Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7]/[C:8](=[N:10]/[OH:11])/[NH2:9])=[CH:4][CH:3]=1.[O:14]=[C:15]1[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH2:18][CH2:17][N:16]1[CH2:33][C:34](O)=O.Cl.C(N=C=NCCCN(C)C)C.CO>ClCCCl.C(Cl)Cl>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C:8]2[N:9]=[C:34]([CH2:33][N:16]3[CH2:17][CH2:18][CH2:19][C:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:15]3=[O:14])[O:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: N/C(COc1ccc(Cl)cc1)=N\O
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCCl
Solvent: CO
Solvent: ClCCl
Product: O=C1N(Cc2nc(COc3ccc(Cl)cc3)no2)CCCC1(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
A mixture of the product of Example 263A (148 mg, 0.738 mmol), the product of Example 68E (228 mg, 0.738 mmol), and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (283 mg, 1.48 mmol) in 1,2-dichloroethane (4 mL) was stirred at ambient temperature for 3 hours, then heated to reflux for 24 hours. The cooled reaction mixture was diluted with CH2Cl2 (100 mL) and washed with 1 N aqueous HCl (2×30 mL) and saturated aqueous NaHCO3 solution and brine, dried with Na2SO4, filtered, and concentrated in vacuo. The crude product was chromatographed on silica gel (Analogix® Intelliflash™ 280; SF15-24 g column; 40% ethyl acetate/hexanes) to give a viscous oil which was left standing overnight. Methanol (1 mL) was then added causing a solid to form which was collected by vacuum filtration, washed with hexanes, and air-dried to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.40-7.33 (m, 2H), 7.31-7.07 (m, 12H), 5.32 (s, 2H), 4.87 (s, 2H), 3.58 (t, J=6.3, 2H), 2.62-2.54 (m, 2H), 1.78-1.67 (m, 2H); MS (ESI+) m/z 474 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([O:17][CH3:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:19]=[N+:20]=[N-:21].[Na+].Cl.C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]2[N:19]=[N:20][NH:21][N:14]=2)=[C:11]([O:17][CH3:18])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc(OCc2ccccc2)ccc1C#N
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(OCc2ccccc2)ccc1-c1nn[nH]n1
Reaction time: 0.5 h

Procedure:
A vigorously stirred suspension of 4-benzyloxy-2-methoxybenzonitrile (1-B) (1.20 g, 5.0 mmol), sodium azide (732 mg, 11.3 mmol), and triethylamine hydrochloride (1.54 g, 11.3 mmol) in toluene (6 mL) was heated at 110° for 48 h. The brown suspension was cooled, water (15 mL) was added, and the mixture stirred for 30 min. The organic layer was separated and extracted with water (5 mL). The combined aqueous extracts were acidified to about pH 1 with concentrated HCl. The gum that initially precipitated solidified upon stirring for 30 min. The solid was filtered, washed with water, and dried to give 5-[4-(benzyloxy)2-methoxyphenyl]-2H-tetrazole (1-C). 1H NMR (500 MHz, CDCl3): δ 12.9 (vbs, 1H), 7.37 (d, 1H, J=8.7 Hz), 7.34-7.48 (m, 5H), 6.78 (dd, 1H, J=2.3, 8.7 Hz), 6.70 (d, 1H, J=2.3 Hz), 5.15 (s, 2H), 4.05 (s, 3H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=[O:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([OH:15])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C1CCCc2c1[nH]c1ccc(Br)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCCc2c1[nH]c1ccc(Br)cc21
Reaction time: 1 h
Yield: 50.4 %

