Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:48][O:49][C:50](=[O:55])[C:51]([NH2:54])([CH3:53])[CH3:52]>CN(C=O)C.O>[CH3:48][O:49][C:50](=[O:55])[C:51]([NH:54][C:22](=[O:24])[C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:26][CH:25]=1)([CH3:53])[CH3:52]
Reactant: COC(=O)C(C)(C)N
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)C(C)(C)NC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 70.2 %

Procedure:
DIPEA (407 mg, 0.28 mL, 3.15 mmol) was added to a stirred solution of 4-benzyloxy-benzoic acid (200 mg, 0.87 mmol)(prepared by the method as described above) in DMF (2 mL). HOBT (142 mg, 1.05 mmol) and EDCI (201 mg, 1.05 mmol) were then added at room temperature. After 2 minutes, 2-amino-2-methyl-propionic acid methyl ester (161 mg, 1.05 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and filtered the solid precipitated out to afford 200 mg (70% yield) of 2-(4-benzyloxy-benzoylamino)-2-methyl-propionic acid methyl ester. LCMS Purity: 93%.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[Br-].O>CN(C)C=O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Sc1ccccn1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(Sc2ccccn2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.22 g of 2-mercaptopyridine and 0.96 g of 50% sodium hydride were dissolved in 50 ml of dimethylformamide, and the mixture was stirred at room temperature for one hour. Thereafter, 13.0 g of polyprenyl bromide of general formula (II) in which n=15 and A=Br were added. After the addition, the mixture was stirred overnight at room temperature. The reaction mixture was poured into about 50 ml of water and extracted with diethyl ether. The diethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The ether was distilled off to give a yellow liquid. The liquid was purified by silica gel column chromatography using hexane-ethyl acetate as the eluent to give 7.8 g of a slightly yellow liquid. NMR analysis of this liquid demonstrated that the signal (doublet, δ=3.91) assignable to --CH2Br of the starting polyprenyl bromide had disappeared and a signal (doublet, δ=3.78) assignable to --CH2S and a signal (multiplet, δ=6.75-8.35) assignable to --S--C5H4N had newly appeared. FD-MASS of this liquid gave m/e=1335.
Reaction SMILES: [N+:1]([CH2:4][CH:5]([CH3:9])[CH:6](C)O)([O-:3])=[O:2].[CH3:10][NH2:11]>>[CH3:10][NH:11][CH2:6][CH:5]([CH2:4][N+:1]([O-:3])=[O:2])[CH3:9]
Reactant: CC(O)C(C)C[N+](=O)[O-]
Reactant: CN
Product: CNCC(C)C[N+](=O)[O-]

Procedure:
2-Nitromethylmethylpropanol is reacted with methylamine to form N-methyl-2-nitromethylpropylamine which is hydrogenated to the diamine. The latter is then reacted with acetic acid to form 1,2,4,4-tetramethyl-2-imidazoline. It is tested as a polyurethane foam catalyst by the method of Example 1 and is found to be effective.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12]
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Reactant: Fc1ccccc1
Product: O=S(=O)(c1ccc(F)cc1)c1ccc(Br)c(F)c1
Temperature: 25 °C

Procedure:
Ferric chloride (0.5 g) was added to a mixture of 4-bromo-3-fluoro-benzenesulfonyl chloride (2.5 g) and fluorobenzene (3 ml) and then stirred at reflux for 18 hours. The flask was cooled to room temperature and the residue was partitioned between aqueous NaHCO3 and DCM, The DCM layer was washed with brine, dried (MgSO4) and evaporated under reduced pressure. The residue was recrystallised from ethanol to give buff coloured crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][NH:5][CH2:6][CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[NH:17]([C:47]([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:48])[C@H:18]([C:44](O)=[O:45])[CH2:19][C:20]1[N:24]=[CH:23][N:22]([C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C)C=O>[CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]([C:44](=[O:45])[C@@H:18]([NH:17][C:47]([O:49][CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)=[O:48])[CH2:19][C:20]1[N:24]=[CH:23][N:22]([C:25]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:21]=1)[CH2:6][CH2:7][NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10]
Reactant: COC(=O)CNCCNC(=O)OC(C)(C)C
Reactant: O=C(N[C@@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)CN(CCNC(=O)OC(C)(C)C)C(=O)[C@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
The product from Step 1 (0.67 g, 2.5 mmol) was dissolved in methylene chloride (10 mL) and Cbz-His(Trt)-OH (1.46 g, 2.75 mmol) was then added, followed by diisopropylethylamine (1.3 mL, 7.5 mmol), HATU (1.05 g, 2.76 mmol), HOAt (0.374 g, 2.75 mmol), and dimethylformamide (10 mL). The reaction was stirred overnight at room temperature. The solution was concentrated, the residue taken up in ethyl acetate and washed three times with saturated NaHCO3, brine, dried over MgSO4, filtered and concentrated in vacuo to give a white solid; 1.8 g (97% yield). MS-APCI: M+1=747.
