Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13].[F:16][C:17]([F:38])([F:37])[C:18]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:26][CH:25]=1)([OH:23])[C:19]([F:22])([F:21])[F:20].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl.C(=O)([O-])O.[Na+]>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:34]2[CH2:35][CH2:36][N:31]([CH2:30][C:27]3[CH:28]=[CH:29][C:24]([C:18]([OH:23])([C:19]([F:20])([F:21])[F:22])[C:17]([F:38])([F:16])[F:37])=[CH:25][CH:26]=3)[CH2:32][CH2:33]2)=[O:8])=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13]
Reactant: OC(c1ccc(CN2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: Nc1ccc(C(=O)O)cc1OC(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1OC(F)(F)F
Reaction time: 1 h
Yield: 113 %

Procedure:
4-Amino-3-(trifluoromethoxy)benzoic acid (2.045 mmol, 0.452 g), 1,1,1,3,3,3-hexafluoro-2-(4-(piperazin-1-ylmethyl)phenyl)propan-2-ol (2.045 mmol, 0.700 g) and triethylamine (6.14 mmol, 0.853 mL, 0,621 g) were combined and stirred at room temperature in dichloromethane (5 mL). 1-Propanephosphonic acid cyclic anhydride (3.07 mmol, 1.826 mL, 1.952 g; 50% solution in ethyl acetate) was added and the reaction stirred for 1 hour. The reaction mixture was diluted with dichloromethane and saturated sodium hydrogen carbonate solution and the layers separated. The organic layer was dried over magnesium sulfate and concentrated under vacuum to afford the title compound (1.26 g). MS (ESI) m/z 546.5 [M+H]+
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([O:9]C)[CH:6]=[CH:7][CH:8]=1.CC(=[CH:15][CH2:16][CH3:17])C=O>BrC1C=C(OC)C=CC=1.C1COCC1.[Cu]I>[CH:5]([O:9][CH:16]([CH3:15])[CH3:17])([CH3:6])[CH3:4].[CH3:5][CH2:4][CH2:3][CH2:8][CH2:7][CH3:6]
Reactant: COc1cccc(Br)c1
Reactant: CCC=C(C)C=O
Agent: [Cu]I
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)OC(C)C
Product: CCCCCC
Temperature: -70 °C
Reaction time: 1 h

Procedure:
To 1.46 g (0.06 mol) of magnesium were added 50 mL of dry THF. 5 drops of 3-bromoanisole were added to this mixture and the resulting suspension was refluxed until the reaction started. Then, a solution of 7.63 mL of 3-bromoanisole (0.06 mol) in 15 mL of dry THF was slowly added dropwise, thereby maintaining a constant reflux of the reaction mixture. After addition and refluxing of the reaction mixture for another hour, the mixture was cooled to −70° C. At this temperature 11.4 g (0.06 mol) copper(I) iodide (CuI) and 30 mL of dry THF were added. The mixture was then allowed to warm to around −65 to −60° C. At this temperature, commercially available 2-methyl-2-pentenal, dissolved in 15 mL of dry THF were added slowly to the reaction mixture. After stirring for 1 h at −65-−60° C., the reaction mixture was allowed to warm to 0° C. The reaction mixture was hydrolyzed by addition of 50 mL of a saturated aqueous solution of NH4HSO4. The mixture was then extracted three times with 100 mL of diethyl ether. The combined organic layers were dried over MgSO4. The organic solvent was evaporated and the remaining residue was dried in vacuo. CC (eluent: diisopropyl ether/n-hexane (1:30)) yielded 2.3 g (29%) of B2 as a colorless oil.
Reaction SMILES: B(Br)(Br)Br.[CH:5]1([CH2:10][C:11]2[NH:12][C:13](=[O:29])[C:14]3[CH:19]=[N:18][N:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26]CC)[C:15]=3[N:16]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1>ClCCl>[CH:5]1([CH2:10][C:11]2[NH:12][C:13](=[O:29])[C:14]3[CH:19]=[N:18][N:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[OH:26])[C:15]=3[N:16]=2)[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: CCOc1ccccc1-n1ncc2c(=O)[nH]c(CC3CCCC3)nc21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1[nH]c(CC2CCCC2)nc2c1cnn2-c1ccccc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4 ml of 1 M boron tribromide solution in dichloromethane are added to 0.2 g (0.59 mmol) of 6-cyclopentylmethyl-1-(2-ethoxyphenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 12), and the reaction mixture was stirred at room temperature for 1 h. Aqueous hydrolysis is followed by extraction with dichloromethane. The product is purified by preparative HPLC(YMC Gel ODS-AQ S 5/15 μm; eluent A: water, eluent B: acetonitrile; gradient: 0 min 30% B, 5 min 30% B, 50 min 95% B). 0.167 g (91% of theory) of the product is obtained as a colourless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.OO.NC(N)=[O:13].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N+:6]([O-:13])[CH:7]=1
Reactant: NC(N)=O
Reactant: Cc1ccc(Br)cn1
Agent: OO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(Br)c[n+]1[O-]
Temperature: 25 °C
Yield: 60.4 %

