Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([C:16]([F:19])([F:18])[F:17])=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[CH3:27][O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>CN(C)C=O.Cl>[Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([NH:33][C:32]2[CH:34]=[CH:35][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)[C:9]2[C:4](=[CH:5][C:6]([C:16]([F:19])([F:18])[F:17])=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2cc(C(F)(F)F)ccc2c1Cl
Reactant: COc1ccc(N)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(Nc2c([N+](=O)[O-])c(Cl)nc3cc(C(F)(F)F)ccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 2,4-dichloro-3-nitro-7-trifluoromethyl-quinoline (220 mg; 0.70 mmol; 1 eq) in dimethylformamide (3.5 mL), are added successively triethylamine (105 μL; 0.76 mmol; 1.08 eq) and 4-methoxyaniline (88 mg; 712 mmol; 1.01 eq.). The reaction mixture is allowed to stir for 1 hour at room temperature until the reaction is complete on TLC. The crude solution is diluted with a 1M aqueous solution of HCl (5 mL) and then extracted with ethyl acetate (40 mL). The organic layer is separated and washed 3 times with a 1M aqueous solution of HCl (3×40 mL), dried over sodium sulfate, filtrated and concentrated under vacuum to afford the title compound as a yellow powder (280 mg; 0.70 mmol; 100%) which is used without further purification.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH3:9])[CH2:4]1.[Mg].[F:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#N)=[CH:14][CH:13]=1.Cl.[O:21]1CCCC1>O>[F:11][C:12]1[CH:19]=[CH:18][C:15]([C:16](=[O:21])[CH2:2][CH:3]2[CH2:8][CH2:7][CH2:6][N:5]([CH3:9])[CH2:4]2)=[CH:14][CH:13]=1
Reactant: CN1CCCC(CCl)C1
Reactant: C1CCOC1
Reactant: N#Cc1ccc(F)cc1
Agent: Cl
Agent: [Mg]
Solvent: O
Product: CN1CCCC(CC(=O)c2ccc(F)cc2)C1
Temperature: 10 °C
Reaction time: 3 h

Procedure:
25 A solution of 33.7 g of 3-chloromethyl-N-methylpiperidine in 80 ml of tetrahydrofuran is added under nitrogen to 5.55 g of magnesium suspended in 25 ml of tetrahydrofuran. The mixture is brought to reflux for 2 hours, then cooled to 10° C. and a solution containing 30.5 g of 4-fluorobenzonitrile dissolved in 100 ml of tetrahydrofuran is added. The mixture is brought to 40° C. for 3 hours and then hydrolyzed with a solution of 68 ml of hydrochloric acid (d =1.18) in 42 ml of water. The mixture is heated to reflux for 1 hour, cooled and extracted with ethyl ether. After removal of the organic phase, the aqueous phase is alkalinized (pH 9) using caustic soda solution and filtered on celite, and the aqueous phase is extracted with dichloromethane, dried over sodium sulfate and concentrated to obtain an oil.
Reaction SMILES: O.[CH3:2][N:3]([C:5]([CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:7])[CH3:6])[CH3:4].[CH3:13][I:14]>ClCCl>[I-:14].[CH3:4][N+:3]([C:5]([CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:6])[CH3:7])([CH3:13])[CH3:2]
Reactant: CI
Reactant: CN(C)C(C)(C)CC(C)(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)CC(C)(C)[N+](C)(C)C
Product: [I-]
Reaction time: 24 h

