Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:9]1[C:10]([O:18][CH3:19])=[N:11][CH:12]=[C:13]([CH:17]=1)[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN([C:39]([O:43][N:44]1N=NC2C=CC=N[C:45]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CONC>CN(C=O)C>[CH3:19][O:18][C:10]1[C:9]([N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:17][C:13]([C:14](=[O:16])[N:44]([O:43][CH3:39])[CH3:45])=[CH:12][N:11]=1
Reactant: COc1ncc(C(=O)O)cc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc(C(=O)N(C)OC)cc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-[bis(tert-butoxycarbonyl)amino]-6-methoxynicotinic acid (Preparation 70, 500 mg, 1.358 mmol) and DIPEA (730 uL, 4.076 mmol) in DMF (4 mL) was added HATU (774 mg, 2.038 mmol) and N-methoxy-methylamine hydrochloride (198 mg, 2.038 mmol) and the reaction stirred at room temperature for 16 hours. The reaction was partitioned between saturated aqueous NaHCO3 solution and EtOAc, the organic layer collected, dried over sodium sulfate and concentrated in vacuo to afford the title compound that was used directly in the next step.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:4]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.ClC1C=CC=C(C(OO)=[O:29])C=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[CH3:2][C:3]1[C:4]([S:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[O:29])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: Cc1nc2ccccc2nc1SCc1ccccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1nc2ccccc2nc1S(=O)Cc1ccccn1
Yield: 67.2 %

Procedure:
In a mixture of 36 ml of chloroform and 18 ml of methanol was dissolved 2.6 g of 3-methyl-2-(2-pyridylmethylthio)quinoxaline hydrochloride. To the chilled solution kept at a temperature of lower than 0° C. (temperature of solution) was added 1.77 g of m-chloroperbenzoic acid (purity 70%). After the reaction was complete, chloroform and saturated aqueous NaHCO3 solution were added to the reaction mixture under chilling. The organic layer was separated and dried over sodium sulfate. The sodium sulfate was then removed by filtration, and the solvent was evaporated under reduced pressure from the filtrate. The residue was purified by silica gel column chromatography (chloroform/methanol), and recrystallized from ether/hexane to give 1.63 g of 3-methyl-2-(2-pyridylmethylsulfinyl)quinoxaline as an orange crystalline powder, m.p. 85°-88° C. (decompn.).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1([CH2:13][CH:14]2[N:19]([N:20]=O)[C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[O:16][CH2:15]2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>C1COCC1>[N:7]1([CH2:13][CH:14]2[N:19]([NH2:20])[C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[O:16][CH2:15]2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: O=NN1c2ccccc2OCC1CN1CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NN1c2ccccc2OCC1CN1CCOCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 56 g of lithium aluminum hydride in 500 ml of THF was added the (-)-3-(4-morpholinylmethyl)- 4-nitroso-3,4-dihydro-2H-1,4-benzoxazine described above while cooling the reaction mixture to 0° C. with an external cooling bath. When addition was complete the cooling bath was removed, the reaction mixture was stirred for one hour at ambient temperature, cooled again to 0° C. and the excess hydride carefully quenched by the dropwise addition of 5 ml of water, followed by 8 ml of 10% aqueous sodium hydroxide, followed by an additional 5 ml of water. The mixture was stirred, filtered through filter aid, and the filtrate taken to dryness to afford 14.3 g of (-)-3-(4-morpholinylmethyl)-4-amino-3,4-dihydro-2H-1,4-benzoxazine, which was used as such in the next synthetic step without further characterization or purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:59]=[CH:58][C:6]([C:7]([O:22][CH2:23][C@@:24]2([CH:46]=[CH:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]OS(C)(=O)=O)[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26][C@@H:25]2[O:38][SiH2:39][C:40]([CH3:45])([CH3:44])[CH:41]([CH3:43])[CH3:42])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[N-:60]=[N+:61]=[N-:62].[Na+].C1C=CC=CC=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.CCCCCC>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]([O:22][CH2:23][C@@:24]2([CH:46]=[CH:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][N:60]=[N+:61]=[N-:62])[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26][C@@H:25]2[O:38][SiH2:39][C:40]([CH3:45])([CH3:44])[CH:41]([CH3:43])[CH3:42])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:59][CH:58]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(C(OC[C@@]2(C=CCCCCCOS(C)(=O)=O)O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O[SiH2]C(C)(C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COc1ccc(C(OC[C@@]2(C=CCCCCCN=[N+]=[N-])O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O[SiH2]C(C)(C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 96.5 %

