Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:34]([O:41][C:42]([NH:44][C@@H:45]([CH2:50][CH2:51][CH2:52][NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:46][C:47]([OH:49])=O)=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl.[NH2:62][CH2:63][CH2:64][NH:65][C:66](=[O:72])[O:67][C:68]([CH3:71])([CH3:70])[CH3:69]>CN(C=O)C>[CH2:34]([O:41][C:42](=[O:43])[NH:44][C@H:45]([CH2:46][C:47]([NH:62][CH2:63][CH2:64][NH:65][C:66]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:72])=[O:49])[CH2:50][CH2:51][CH2:52][NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CC(=O)O)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCC[C@@H](CC(=O)NCCNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
836.5 mg (2.2 mmol) of HATU and 517.0 mg (4 mmol) of N,N-diisopropylethylamine are added to a solution of 760.9 mg (2 mmol) of (3S)-3-{[(benzyloxy)carbonyl]amino}-6-[(tert-butoxycarbonyl)amino]hexanoic acid in 25 ml of anhydrous DMF. After stirring at RT for 45 min 352.5 mg (2.2 mmol) of tert-butyl (2-aminoethyl)carbamate hydrochloride are added. The reaction mixture is stirred at RT for 15 h. The solvent is then evaporated and the residue is taken up in dichloromethane. The organic phase is washed with water, dried over magnesium sulfate and concentrated. The crude product is purified by preparative HPLC.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([N:2]([CH3:1])[CH2:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=2)=[O:24])=[CH:21][CH:20]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CNCc1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N(C)Cc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 21.3 %

Procedure:
To a solution of N-methyl-N-(4-picolyl)amine (0.40 g, 3.3 mmol) and triethylamine (1.5 mL, 10.8 mmol) in CH2Cl2 (15 mL) was added 4-methoxybenzoyl chloride (1.2 g, 7.3 mmol). The resulting mixture was stirred at rt for 15 min, and then partitioned between 2.5N NaOH and Et2O. The organic extract was washed with saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with a solvent gradient of 2-4% MeOH/CHCl3. The material that was isolated was triturated with Et2O to provide the title compound as a light yellow solid (0.18 g, 21%): 1H NMR (CDCl3): d 8.60 (d, 2H); 7.43 (br d, 2H); 7.20 (br s, 2H); 6.90 (br d, 2H); 4.66 (br s, 2H); 3.80 (s, 3H); 3.00 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([Cl:16])=[C:11](Cl)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][O-:19].[Na+]>CN(C)P(N(C)C)(N(C)C)=O>[Cl:16][C:12]1[C:13]([Cl:15])=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][C:11]=1[O:19][CH3:18]
Reactant: Clc1cc(OCc2ccccc2)cc(Cl)c1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1cc(OCc2ccccc2)cc(Cl)c1Cl
Temperature: 0 °C
Reaction time: 20 h
Yield: 14.9 %

Procedure:
A mixture of 3,4,5-trichlorophenol benzyl ether (7.5 g, 0.026 mole) and sodium methoxide (1.7 g, 0.032 mole) in hexamethylphosphoramide (60 ml) was heated with stirring on a steam bath for 20 hours. The reaction mixture was poured into ice water, extracted into ether, washed with water, brine, and dried over magnesium sulfate. The solvent was evaporated at reduced pressure and the residual oil chromatographed on silica gel (320 g) eluting with ethyl acetate-hexane; 1:4 to obtain 1.1 g of 2,3-dichloro-5-benzyloxyanisole which melted at 79°-81° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([N:16](CC)[CH2:17]C)C.ClC(OCC)=O.C(NCC)C>O1CCCC1>[CH3:14][N:16]([CH3:17])[C:11](=[O:13])[CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CCOC(=O)Cl
Solvent: CCNCC
Solvent: C1CCOC1
Product: CN(C)C(=O)CCNC(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 90 %

