Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:26])([F:25])[C:12]3[CH:13]=[CH:14][C:15]4[N:16]([CH:18]=[C:19]([C:21]([O:23]C)=[O:22])[N:20]=4)[N:17]=3)=[N:9][N:10]=2)[CH:7]=1.[Li+].[OH-]>O.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:26])([F:25])[C:12]3[CH:13]=[CH:14][C:15]4[N:16]([CH:18]=[C:19]([C:21]([OH:23])=[O:22])[N:20]=4)[N:17]=3)=[N:9][N:10]=2)[CH:7]=1
Reactant: COC(=O)c1cn2nc(C(F)(F)c3nnc4ccc(Br)cn34)ccc2n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cn2nc(C(F)(F)c3nnc4ccc(Br)cn34)ccc2n1
Yield: 90.5 %

Procedure:
A solution of 3.methyl 6-((6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)imidazo[1,2-b]pyridazine-2-carboxylate (4.0 g, 9.45 mmol) and LiOH (0.340 g, 14.18 mmol) in 10% H2O/MeOH (150 mL) was stirred at ambient temperature for 4 hrs. Solvent was removed via rotary evaporation, and the resulting residue was diluted with H2O (100 mL). The aqueous phase was adjusted to pH=5 with concentrated HCl. The resulting precipitate was collected, rinsed with water, rinsed with EtOAc, and dried under vacuum over P2O5 for 18 hrs to provide the title compound, 6-((6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)imidazo[1,2-b]pyridazine-2-carboxylic acid 45J (3.5 g, 8.55 mmol, 90%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.76 (dd, J=9.85, 1.77 Hz, 1 H) 7.82 (d, J=9.60 Hz, 1H) 8.02 (d, J=9.60 Hz, 1 H) 8.51 (d, J=9.85 Hz, 1 H) 8.90 (s, 1 H) 8.97 (s,1 H). ESI-MS:m/z 4.09 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH:5]=[N+]=[N-])[CH3:2].C(OC(OCC)CNC(N)=O)C.[Cl:23][CH2:24][C:25](=[O:50])[C@:26]1([OH:49])[C@:43]2([CH3:44])[C@H:29]([C@H:30]3[C@:40]([F:46])([C@@H:41]([OH:45])[CH2:42]2)[C@:38]2([CH3:39])[C:33](=[CH:34][C:35](=[O:47])[CH:36]=[CH:37]2)[CH2:32][CH2:31]3)[CH2:28][C@H:27]1[OH:48]>CO>[Cl:23][CH2:24][C:25](=[O:50])[C@:26]1([OH:49])[C@:43]2([CH3:44])[C@H:29]([C@H:30]3[C@:40]([F:46])([C@@H:41]([OH:45])[CH2:42]2)[C@:38]2([CH3:39])[C:33](=[CH:34][C:35](=[O:47])[CH:36]=[CH:37]2)[CH2:32][CH2:31]3)[CH2:28][C@H:27]1[O:48][CH2:5][CH:4]([O:8][CH2:9][CH3:10])[O:3][CH2:1][CH3:2]
Reactant: CCOC(C=[N+]=[N-])OCC
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](O)[C@](O)(C(=O)CCl)[C@@]3(C)C[C@H](O)[C@@]12F
Agent: CCOC(CNC(N)=O)OCC
Solvent: CO
Product: CCOC(CO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CCl)OCC
Temperature: 0 °C

Procedure:
A solution of 2,2-diethoxy-1-diazoethane (prepared from 0.0935 mole of N-2,2-diethoxyethyl urea by the method of W. Kirmse and M. Buschhoff, Chem. Ber., 100, 1491 (1967)) in 300 ml of 3:2 ether-pentane is diluted with 100 ml of methanol and cooled to 0°C. A total of 2.5 g of 21-chloro-9-fluoro-11β,16α,17-trihydroxypregna-1,4-diene-3,20-dione, 16,17-cycloborate is added in portions until nitrogen evolution ceases. The solvent is removed in vacuo and the residue is dissolved in chloroform and chromatographed on an 80 g -- silica gel column. Elution with chloroform gives 2.16 g of TLC pure material that is recrystallized from acetone-hexane to give 1.75 g of 21-chloro-16α-(2,2-diethoxyethoxy)-9-fluoro-11β,17-dihydroxypregna-1,4-diene-3,20-dione, melting point 200°-202°C.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)(C)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2cncc(Cl)n2)CC1