Procedure:
5'-O-(4,4'-dimethoxytrityl)-3'-O-[(dimethyl-1,1-dimethylethyl)silyl]-4'-(7-methanesulfonyloxy-1-hepten-1-yl)-thymidine (219 mg, 0.25 mmole), sodium azide (100 mg, 1.5 mmole) and tetrabutyl ammonium iodide (10 mg, 0.025 mmole) were placed in a dry flask under nitrogen and benzene (5 mL) was added. The mixture was heated under reflux for 14 hours, poured onto ice (15 mL) and extracted four times with dichloromethane (30 mL each). The combined organic extracts were washed with brine (20 mL), dried over magnesium sulfate and the solvent was removed under reduced pressure to provide a white solid. Chromatography on a silica gel column with ethyl acetate/hexane mixtures gave 5'-O-(4,4'-dimethoxytrityl)-3'-O-[(dimethyl-1,1-dimethylethyl)silyl]-4'-(7-azido-1-hepten-1-yl)-thymidine (5) (192 mg, 94%), m.p. 72°-74° C.
Reaction SMILES: C1(O)CCCC1.[H-].[Na+].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]=[CH:15][N:16]=[C:17]([O:20][CH:21]3[CH2:26][CH2:25]O[CH2:23][CH2:22]3)[C:18]=2[N:19]=1>CN(C=O)C.O>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]=[CH:15][N:16]=[C:17]([O:20][CH:21]3[CH2:26][CH2:25][CH2:23][CH2:22]3)[C:18]=2[N:19]=1
Reactant: Clc1ccc2ncnc(OC3CCOCC3)c2n1
Agent: OC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc2ncnc(OC3CCCC3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a solution of cyclopentanol (0.050 ml, 0.550 mmol) in DMF (2.500 ml) was added NaH (0.026 g, 55% dispersion in mineral oil, 0.600 mmol) at 0° C. The reaction mixture was stirred for 30 min at room temperature, 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, step D) (0.1 g, 0.500 mmol) was added to the mixture at 0° C. After being stirred for 2 hours at room temperature, the reaction mixture was diluted with water, and extracted with EtOAc. The organic layers were dried over MgSO4 filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=5:1) to give 6-chloro-4-(cyclopentyloxy)pyrido[3,2-d]pyrimidine (0.04 g, 32%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz): δ 1.63-1.74 (2H, m), 1.86-1.96 (2H, m), 1.99-2.07 (2H, m), 2.12-2.20 (2H, m), 5.72-5.77 (1H, m), 7.72 (1H, d, J=8.8 Hz), 8.18 (1H, d, J=8.8 Hz), 8.83 (1H, s).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:15]([O:19][C:20](=[O:29])[NH:21][C@H:22]1[CH2:27][CH2:26][C@@H:25]([NH2:28])[CH2:24][CH2:23]1)([CH3:18])([CH3:17])[CH3:16].C([O-])(O)=O.[Na+]>CC(O)C>[C:15]([O:19][C:20](=[O:29])[NH:21][C@H:22]1[CH2:23][CH2:24][C@@H:25]([NH:28][C:2]2[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:26][CH2:27]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CN(C)c1nc(Cl)nc2ccccc12
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CN(C)c1nc(N[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)nc2ccccc12