Procedure:
N-(t-Butyloxycarbonyl)-β-alanine, 3.8 g (20 mmol) was dissolved in 50 ml of tetrahydrofuran, and the solution was cooled to 0° C. and stirred. To this mixture, 2.4 g (24 mmol) of triethylamine was added and 2.16 g (20 mmol) of ethyl chloroformate was slowly added. After stirring the reaction mixture for an hour at 0° C., 4 ml of 40% diethylamine aqueous solution was slowly added and stirred vigorously for an hour. The mixture was extracted by adding 100 ml of dichloromethane and 50 ml of water. The organic layer was washed with 1 N HCl aqueous solution and subsequently with saturated sodium bicarbonate aqueous solution. The washed mixture was dried to obtain 3.9 g (90%) of N-(t-butyloxy-carbonyl)-β-alanine dimethylamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:21]([N+:22]([O-])=O)=[CH:20][CH:19]=[C:18]([O:25][CH3:26])[C:4]=1[CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH3:17])[CH:13]=[CH:12]2.[Cl-].O.NN>CO>[NH2:22][C:21]1[C:3]([O:2][CH3:1])=[C:4]([C:18]([O:25][CH3:26])=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH3:17])[CH:13]=[CH:12]2
Reactant: COc1ccc([N+](=O)[O-])c(OC)c1COc1cccc2ccc(C)nc12
Agent: NN
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: COc1ccc(N)c(OC)c1COc1cccc2ccc(C)nc12
Yield: 63.7 %

Procedure:
To a mixture of 8-[2,6-dimethoxy-3-nitrobenzyloxy]-2-methylquinoline (2.28 g), ferrric chloride (68 mg), carbon (68 mg) and methanol (34 ml) was added hydrazine monohydrate (1.25 ml) at 60° C., and the mixture was refluxed for 4 hours. Ferric chloride (68 mg), carbon (68 mg), hydrazine monohydrate (1.25 ml) and methanol (10 ml) was further added, and the mixture was refluxed overnight. Insoluble materials were filtered off, and the filtrate was concentrated. The residue was dissolved in chloroform, and the solution was washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform-methanol) and crystallized with methanol to give 8-[3-amino-2,6-dimethoxybenzyloxy]-2-methylquinoline (1.33 g) as pale brown crystals.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25](O)=[O:26])[CH:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][NH:32][O:33][CH3:34].Cl.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:34][O:33][N:32]([CH3:31])[C:25](=[O:26])[C:24]1[CH:28]=[CH:29][CH:30]=[C:22]([NH:21][C:17]2[CH:16]=[C:15]([NH:14][C:11]3[CH:12]=[CH:13][C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:9][CH:10]=3)[N:20]=[CH:19][N:18]=2)[CH:23]=1
Reactant: CNOC
Reactant: O=C(O)c1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
To a stirred solution of 3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)benzoic acid (0.05 g, 0.12 mmol) in DMF (2 mL) were added MeNH-OMe.HCl (0.0084 g, 0.12 mmol), EDCI.HCl (0.0361 g, 0.18 mmol), HOBT (0.0084 g, 0.062 mmol) and DIPEA (0.023 g, 0.18 mmol). The reaction mixture was stirred at room temperature for 1 h and was quenched with water. A white solid was isolated by filtration and dried under vacuum to give N-methoxy-N-methyl-3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)benzamide (0.025 g, 44.5%) as a white solid.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:15]1[C:13]2=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]2[N:17]=[CH:16]1
Reactant: COc1ccccc1B(O)O
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Product: COc1ccccc1-n1cnc2ccc(O)nc21

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and 2-methoxyphenylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=241.9 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.Cl[CH2:41][C:42]([N:44]([CH3:46])[CH3:45])=O>>[CH3:45][N:44]([CH3:46])[CH2:42][CH2:41][O:39][C:38]1[CH:37]=[CH:36][C:4]([CH2:5][N:7]([CH:33]([CH3:34])[CH3:35])[C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=2[C@@H:16]2[CH2:25][CH2:24][C:23]3[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=3[CH2:17]2)=[CH:3][C:2]=1[F:1]
Reactant: CN(C)C(=O)CCl
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN(C)C)c(F)c2)C(C)C)c1
Yield: 50.2 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (21 mg) and 2-chloro-N,N-dimethylacetamide (9.4 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (10 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[SH:18].C([O-])([O-])=O.[K+].[K+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].CN(C=O)C>O>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][S:18][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:8][O:9][C:10]=2[C:2]=1[Cl:1])[CH3:31]
Reactant: Fc1ccccc1-c1noc2c(Cl)c(S)ccc12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CSc1ccc2c(-c3ccccc3F)noc2c1Cl
Temperature: 50 °C