Procedure:
A mixture of 2,6-dichloropyrazine (2.98 g, 20 mmol), piperazine-1-carboxylic acid tert-butyl ester (3.72 g, 20 mmol) and sodium carbonate (2.12 g, 20 mmol) in t-butanol (50 mL) was heated at reflux under nitrogen for 65 h. The solution was concentrated in vacuo. The residue was partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous phase was extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with brine (50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give the title compound (I-1a) as a white solid.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N+:15]([O-])=[CH:14][C:13]=2[N:12]=[CH:11]1)[CH:7]([CH3:9])[CH3:8].[OH-].[NH4+]>CN(C)C=O>[Cl:3][C:14]1[C:13]2[N:12]=[CH:11][N:10]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)Cn1cnc2c[n+]([O-])c3ccccc3c21
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)Cn1cnc2c(Cl)nc3ccccc3c21
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
To 40 ml of cold N,N-dimethylformamide (10°-20° C.) was added slowly 5.9 g (0.0385 mole) of phosphorus oxychloride with swirling, the temperature of the mixture being maintained at 10-20° C. 1-Isobutyl-1H-imidazo[4,5-c]quinolin-5-oxide (6.2 g; 0.0257 mole) from Step (C) above was added gradually with swirling and cooling. After addition was complete, the solution was allowed to stand at room temperature for about 30 minutes with occasional swirling. The solution was then heated on a steam bath for thirty minutes. After allowing it to cool, the solution was poured onto ice with stirring, and the resulting mixture was brought to pH 8-9 with concentrated ammonium hydroxide. The resulting off-white solid was filtered, washed with water, rinsed with ether, and dried to provide 6.0 g of crude 4-chloro-1-isobutyl-1H-imidazo[4,5-c]quinoline having a m.p. of 135°-138° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH2:8].Cl[C:10]1[N:22]=[CH:21][CH:20]=[CH:19][C:11]=1[C:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[O:13].[H-].[Na+].O>O1CCOCC1>[CH2:17]([N:14]([CH2:15][CH3:16])[C:12](=[O:13])[C:11]1[CH:19]=[CH:20][CH:21]=[N:22][C:10]=1[NH:8][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[CH3:1])[CH3:18]
Reactant: CCN(CC)C(=O)c1cccnc1Cl
Reactant: Cc1ccncc1N
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCN(CC)C(=O)c1cccnc1Nc1cnccc1C
Yield: 84.9 %

Procedure:
Into a 1-neck round-bottom flask was added 4-methylpyridin-3-amine (1.02 g, 0.00940 mol) and 2-chloro-N,N-diethylnicotinamide (2.00 g, 0.00940 mol) in 1,4-dioxane (20 mL), and then sodium hydride (0.94 g, 0.024 mol) was added. The reaction was heated at reflux for 1 hour. The mixture was allowed to cool and water was added. The mixture was then extracted with ethyl acetate 3× and the combined organic extracts were washed with water, brine, dried over MgSO4, and concentrate in vacuo. Upon cooling, the product crystallized. The crystalline solid was filtered off, washed with ether and dried to give 2.27 g of the desired product. 1H NMR (300 MHz, CDCl3): δ 9.15 (s, 1H), 8.21-8.24 (m, 2H), 7.90 (br s, 1H), 7.47 (dd, 1H J1=7.5, J2=1.8 Hz), 7.11 (d, 1H, J=4.8 Hz), 6.75 (dd, 1H, J1=7.5, J2=5.1 Hz), 3.46-3.51 (m, 4H), 2.29 (s, 3H), 1.25 (t, 6H). MS [M+1]=285.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]3[CH:13]=[C:14]([NH:18][C:19]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[O:20])[CH:15]=[CH:16][CH:17]=3)=[CH:10][N:11]=[C:5]2[CH:4]=1)=O.Cl.[NH2:28][OH:29].C(N(CC)CC)C.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[OH:29][N:28]=[CH:1][C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]3[CH:13]=[C:14]([NH:18][C:19]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[O:20])[CH:15]=[CH:16][CH:17]=3)=[CH:10][N:11]=[C:5]2[CH:4]=1
Reactant: NO
Reactant: O=Cc1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(C=NO)ccn23)c1
Reaction time: 18 h
Yield: 43.5 %