Procedure:
To a solution of 5-bromo-2-methylpyridine (1 g, 5.81 mmol) and urea hydrogen peroxide (1.1 g, 12.2 mmol) in DCM (30 mL) at 0° C. was added trifluoroacetic anhydride (1.6 mL, 11.6 mmol). After warming to 25° C. over 12 h, the solution was partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 1% MeOH in DCM (1% NH4OH)) yielding the title compound (660 mg, 60%) as a white solid: LCMS (ES) m/z=190 (M+H)+.
Reaction SMILES: CN([CH:4]=[O:5])C.O=P(Cl)(Cl)[Cl:8].O=[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1>>[Cl:8][C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][C:13]=1[CH:4]=[O:5]
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: CN(C)C=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)N1CCC(Cl)=C(C=O)C1
Reaction time: 2 h

Procedure:
A solution of DMF (2.5 eq) and POCl3 (1.5 eq.) at 0° C. was stirred for 15 min. To that ethyl 4-oxopiperidine-1-carboxylate (1.0 eq) obtained from step I was added at 40° C. and reaction was continued at room temperature for 2 h Reaction was quenched with water and extracted with ethyl acetate, organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the desired ethyl 4-chloro-5-formyl-3,6-dihydropyridine-1(2H)-carboxylate.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[N:10]([CH2:18][CH3:19])[C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:17]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.B([C:23]1[N:24]([C:32]([O:34]C(C)(C)C)=[O:33])[C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)(O)O.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:32]([OH:34])=[O:33].[CH2:18]([N:10]1[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:17]=[C:9]1[C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:23]2[NH:24][C:25]3[C:30]([CH:31]=2)=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:3]=1)[CH3:19]
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Reactant: CCn1c(-c2nc(Br)cnc2N)nc2cnccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(-c2nc(-c3cc4ccccc4[nH]3)cnc2N)nc2cnccc21
Product: O=CO
Temperature: 200 °C
Yield: 31.6 %

Procedure:
5-Bromo-3-(1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)pyrazin-2-amine (0.020 g, 0.063 mmol) (made in example 2), tert-butyl 2-borono-1H-indole-1-carboxylate (0.062 g, 0.25 mmol), Pd(PPh3)2Cl2 (0.004 g, 0.0056 mmol) and K2CO3 (0.050 g, 0.25 mmol) were combined in 0.5 mL of N,N-dimethylformamide and heated to 200° C. in the SmithSynthesizer microwave for 8 minutes. The reaction mixture was concentrated in vacuo and the residue purified by HPLC to give 0.008 g of the title compound.
Reaction SMILES: [ClH:1].C[C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[C:5]([Br:15])[CH:4]=1.Cl.Br[C:18]1C(C)=CC=CC=1NN>>[ClH:1].[CH3:18][C:4]1[C:5]([Br:15])=[C:6]2[C:13](=[CH:14][CH:3]=1)[C:9]([CH2:10][CH2:11][NH2:12])=[CH:8][NH:7]2
Reactant: Cc1cc(Br)c2[nH]cc(CCN)c2c1
Reactant: Cc1cccc(NN)c1Br
Agent: Cl
Product: Cc1ccc2c(CCN)c[nH]c2c1Br