Procedure:
3.2 g of 7-chloro-3-(2-fluorophenyl)-6-mercapto-1,2-benzisoxazole, 3.1 g K2CO3 and 3.67 g of ethyl bromoacetate are added to 60 ml DMF and warmed for two hours at 50° C. with stirring. The solution is poured into 700 ml H2O and extracted with ethyl acetate. The combined organic extracts are dried over K2CO3, and the solvent is removed in vacuo to afford ethyl{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazole-6-yl]thio}acetate.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[N:6]2.[CH2:13]([NH2:17])[CH2:14][CH2:15][CH3:16]>>[CH2:13]([NH:17][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[N:6]2)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCN
Reactant: BrCc1ccc2nccnc2c1
Product: CCCCNCc1ccc2nccnc2c1

Procedure:
Example 10 shows that some organic solvent-soluble nucleophiles (alkylamines, for example) can readily react with 6-bromomethyl-quinoxaline because the compound is completely soluble in the organic phase. Example 10 shows that 6-bromomethyl-quinoxaline completely reacted with n-butylamine in few minutes at room temperature to give 6-n-butylaminomethyl-quinoxaline. In this example, n-butylamine acted as both the nucleophile and the solvent.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([N+:12]([O-])=O)[CH:11]=[C:6]2[CH:5]=[C:4]1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[CH3:2]>CCOC(C)=O.CCO>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([NH2:12])[CH:11]=[C:6]2[CH:5]=[C:4]1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[CH3:2]
Reactant: CCn1c(-c2ccc(C)cc2)cc2cc([N+](=O)[O-])cnc21
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCn1c(-c2ccc(C)cc2)cc2cc(N)cnc21

Procedure:
A solution of 1-ethyl-2-(4-methylphenyl)-5-nitro-1H-pyrrolo[2,3-b]pyridine (0.36 g, 1.3 mmol) in a EtOAc/EtOH (absolute)=4:7 mixture (110 ml) was hydrogenated in H2 atmosphere with the presence of 10% Pd(C) (110 mg) for 2 h. The residue was filtered under vacuum through Celite to remove the catalyst and the solvent evaporated to give crude 1-ethyl-2-(4-methylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-amine which was used without any further purification:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:13][C:14](OCC)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH2:29][OH:30].C[O-].[Na+]>CO>[OH:30][NH:29][C:14](=[O:15])[CH2:13][N:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CN(CC(=O)NO)S(=O)(=O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-[[4-methoxybenzenesulfonyl](4-methoxybenzyl)amino]acetate (0.90 g, 2.3 mmol) is dissolved in methanol (20 mL). To this solution is added hydroxylamine hydrochloride (0.80 g, 11.5 mmol), followed by the addition of sodium methoxide (5.2 mL of a 2.67M solution). The reaction is stirred overnight at room temperature. The reaction is worked up by partitioning between dilute hydrochloric acid (pH=~3) and ethyl acetate. The aqueous phase is extracted well with ethyl acetate, the combined organic layers are washed with brine, dried (Na2SO4), and the solvent is evaporated. The product is recrystallized from ether/ethyl acetate to give N-hydroxy-2-[[4-methoxybenzenesulfonyl](4-methoxybenzyl)amino]acetamide, m.p. 134°-135.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]=[CH:15][S:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17](=[O:19])=[O:18].[OH-].[Na+].C(OCC)C>O1CCCC1.C([Li])CCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]=[C:15]([C:17]([OH:19])=[O:18])[S:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=O
Reactant: CC(C)(C)OC(=O)N1CCc2ncsc2C1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2nc(C(=O)O)sc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (845 mg) in absolute tetrahydrofuran (20 ml), n-butyllithium (1.65N hexane solution, 2.13 ml) was added dropwise at −78° C., and the mixture was stirred for 30 minutes with ice cooling. After passing carbon dioxide gas into the reaction mixture at −78° C. for 1 hour, the reaction mixture was warmed to room temperature. A 5N aqueous solution of sodium hydroxide and diethyl ether were added to the reaction mixture to separate a water layer. 6N Hydrochloric acid was added to the water layer to adjust the pH thereof to 1 to 2. After addition of dichloromethane, an organic layer separated was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (562 mg) as a pale yellow foamy substance.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[CH:18][C:17]=2[O:32][CH3:33])=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[NH:8]2.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][C:37]=1O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:33][O:32][C:17]1[CH:18]=[C:19]([O:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH:20]=[CH:21][C:16]=1[C:4]1[C:3]([CH2:2][O:1][C:37]2[CH:38]=[C:39]([N+:42]([O-:44])=[O:43])[CH:40]=[CH:41][C:36]=2[O:35][CH3:34])=[C:12]2[C:7]([NH:8][C:9]([CH3:14])([CH3:15])[C:10](=[O:13])[NH:11]2)=[CH:6][CH:5]=1
Reactant: COc1cc(OC(=O)c2ccccc2C)ccc1-c1ccc2c(c1CO)NC(=O)C(C)(C)N2
Reactant: COc1ccc([N+](=O)[O-])cc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])cc1OCc1c(-c2ccc(OC(=O)c3ccccc3C)cc2OC)ccc2c1NC(=O)C(C)(C)N2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 41.2 %