Procedure:
To a suspension of 1-[3-(7-Formyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (50 mg, 0.14 mmol) in toluene (5 ml) was added hydroxylamine hydrochloride (11 mg, 0.15 mmol) and triethylamine (21 μl, 0.15 mmol). The reaction mixture was stirred for 10 min before tosic acid (3 mg, 0.014 mmol) was added and then stirred for a further 18 h. The resulting precipitate was filtered off and washed with Et2O to give the product (23 mg). MS: [M+H]+ 378.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>O1CCOCC1.C(OCC)(=O)C>[CH:15]1([NH:21][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NC1CCCCC1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(NC2CCCCC2)c([N+](=O)[O-])c1

Procedure:
A room temperature solution of Example 1C (2.36 g, 10.0 mmol) and cyclohexylamine (2.0 mL) in dioxane (5 mL) was stirred for 16 hours, diluted with ethyl acetate (100 mL), washed sequentially with 3M HCl (20 mL), water (20 mL) and brine (10 mL), dried (MgSO4), filtered, and concentrated to provide the desired product of sufficient purity for subsequent use.
Reaction SMILES: [CH3:1][N:2]([C:4]1[N:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[C:7]([OH:14])=[CH:6][CH:5]=1)[CH3:3].[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19](S(C)(=O)=O)[N:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19]([O:14][C:7]2[C:8]([C:10]([O:12][CH3:13])=[O:11])=[N:9][C:4]([N:2]([CH3:1])[CH3:3])=[CH:5][CH:6]=2)[N:18]=1
Reactant: COC(=O)c1nc(N(C)C)ccc1O
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc(N(C)C)ccc1Oc1nc(OC)cc(OC)n1

Procedure:
1.4 g (7 mmol) of methyl 6-(N,N-dimethylamino)-3-hydroxypicolinate, 1.6 g (7 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 0.6 g (4 mmol) of potassium carbonate were added to 100 ml of dimethylformamide (DMF), and were reacted at 90° C. for 2 hours. After the reaction, the reaction content was poured into water, and was extracted with diethyl ether, and then washed with water, dried and concentrated to obtain an oily product which was thereafter crystallized with isopropyl ether. The crystal thus obtained was recrystallized with ethyl acetate/n-hexane to obtain an aimed product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][C:12]([OH:19])=[C:11]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:25]1[CH:26]=[CH:27][C:28]([N+:40]([O-:42])=[O:41])=[C:29]([N:31]([CH3:39])[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH:30]=1.[H-].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:14]([C:15]([CH3:16])([CH3:17])[CH3:18])=[CH:13][C:12]([O:19][C:25]2[CH:26]=[CH:27][C:28]([N+:40]([O-:42])=[O:41])=[C:29]([N:31]([CH3:39])[C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37])[CH:30]=2)=[C:11]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)c1cc(OCc2ccccc2)c(C(C)(C)C)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2cc(C(C)(C)C)c(OCc3ccccc3)cc2C(C)(C)C)ccc1[N+](=O)[O-]
Yield: 103.1 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 4-benzyloxy-2,5-di-t-butylphenol (4.3 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (3.51 g), sodium hydride (55 wt. %, 0.72 g) and anhydrous N,N-dimethylformamide (15 ml) and the reaction mixture was purified to give the title compound (7.1 g).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:37][CH3:38])[C:7]([O:24][CH:25]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCCl>[CH2:37]([C:6]1[N:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:9]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]3)=[CH:15][CH:16]=2)=[N:8][C:7]=1[O:24][CH:25]1[CH2:29][CH2:28][NH:27][CH2:26]1)[CH3:38]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1OC1CCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1OC1CCNC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.8 %

Procedure:
To a mixture of tert-butyl 3-[(5-carbamoyl-3-ethyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazin-2-yl)oxy]pyrrolidine-1-carboxylate (355 mg) and 1,2-dichloroethane (6 mL) was added trifluoroacetic acid (2 mL) under ice-cooling, followed by stirring at room temperature for 12 hours. The reaction mixture was concentrated, then diluted with chloroform, and neutralized with a 10% aqueous potassium carbonate solution. After extraction with chloroform, the organic phase was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-100:10:1), and dried under reduced pressure to obtain 6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(pyrrolidin-3-yloxy)pyrazine-2-carboxamide (212 mg) as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30](=[O:33])[CH:31]=[CH2:32])[CH:24]=3)[S:10][C:11]=2[C:12]2[N:16]=[CH:15][N:14](C3CCCCO3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:34][O:35][CH2:36][C@@H:37]1[CH2:41][CH2:40][CH2:39][NH:38]1>O1CCCC1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH3:34][O:35][CH2:36][C@@H:37]1[CH2:41][CH2:40][CH2:39][N:38]1[CH2:32][CH2:31][C:30]([NH:29][C:25]1[CH:24]=[C:23]([C:9]2[S:10][C:11]([C:12]3[NH:16][CH:15]=[N:14][N:13]=3)=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH:28]=[CH:27][N:26]=1)=[O:33]
Reactant: COC[C@@H]1CCCN1
Reactant: C=CC(=O)Nc1cc(-c2nc(-c3ccccc3)c(-c3ncn(C4CCCCO4)n3)s2)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC[C@@H]1CCCN1CCC(=O)Nc1cc(-c2nc(-c3ccccc3)c(-c3nnc[nH]3)s2)ccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.3 %

