Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([O:6][C:7]1[CH:8]=[C:9]([C:24]2[NH:28][C:27]([C:29]3[O:30][CH2:31][C@@H:32]([C@H:34]([OH:36])[CH3:35])[N:33]=3)=[CH:26][CH:25]=2)[CH:10]=[C:11]([O:13][Si](C(C)C)(C(C)C)C(C)C)[CH:12]=1)[CH3:5].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>O1CCCC1>[OH:36][C@@H:34]([C@@H:32]1[CH2:31][O:30][C:29]([C:27]2[NH:28][C:24]([C:9]3[CH:10]=[C:11]([OH:13])[CH:12]=[C:7]([O:6][C@@H:4]([CH3:5])[CH2:3][O:2][CH3:1])[CH:8]=3)=[CH:25][CH:26]=2)=[N:33]1)[CH3:35]
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C3=N[C@H]([C@@H](C)O)CO3)[nH]2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=N[C@H]([C@@H](C)O)CO3)[nH]2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
(1R)-1-{(4S)-2-[5-(3-{[(2S)-1-Methoxypropan-2-yl]oxy}-5-[(tripropan-2-ylsilyl)oxy]phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol (1.30 g, 2.52 mmol) synthesized in Example (114b) was dissolved in tetrahydrofuran (15 mL), and tetrabutylammonium fluoride (1.0 mol/L tetrahydrofuran solution, 4.00 mL, 4.00 mmol) was added at room temperature, followed by stirring at room temperature for 1 hour under nitrogen atmosphere. To this reaction solution, a saturated aqueous ammonium chloride solution (50 mL) was added, and extraction was carried out with methylene chloride (50 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/ethyl acetate=8%-12%) to afford the desired compound (766 mg, yield 85%) as a white foam.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:2]1[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>O.C1COCC1>[N:1]1([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:9][CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4]
Reactant: O=C(O)C1CCCCN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CCCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
To a 0° C. suspension of pipecolic acid (0.15 g, 1.16 mmol) and potassium carbonate (4.64 mmol) in water (5 mL) and THF (5 mL) was added benzyl chloroformate (0.24 g, 1.41 mmol). The mixture was rapidly stirred for one hour then allowed to warm to ambient temperature. After 6 hours, the reaction was diluted with water and washed with ether. The aqueous layer was acidified and extracted with methylene chloride. The organic phase was washed with brine then dried over sodium sulfate. The solvent was evaporated and the residue recrystallized from hexane-ethyl acetate to yield 0.23 g (75% yield) of the title compound as a white solid. MS(CI) m/e 264 (M+H)+. 1H NMR (300 MHz, CDCl3) δ1.24-1.80 (m, 5H), 2.26 (br t, 1H), 2.93-3.14 (m, 1H), 4.00-4.19 (m, 1H), 4.87-5.05 (m, 1H), 5.15 (br s, 2H), 7.27-7.41 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28]C)=[C:6]([C:8]([C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=2[NH:20]C(OC(C)(C)C)=O)=[O:9])[CH:7]=1>C(Cl)Cl.B(Br)(Br)Br>[NH2:20][C:11]1[CH:12]=[CH:13][C:14]([C:16]([F:17])([F:18])[F:19])=[CH:15][C:10]=1[C:8]([C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[OH:28])=[O:9]
Reactant: COc1ccc(Cl)cc1C(=O)c1cc(C(F)(F)F)ccc1NC(=O)OC(C)(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1ccc(C(F)(F)F)cc1C(=O)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
To a cold solution (−78° C.) of N-[2-[(5-chloro-2-methoxyphenyl) carbonyl]-4-(trifluoromethyl) phenyl]aminocarboxylic acid, 1,1-dimethylethyl ester prepared in Example 1, Step A (7.0 g, 21.2 mmol) in methylene chloride (60 mL), 1.0 M BBr3 solution in methylene chloride (46.7 mL, 46.7 mmol) was added dropwise. The resultant red solution was allowed to warm to room temperature and stirred overnight. The reaction mixture was quenched with saturated NaHCO3 solution. The organic layer was separated and washed with water, brine and then dried (MgSO4). Evaporation of the solvent gave a yellow-reddish solid which was recrystallized from CH2Cl2/hexanes to afford the title compound as a yellow solid (6.58 g, 98%).