Procedure:
To a stirred and cooled (water bath) solution of N,N-dimethyl t-octylamine (5 g, 31.8 mmol) in dichloromethane (30 mL) was added methyl iodide (6.7 g, 47.7 mmol) drop-wise. A slight increase in temperature was observed along with the formation light yellow precipitate. Stirring was continued for 24 h at room temperature, and at the end of this period, the solvent and excess methyl iodide were evaporated to produce a light yellow powder. This solid was washed with excess of n-pentane (3×75 mL), filtered, and suction dried (9.0 g, 95%). mp: ca. 260° C. (by DSC). 1H NMR (CDCl3): δ3.33 (s, 9H, —N+(CH3)3), 1.82 (s, 2H, —CH2—), 1.61 (bt, 6H, —C(CH3)2—), 1.12 (s, 9H, —C(CH3)3) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](B(O)O)[CH:5]=[CH:4][N:3]=1.Br[C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:37])[C@@H:21]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:15]=[C:16]([Cl:18])[CH:17]=1.[F-].[Cs+].COCCOC>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>[Cl:18][C:16]1[CH:15]=[C:14]([NH:19][C:20](=[O:37])[C@@H:21]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:13]=[C:12]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)[CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1cc(Cl)cc(Br)c1
Reactant: Cc1cc(B(O)O)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: Cc1cc(-c2cc(Cl)cc(NC(=O)[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)c2)ccn1
Temperature: 85 °C
Yield: 66.2 %

Procedure:
2-methylpyridin-4-ylboronic acid (327 mg, 2.39 mmol), (S)-tert-butyl 1-(3-bromo-5-chlorophenylamino)-1-oxo-3-phenylpropan-2-ylcarbamate (542 mg, 1.19 mmol), tetrakis(triphenylphosphine)palladium (345 mg, 0.30 mmol), cesium fluoride (544 mg, 3.58 mmol) were added to a vial then DME (4778 μl, 1194 μmol) was added and the mixture was heated to 85° C. for 8 h. The reaction was loaded and purified on Phenomenex Geminni C18 HPLC 50 mm×250 mm running ACN/Water/0.1% TFA in a linear gradient. The fractions containing the desired product were combined and concentrated to afford tert-butyl (S)-1-(3-chloro-5-(2-methylpyridin-4-yl)phenylamino)-1-oxo-3-phenylpropan-2-ylcarbamate (367 mg, 66% yield). tert-butyl (S)-1-(3-chloro-5-(2-methylpyridin-4-yl)phenylamino)-1-oxo-3-phenylpropan-2-ylcarbamate (367 mg, 0.78 mmol) was dissolved in DCM (3 mL) and TFA (1 mL) add stirred for 3 h. The solution was concentrated to afford (2S)-2-amino-N-(3-chloro-5-(2-methylpyridin-4-yl)phenyl)-3-phenylpropanamide (280 mg, 99%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:7](=[O:18])[O:8][C:9]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[C:10]=2[C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4].Br[CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH2:1]([O:5][C:6]1[C:7](=[O:18])[O:8][C:9]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:10]=2[C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)CCBr
Reactant: CCCCOc1c(O)c2c(O)cccc2oc1=O
Product: CCCCOc1c(O)c2c(OCCC(=O)OCC)cccc2oc1=O

Procedure:
In the same manner as in Reference Example 3, except that an equimolar amount of 3-butoxy-4,5-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-hexyloxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and ethyl 3-bromopropionate was used in place of ethyl bromoacetate in Reference Example 3, 3-butoxy-4-hydroxy-5-(2-ethoxycarbonylethoxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.Cl.[N:15](OCCC(C)C)=[O:16]>C(O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[N:15]=[O:16]
Reactant: Cc1cc(N)n(-c2ccccc2)n1
Reactant: CC(C)CCON=O
Agent: Cl
Solvent: CCO
Product: Cc1nn(-c2ccccc2)c(N)c1N=O
Reaction time: 4 h