Procedure:
To a solution of 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-one (500 mg, 1.9 mmol) in methanol (20 mL) was added sodium borohydride (144 mg, 3.8 mmol) portionwise. The reaction mixture was stirred for one hour and quenched with water (5 mL). The reaction was concentrated, diluted with methylene chloride, and washed with water. The organic phase was concentrated and the crude alcohol purified by flash chromatography on silica (5% to 30% ethyl acetate/hexanes gradient) to provide 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-ol (255 mg, 50%). as a light brown solid. 1H-NMR (DMSO-d6): δ 10.99 (s, 1H), 7.54 (d, 1H), 7.25 (d, 1H), 7.12 (dd, 1H), 5.18 (d, 1H), 4.75-4.70 (m, 1H), 2.64-2.53 (m, 2H), 2.02-1.91 (m, 2H), 1.77-1.66 (m, 2H); MS m/z (M+1) 267.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:31]=[CH:30][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:25]=4[N:26]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:7][N:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[C:10]([F:17])[CH:9]=2)[CH2:5]1)#[N:2].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[CH:64]1([C@@H:70]([NH2:72])[CH3:71])[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]1>ClCCCl>[C:1]([CH2:3][C:4]1([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:31]=[CH:30][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:25]=4[N:26]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:5][N:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH:72][C@H:70]([CH:64]3[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]3)[CH3:71])=[O:13])=[C:10]([F:17])[CH:9]=2)[CH2:7]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5ccc(C(=O)O)c(F)c5)C4)c3)ncnc21
Reactant: C[C@H](N)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCCl
Product: C[C@H](NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cc1F)C1CCCCC1

Procedure:
The 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2-fluorobenzoic acid (0.015 g, 0.027 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.016 g, 0.042 mmol), and (1S)-1-cyclohexylethanamine (0.0080 mL, 0.055 mmol, Aldrich: Cat. #336513) in dry 1,2-dichloroethane (0.501 mL) (not all in solution) was stirred for 30 minutes at 60° C., then 14 hours at room temperature (all in solution). LC/MS data showed that the reaction was complete and the desired product was formed. The product was used as is without further purification. LCMS (M+H)+: m/z=657.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1>[Pd].C(OCC)(=O)C>[NH2:20][C:17]1[CH:18]=[CH:19][C:10]([CH2:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1C#Cc1ccc(F)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N)ccc1CCc1ccc(F)cc1
Reaction time: 6 h
Yield: 88.7 %

Procedure:
A mixture of compound 74 (29 g), 10% Pd/C (3 g), and ethyl acetate (400 ml) was stirred under an hydrogen atmosphere for 6 hours. The catalyst was removed by filtration and replaced by fresh catalyst (3 g). The hydrogenation was then continued for another 16 hours, the catalyst was again filtered off, the filtrate evaporated to dryness and the residue treated with iso-hexane to give a white precipitate which was isolated by filtration and dried to give compound 75 (23.5 g).
Reaction SMILES: Cl.[N:2]1[N:3]=[CH:4][N:5]2[CH:10]=[CH:9][N:8]=[C:7]([N:11]3[CH2:15][CH2:14][C@H:13]([NH2:16])[CH2:12]3)[C:6]=12.[CH:17]([C:20]1[CH:21]=[N:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=1)([CH3:19])[CH3:18].C(N(CC)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[N:2]1[N:3]=[CH:4][N:5]2[CH:10]=[CH:9][N:8]=[C:7]([N:11]3[CH2:15][CH2:14][C@H:13]([NH:16][C:26]([C:23]4[N:22]=[CH:21][C:20]([CH:17]([CH3:19])[CH3:18])=[CH:25][N:24]=4)=[O:27])[CH2:12]3)[C:6]=12
Reactant: CC(C)c1cnc(C(=O)O)nc1
Reactant: N[C@H]1CCN(c2nccn3cnnc23)C1
Agent: CCN(CC)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1cnc(C(=O)N[C@H]2CCN(c3nccn4cnnc34)C2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.7 %

Procedure:
To a suspension of =(S)-1-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)pyrrolidin-3-amine hydrochloride salt (84 mg, 0.3 mmol), 5-isopropylpyrimidine-2-carboxylic acid (51 mg, 0.3 mmol) in DMF (5 mL) was added diethylisopropyl amine (650 mg, 5 mmol), followed by HATU (120 mg, 0.31 mmol). The resulting solution was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous solutions of KH2PO4 and NaHCO3, followed by brine. The organic layer was concentrated in vacuo and the residue purified by reverse phase HPLC (acetonitrile-H2O with 0.1% TFA as eluent) to give 6 mg of the title compound (5% yield) as a white solid. MS: (ES) m/z found 353.1.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21]C(=O)OC(C)(C)C)[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].Cl.C(=O)(O)[O-].[Na+].O>ClCCl>[CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCNC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCCc1nc2cnc3ccccc3c2n1CCCCN
Reaction time: 1.5 h
Yield: 97.3 %

