c1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1c(F)cccc1Br
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of n-BuLi (25 mL of 1.6 M solution in hexane, 40 mmol) in THF (100 mL) is added 2,2,6,6-teramethylpiperidine (6.8 mL, 40 mmol) at −78° C. and the mixture is stirred for 20 minutes. To this is added 3-bromofluorobenzene (7.0 g, 40 mmol). After stirring for 3 hours at −78° C., DMF (15 mL, 200 mmol) is added and the mixture is warmed to room temperature and stirred for 1 hour. The mixture is quenched with 1N HCl and extracted with EtOAc. The combined extracts are dried (MgSO4) and concentrated in vacuo. The residue is purified by flash chromatography (elution with Hex/EtOAc 10:1) to yield 2-bromo-6-fluoro-benzaldehyde. 1H NMR (CDCl3) 10.4 (s, 1H), 7.48-7.39 (m, 2H), 7.18-7.14 (m, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14](=O)[NH:15][CH:16]=[N:17]2)=[CH:12][CH:11]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:14]1[C:13]2[C:18](=[CH:19][C:10]([O:9][CH2:8][CH2:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][NH:1]3)=[CH:11][CH:12]=2)[N:17]=[CH:16][N:15]=1
Reactant: O=c1[nH]cnc2cc(OCCC3CCCCN3)ccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2cc(OCCC3CCCCN3)ccc12
Yield: 95 %

Procedure:
The intermediate 4-piperazinyl-7-(2-piperidylethoxy)quinazoline was prepared using the procedures as generally described in Scheme 1 as follows: Step A To the ethanol solution (15 mL) of 2-amino-4-fluorobenzoic acid (840 mg, 5.41 mmol) was added thionyl chloride (1.18 mL, 16.23 mmol) and the resulting suspension was refluxed overnight. The solvent was evaporated to the residue added EtOAc, washed with 10% NaOH solution, dried, filtered and evaporated to afford desired ethyl ester as a solid 981 mg, 82%). MS (ES) 184(M+H) Step B: To the formamide (6 mL) solution of ethyl-2-amino-4-fluorobenzoate (811 mg, 4.43 mmol) added ammonium formate (0.450 g, 7.14 mmol) and the reaction mixture was heated at 140° C. overnight. After cooling added water and ethyl acetate. The layers were separated, the EtOAc layer was dried, filtered and evaporated to give desired quinazolinone (1 g, quantitative). MS (ES) 165 (M+H) Step C: To the DMF solution (3 mL) of 1-piperidineethanol (0.689 mL, 5.18 mmol) at 0° C. added sodium hydride (0.518 g, 12.95 mmol) and the mixture was stirred for 30 min. To this cold solution added DMF solution (3 mL) of intermediate quinazolinone (0.284 g, 1.73 mmol, from Step B) and the mixture was heated at 75° C. overnight. The solvent was evaporated and the residue purified by RP-HPLC to afford desired product as a creamy solid (0.459 g, 97%) Step D: A mixture of 7-(2-piperidylethoxy)-4-quinazolinone (0.459 g, 1.68 mmol), from Step C) and POCl3 (5 mL) was heated at 75° C. overnight. After cooling excess POCl3 was removed by evaporation and the residue azeotroped with toluene to afford intermediate, 4-chloro-7-(2-piperidylethoxy)quinazoline (600 mg, 95%) Step E: To the isopropanol solution (10 mL) of 4-chloroquinazoline (0.615 g, 2.11 mmol, from Step D) added piperazine (0.727 g, 8.44 mmol) and heated the reaction for 4 h at 100° C. The solvent was evaporated and the residue purified by RP-HPLC to afford 4-piperazinyl-7-(2-piperidylethoxy)quinazoline as a white solid (0.630 g, 87%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C@H:6]2[C@H:10]([NH:11][C:12]3[C:13](=[O:24])[N:14]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:15]=[CH:16][N:17]=3)[CH2:9][O:8][CH2:7]2)[CH2:3][CH2:2]1.[Cl:25]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[CH:1]1([CH2:4][O:5][C@H:6]2[C@H:10]([NH:11][C:12]3[C:13](=[O:24])[N:14]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:15]([Cl:25])=[CH:16][N:17]=3)[CH2:9][O:8][CH2:7]2)[CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)Cn1ccnc(N[C@@H]2COC[C@H]2OCC2CC2)c1=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cn1c(Cl)cnc(N[C@@H]2COC[C@H]2OCC2CC2)c1=O
Reaction time: 6 h

Procedure:
A stirred solution of 3-(trans-3-cyclopropylmethoxytetrahydrofuran-4-ylamino)-1-ethoxycarbonylmethylpyrazinone from step 5 above (1.4 g, 4.15 mmol) and N-chlorosuccinimide (0.61 g, 4.57 mmol) in CHCl3 was heated to reflux for 6 h. More N-chlorosuccinimide (0.11 g, 0.83 mmol) was added and refluxing was continued for an additional 6 h. The reaction was diluted with CHCl3 and washed with aqueous NaHCO3. The organic phase was separated, dried over Mg SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using a gradient elution of 25-50% EtOAc:hexanes to give the title compound as an amorphous solid (1.1 g, TLC Rf=0.5, 1:1 EtOAc:hexanes; HPLC RT=7.97 min, method A).