Reaction SMILES: [CH:1]1([C:7]2[CH:15]=[CH:14][C:10]3[CH2:11][CH2:12][O:13][C:9]=3[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH:17]([O:19]C)Cl>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH:1]1([C:7]2[C:15]([CH2:17][OH:19])=[CH:14][C:10]3[CH2:11][CH2:12][O:13][C:9]=3[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: c1cc2c(cc1C1CCCCC1)OCC2
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: OCc1cc2c(cc1C1CCCCC1)OCC2

Procedure:
5 g of 6-Cyclohexyl-2,3-dihydro-benzofuran are dissolved in methylene chloride. 9.5 ml of TiCl4 are slowly added dropwise whilst cooling and stirring, followed by 2.9 g of dichloromethylmethylether in 10 ml of Ch2Cl2. The mixture is stirred for 5 hours at 22°, poured onto ice-water and extracted with ethyl acetate. The organic phase is washed with water, dried over Na2SO4 and reduced in volume. The residue is dissolved in tetrahydrofuran without further purification. An excess of NaBH4 is added and the mixture refluxed for 3 hours. Natural working of the mixture yields 6-cyclohexyl-2,3-dihydro-5-hydroxymethyl-benzofuran.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1/[CH:19]=[CH:20]/[CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl.C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:10][N:24]2[CH2:25][CH2:26][CH:21](/[CH:20]=[CH:19]/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[F:12])[CH2:22][CH2:23]2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: Fc1ccccc1/C=C/C1CCNCC1
Reactant: COc1ncc(F)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ncc(F)cc1CN1CCC(/C=C/c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
117 mg of 5-fluoro-2-methoxy-3-pyridinecarboxaldehyde and 291 mg of 4-[(E)-2-(2-fluorophenyl)-1-ethenyl]piperidine were dissolved in 3 ml of 1,2-dichloroethane, 0.06 ml of acetic acid and 238 mg of sodium triacetoxyborohydride were added thereto, and the mixture was stirred at room temperature overnight. An aqueous saturated sodium carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (n-hexane:ethyl acetate=8:1), to give 221 mg of the title compound as a colorless oil.
Reaction SMILES: N1C2C(=NC=CC=2)N([N:10]2[C:14](/[CH:15]=[C:16]3\[C:17](=[O:26])[NH:18][C:19]4[C:24]\3=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)=[C:13]([CH3:27])[C:12]([C:28]([O-:30])=O)=[C:11]2[CH3:31])N=1.[NH2:32][C@@H:33]1[CH2:37][O:36][N:35]([CH:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[C:34]1=[O:44].CCN(C(C)C)C(C)C>CN(C=O)C>[O:44]=[C:34]1[C@H:33]([NH:32][C:28]([C:12]2[C:13]([CH3:27])=[C:14](/[CH:15]=[C:16]3\[C:17](=[O:26])[NH:18][C:19]4[C:24]\3=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[NH:10][C:11]=2[CH3:31])=[O:30])[CH2:37][O:36][N:35]1[CH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1
Reactant: Cc1c(C(=O)[O-])c(C)n(-n2nnc3cccnc32)c1/C=C1\C(=O)Nc2ccc(F)cc21
Reactant: N[C@@H]1CON(C2CCOCC2)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)N[C@@H]1CON(C2CCOCC2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a solution of A4 (84 mg, 2 mmol) in 10 mL of DMF, were added the crude 48c from last step and DIEA (2 mL), the reaction mixture was stirred at room temperature overnight. LC/MS was applied to determine completion of the reaction. The reaction mixture was evaporated under reduced pressure and the residue was triturated with 5% diethylamine/methanol (25 mL). The solid was collected by filtration and washed with methanol, dried under vacuum to provide the title compound (58 mg, 62%) as orange solid. 1H NMR (300 MHz, DMSO-d6): δ=13.73 (s, 1H), 10.94 (s, 1H), 8.12-8.15 (d, 1H), 7.73-7.80 (m, 2H), 6.82-6.87 (m, 2H), 5.02-5.05 (q, 1H), 4.58-4.64 (t, 1H), 3.86-4.14 (m, 4H), 3.38-3.44 (m, 2H), 2.42-2.50 (ds, 6H), 1.65-1.88 (m, 4H). LC/MS: 469.0 [M+H]+.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH2:2]1.B.C1COCC1.O.[OH-].[Na+]>FC(F)(F)C(O)=O.O1CCCC1>[CH2:1]1[CH:13]2[CH:5]([C:6]3[C:11]([NH:12]2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c3c([nH]c2c1)CCCC3