Procedure:
Tert-butyl 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butylcarbamate (5.00 g, 13.1 mmol) was combined with hydrochloric acid (50 mL of 4.0 M in dioxane) and stirred for 1.5 hours. The reaction mixture was diluted with dichloromethane (˜200 mL). Saturated sodium bicarbonate solution was added until a pH of 8 was obtained. A precipitate formed in the aqueous phase. The layers were separated. The precipitate in the aqueous layer was isolated by filtration, slurried with water and then isolated by filtration to provide 3.6 g of 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-amine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]1.[CH2:17]([NH2:20])[CH:18]=[CH2:19]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11]([NH:20][CH2:17][CH:18]=[CH2:19])=[O:12])[CH2:8]1
Reactant: COc1cccc(OC2CN(C(=O)Cl)C2)c1
Reactant: C=CCN
Solvent: C1CCOC1
Solvent: O
Product: C=CCNC(=O)N1CC(Oc2cccc(OC)c2)C1
Reaction time: 17 h
Yield: 76.8 %

Procedure:
A solution of 4.85 g (0.02 mole) of 3-(3-methoxyphenoxy)-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was treated with 4.5 g (0.06 mole) of 2-propenylamine and stirred for 17 hr, diluted with 200 ml of water and extracted with 3×50 ml of methylene chloride. The combined extracts were dried then concentrated in vacuo to yield 4.03 g of oil residue. The residue was chromatographed on a spinning TLC plate (chromatotron) in 3 portions (3 runs) using a ethyl acetate/methylene chloride gradient. The 4th fraction of each run was combined and concentrated in vacuo to yield a white solid (1.2 g), which was recrystallized from benzene-ligroin yielding 0.94 g (18%) of fine white crystals, m.p. 121°-123° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9](O)=[O:10].S(Cl)(Cl)=O.C1C=CC=CC=1.C[N:25](C)C=O>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]([NH2:25])=[O:10]
Reactant: O=C(O)c1cnccc1C(F)(F)F
Reactant: CN(C)C=O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cnccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution comprising 3 g of 4-trifluoromethyl-3-pyridine carboxylic acid, 6.7 ml of thionyl chloride and 20 ml of benzene, was refluxed under heating for 1.5 hours in the presence of a catalytic amount of dimethylformamide. Excess thionyl chloride and benzene were distilled off. Then, the residue was dissolved in 5 ml of ethyl acetate. This solution was gradually dropwise added to 20 ml of ammonia under cooling with ice. After completion Of the dropwise addition, the mixture was stirred at room temperature for 30 minutes. Then, water and ethyl acetate were distilled off under reduced pressure. The residue was extracted with heated ethyl acetate to obtain 2.1 g of 4-trifluoromethyl-3-pyridine carboxamide (melting point: 162.7° C.) as the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25][CH:26]=[C:27]([CH3:32])[CH:28]([OH:31])[CH:29]=[CH2:30].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25][CH:26]=[C:27]([CH3:32])[C:28](=[O:31])[CH:29]=[CH2:30]
Reactant: C=CC(O)C(C)=CCc1c(OC)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C=CC(=O)C(C)=CCc1c(OC)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2
Reaction time: 3 h

Procedure:
The oil product from Example ZC-1B, 6-(1,3-dihydro-6-methoxy -7-methyl-3-oxo-4-p-toluenesulfonyloxy-5-isobenzofuranyl)-3-hydroxy -4-methylhexa-1,4-diene, was dissolved in methylene chloride (20 mL) and 4A molecular sieves (2 g) were added. With vigorous stirring, pyridinium dichromate (2 g) was added and the reaction allowed to proceed for 3 hours. The mixture was then filtered through a celite filled fritted funnel capped with silica gel. Solvent removal was followed by flash chromatography (hexanes/methylene chloride/ether, 4/4/1) to provide the solid product 6-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy -5-isobenzofuranyl)-4-methylhexa-1,4-dien-3-one (0.45 g), which was carried on without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7](Cl)[S:8][C:4]=2[CH:3]=1.[N:12]1([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:16][CH2:15][CH2:14][CH2:13]1.CN(C)C=O.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([N:20]3[CH2:21][CH2:22][CH:17]([N:12]4[CH2:16][CH2:15][CH2:14][CH2:13]4)[CH2:18][CH2:19]3)[S:8][C:4]=2[CH:3]=1
Reactant: Clc1nc2ccc(Br)cc2s1
Reactant: C1CCN(C2CCNCC2)C1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Brc1ccc2nc(N3CCC(N4CCCC4)CC3)sc2c1
Temperature: 150 °C