Procedure:
A mixture of (2-chloro-quinazolin-4-yl)-dimethyl-amine obtained in step B of example 1 (3.00 g, 14.4 mmol) and cis-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester (3.72 g, 17.4 mmol) in 2-propanol (10 mL) was stirred at reflux for 5.5 days, poured into saturated aqueous NaHCO3, and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica, 20% EtOAc in hexane) to give cis-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester including solvent (5.44 g) as a colorless oil. To a solution of the above material (5.44 g) in EtOAc (10 mL) was added 4 M hydrogen chloride in EtOAc (50 mL). The reaction mixture was stirred at ambient temperature for 2 hr, and concentrated. The residue was alkalized with saturated aqueous NaHCO3, and the precipitate was collected by filtration to give cis-N2-(4-amino-cyclohexyl)-N4,N4-dimethyl-quinazoline-2,4-diamine (2.26 g, 55%) as a white solid. The aqueous layer was extracted CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, and concentrated to give cis-N2-(4-amino-cyclohexyl)-N4,N4-diethyl-quinazoline-2,4-diamine (687 mg, 17%) as a white solid.
Reaction SMILES: Cl.[OH:2][C:3]1[C:8](=[O:9])[CH:7]=[CH:6][N:5]([CH3:10])[CH:4]=1.C[O:12][CH:13](O)[C:14]([F:17])([F:16])[F:15].Cl>[OH-].[Na+]>[OH:2][C:3]1[C:8](=[O:9])[CH:7]=[CH:6][N:5]([CH3:10])[C:4]=1[CH:13]([OH:12])[C:14]([F:17])([F:16])[F:15]
Reactant: Cn1ccc(=O)c(O)c1
Reactant: COC(O)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1ccc(=O)c(O)c1C(O)C(F)(F)F
Temperature: 95 °C
Yield: 34260.3 %

Procedure:
To a solution of 3-hydroxy-1-methylpyridin-4(1H)-one hydrochloride (100.0 g, 0.62 mol) dissolved in a solution of 6N NaOH (206.9 mL) at ice-water bath was added trifluoroacetaldehyde methyl hemiacetal (131.9 mL, 1.24 mmol). The resulting solution was heated to 95° C. for overnight. The reaction mixture was then cooled, and at ice-water bath the pH of the mixture was adjusted to about 5 using a 6N HCl solution. The precipitated solid was collected by filtration, and the solid was thoroughly washed with de-ionized water (100 mL×2), and then dried under vacuum at 43° C. for overnight to afford 3-hydroxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one (94.8 g) as a white solid. Yield=68% yield; 1H NMR (90 MHz, MeOD-D4) δ (ppm): 7.60 (d, J=7.1 Hz, 1H), 6.40 (d, J=7.2 Hz, 1H), 5.92 (q, J=8.2 Hz, 1H), 3.98 (s, 3H); MS m/z 224 [M+1], 158 (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24]([F:27])([F:26])[F:25])[C:5]2[N:6]([N:9]=[C:10]([CH2:12][CH2:13][C:14]3[NH:18][N:17]=[C:16]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[N:15]=3)[N:11]=2)[C:7]=1[CH3:8].[CH:28]1(B(O)O)[CH2:30][CH2:29]1.N1C=CC=CC=1.C(N(CC)CC)C>O1CCCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]([F:25])([F:27])[F:26])[C:5]2[N:6]([N:9]=[C:10]([CH2:12][CH2:13][C:14]3[N:15]=[C:16]([N:19]4[CH2:20][CH2:21][CH2:22][CH2:23]4)[N:17]([CH:28]4[CH2:30][CH2:29]4)[N:18]=3)[N:11]=2)[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)cc(C(F)(F)F)c2nc(CCc3nc(N4CCCC4)n[nH]3)nn12
Reactant: OB(O)C1CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(Cl)cc(C(F)(F)F)c2nc(CCc3nc(N4CCCC4)n(C4CC4)n3)nn12
Temperature: 100 °C
Yield: 14.5 %