Procedure:
A mixture of 8-hydroxymethyl-7-[2-methoxy-4-(2-methylbenzoyloxy)phenyl]-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 23, 40.1 mg, 0.0898 mmol), 2-methoxy-5-nitrophenol (22.8 mg, 0.135 mmol), and tri n-butylphosphine (33.7 μL, 0.135 mmol) was dissolved in anhydrous tetrahydrofuran (1 mL), 1,1′-(azodicarbonyl)dipiperidine (34.0 mg, 0.135 mmol) was added thereto, and then the mixture was stirred at room temperature. After 20 minutes, 2-methoxy-5-nitrophenol (23.1 mg, 0.137 mmol), tri n-butylphosphine (33.7 μL, 0.135 mmol), and 1,1′-(azodicarbonyl)dipiperidine (33.9 mg, 0.134 mmol) were added thereto, and after 80 minutes, 2-methoxy-5-nitrophenol (22.9 mg, 0.135 mmol), tri-n-butylphosphine (33.7 μL, 0.135 mmol), and 1,1′-(azodicarbonyl)dipiperidine (34.0 mg, 0.135 mmol) were added further. The stir was stopped 3 hours later and the reaction mixture was concentrated. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (22.1 mg) as a pale yellow amorphous product. (Yield 41%)
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][C:4]([C:7]([CH2:9][NH2:10])=[O:8])=[CH:3]1.C(=O)(O)[O-].[Na+].[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[Cl:26])[C:20](Cl)=[O:21]>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[Cl:26])[C:20]([NH:10][CH2:9][C:7]([C:4]1[CH:5]=[CH:6][O:2][CH:3]=1)=[O:8])=[O:21]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: NCC(=O)c1ccoc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(CNC(=O)c1ccc(Cl)c(Cl)c1)c1ccoc1
Yield: 82.4 %

Procedure:
5.0 g of (3-furylcarbonyl)methylamine hydrochloride, 6.5 g of sodium bicarbonate and 6.8 g of 3,4-dichlorobenzoyl chloride are treated in the same manner as described in Preparation 1-(1). 7.6 g of N-(3,4-dichlorobenzoyl)-(3-furylcarbonyl)methylamine are thereby obtained. Yield: 82.0%
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]=[CH:7]2.CN(C=O)C.[CH3:18][C:19]([NH2:22])([CH3:21])[CH3:20]>O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:22][C:19]([CH3:21])([CH3:20])[CH3:18])[N:8]=[CH:7]2
Reactant: Clc1ncc2cccc(Br)c2n1
Reactant: CC(C)(C)N
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)Nc1ncc2cccc(Br)c2n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 41.5 %