Procedure:
To a solution of 17.3 g (0.1 mol) of 5-amino-3-methyl-1-phenylpyrazole in 200 cm3 of absolute ethanol were added dropwise 0.5 cm3 of 12N hydrochloric acid and then 13.5 cm3 of isoamyl nitrite, at 0° C. The solution was then warmed to and left at room temperature for 4 hours. An orange-coloured solid crystallized out. This solid was filtered off on a sinter funnel and washed with 100 cm3 of isopropyl ether. After drying under vacuum at room temperature, 17 g of 5-amino-3-methyl-4-nitroso-1-phenylpyrazole were obtained in the form of an orange-coloured solid, the melting point of which was from 202 to 204° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([O:11][CH2:12][C:13]([O:15]CC)=[O:14])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[OH-].[Na+]>C(O)C>[CH:1]1[C:10]2[C:5](=[C:6]([O:11][CH2:12][C:13]([OH:15])=[O:14])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CCOC(=O)COc1cccc2cnccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1cccc2cnccc12
Reaction time: 12 h

Procedure:
In 10 ml of acetonitrile, 1.0 g of 5-hydroxyisoquinoline and 1.52 ml of ethyl bromoacetate were added in the presence of 2.07 ml of DBU and the resultant mixture was refluxed for 8 hr. The reaction mixture was evaporated under reduced pressure and the resultant residue was redissolved in 1N-HCl, washed with ethyl acetate. The aqueous layer was made alkaline with sodium hydrogencarbonate and extracted with ethyl acetate. The extract was washed with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The dried solution was evaporated under reduced pressure and subjected to a silica gel column chromatography (chloroform) to give 1.46 g of ethyl 5-isoquinolyloxyacetate. The ester was dissolved in 30 ml of ethanol, mixed with 6.5 ml of 1N-NaOH aqueous solution and stirred for 12 hr. The reaction mixture was evaporated under reduced pressure, neutralized by the addition of 1N-HCl and the precipitated crystals were filtered, washed with water and dried to give 0.68 g of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]([C:18]3[N:27]=[C:26]([NH:28][C:29]4[CH:30]=[C:31]5[C:35](=[CH:36][CH:37]=4)[N:34](C(OC(C)(C)C)=O)[N:33]=[CH:32]5)[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)[CH:15]=[CH:16][CH:17]=2)=[O:10])[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:34]1[C:35]2[C:31](=[CH:30][C:29]([NH:28][C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=[C:18]([C:14]4[CH:13]=[C:12]([NH:11][C:9](=[O:10])[CH2:8][N:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)[CH:17]=[CH:16][CH:15]=4)[N:27]=3)=[CH:37][CH:36]=2)[CH:32]=[N:33]1
Reactant: CN1CCN(CC(=O)Nc2cccc(-c3nc(Nc4ccc5c(cnn5C(=O)OC(C)(C)C)c4)c4ccccc4n3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(CC(=O)Nc2cccc(-c3nc(Nc4ccc5[nH]ncc5c4)c4ccccc4n3)c2)CC1

Procedure:
To tert-butyl 5-(2-(3-(2-(4-methylpiperazin-1-yl)acetamido)phenyl)-quinazolin-4-ylamino)-1H-indazole-1-carboxylate (22 mmol) was added a solution of 1:1 TFA:CH2Cl2 (2 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the crude product was purified by prep HPLC (method 10-35—90 mins) to afford N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-2-(4-methylpiperazin-1-yl)acetamide. (33 mg, 33%)
Reaction SMILES: C(OC(N1CCC[C@@H]1C(O)=O)=O)(C)(C)C.[Cl:16][C:17]1[CH:18]=[C:19]([CH:34]=[CH:35][C:36]=1[Cl:37])[C:20]([C@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=O.BrC1C=CC(Cl)=C(Cl)C=1.CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.[C:68]1(=[O:78])[C:76]2[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=2)[C:70](=[O:77])[NH:69]1>>[Cl:16][C:17]1[CH:18]=[C:19]([C@H:20]([N:69]2[C:70](=[O:77])[C:71]3[C:76](=[CH:75][CH:74]=[CH:73][CH:72]=3)[C:68]2=[O:78])[C@H:22]2[CH2:26][CH2:25][CH2:24][N:23]2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:34]=[CH:35][C:36]=1[Cl:37]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)c1ccc(Cl)c(Cl)c1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: Clc1ccc(Br)cc1Cl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1[C@H](c1ccc(Cl)c(Cl)c1)N1C(=O)c2ccccc2C1=O