Procedure:
One equivalent of 6-bromo-2-chlorobenzo[d]thiazole (248 mg, 1.0 mmol) and 1.1 equivalents of 4-(pyrrolidin-1-yl)piperidine (0.170 g, 1.1 mmol) were weighed into a 10 mL CEM microwave vial equipped with a magnetic stirbar. N,N-Dimethylformamide (1.0 mL) and three equivalents of N,N-diisopropylethylamine (0.524 ml, 3.00 mmol) were added via syringe. The reaction mixture was heated to 150° C. under microwave irradiation with the cooling power on for 15 minutes. The reaction mixture was transferred to a 250 mL round bottom flask (methanol rinse) and volatiles were removed under reduced pressure. The residue was partitioned between saturated aqueous sodium carbonate and CHCl3. The aqueous layer was extracted once more with CHCl3, then the combined organic extracts were washed with brine, dried (MgSO4), and filtered. The filtrate was concentrated under reduced pressure to give a solid. This crude solid was purified by column chromatography on an Analogix IF-280 (Analogix SF15-12g, 100% dichloromethane to 97:3 dichloromethane/2 M ammonia in methanol). Fractions containing product were combined and concentrated under reduced pressure to give a solid that was dissolved in hot ethyl acetate, dried (MgSO4), and filtered. The filtrate was placed in a 0° C. freezer to promote crystallization. Crystals were collected by filtration and dried in a vacuum oven to give 6-bromo-2-(4-(pyrrolidin-1-yl)piperidin-1-yl)benzo[d]thiazole. 1H NMR (300 MHz, CD3OD) δ ppm 1.51-1.66 (m, 2H), 1.78-1.88 (m, 4H), 2.04-2.14 (m, 2H), 2.34-2.46 (m, 1H), 2.63-2.72 (m, 4H), 3.16-3.27 (m, 2H), 4.06-4.15 (m, 2H), 7.33 (d, J=9 Hz, 1H), 7.39 (dd, J=2, 9 Hz, 1H), 7.79 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 366 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1([CH3:15])[O:7][C:6]2[CH:8]=[CH:9][C:10]([N:12]=[C:13]=[S:14])=[CH:11][C:5]=2[O:4]1)[CH3:2].[CH3:16][NH:17][NH2:18]>C(O)C>[CH2:1]([C:3]1([CH3:15])[O:7][C:6]2[CH:8]=[CH:9][C:10]([NH:12][C:13](=[S:14])[N:17]([CH3:16])[NH2:18])=[CH:11][C:5]=2[O:4]1)[CH3:2]
Reactant: CCC1(C)Oc2ccc(N=C=S)cc2O1
Reactant: CNN
Solvent: CCO
Product: CCC1(C)Oc2ccc(NC(=S)N(C)N)cc2O1
Yield: 66.9 %

Procedure:
Following procedures similar to those employed in Step A of Example 2, the reaction of 2.1 g (0.0095 mole) of (2-ethyl-2-methyl-1,3-benzodioxol-5-yl) isothiocyanate with 0.44 g (0.0095 mole) of methylhydrazine in 50 ml of ethanol yielded 1.7 g of 4-(2-ethyl-2-methyl-1,3-benzodioxol-5-yl)-2-methyl-3-thiosemicarbazide as a solid. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH:10]([C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([Cl:19])[C:13]=1[Cl:20])[CH3:11])[NH2:5].[S-:21][C:22]#[N:23].[K+].BrBr>>[F:1][C:2]1[C:8]([O:9][CH:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([Cl:19])[C:13]=2[Cl:20])[CH3:11])=[CH:7][C:6]2[S:21][C:22]([NH2:23])=[N:5][C:4]=2[CH:3]=1
Reactant: CC(Oc1ccc(N)cc1F)c1c(Cl)ccc(Cl)c1Cl
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Product: CC(Oc1cc2sc(N)nc2cc1F)c1c(Cl)ccc(Cl)c1Cl
Yield: 74.7 %