Procedure:
A mixture of 6-chloro-5-methyl-2-(2-(3-(pyrrolidin-1-yl)-1H-1,2,4-triazol-5-yl)ethyl)-8-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine (30 mg, 75.0 μmol, Eq: 1.00), cyclopropyl-boronic acid (19.3 mg, 225 μmol, Eq: 3), copper (II) acetate (27.3 mg, 150 μmol, Eq: 2), molecular sieves, pyridine (47.5 mg, 48.6 μl, 600 μmol, Eq: 8), triethylamine (38.0 mg, 52.3 μl, 375 μmol, Eq: 5) in tetrahydrofuran (4 ml) was heated under air in a sealed tube for 2 h at 100° C. The mixture was filtered and concentrated to an oil. Water was added and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and then concentrated. The mixture was separated by preparative HPLC to give the product (4.8 mg, 14.5%) as a colorless oil. MS: m/z=440.2 (M+H+)
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][CH:8]1[CH2:16][C:15]2[C:10](=[C:11]([Cl:20])[C:12]([Cl:19])=[C:13]([O:17][CH3:18])[CH:14]=2)[C:9]1=[O:21].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>C(O)(C)(C)C.C1C=CC=CC=1>[CH2:22]([C:8]1([CH3:7])[CH2:16][C:15]2[C:10](=[C:11]([Cl:20])[C:12]([Cl:19])=[C:13]([O:17][CH3:18])[CH:14]=2)[C:9]1=[O:21])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)C2
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Solvent: CC(C)(C)O
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(Cc1ccccc1)C2

Procedure:
Potassium tert-butoxide (1.68 g., 0.015 mole) in dry tert-butyl alcohol (40 ml.) is added to a refluxing solution of 2-methyl-5-methoxy-6,7-dichloro-1-indanone in benzene (50 ml.). After refluxing for 30 minutes, benzyl bromide (1.72 g., 0.01 mole) in benzene (10 ml.) is added dropwise. After refluxing for an additional 30 minutes the mixture is cooled, water (10 ml.) is added and the mixture is evaporated to dryness. The residue is washed with water and taken up in ether. The ether solution is washed with water and a saturated sodium chloride solution, dried over solium sulfate and evaporated. The syrupy residue of 2-benzyl-2-methyl-5-methoxy-6,7-dichloro-1-indanone (3 g.) is used directly in the next step without purification.
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([NH:10][C:11]3[N:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH:13]=O)[CH:7]=[CH:6][C:5]=12.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH2:26][CH2:27][CH2:28][C:29](OCC)=[O:30].[Li+].CC([N-]C(C)C)C>>[N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([N:10]3[C:11]4[C:12](=[CH:15][CH:16]=[CH:17][N:18]=4)[CH:13]=[C:28]([CH2:27][CH2:26][CH2:25][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=4)[C:29]3=[O:30])[CH:7]=[CH:6][C:5]=12
Reactant: CCOC(=O)CCCCc1ccccn1
Reactant: O=Cc1cccnc1Nc1ccc2nsnc2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: O=c1c(CCCc2ccccn2)cc2cccnc2n1-c1ccc2nsnc2c1
Yield: 27 %

Procedure:
The procedure of Example 1 was repeated using 2-(2,1,3-benzothiadiazol-5-ylamino)nicotinaldehyde (1.0 eq., prepared in Synthetic Example 1a)), ethyl 5-(pyridin-2-yl)pentanoate (1.5 eq., prepared in Synthetic Example 4) and LDA (1.5 eq.) to obtain 1-(2,1,3-benzothiadiazol-5-yl)-3-[3-(pyridin-2-yl)propyl]-1,8-naphthyridin-2(1H)-one (yield, 27%). The product was purified through flash column chromatography and recrystallization (mp 169.5–170.5° C./DMF).
Reaction SMILES: [N:1]#[C:2][C@@H:3]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[NH2:4].C(OCC)(OCC)OCC.[CH3:20]N.[C:22](#[N:24])C>CCO.CCOC(C)=O>[NH2:1][C:2]1[N:24]([CH3:22])[CH:20]=[N:4][C:3]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CC#N
Reactant: CN
Reactant: CCOC(=O)[C@@H](N)C#N
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCOC(OCC)OCC
Product: CCOC(=O)c1ncn(C)c1N
Temperature: 90 °C
Reaction time: 1.17 h