Procedure:
(R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid and be converted to (R)-tert-butyl 2-(3,4-dichlorobenzoyl)-pyrrolidine-1-carboxylate in accord with steps 1 and 2 of example 11, except in step 2,4-bromo-1-(trifluoromethyl)benzene was replaced with 1-bromo-3,4-dichlorobenzene. Reduction of the ketone with (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole and condensation with isoindoline-1,3 dione can be carried out in accord with procedures in steps 4 and 5 of example 11 to afford (R)-tert-butyl 2-((S)-(3,4-dichlorophenyl)(1,3-dioxoisoindolin-2-yl)methyl)pyrrolidine-1-carboxylate (242).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([Br:26])[C:22]([N+:23]([O-])=O)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][CH:29]1[CH2:34][CH2:33][CH2:32]N[CH2:30]1>CN(C=O)C>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([Br:26])[C:22]([N:23]3[CH2:32][CH2:33][CH2:34][CH:29]([CH3:30])[CH2:28]3)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2cccc3c([N+](=O)[O-])c(Br)cc(c23)C(=O)N1OCc1ccccc1
Reactant: CC1CCCNC1
Solvent: CN(C)C=O
Product: CC1CCCN(c2c(Br)cc3c4c(cccc24)C(=O)N(OCc2ccccc2)C3=O)C1
Yield: 86.9 %

Procedure:
To a solution of 2-benzyloxy-5-bromo-6-nitro-benzo[de]isoquinoline-1,3-dione (0.50 g, 1.2 mmol, from Example S1-A) in DMF (5 mL) was added 3-methylpiperidine (0.47 g, 4.7 mmol). The reaction was reacted at 120° C. for 5 hours, cooled, and concentrated under vacuum. The resulting residue was purified by column chromatography on silica gel using hexane/ethyl acetate (5:1) to give 0.50 g of the title compound.
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][C:7]1=O)=[O:5])C.FC(F)(F)C([O-])=O.[CH2:28]([N+:30]([CH2:34][CH3:35])=[C:31]([NH2:33])[NH2:32])[CH3:29].[O-]CC.[Na+]>CCO.O>[C:16]([O:15][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C:6]2[C:4]([OH:5])=[N:32][C:31]([N:30]([CH2:34][CH3:35])[CH2:28][CH3:29])=[N:33][C:7]=2[CH2:8]1)=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)CC1=O
Reactant: CC[N+](CC)=C(N)N
Agent: CC[O-]
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCN(CC)c1nc(O)c2c(n1)CN(C(=O)OC(C)(C)C)CCC2
Temperature: 25 °C
Yield: 0 %