Procedure:
5-Fluoro-6-[1-(2,3,6-trichlorophenyl)ethoxy]-1,3-benzothiazol-2-amine was prepared according to the method described in Example 20d but from 1.35 g of 3-fluoro-4-[1-(2,3,6-trichlorophenyl)ethoxy]aniline, 1.56 g of potassium thiocyanate and 0.207 cm3 of dibromine. We obtain 1.18 g of 5-fluoro-6-[1-(2,3,6-trichlorophenyl)ethoxy]-1,3-benzothiazol-2-amine in the form of an orange-coloured powder, which has the following characteristics:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=4)=[CH:13][C:12]3=[O:29])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:30][N:31](C(OC(C)(C)C)=O)[CH2:32][CH2:33][C:3]1=2.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:53].Cl>>[ClH:53].[ClH:53].[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][N:20]=4)=[CH:13][C:12]3=[O:29])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:30][NH:31][CH2:32][CH2:33][C:3]1=2
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(C(F)(F)F)cn5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(C(F)(F)F)cn5)cc4=O)cc31)CNCC2
Yield: 90 %

Procedure:
tert-Butyl 5-methyl-7-(2-oxo-4-((5-(trifluoromethyl)pyridin-2-yl)methoxy)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (90 mg, 0.16 mmol) was deprotected and converted to the dihydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (76 mg, 90%) as a white solid: mp 296-300° C.; 1H NMR (300 MHz, CD3OD) δ 8.93 (s, 1H), 8.23 (dd, J=8.2, 2.1 Hz, 1H), 7.82 (d, J=8.2 Hz, 1H), 7.70 (d, J=7.5 Hz, 1H), 7.59 (d, J=8.3 Hz, 1H), 7.49 (d, J=1.7 Hz, 1H), 7.06 (dd, J=8.3, 1.8 Hz, 1H), 6.47 (dd, J=7.5, 2.7 Hz, 1H), 6.20 (d, J=2.6 Hz, 1H), 5.42 (s, 2H), 4.48 (s, 2H), 3.73 (s, 3H), 3.67 (t, J=6.1 Hz, 2H), 3.20 (t, J=6.1 Hz, 2H); ESI MS m/z 455 [M+H]+; HPLC (Method B) 97.6% (AUC), tR=12.6 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][C:26]([CH2:28][O:29][P:30]([O:40]CC2C=CC=CC=2)([O:32]CC2C=CC=CC=2)=[O:31])=[O:27])=[C:6]([CH2:8][N:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[O:11][C:10]2=[O:24])[CH:7]=1.C1COCC1>C(OCC)(=O)C.O=[Pt]=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][C:26]([CH2:28][O:29][P:30]([OH:32])([OH:40])=[O:31])=[O:27])=[C:6]([CH2:8][N:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=3)[O:11][C:10]2=[O:24])[CH:7]=1
Reactant: O=C(COP(=O)(OCc1ccccc1)OCc1ccccc1)Oc1ccc(Cl)cc1Cn1nc(-c2ccc(C(F)(F)F)cc2)oc1=O
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(COP(=O)(O)O)Oc1ccc(Cl)cc1Cn1nc(-c2ccc(C(F)(F)F)cc2)oc1=O
Yield: 81.6 %