Procedure:
A mixture of ethyl 3-nitriloalaninate (26.7 g, 208 mmol) and triethyl orthoformate (34.6 mL, 208 mmol) in 340 mL of acetonitrile is heated to 90° C. and stirred for 70 min. After cooling to RT, methylamine (25.9 mL of a 33 wt % solution in EtOH, 208 mmol) is added, followed by 20 h of stirring at RT. The reaction mixture is then concentrated in vacuo and dissolved in approx. 200 mL of 1N HCl. The aqueous solution is washed with CH2Cl2 (3×100 mL), basified to pH=9-10 with solid NaHCO3, and extracted with CH2Cl2 (5×100 mL). The combined CH2Cl2 extracts are dried (Na2SO4), filtered, and concentrated to give a brown solid. The solid is slurried in EtOAc, filtered, and washed with Et2O to give the title compound as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.03 (1H, s), 4.88 (2H, bs), 4.33 (2H, q, J 7.2), 3.45 (3H, s), 1.37 (3H, t, J 7.2).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:6](=[NH:9])OC.[NH3:15]>CO>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:6]([NH2:15])=[NH:9]
Reactant: COC(=N)c1ccc(OC)c(Cl)c1
Reactant: N
Agent: Cl
Solvent: CO
Product: COc1ccc(C(=N)N)cc1Cl
Temperature: -78 °C
Reaction time: 20 h
Yield: 191.7 %

Procedure:
Methyl 3-chloro-4-methoxybenzimidate hydrochloride, (19.9 g, 0.084 mole) was added to a solution of ammonia (12 g) in CH3OH (100 ml) cooled to -78° C. The stirred mixture was allowed to warm to room temperature. After 20 hours, the solution was evaporated to dryness under reduced pressure. The solid residue was triturated with Et2O and collected to yield 17.8 g (96%) of 27, m.p. dec. 243°-245° C. A sample triturated with acetone melted at 241°-243° C. dec.
Reaction SMILES: B(F)(F)F.CCOCC.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:15]=O.[CH2:22]([SH:26])[CH2:23][CH2:24][SH:25]>C(Cl)Cl>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:15]2[S:26][CH2:22][CH2:23][CH2:24][S:25]2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(C=O)cc1OC
Reactant: SCCCS
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(C2SCCCS2)cc1OC

Procedure:
The first step in the process for making Justicidin P can be conducted by adding boron trifluoride etherate (BF3.Et2O) to a solution containing 3,4-dimethoxybenzaldehyde and 1,3-propanedithiol in methylene chloride. After a suitable reaction time, the mixture is washed with a NaOH solution and a saturated solution of NaCl. The product is dried and then recovered by evaporation under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH:5](O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13].[C:19]([O:23][CH3:24])(=[O:22])[CH2:20][SH:21]>>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])[S:21][CH2:20][C:19]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)CS
Reactant: COc1ccccc1C(O)c1ccccc1OC
Product: COC(=O)CSC(c1ccccc1OC)c1ccccc1OC
Reaction time: 18 h
Yield: 72 %

Procedure:
Following the procedure of Example 4, 2,2'-dimethoxybenzhydrol, synthesized in accordance with M. L. Hoefle, et. al. in J. Med. Chem. 34, 7 (1971)] is reacted with methyl thioglycolate for 3 hours at 50°-60° C. followed by 18 hours at room temperature. Chromatography on silica gel, eluting with a gradient of 10% ethyl acetate in hexane to 20% ethyl acetate in hexane, followed by additional chromatography, eluting with a gradient of 5% ethyl acetate in hexane to 10% ethyl acetate in hexane, gives methyl [[bis-(2-methoxyphenyl)methyl]thio]acetate as a white solid in 72% yield: melting point 65°-67° C.
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]([C:7]1[S:11][C:10]([C:12]([O:14]C)=O)=[CH:9][CH:8]=1)=[O:6])[CH3:3].O.[NH2:17][NH2:18]>C(O)C>[CH3:1][CH:2]([NH:4][C:5]([C:7]1[S:11][C:10]([C:12]([NH:17][NH2:18])=[O:14])=[CH:9][CH:8]=1)=[O:6])[CH3:3]
Reactant: NN
Reactant: COC(=O)c1ccc(C(=O)NC(C)C)s1
Solvent: CCO
Solvent: O
Product: CC(C)NC(=O)c1ccc(C(=O)NN)s1
Yield: 45 %