Procedure:
To a solution of N-(4-(4-phenyl-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl)pyridin-2-yl)prop-2-enamide (92 mg, 0.2 mmol) prepared in Example 4-B (iii) in tetrahydrofuran (2.0 mL) was added (2S)-2-(methoxymethyl)pyrrolidine (120 mg, 1.0 mmol), and the mixture was heated under reflux for 14 hr. The reaction solution was cooled to room temperature, and diluted with ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (30 mL). The aqueous layer was separated, extracted with ethyl acetate (40 mL), and the combined organic layer was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated. The obtained residue was dissolved in trifluoroacetic acid (4.0 mL), and the mixture was stirred at room temperature for 3 hr. Trifluoroacetic acid was evaporated under reduced pressure, and the residue was diluted with ethyl acetate (30 mL), and washed with saturated aqueous sodium bicarbonate solution (30 mL). The aqueous layer was separated and extracted with ethyl acetate (30 mL), and the combined organic layer was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (methanol/ethyl acetate=0/100→50/50) to give the title compound (60 mg, 62%) as a pale-yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([NH2:16])[CH3:15]>O>[C:1]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH:16][CH2:14][CH3:15])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN
Reactant: CC(C)(C)c1ccccc1C(=O)Cl
Solvent: O
Product: CCNC(=O)c1ccccc1C(C)(C)C

Procedure:
2-tert-butyl-N-ethylbenzamide was prepared from 2-tert-butylbenzoyl chloride, prepared in Example 186, and 70% ethylamine in water according to the method of step b of Example 248.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:12][S@](C(C)(C)C)=O)[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([Br:11])[CH:5]=1.N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].Cl>C(Cl)Cl>[NH2:12][C@@H:3]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([Br:11])[CH:5]=1)[CH2:2][NH:1][C:25](=[O:27])[CH3:26]
Reactant: CC(C)(C)[S@](=O)N[C@H](CN)c1cc(F)cc(Br)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NC[C@@H](N)c1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)—N—((S)-2-amino-1-(3-bromo-5-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (100 mg, 0.297 mmol) was dissolved in DCM (988 μl), followed by pyridine (71.9 μl, 0.890 mmol) and acetic anhydride (28.0 μl, 0.297 mmol). The reaction mixture was stirred at room temperature for 1 h, extracted by EtOAc, washed by water and brine, dried over Na2SO4and concentrated. The residue was dissolved in Et2O (1 mL), then HCl (4 M in dioxane) (148 μl, 0.593 mmol) was added. The reaction mixture was stirred at room temperature for 30 min. After the solvent was decant out, the residue solid was used in next step reaction without purification. LCMS (m/z): 275.1/277.1 (MH+), 0.41 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1.O.O.O.O.O.[OH-].C[N+](C)(C)C.[CH3:33][O:34][CH2:35][CH2:36]Br.Cl>CN(C=O)C.O>[ClH:1].[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH2:36][CH2:35][O:34][CH3:33])=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: COCCBr
Reactant: Oc1ccc2c(N3CCc4ccc(Cl)cc43)ncnc2c1
Agent: C[N+](C)(C)C
Agent: Cl
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc2c(N3CCc4ccc(Cl)cc43)ncnc2c1
Temperature: 50 °C
Reaction time: 36 h
Yield: 110.5 %