Procedure:
6-Methyl-7-bromotryptamine hydrochloride was prepared (2.42 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 7, except using 2-bromo-3-methylphenylhydrazine hydrochloride as starting material. ##STR42##
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17](=[CH2:37])[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1)=[O:19].[CH3:38][O:39][C:40]1[CH:45]=[CH:44][C:43](O)=[CH:42][CH:41]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:37][C:17](=[CH2:16])[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([C:32]([O:34][C:43]2[CH:44]=[CH:45][C:40]([O:39][CH3:38])=[CH:41][CH:42]=2)=[O:33])=[CH:35][CH:36]=1)=[O:19]
Reactant: COc1ccc(O)cc1
Reactant: C=C(C)C(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=C(C)C(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.4 %

Procedure:
6.8 g (33 mmol) of N,N′-dicyclohexylcarbodiimide were added at 0° C. while stirring to a solution of 7.8 g (25.4 mmol) of 4-[6-(2-methyl-acryloyloxy)-hexyloxy]-benzoic acid, 2.9 g (23.4 mmol) of 4-methoxy-phenol and 0.5 g of 4-(dimethyl-amino)-pyridine in 200 ml of dichloromethane. The reaction mixture was stirred at room temperature for a further 16 hours, then filtered and the filtrate was extracted twice with saturated K2CO3 solution. The combined organic phases were washed twice with saturated sodium chloride solution, dried over magnesium sulphate, filtered and subsequently concentrated. Chromatographic purification of the residue on silica gel with methylene chloride: acetone=19:1 and two-fold recrystallization of the fractions which were pure according to thin-layer chromatography from methyl alcohol gave 7.76 g of 4-methoxy-phenyl 4-[6-(2-methyl-acryloyloxy)-hexyloxy]-benzoate as a white solid. The substance is monotropic nematic, m.p. (C-l) 550C, (cl.p. (N-l) 35.7° C.). Mass spectrometric analysis yields the mol peak at m/e=412.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.N1C=CC=CC=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:18][S:19]([N:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1)(=[O:21])=[O:20]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1CCN(S(C)(=O)=O)CC1
Reaction time: 1.5 h
Yield: 72 %

Procedure:
A solution of ethyl isonipecotate (4.9 mL, 31.8 mmol) and pyridine (2.8 mL, 34.6 mmol) was cooled to 0° C. Methanesulfonyl chloride (2.7 mL, 34.9 mmol) was added. After 1.5 hours, the reaction mixture was diluted with CH2Cl2 (300 mL) and extracted with saturated aqueous NaHCO3 (3×100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The crude material was dissolved in EtOAc (400 mL), extracted with H2O (3×50 mL), dried over Na2SO4, filtered, and concentrated to give the pure product (5.42 g, 22.9 mmol, 72%) as a yellow solid. IR(CHCl3): 3027, 1726, 1331, 1158, 963.
Reaction SMILES: Cl.CN(C)C.C(N(CC)CC)C.[F:13][C@H:14]1[C@@H:19]([CH2:20][CH2:21][OH:22])[CH2:18][CH2:17][O:16][CH2:15]1.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1.O>[CH3:33][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O:22][CH2:21][CH2:20][C@H:19]2[CH2:18][CH2:17][O:16][CH2:15][C@H:14]2[F:13])(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC[C@H]1CCOC[C@H]1F
Agent: CN(C)C
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC[C@H]2CCOC[C@H]2F)cc1
Reaction time: 1 h