Reaction SMILES: [CH:1]([N:4]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[C:8]([N+:17]([O-])=O)[CH:9]=2)([CH3:3])[CH3:2]>C(O)(=O)C.[Fe]>[CH:1]([N:4]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[C:8]([NH2:17])[CH:9]=2)([CH3:3])[CH3:2]
Reactant: CC(C)n1c2c(c3cc([N+](=O)[O-])ccc31)CCCC2
Agent: [Fe]
Solvent: CC(=O)O
Product: CC(C)n1c2c(c3cc(N)ccc31)CCCC2
Temperature: 50 °C
Reaction time: 3 h
Yield: 58.7 %

Procedure:
The N-isopropyl-6-nitro-1,2,3,4-tetrahydrocarbazole (2.60 g) was dissolved in 100 mL of acetic acid, and the solution was added with 2.75 g of iron powder, warmed to 50° C. and stirred for 3 hours. The reaction mixture was filtered, and the filtrate was diluted by addition of water. The reaction mixture was made basic with 1 N sodium hydroxide solution, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent: dichloromethane/ethyl acetate=7/3) to obtain 1.35 g of N-isopropyl-6-amino-1,2,3,4-tetrahydrocarbazole.
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:11]=[C:12]([NH:24][C:25]([NH:27][CH3:28])=[NH:26])[CH:13]=[CH:14][C:15]=1[O:16]CC1C=CC=CC=1)C1C=CC=CC=1>[Pd].C(O)C>[ClH:1].[OH:9][C:10]1[CH:11]=[C:12]([NH:24][C:25]([NH:27][CH3:28])=[NH:26])[CH:13]=[CH:14][C:15]=1[OH:16]
Reactant: CNC(=N)Nc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CNC(=N)Nc1ccc(O)c(O)c1
Reaction time: 4 h

Procedure:
1-(3',4'-Dihydroxyphenyl)-3-methylguanidine hydrochloride is prepared from a mixture of 28 gm (0.07 mole) of the 1-(3', 4'-dibenzyloxyphenyl)-3-methylguanidine hydrochloride (prepared in Example I), 1.0 gm of 5 percent palladium on charcoal, and 250 ml of ethyl alcohol. The mixture was shaken under an initial hydrogen pressure of 50 psi and, after 4 hours of agitation, the reaction mixture was filtered and the filtrate evaporated to a thick residue which solidified after standing 2 hours. This solid was purified by recrystallization from a mixture of ethyl alcohol and ether (3:2 ratio). The resulting white crystalline solid melted at 185°-8° C and the infrared spectrum was consistent with the assigned structure.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:11]=[C:12]([C:21]4[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=4)[NH:13][C:14]=3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C(Cl)(=O)C([Cl:33])=O>ClCCl.CN(C)C=O>[ClH:33].[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:11]=[C:12]([C:21]4[CH:29]=[CH:28][C:24]([C:25]([Cl:33])=[O:26])=[CH:23][CH:22]=4)[NH:13][C:14]=3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(-c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cl
Product: O=C(Cl)c1ccc(-c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(4-Benzo[1,3]dioxol-5-yl-5-pyridin-2-yl-1H-imidazol-2-yl)benzoic acid (379 mg; 0.98 mmol) was suspended in dry dichloromethane (20 ml) under argon and treated sequentially with oxalyl chloride (0.1 ml) then N,N-dimethylformamide (1 drop). The mixture was stirred at ambient temperature for 1 h. More oxalyl chloride (2×0.1 ml) was added at 1 h and 2 h and the mixture stirred at ambient temperature for 5 h. Volatiles were removed under reduced pressure to give the title compound as an orange powder: m/z (methyl ester; API): 400.3 (M+H)+.