Procedure:
A solution of 3-[[5-chloro-2-[[[[bis-(phenylmethyl)phosphonooxy]methyl]carbonyl]oxy]phenyl]methyl]-5-[4-(trifluoromethyl)phenyl]- 1,3,4 -oxadiazol-2(3H)-one (138 mg, 0.20 mmol) in ethyl acetate (30 mL) and PtO2 (30 mg) was hydrogenated at 30 psi in a Parr apparatus for 1 hr. After hydrogenation is complete, THF (30 mL) was added to solublize the product and then filtered through a pad of Celite to remove the catalyst. The filtrate was evaporated and the residue was recrytallized twice from ether-hexanes and then acetone-hexanes to afford the title compound as a white powder (83 mg, 82%). MS m/e 509 (MH+).
Reaction SMILES: CO.C(O)(=O)C.[Br:7][C:8]1[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:10]([N+:21]([O-])=O)[CH:9]=1.C(=O)([O-])O.[Na+]>[Fe].C(OCC)(=O)C>[NH2:21][C:10]1[CH:9]=[C:8]([Br:7])[CH:20]=[CH:19][C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)c1ccc(Br)cc1N
Temperature: 25 °C

Procedure:
3.0 g of iron powder was added to a mixed solution of 28 mL of methanol and 28 mL of acetic acid containing 5.5 g of tert-butyl 4-bromo-2-nitrobenzoate, and the resulting mixture was heated to reflux for 1 hour. After one reaction mixture was cooled to room temperature, a saturated sodium hydrogen carbonate aqueous solution and ethyl acetate were added and insoluble were removed by filtration. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure to obtain 4.3 g of tert-butyl 2-amino-4-bromobenzoate as pale yellow oil.
Reaction SMILES: ClCl.[C:3]([N:7]1[C:13](=[O:14])[C:12]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:11]=2[NH:10][C:9](=[O:20])[CH2:8]1)([CH3:6])([CH3:5])[CH3:4].O.C(Cl)[Cl:23].C(OCC)(=O)C>C(O)(=O)C>[Cl:23][C:18]1[C:11]2[NH:10][C:9](=[O:20])[CH2:8][N:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[C:13](=[O:14])[C:12]=2[CH:15]=[C:16]([CH3:19])[CH:17]=1
Reactant: Cc1ccc2c(c1)C(=O)N(C(C)(C)C)CC(=O)N2
Reactant: ClCCl
Agent: ClCl
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)c2c(c1)C(=O)N(C(C)(C)C)CC(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Chlorine gas (100 mL, 4.1 mmol) is added via syringe to a mixture of 4-tert-butyl-3,4-dihydro-7-methyl-1H-1,4-benzodiazepine-2,5-dione (1.0 g, 4.1 mmol) and a few grains of ferric chloride hexahydrate in acetic acid. The reaction mixture is stirred at room temperature overnight, poured into water and extracted with ethyl acetate. The combined organic extracts are washed sequentially with water, dilute sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a foam. Flash column chromatography of the foam using silica gel and a 20:1 methylene chloride/ethyl acetate solution gives the title product as a white solid (0.5 g, mp 151°-152° C.).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([OH:10])=[CH:5][C:3]=1[NH2:4].Cl.[CH2:12]([O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]([Cl:30])=[N:25][CH:26]=[N:27]2)=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(O)CCC>[ClH:30].[CH2:12]([O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]([NH:4][C:3]3[CH:5]=[C:6]([OH:10])[C:7]([CH3:9])=[CH:8][C:2]=3[F:1])=[N:25][CH:26]=[N:27]2)=[CH:22][CH:21]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Clc1ncnc2cc(OCc3ccccc3)ccc12
Reactant: Cc1cc(F)c(N)cc1O
Agent: Cl
Solvent: CCCC(C)O
Product: Cc1cc(F)c(Nc2ncnc3cc(OCc4ccccc4)ccc23)cc1O
Temperature: 120 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
2-Fluoro-5-hydroxy-4-methylaniline (170 mg, 1.2 mmol), (prepared as described for the starting material in Example 13), was added to a solution of 7-benzyloxy-4-chloroquinazoline hydrochloride (307 mg, 1mmol) in 2-pentanol (5 ml) and the mixture stirred at 120° C. for 2 hours. The mixture was allowed to cool and the resulting precipitate was collected by filtration, washed with isopropanol and then ether and dried under vacuum at 70° C. to give 7-benzyloxy-4-(2-fluoro-5-hydroxy-4-methylanilino)quinazoline hydrochloride (331 mg, 80%).