Procedure:
Trimethylamine hydrochloride (128 mg, 1.34 mmol) and triethylamine (0.39 mL, 2.81 mmol) were added to a solution of (±)-cis-2-(3-fluorotetrahydro-2 H-pyran-4-yl)ethanol obtained (198 mg, 1.34 mmol) in toluene (5 mL). Subsequently, p-toluenesulfonyl chloride (382 mg, 2.00 mmol) was added thereto while cooling in ice, and the mixture was stirred for 1 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane only→hexane:ethyl acetate=1:1) to afford the title compound (354 mg) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([Cl:9])[CH:3]=1.C([Mg]Cl)(C)C.[Cl:15][C:16]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:17]=1[CH:18]=[O:19]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:18]([C:17]2[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:16]=2[Cl:15])[OH:19])=[C:4]([Cl:9])[CH:3]=1
Reactant: COc1ccc(Cl)c(C=O)c1
Reactant: Clc1cc(Br)ccc1I
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1ccc(Cl)c(C(O)c2ccc(Br)cc2Cl)c1
Temperature: -40 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-bromo-2-chloro-1-iodo-benzene (10.0 g, 31.5 mmol) in THF (120 ml) was added 2 M solution of isopropylmagnesium chloride in THF (17.3 ml, 34.60 mmol) at −65° C. The reaction mixture was stirred at −40° C. for 20 min. After 2-chloro-5-methoxy-benzaldehyde (5.5 g, 32.20 mmol) was added, the reaction mixture was warmed to room temperature and stirred overnight. Then the solution was quenched with saturated aqueous solution of NH4Cl. The aqueous phase was extracted twice with diethyl ether. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The crude material was purified by chromatography (petroleum ether/CH2Cl2 1:1) to provide title compound as a yellowish oil.
Reaction SMILES: CO[C:3](OC)([CH3:29])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)[NH:12][S@@](C(C)(C)C)=O.O1CCOCC1.C(OC)(OC)OC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.Cl>[CH3:29][CH:3]1[CH2:4][C:5]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:11]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[NH:12]1
Reactant: COC(C)(Cc1ccccc1C(N[S@](=O)C(C)(C)C)c1ccc(C(F)(F)F)cc1)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: C1COCCO1
Solvent: ClCCCl
Product: CC1Cc2ccccc2C(c2ccc(C(F)(F)F)cc2)N1
Reaction time: 0.33 h