Procedure:
To 4-(6-chloro-2,3-dihydro-indol-1-yl)-quinazolin-7-ol (125 mg, 0.42 mmol; from Example 65) in DMF (2 mL) was added H2O (50 μL), K2 CO3 (s) (116 mg, 0.84 mmol), and tetramethylammonium hydroxide pentahydrate (15 mg, 0.08 mmol) followed by 2-bromoethyl methyl ether (43 μL, 0.46 mmol). The mixture was stirred at 50° C. under N2(g) for 24 hours before another aliquot (43 μL) of 2-bromoethyl methyl ether was added. Stirring at 50° C. was continued for another 36 hours before extractive workup and chromatography analogous to that described in Example 1 followed by conversion to the HCl salt as outlined for Example 2 afforded 91 mg (61%) of product. (M.P. 213°-216° C. (dec); LC-MS: 356 (MH+); anal. RP18-HPLC RT: 4.73 min.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]#[N:16])([CH3:4])([CH3:3])[CH3:2].[N-:18]=[N+:19]=[N-:20].[Na+].[Cl-].[NH4+].C(OCC)(=O)C>CN(C)C=O>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[NH:20][N:19]=[N:18][N:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1C#N
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1ccccc1-c1nnn[nH]1
Temperature: 25 °C

Procedure:
A solution of (2-cyano-benzyl)-carbamic acid tert-butyl ester (35 mg, 0.15 mmol), sodium azide (49 mg, 0.75 mmol), ammonium chloride (40 mg, 0.75 mmol) in dimethylformamide (0.5 ml) was heated to 110° C. for 8 h. After cooling to room temperature, ethyl acetate was added and the resultant solid filtered. Concentration of the filtrate gave [2-(1H-tetrazol-5-yl)-benzyl]-carbamic acid tert-butyl ester; 1H NMR (CD3OD, 400 MHz) δ 7.71(d, 1H, J=7.5 Hz), 7.58 (m, 2H), 7.48 (m, 1H), 4.44 (s, 2H), 1.42 (s, 9H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[CH:22]=[C:21]([F:23])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:31][O:32][C:33]1[C:41]([O:42][CH3:43])=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36]>O1CCOCC1>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[CH:22]=[C:21]([F:23])[C:19](=[O:20])[N:18]([C:35](=[O:36])[C:34]3[CH:38]=[CH:39][CH:40]=[C:41]([O:42][CH3:43])[C:33]=3[O:32][CH3:31])[C:16]2=[O:17])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OC(C)=O
Reactant: COc1cccc(C(=O)Cl)c1OC
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)n2c(=O)c(F)cn([C@H]3C[C@H](OC(C)=O)[C@@H](COC(C)=O)O3)c2=O)c1OC
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
15.0 g of 2'-deoxy-3',5'-di-O-acetyl-5-fluorouridine and 15 ml of triethylamine were dissolved in 75 ml of dry dioxane, and the resulting solution was cooled with ice. To the solution was added 13.6 g of 2,3-dimethoxybenzoyl chloride, and the resulting mixture was allowed to stand at room temperature for 30 minutes and then at 90° C. for 30 minutes. The crystals produced were filtered off, and the filtrate was concentrated under reduced pressure. To the oily residue was added 200 ml of ethanol. Upon heating, the mixture began to separate crystals while the oily residue was dissolved. After dissolving the oily residue completely, the mixture was cooled, and there was obtained 2'-deoxy-3',5'-di-O-acetyl-3-(2,3-dimethoxybenzoyl)-5-fluorouridine as crystals. Recrystallization of the product from ethanol afforded 19.65 g (yield: 88.4%) or colorless needles having a melting point of 139 to 141° C. The structure was supported by the absorption spectra and elemental analysis.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH:33]1[CH2:38][CH2:37][O:36][C:35]([CH3:40])([CH3:39])[CH2:34]1>CN(C=O)C>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH:33]2[CH2:38][CH2:37][O:36][C:35]([CH3:40])([CH3:39])[CH2:34]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CC1(C)CC(CBr)CCO1
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CC3CCOC(C)(C)C3)c2n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
A mixture of 2-butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt (223 mg) and potassium carbonate (264 mg) in dry DMF (2 mL) were heated at 60° C. under nitrogen with stirring for 1 h. 4-(Bromomethyl)-2,2-dimethyltetrahydro-2H-pyran (158 mg) was added and the reaction was stirred for 16 h at 60° C. The mixture was quenched with water and extracted with EtOAc (×3). The combined organics were washed with water and brine, dried using a hydrophobic frit and evaporated to give a brown oil. The crude material was purified by normal phase chromatography (ISCO) using 5-20% methanol/EtOAc as eluent to give a pale oil (181 mg). The material was re-purified by normal phase chromatography (ISCO) using 0-15% methanol/EtOAc as eluent to give the title compound (161 mg).