Procedure:
To a solution of 3-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (0.67 g, 2.3 mmol) in EtOH (10 mL) was added diethyl guanidinium trifluoroacetate (0.54 g, 2.3 mmol) and sodium ethoxide (21 wt % in EtOH, 2.3 mL). The reaction was heated at reflux for 16 h then cooled to room temperature (rt). The reaction mixture was diluted with H2O and extracted with CH2Cl2 (2×). The combined organic extracts were dried and concentrated. The resulting material was triturated with hexanes/Et2O (9:1) to give the title compound (0.334 mg, 43%) as a light brown solid. MS (ESI): mass calcd. for C17H28N4O3, 336.4; m/z found, 337.4 [M+H]+. 1H NMR (CDCl3): 4.34-4.25 (m, 2H), 3.62-3.46 (m, 6H), 2.66-2.58 (m, 2H), 1.88-1.77 (m, 2H), 1.50-1.36 (m, 9H), 1.21-1.14 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20].[OH-].[Na+]>C(Cl)(Cl)Cl>[ClH:1].[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=1[C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:20]
Reactant: O=C(c1ccccc1)c1ccccc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccccc3C(=O)c3ccccc3)c2cc1OC
Product: Cl
Temperature: 25 °C
Yield: 10 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (0.92 g) and 2-hydroxybenzophenone (1.64 g) were stirred at 180° C. for one hr, and the reaction solution was cooled to room temperature. Chloroform was then added to the reaction solution, and separation was carried out with a 10% aqueous sodium hydroxide solution. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography on silica gel using hexane-acetone. Thereafter, 10% hydrochloric acid-methanol (10 ml) was added to the product, followed by concentration. The concentrate was suspended in ether. The suspension was filtered to give the title compound (174 mg, yield 10%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH3:20])[N:12]=[CH:11][NH:10][C:9]2=O)[CH2:2][CH2:3][CH3:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:42].[C:46]([C:48]1[CH:49]=[C:50]([CH:52]=[CH:53][CH:54]=1)[NH2:51])#[CH:47]>C(O)(C)C>[ClH:42].[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH3:20])[N:12]=[CH:11][N:10]=[C:9]2[NH:51][C:50]1[CH:52]=[CH:53][CH:54]=[C:48]([C:46]#[CH:47])[CH:49]=1)[CH2:2][CH2:3][CH3:4]
Reactant: ClC(Cl)(Cl)Cl
Reactant: C#Cc1cccc(N)c1
Reactant: CCCCOc1cc2nc[nH]c(=O)c2cc1OCCCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)O
Product: C#Cc1cccc(Nc2ncnc3cc(OCCCC)c(OCCCC)cc23)c1
Product: Cl

Procedure:
6,7-Dibutoxyquinazolin-4-one (105 mg, 0.362 mmol), triphenylphosphine (208 mg, 0.796 mmol) and 5 mL of carbon tetrachloride were refluxed for 16 hours and the reaction mixture was concentrated in vacuo to a residue which was diluted with 3 mL of isopropyl alcohol and 3-ethynylaniline (47 mg, 0.398 mmol) and refluxed for 3 hours. The cooled reaction mixture was filtered to afford solid (6,7-dibutoxy-quinazolin-4-yl)-(3-ethynyl-phenyl)-amine hydrochloride which was washed with 10 mL of isopropyl alcohol and dried in vacuo at 70° C., 92 mg (60%); mp 247°-248° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([O-])=[O:26])=[CH:23][CH:22]=4)[CH:15]=3)[CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)(C)C(Cl)=O.[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(=O)(O)[O-].[Na+]>C1COCC1.C(N(CC)CC)C>[C:38]1([NH:37][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([CH2:20][O:19][C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[CH2:10][CH:9]([CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:18][CH2:17]4)=[CH:29][CH:28]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C([O-])c1ccc(COc2ccc3c(c2)CCC(CCN2CCCCC2)C3)cc1
Reactant: Nc1ccccc1
Agent: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)c1ccc(COc2ccc3c(c2)CCC(CCN2CCCCC2)C3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
Triethylamine (0.11 ml) was added to THF suspension (3 ml) of 4-[[2-(2-piperidinoethyl)-6-tetralinyl]oxymethyl]benzoate (300 mg). Further, THF solution (0.5 ml) of trimethylacetyl chloride (92 mg) was added dropwise under ice-cooling, which was stirred for 30 minutes. The temperature of the reaction mixture was raised to room temperature, which was stirred for 1 hour. THF solution (0.5 ml) of aniline (85 mg) was added dropwise to the reaction mixture under ice-cooling, which was stirred for 1 hour. After the reaction mixture was stirred for 24 hours at room temperature, saturated sodium bicarbonate solution was added, and extraction was conducted using a mixed solution of ethyl acetate and THF. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was recrystallized from THF-methanol-IPE to give the titled compound (150 mg).
Reaction SMILES: [OH:1][C:2]1([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][C:14]=2[OH:22])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].[C:23](Cl)(=[O:26])[CH2:24][CH3:25].C(N(CC)CC)C.[CH2:35]1C[O:38][CH2:37][CH2:36]1>>[C:23]([O:22][C:14]1[CH:15]=[C:16]([CH:19]([CH3:20])[CH3:21])[CH:17]=[CH:18][C:13]=1[C:2]1([O:1][C:37](=[O:38])[CH2:36][CH3:35])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12])(=[O:26])[CH2:24][CH3:25]
Reactant: CC(C)c1ccc(C2(O)C(=O)c3ccccc3C2=O)c(O)c1
Reactant: C1CCOC1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Product: CCC(=O)Oc1cc(C(C)C)ccc1C1(OC(=O)CC)C(=O)c2ccccc2C1=O
Yield: 17 %