Procedure:
(R)—N-((2-(2,2-Dimethoxypropyl)phenyl)(4-(trifluoromethyl)phenyl)methyl)-2-methylpropane-2-sulfinamide (6.650000 g, 15 mmol) was dissolved in 150 mL of DCE and hydrogen chloride, 4.0 m solution in 1,4-dioxane (11 mL, 44 mmol) was added. Stirring was continued for 20 min and trimethyl orthoformate (8.0 mL, 73 mmol) and sodium triacetoxyborohydride (11 g, 51 mmol) were added. TLC-analysis showed a complex product mixture but LCMS showed the formation of some desired product along with a lot of fully aromatized product. The crude was semi-purified via glass colm chrom and used w/o further clean up in the next steps. MS (ESI, positive ion) m/z: 292.0 (M+1)
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH:4]([NH:12][C:13]1[C:22]2[C:17](=[C:18]([C:24]([NH2:26])=[O:25])[CH:19]=[C:20]([OH:23])[CH:21]=2)[N:16]=[CH:15][N:14]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:34](Br)[CH3:35]>CN(C=O)C>[CH3:1][N:2]([CH3:27])[CH2:3][CH:4]([NH:12][C:13]1[C:22]2[C:17](=[C:18]([C:24]([NH2:26])=[O:25])[CH:19]=[C:20]([O:23][CH2:34][CH3:35])[CH:21]=2)[N:16]=[CH:15][N:14]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1
Reactant: CN(C)CC(Nc1ncnc2c(C(N)=O)cc(O)cc12)c1cccc(F)c1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOc1cc(C(N)=O)c2ncnc(NC(CN(C)C)c3cccc(F)c3)c2c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
A Wheaton vial equipped with a stir bar was charged with 4-[2-dimethylamino-1-(3-fluoro-phenyl)-ethylamino]-6-hydroxy-quinazoline-8-carboxylic acid amide, (37 mg, 0.1 mmol) Cs2CO3, (100 mg, 0.3 mmol) and dry DMF, (1 mL). The mixture was heated at 60° C. for 1 h. It was then cooled to RT and ethylbromide (11 mg, 0.1 mmol) was added a solution in DMF (0.5 mL). The mixture was left to stir overnight. After 18 h, LCMS indicated consumption of SM. The mixture was diluted with EtOAc, (30 mL) and added to water, (30 mL). The phases were separated and the aqueous was extracted with EtOAc, (30 mL) (×2). The EtOAc phase was washed with sat. LiCl, (30 mL) dried (Na2SO4) and the solvent was evaporated under reduced pressure. The material was purified by chromatography using a 4 g silica cartridge eluting with DCM-[DCM-MeOH—NH4OH (9:1:0.1)], gradient 0 to 100% cocktail. Amount obtained: 6 mg, 0.015 mmol, 15% yield.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=2)[C:9]2[C:4](=[CH:5][C:6]([O:21][CH3:22])=[C:7]([O:19][CH3:20])[CH:8]=2)[N:3]=1.O1CCCC1.C(O)(C)C.[CH3:32][NH2:33]>CO>[NH2:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:21][CH3:22])=[C:7]([O:19][CH3:20])[CH:8]=3)[N:3]=[C:2]([CH2:32][NH2:33])[N:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cc2nc(Cl)nc(-c3cccc(N)c3)c2cc1OC
Reactant: CN
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: CO
Product: COc1cc2nc(CN)nc(-c3cccc(N)c3)c2cc1OC
Temperature: 90 °C
Reaction time: 15 h
Yield: 38.7 %

Procedure:
Two hundred grams of crude 3-(2-chloro-6,7-dimethoxyquinazolin-4-yl)phenylamine (content 124 g; 0.394 mol) was suspended in a mixed solution consisting of 1.2 L of tetrahydrofuran and 0.6 L of isopropanol. To the mixture was added 1.2 L of a methylamine solution in methanol, and the mixture was stirred in a SUS autoclave at 90° C. for 15 hours. The reaction mixture was allowed to cool down to 25° C., and concentrated under reduced pressure. To the residue were added 1.0 L of water and 4.0 L of chloroform, and the mixture was stirred at 50° C. for 0.5 hours and allowed to cool down to 25° C. The mixture was filtered through celite to remove the insoluble matter, and the filtrate was transferred to separatory funnel and the organic layer was separated. To the separated organic layer were added 50.0 g of anhydrous magnesium sulfate and 20.0 g of activated carbon, and the mixture was stirred at 50° C. for 1 hour and allowed to cool down to 25° C. The mixture was filtered through celite to remove the insoluble matter, and the filtrate was concentrated under reduced pressure. To the residue was added 904 mL of chloroform, and the mixture was stirred at 50° C. for 1 hour and stirred overnight after turning off the heater. Then the mixture was stirred in an ice bath for 2 hours and precipitated crystals were collected by filtration. The collected crystals were dried at 50° C. under reduced pressure to yield 76.3 g of a product of interest. Yield: 38.7%
Reaction SMILES: C1COCC1.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:23])O[C:14]=2[C:24]([OH:26])=[O:25])=[CH:9][CH:8]=1.Br.[Br:28][CH2:29][CH2:30][CH2:31][NH2:32].C(N(CC)CC)C>CO>[Br:28][CH2:29][CH2:30][CH2:31][N:32]1[C:14]([C:24]([OH:26])=[O:25])=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH3:6])=[CH:8][CH:9]=2)[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:23]
Reactant: NCCCBr
Reactant: Cc1ccc(-c2c(C(=O)O)oc(=O)c3ncccc23)cc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(C(=O)O)n(CCCBr)c(=O)c3ncccc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.2 %