Procedure:
Methyl 5-(2-propylcarbamyl)-thiophene-2-carboxylate (1.22 g, 5.37 mmol) in ethanol (40 ml) was refluxed with heating with hydrazine monohydrate (2.7 g) at 85° C. for 16 hours. After cooling, the solvent was evaporated, and the resulting solid was recrystallized from chloroform to give 549.2 mg of the desired product (yield 45%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8])[CH3:2].[OH-].[Na+].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH2:15]([O:12][C:11]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[O:3][CH2:1][CH3:2])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOc1cc(C=O)ccc1O
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)ccc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To the solution of 3-ethoxy-4-hydroxy-benzaldehyde (83 g) in N,N-dimethylformamide (400 ml) was gradually added 10 M sodium hydroxide (55 ml) and then benzyl chloride (60 ml) was added at a temperature under 40° C. The mixture was stirred at room temperature for a half an hour and for 2 hours at 60° C. The solution was poured into ice-cold water (2 l) and extracted with diethyl ether. The organic phase was washed with water and 5M sodium hydroxide and then it was dried and evaporated. The product was recrystallized from toluene-heptane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[NH:5][CH3:6].[CH:10]([OH:12])=O>O>[Br:1][C:2]1[CH:3]=[C:4]([N:5]([CH3:6])[CH:10]=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CNc1cccc(Br)c1
Reactant: O=CO
Solvent: O
Product: CN(C=O)c1cccc(Br)c1
Temperature: 25 °C

Procedure:
A solution of 3-bromo-N-methyl aniline (made as described by Lopez et al. in Tet. Lett., 1999, 40, 11, p 2071-2074 incorporated herein by reference; 7.4 g, 39.5 mmol) in formic acid (20 mL) was refluxed for 3 h. The reaction mixture was then cooled to ambient temperature, diluted with water and extracted with diethyl ether. The organic phase was washed with saturated, aqueous sodium bicarbonate solution, water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a dark brown oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:41])[N:10]([CH:12]([C:14](=[O:40])[NH:15][CH:16]([C:21]([N:23]1[CH2:27][CH2:26][CH:25]2[NH:28][CH2:29][CH:30]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[CH:24]12)=[O:22])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:42]([N:49]=[C:50]=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.CO.[NH4+].[OH-]>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:41])[N:10]([CH:12]([C:14](=[O:40])[NH:15][CH:16]([C:21]([N:23]1[CH2:27][CH2:26][CH:25]2[N:28]([C:50](=[O:51])[NH:49][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:29][CH:30]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[CH:24]12)=[O:22])[C:17]([CH3:19])([CH3:18])[CH3:20])[CH3:13])[CH3:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=NCc1ccccc1
Reactant: CC(C(=O)NC(C(=O)N1CCC2NCC(OCc3ccc(F)cc3)C21)C(C)(C)C)N(C)C(=O)OCc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC(C(=O)NC(C(=O)N1CCC2C1C(OCc1ccc(F)cc1)CN2C(=O)NCc1ccccc1)C(C)(C)C)N(C)C(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 121 %

Procedure:
Bicyclic amine 49 (300 mg, 0.53 mmol) and TEA (150 μL) were dissolved in DCM (5 mL) at ambient temperature and benzyl isocyanate (135 μL, 1.06 mmol) was added. After 3 h, MeOH (20 mL) and 30% NH4OH (1 mL) were added and the solution was stirred for 15 min before being concentrated in vacuo. The residue was dissolved in EtOAc and washed successively with 1N HCl, water, aqueous NaHCO3, water, and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to afford 450 mg of 50 as an amorphous solid which was used without further purification. Mass spectrum, m/z [702.3] (M+Na)+.