Reaction SMILES: [OH-].[Na+].C(OC([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:25]3[C:20](=[CH:21][C:22]([N:26]4[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]4)=[CH:23][CH:24]=3)[N:19]([C:39]3[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=3)[CH:18]=2)=[CH:13][CH:12]=1)=O)(C)(C)C.O>CO>[OH:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[C:25]3[C:20](=[CH:21][C:22]([N:26]4[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]4)=[CH:23][CH:24]=3)[N:19]([C:39]3[CH:40]=[CH:41][N:42]=[CH:43][CH:44]=3)[CH:18]=2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)Oc1ccc(-c2cn(-c3ccncc3)c3cc(N4CCN(C(=O)OC(C)(C)C)CC4)ccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(-c4ccc(O)cc4)cn(-c4ccncc4)c3c2)CC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
2 N sodium hydroxide aqueous solution (18 μL, 0.035 mmol) was added to a mixture solution of tert-butyl 4-(3-(4-(tert-butoxycarbonyloxy)phenyl)-1-(pyridin-4-yl)-1H-indol-6-yl)piperazine-1-carboxylate (10 mg, 0.018 mmol) in methanol (0.5 mL) at room temperature. After stirring at room temperature for 3.5 hours, followed by addition of water, the mixture was extracted with ethyl acetate. The collected organic layer was washed with brine and concentrated under reduced pressure by drying with anhydrous magnesium sulfate. The target compound was obtained as white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=O)[CH3:5].[CH2:7]([O:9][C:10](=[O:20])[CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:8].C[Si]([C:25]#[N:26])(C)C>C(O)(=O)C>[CH2:7]([O:9][C:10](=[O:20])[CH2:11][N:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:4]([C:25]#[N:26])([CH3:5])[CH2:3][O:2][CH3:1])[CH3:8]
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: COCC(C)=O
Reactant: C[Si](C)(C)C#N
Solvent: CC(=O)O
Product: CCOC(=O)CN(Cc1ccccc1)C(C)(C#N)COC
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 500 μL (5.43 mmol) methoxyacetone and 1.05 g (5.43 mmol) N-benzylglycine ethyl ester in 2.0 mL acetic acid was added 780 μl (6.18 mmol) trimethylsilyl cyanide dropwise. The resulting mixture was stirred at 80° C. for 30 min and then poured into ice water. The water was decanted and the oily residue was triturated with DIPE. The precipitate was filtered off and the solvent was washed with saturated aqueous NaHCO3 solution, dried over sodium sulfate, filtered and concentrated in vacuo.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([F:14])=[CH:7][C:8]([F:13])=[C:9]([CH:12]=1)[C:10]#[N:11])=[O:4].[OH:15][CH2:16][C@H:17]1[NH:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1.CCN(C(C)C)C(C)C>C1COCC1>[C:10]([C:9]1[C:8]([F:13])=[CH:7][C:6]([F:14])=[C:5]([C:3](=[O:4])[CH2:2][N:22]2[CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:18][C@H:17]2[CH2:16][OH:15])[CH:12]=1)#[N:11]
Reactant: N#Cc1cc(C(=O)CBr)c(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)c2cc(C#N)c(F)cc2F)[C@H](CO)C1
Temperature: 20 °C
Reaction time: 10 h

Procedure:
A suspension of 5-(bromoacetyl)-2,4-difluorobenzonitrile (2.5 g, 9.6 mmol), tert-butyl (3S)-3-(hydroxymethyl)piperazine-1-carboxylate (2.1 g, 9.6 mmol) and DIEA (1.90 g, 14.4 mmol) in 50 mL of THF was stirred at 20° C. for 10 hours. The reaction mixture was poured into ice water and extracted with EtOAc (3×200 mL). The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by column chromatography eluting with 5% MeOH in DCM to afford the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH:3]=[CH:4][C:5]1[NH:6][C:7](=[O:29])[C:8]2[C:9]3[N:18]([CH3:19])[C:17]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[CH3:28])=[N:16][C:10]=3[CH:11]=[CH:12][C:13]=2[C:14]=1[CH3:15].[CH3:30][P:31]1(=[O:40])[CH2:36][CH2:35][CH:34]([C:37](O)=[O:38])[CH2:33][CH2:32]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(N(CC)CC)C.CN(C)C=O>[F:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:17]2[N:18]([CH3:19])[C:9]3[C:8]4[C:7](=[O:29])[NH:6][C:5]([CH:4]=[CH:3][CH2:2][NH:1][C:37]([CH:34]5[CH2:35][CH2:36][P:31]([CH3:30])(=[O:40])[CH2:32][CH2:33]5)=[O:38])=[C:14]([CH3:15])[C:13]=4[CH:12]=[CH:11][C:10]=3[N:16]=2)=[C:22]([CH3:28])[CH:23]=1
Reactant: Cc1cc(F)ccc1Nc1nc2ccc3c(C)c(C=CCN)[nH]c(=O)c3c2n1C
Reactant: CP1(=O)CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(F)ccc1Nc1nc2ccc3c(C)c(C=CCNC(=O)C4CCP(C)(=O)CC4)[nH]c(=O)c3c2n1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 6.1 %

Procedure:
To scintillation vial with a magnetic stir-bar was added 7-(3-amino-propenyl)-2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (68 mg, 173 mmol), followed by dimethylformamide (DMF) (1.0 mL) and triethylamine (TEA) (0.25 mL). To a separate scintillation vial was added 1-methyl-1-oxo-1λ5-phosphinane-4-carboxylic acid (130 mg, 0.74 mmol, mixture of cis/trans isomers), HATU (300 mg, 0.79 mmol), and DMF (2.0 mL), followed by TEA (0.25 mL). The solution was sonicated until most of the solids were dissolved. A solution of the activated ester (1.0 mL, or roughly half) was transferred to the solution of amine and stirred for 2.5 hours at room temperature, after which time the starting material was completely consumed as determined by LC-MS. The reaction mixture was quenched by addition of water (0.5 mL), then acidified with TFA. The mixture was filtered (syringe membrane filter) and purified directly by reverse-phase HPLC to provide 2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-{3-[(1-methyl-1-oxo-phosphinan-4-yl)carbonylamino]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (24.9 mg, 26%) as a mixture of cis/trans isomers. 1H NMR (400 MHz, d6-DMSO) δ 11.12 (s, 1H), 10.55 (s, 1H), 8.21-8.17 (m, 1H), 7.74 (d, J=8.6Hz, 1H), 7.69 (d, J=8.6Hz, 1H), 7.55 (dd, J1=5.9 Hz, J2=9.0 Hz, 1H), 7.27 (td, J1=2.7 Hz, J2=8.6 Hz, 1H), 6.66 (d, J=15 Hz, 1H), 6.55-6.49 (m, 1H), 4.18 (s, 3H), 3.92 (m, 2H), 2.31 (s, 3H), 2.30 (s, 3H), 2.35-2.30 (m, 1H), 2.08-1.90 (m, 6H), 1.78-1.65 (m, 2H), 1.52-1.47 (m, 3H); ESMS m/z: found, 550 (M+1)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([CH2:26][NH:27][CH2:28][CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31])=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].C=O.[C:37](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl.O.CO>[C:1]([NH:4][C:5]1[S:6][C:7]([CH2:26][N:27]([CH2:28][CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[CH3:37])=[C:8]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[CH:16][CH:17]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(CCc2ccc(NC(=O)OC(C)(C)C)cc2)c(CNCCC(=O)N(C)C)s1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC(=O)Nc1nc(CCc2ccc(NC(=O)OC(C)(C)C)cc2)c(CN(C)CCC(=O)N(C)C)s1
Reaction time: 12 h
Yield: 87.9 %

Procedure:
To a solution of the compound obtained in Step 1 (100 mg) in dichloromethane (1.5 mL) was added formaline (35%, 87.6 μl). To this suspension was added 0.05 ml of MeOH. Then, sodium triacetoxyborohydride (433 mg) was added, and the mixture was stirred for 12 hrs. To the mixture were added water and 1N NaOH to adjust pH of aquaous phase (ca. pH 8–9). The mixture was extracted with dichloromethane. The organic layer was dried with MgSO4 and concentrated under redused pressure. Resulting oil was purified by silica gel column chromatograph (mixed solvent of CH2Cl2/MeOH 15/1 as an eluent) to give tert-butyl {4-[2-(2-(acetylamino)-5-{[[3-(N,N-dimethylamino)-3-oxopropyl](methyl)amino]methyl}-1,3-thiazol-4-yl)ethyl]phenyl}carbamate as pale yellow oil (90.4 mg).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH:10]1([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([NH2:30])=[N:25][CH:26]=[C:27]([CH3:29])[N:28]=3)=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C1COCC1>[CH:10]1([O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[C:24]4=[N:30][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:25]4[CH:26]=[C:27]([CH3:29])[N:28]=3)=[CH:21][CH:22]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Cc1cnc(N)c(-c2ccc(OC3CCCCC3)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=CN2CCS(=O)(=O)N=C2C(c2ccc(OC3CCCCC3)cc2)=N1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 100 mg) in THF (dry) (10 mL) was added 2-chloroethanesulfonyl chloride (0.263 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(4-(cyclohexyloxy)phenyl)-5-methylpyrazin-2-amine (236 mg) in THF (dry) (10 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen for 15 hr and at 50° C. for 1 hr. The mixture was quenched with water at 0° C. carefully and water was added to form precipitates. The precipitate was crystallized from THF/IPE to give the title compound (128 mg) as yellow crystals.
Reaction SMILES: C(P(=O)(OCC)OCC)#N.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:21]([O:25][C:26](=[O:40])[NH:27][C@H:28]1[C:37]2[C:32](=[CH:33][C:34]([CH:38]=O)=[CH:35][CH:36]=2)[CH2:31][CH2:30][CH2:29]1)([CH3:24])([CH3:23])[CH3:22].C[C:42](C)(O)[C:43]#[N:44]>C1COCC1>[C:43](/[CH:42]=[CH:38]/[C:34]1[CH:33]=[C:32]2[C:37](=[CH:36][CH:35]=1)[C@H:28]([NH:27][C:26](=[O:40])[O:25][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:29][CH2:30][CH2:31]2)#[N:44]
Reactant: CC(C)(O)C#N
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCc2cc(C=O)ccc21
Agent: CCOP(=O)(C#N)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CCCc2cc(/C=C/C#N)ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 300 mL flame dry 3-neck round bottom flask was added diethyl cyanophosphonate (14.86 g, 83.89 mmol) and THF (100 mL). After cooled to 0° C., sodium bis(trimethyl-silyl)amide (72.0 mL, 71.90 mmol) was added dropwise via the addition funnel. After stirred for 30 min at 0° C., It was cooled to −78° C. followed by adding (R)-tert-butyl-6-formyl-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate (6.6 g, 23.97 mmol) in TBF (60 mL) dropwise via the addition funnel. It was stirred for 18 h. Acetone cyanohydrin (3.1 mL, 33.48 mmol) was then added dropwise via the addition funnel. The resulting mixture was warmed up to rt and continued to stir for 18 h. The reaction mixture was quenched with sat. NH4Cl. Solvent was evaporated in vacuo. The residue was extracted with EtOAc. The organic layer was washed with H2O, brine, dried over MgSO4 and removed solvent. The crude product was purified by chromatography on silica gel. Elution with Hex:EtOAc mixture (70:30) gave final compound. MS m/z: 299.12 (M+H). Calc'd. for C18H22N2O2-298.23. B. (R,E)-3-(5-amino-5,6,7,8-tetrahydronaphthalen-2-yl)acralonitrile The product from the previous step was deprotected using HCl in dioxane to give the title compound in quantitative yield. MS m/z: 199.12 (M+H). Calc'd. for C13H14N2-198.23. C. N-((R)-6-((E)-2-cyanovinyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-2-((R)-3-oxo-1-tosylpiperazin-2-yl)acetamide To a 250 mL round bottom flask was added (R)-2-(3-oxo-1-tosylpiperazin-2-yl)acetic acid (2.0 g, 6.40 mmol), followed by (R,E)-3-(5-amino-5,6,7,8-tetrahydronaphthalen-2-yl)acrylonitrile (1.26 g, 6.40 mmol), dry CH2Cl2 (70 mL), HATU (1.2 mg, 3.20 mmol), EDCI (1.4 g, 7.04 mmol) and hunig base (2.2 mL, 12.80 mmol). The resulting mixture was stirred at rt for 20 h. Removed solvent to dryness. The residue was purified by chromatography on silica gel. Elution with CH2Cl2:MeOH mixture (95:5) gave final compound (2.1 g, 66%). MS m/z: 493.3 (M+H). Calc'd. for C26H28N4O4S -492.6. D. N-((R)-6-(3-aminopropyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-2-((R)-3-oxo-1-tosylpiperazin-2-yl)acetamide
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]1(=O)[CH2:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH:15]2[CH2:18][CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
A 3-L, 3-necked, round-bottomed flask under a positive pressure of nitrogen was equipped with a mechanical stirrer and charged with tert-butylhomopiperazine-1-carboxylate (1-BOC-homopiperazine) (73.0 g, 365.0 mmol) and anhydrous dichloroethane (800 mL). To this stirred solution was added cyclobutanone (25.5 g, 363.8 mmol). The pale yellow reaction was stirred at rt for 1 h, following which, sodium triacetoxyborohydride (92.5 g, 436.3 mmol) was added portion-wise over 1 h. The reaction mixture was stirred for 48 h. 1 N NaOH(aq) (225 mL) was added to the reaction mixture and stirred for 1 h. The phases were separated and the aqueous layer was extracted with dichloroethane (2×100 mL). The organic layers were pooled, washed with satd. aq. NaCl (1×250 mL), dried over anhydrous Na2SO4 and filtered. The solvent was removed by rotary evaporation under reduced pressure to afford the crude product as pale yellow semi-solid (92.4 g, 98%). 1H-NMR (400 MHz, CDCl3) δ ppm: 3.59-3.40 (m, 4H), 2.98-2.84 (m, 1H), 2.59-2.43 (m, 4H), 2.12-2.03 (m, 2H), 2.00-1.83 (m, 4H), 1.76-1.55 (m, 2H), 1.51-1.41 (s, 9H). MS m/z (ESI+): 255.2 (M+H+).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]3[CH:19]=[CH:18]S[CH:16]=3)[CH:13]=2)[N:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2].BrC1[CH:22]=[C:23]2C(=CC=1)N=[CH:26][N:25]=[C:24]2[O:31]C(C)C.CNC(C1C=CC(B(O)O)=CC=1)=O>>[CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]3[CH:19]=[CH:18][C:23]([C:24]([NH:25][CH3:26])=[O:31])=[CH:22][CH:16]=3)[CH:13]=2)[N:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ncnc2ccc(Br)cc12
Reactant: CC(C)Oc1ncnc2ccc(-c3ccsc3)cc12
Agent: CNC(=O)c1ccc(B(O)O)cc1
Product: CNC(=O)c1ccc(-c2ccc3ncnc(OC(C)C)c3c2)cc1

Procedure:
The title compound was prepared in an analogous method to 4-isopropoxy-6-thiophene-3-yl-quinazoline, starting with 6-Bromo-4-isopropoxy-quinazoline and using 4-(N-methylaminocarbonyl)phenyl boronic acid. The product was characterized by its mass spectrum MS and HPLC retention time: MS (m/z) 321.03 [M+H]+; HPLC Rt=1.66 minutes (Method A).