Procedure:
2-hydroxy-2-(2-hydroxy-4-isopropyl-phenyl)-indan-1,3-dione (1.00 g, 3.37 mmol) was completely dissolved in anhydrous THF (20 ml). This solution was added with propionyl chloride (0.62 g, 6.74 mmol), and triethylamine (0.41 g, 4.04 mmol), followed by heating 12 hrs under reflux. After the reaction mixture was concentrated, extracted with dichloromethane, and the organic layer was concentrated and purified using column chromatography (ethylacetate:hexane=1:4) to afford the title compound (White, 0.23 g, 17%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH:13]=O)[C@H:10]([C:15]([CH3:23])([CH3:22])[O:16][SiH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:24]([NH2:27])([CH3:26])[CH3:25].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:27][CH:24]([CH3:26])[CH3:25])[C@H:10]([C:15]([CH3:23])([CH3:22])[O:16][SiH2:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C=O)[C@H](C(C)(C)O[SiH2]C(C)(C)C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)NC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(C)(C)O[SiH2]C(C)(C)C
Reaction time: 5 h

Procedure:
A solution of (3S,4S)-3-(tert-butyl-dimethyl-silanyloxymethyl)-4-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (7.7 g, 22.41 mmol) and isopropylamine (5.78 mL, 67.24 mmol) in 1,2-dichloroethane (200 mL) is stirred 25 min before the addition of NaBH(OAc)3 (11.88 g, 56.03 mmol). The solution is stirred for 5 h, then diluted with CH2Cl2 and washed with an aqueous saturated solution of NaHCO3. The aqueous layer is back extracted twice with CH2Cl2 and the combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude material is used in the next step without further purification. TLC, Rf (CH2Cl2/MeOH 9:1)=0.39. MS (LC-MS): 387.2 [M+H]+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[C:15]([O:17][CH3:18])=[O:16].[CH3:19][C@H:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[C:21]1([C@@H:20]([NH:27][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]2[C:15]([O:17][CH3:18])=[O:16])[CH3:19])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: C[C@H](N)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N[C@@H](C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
1-tert-Butyl 3-methyl 4-oxopiperidine-1,3-dicarboxylate (13.29 g, 51.6 mmol, 1 eq.), (S)-(−)-α-methylbenzylamine (6.66 mL, 51.6 mmol, 1 eq.), acetic acid (5.91 mL, 103.0 mmol, 2 eq.) and benzene (200 mL) were mixed at room temperature then refluxed using a Dean-Stark trap for 4 hours. Cooled to 0° C. Added acetic acid (23.66 mL, 412.8 mmol, 8 eq.) followed by the addition of sodium triacetoxyborohydride (21.90 g, 103.0 mmol, 2 eq.). Stirred for 20 minutes at 0° C. then allowed the reaction to warm to room temperature and stirred for 20 hours. Worked up by carefully (foaming) adding sodium carbonate until the pH=10. Extracted the aqueous 3 times with ethyl acetate. The ethyl acetate layers were combined, rinsed once with brine, then dried over sodium sulfate and stripped to give (3R,4S)-1-tert-butyl 3-methyl 4-((1S)-1-phenylethylamino)-piperidine-1,3-dicarboxylate (18.7 g) of an oil as product. Yield=100%. Mass Spec (ESI) detects (M+H)+=363.2.