Procedure:
8-Bromo-2-chloroquinazoline (D-L Chiral Chemicals, LLC, Princeton, N.J.) (200 mg, 0.82 mmol) was treated with DMF (2.0 mL) and 2-methylpropan-2-amine (Aldrich Chemical Company, 0.44 mL, 4.11 mmol) and stirred at RT overnight (17 h). The reaction mixture was treated with water, extracted with EtOAc (30 mL), washed with brine (2×), dried over MgSO4, filtered and concentrated. The crude residue was purified on the ISCO Combiflash RF (12 g Thomson SingleStep column, using a gradient of 0-50% EtOAc in hexanes) affording 8-bromo-N-(tert-butyl)quinazolin-2-amine (374a) (94 mg, 0.34 mmol, 41% yield) as a light yellow amorphous solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.87 (1H, s), 7.95 (1H, dd, J=7.5, 1.3 Hz), 7.58 (1H, dd, J=7.9, 1.3 Hz), 7.05 (1H, t, J=7.7 Hz), 5.43 (1H, br. s.), 1.54 (9H, s). m/z (ESI, +ve ion) 280.0/282.0 (M+H)+. A 5-mL glass microwave reaction vessel was charged with 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (609) (120 mg, 0.46 mmol), K2PO4 (182 mg, 0.86 mmol), Pd2dba3 (Strem Chemicals, 13.07 mg, 0.014 mmol), Xphos (Strem Chemicals, 13.61 mg, 0.03 mmol) and 8-bromo-N-(tert-butyl)quinazolin-2-amine (374a) (80 mg, 0.29 mmol) in dioxane (2.5 mL) and water (0.80 mL). The reaction was stirred and heated in a heating block at 110° C. for 1 h. The reaction mixture was treated with water, extracted with EtOAc (30 mL), washed with brine and concentrated. The crude residue was purified on the ISCO Combiflash RF (25 g Thomson SingleStep column, using a gradient of 0-20% MeOH) affording 2-(2-(tert-butylamino)quinazolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (53.9 mg, 0.16 mmol, 56% yield) as a light yellow amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.37 (1H, br. s.), 9.17 (1H, s), 8.10 (1H, d, J=6.8 Hz), 7.64 (1H, d, J=7.0 Hz), 7.35 (1H, s), 7.25 (1H, t, J=7.6 Hz), 7.05 (1H, br. s.), 6.98 (1H, br. s.), 3.40-3.47 (3H, m), 2.92 (2H, br. s.), 1.52 (9H, s). m/z (ESI, +ve ion) 336.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][CH2:18][NH:19]C(=O)OC(C)(C)C)=[CH:15][CH:14]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].Cl.O1CCOCC1>C(Cl)Cl>[NH2:19][CH2:18][CH2:17][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][CH2:10][CH2:9][P:4](=[O:5])([O:3][CH2:1][CH3:2])[O:6][CH2:7][CH3:8])=[CH:28][CH:27]=1
Reactant: CCOP(=O)(CCCOc1ccc(CCNC(=O)OC(C)(C)C)cc1)OCC
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOP(=O)(CCCOc1ccc(CCN)cc1)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-(3-(diethoxyphosphoryl)propoxy)phenethylcarbamate (1 eq) in DCM (0.14 M) was added 4M HCl in dioxane (50 eq). The resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-15% MeOH/DCM to give the product as a yellowish oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[C:10](O)(=O)/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>O>[CH3:9][C:3]1[C:2]2[N:1]=[C:10](/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)/C=C/c1ccccc1
Reactant: Cc1cccc(N)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc2[nH]c(/C=C/c3ccccc3)nc12
Temperature: 180 °C
Yield: 13 %

Procedure:
A mixture of 2,3-diaminotoluene (2.44 g, 20 mmol), (E)-cinnamic acid (2.96 g, 20 mmol) and polyphosphoric acid (10 g) was heated to 180° C. for 90 min. The hot mixture was poured into water (100 ml), basified with 50% aqueous solution of sodium hydroxide and extracted with dichloromethane (3×100 ml). The combined extracts were washed with water (100 ml) and brine (100 ml), dried (magnesium sulfate) and concentrated to dryness. Purification by column chromatography (silica gel, 300 g; n-hexane/ethyl acetate (7/3)) yielded 0.61 g (13%) of the titled compound as red solids. 1H-NMR (CDCl3) δ: 9.53 (1H, br.s), 8.72-8.67 (1H, m), 7.95 (1H ddd, J=7.7, 7.7, 1.8 Hz), 7.60-7.49 (3H, m), 7.43-7.31 (3H, m), 7.23-7.14 (3H, m), 7.09-7.04 (1H, m), 2.63 (3H, br.s)
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:10][O:9][C:7]([C:4]1[S:3][C:2]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:6][CH:5]=1)=[O:8]
Reactant: COC(=O)c1cnc(Br)s1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cnc(N2CCNCC2)s1
Temperature: 80 °C
Yield: 80.2 %

Procedure:
To a solution of methyl 2-bromothiazole-5-carboxylate (1a) (5.00 g, 22.50 mmol) in acetonitrile (50 mL) were added piperazine 2 (2.32 g, 26.97 mmol) and potassium carbonate (6.22 g, 45.05 mmol) under a N2 atmosphere. The reaction mixture was heated to reflux at 80° C. for 10 h. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using silica gel to give the compound 11 as a solid (4.10 g, 79.8%). HPLC: 92% (Rt=3.883 min).