Procedure:
A THF (5 ml) solution of 5-(4-methylphenyl)-8-oxo-8H-pyrano[3,4-b]pyridine-6-carboxylic acid (150 mg) was dropwise added to a mixture of 3-bromopropylamine hydrobromide (1.5 g), triethylamine (2.0 ml) and methanol (5 ml), and stirred at room temperature for 2 hours. Then, the solvent was removed by distillation. Hydrochloric acid (10 ml) was added to the residue, stirred for 14 hours at room temperature and then concentrated. The resulting concentrate was adjusted the pH to 1 with 1 N-NaOH. The crystals thus precipitated were taken out by filtration and washed with water to obtain 7-(3-bromopropyl)-7,8-dihydro-5-(4-methylphenyl)-8-oxo-6-pyrido[3,4-b]pyridinecarboxylic acid as colorless crystals (131 mg).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:20])[C@H:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[NH2:14].C(N(CC)CC)C>C(Cl)Cl.O>[CH3:10][O:11][C:12](=[O:20])[CH:13]([NH:14][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)C[C@H](N)C(=O)OC
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)CC(NC(=O)c1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
A mixture of benzoyl chloride (3.20 mL, 27.7 mmol), L-aspartic acid dimethyl ester (5.0 g, 25.2 mmol) and triethyl amine (5.3 mL, 38 mmol) in CH2Cl2 (50 mL) was stirred at ambient temperature for 2 h and diluted with water. The organic layer was dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (hexanes/EtOAc 1/1) to afford a white solid (5.3 g, 79%). MS (ESI) m/z 266 (M+H)+.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[N:9][O:10][CH2:11][CH2:12][OH:13])[CH3:8])[CH:2]=1.O[C:21]1[CH:53]=[CH:52][C:24]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]2=[O:51])=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[N:9][O:10][CH2:11][CH2:12][O:13][C:21]2[CH:53]=[CH:52][C:24]([CH2:25][CH:26]3[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]3=[O:51])=[CH:23][CH:22]=2)[CH3:8])[CH:2]=1
Reactant: CC(=NOCCO)c1cccc(-c2ccccc2)c1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1cccc(-c2ccccc2)c1
Yield: 84.7 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 511 mg of 2-[1-(3-biphenylyl)ethylideneaminooxy]ethanol (prepared as described in Preparation 16), 716 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 525 mg of triphenylphosphine and 348 mg of diethyl azodicarboxylate, 916 mg of the title compound were obtained as an amorphous solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10]([CH3:14])([CH3:13])[CH2:11][OH:12])[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.C1(C)C=CC=CC=1>CC(N(C)C)=O>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][O:12][CH2:11][C:10]([NH:9][CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)([CH3:14])[CH3:13])=[CH:20][CH:19]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC(C)(CO)NCCCn1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: CC(C)(COCc1ccc(Cl)cc1)NCCCn1ccnc1
Temperature: 30 °C
Reaction time: 0.75 h

Procedure:
A solution of 2-[3-(imidazol-1-yl)propylamino]-2-methyl-1-propanol (1.5 g) in dimethyl acetamide (10 ml) was added dropwise to a stirred suspension of sodium hydride (0.32 g of a 60% dispersion in mineral oil) in dimethyl acetamide (15 ml) at 30° C. under nitrogen. The mixture was stirred for 45 minutes at 30° C. and then a solution of 4-chlorobenzyl chloride (1.63 g) in dimethyl acetamide (5 ml) was added. After the addition, the mixture was heated at 100°-105° C. for 30 minutes and then cooled to 25° C. Toluene (50 ml) was added and the mixture was washed with water. The toluene layer was extracted with 5M hydrochloric acid. The combined acid extracts were basified with concentrated sodium hydroxide solution with cooling and extracted with dichloromethane to give an oil which was distilled under high vacuum to give N-[2-(4-chlorobenzyloxy)-1,1-dimethylethyl]-3-(imidazol-1-yl)propylamine, b.p. 180°-185° C. at 0.3 mbar.