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2c(c1)NC1CCCCC21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 79.1 %

Procedure:
1,2,3,4-Tetrahydrocarbazole (75 milligrams) was dissolved under nitrogen in 3 milliliters of trifluoroacetic acid. To the mixture, cooled in a water bath, was added dropwise about 1.5 milliliters of an about 1 M BH3.THF in tetrahydrofuran. The mixture was stirred at room temperature for about 45 minutes. Thereafter, water (1 milliliter) was added slowly and the resulting solution stirred for 10 minutes. The solution was then made basic with 10 percent aqueous sodium hydroxide, and the basic solution extracted with methylene chloride. The organic methylene chloride layer was washed once with saturated sodium chloride, dried over potassium carbonate, and evaporated in vacuo to obtain 60 milligrams (80 percent yield) of a crystalline 1,2,3,4,4a,9a-hexahydrocarbazole product, m.p., 93°-96° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][NH:7]2.[H-].[Na+].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>CS(C)=O.CCCCCC.O>[CH3:1][NH:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CNc1ncnc2[nH]cnc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CS(C)=O
Product: CNc1ncnc2c1ncn2-c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
In 120 mL of dimethyl sulfoxide, 10.78 g (80 mmol) of methyl-(9H-purin-6-yl)amine was dissolved, and 1.98 g (82.5 mmol) of sodium hydride (60%) after washing with hexane was added thereto and the mixture solution was stirred at room temperature for one hour. To the reaction solution, 13.0 g (92 mmol) of 4-fluoronitrobenzene was added dropwise and the resulting solution was stirred at 80° C. for two hours. The reaction solution was diluted with 300 mL of water, and the crystal deposited was collected on a filter, then washed with 100 mL of water and subsequently with 500 mL of ethanol, and vacuum dried to obtain 16.14 g (83%) of a target product as a yellow solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(=NC1CCCCC1)C.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])C=O)=[CH:21][CH:20]=1.[O:40]1C[CH2:43][CH2:42][CH2:41]1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)=[C:26]([C:29]([CH3:31])([CH3:32])[CH3:30])[CH:43]=[CH:42][CH:41]=[O:40])=[CH:21][CH:20]=1
Reactant: CC(C)(C)C(C=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: CC=NC1CCCCC1
Agent: [Li+]
Product: CC(C)(C)C(C=CC=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
Lithium diisopropylamide (5.4 mL of 1.84M solution, 10 mmol) was added to N-ethylidenecyclohexanamine (5 mL of 2M solution, 10 mmol) in tetrahydrofuran at -20° C. After stirring for 30 minutes and further cooling to -50° C., 3,3-bis(4-fluorophenyl)-2-(1,1-dimethylethyl)propenal (0.9 g, 3.0 mmol) was added and the solution stirred for 4 hours during which time the temperature was allowed to rise to -20° C. The solution was quenched with 2N hydrochloric acid and the mixture extracted with diethyl ether. The extracts were dried and concentrated in vacuo. The residue was stirred for 18 hours with a mixture of 50 mL benzene, 15 mL of water and 35 mL of acetic acid. The mixture was diluted to 200 mL with water. The organic layer was separated, washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica eluting with 1% ethyl acetate in hexane to give 0.5 g of the title compound; m.p. =87°-89° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](F)=[CH:4][CH:3]=1.[CH2:9]([NH2:12])[CH2:10][NH2:11]>C(Cl)(Cl)Cl>[NH2:11][CH2:10][CH2:9][NH:12][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Fc1ccc(Cl)cc1
Reactant: NCCN
Solvent: ClC(Cl)Cl
Product: NCCNc1ccc(Cl)cc1
Temperature: 200 °C
Reaction time: 48 h
Yield: 97 %

Procedure:
4-Chlorofluorobenzene (92.00 g) and ethylenediamine (290.0 g) were placed in a pressure-resistant stainless-steel reactor. A stirrer was placed in the reactor and the reactor was sealed. Subsequently, the reaction mixture was stirred for 2 days at an external temperature of 200° C. The reaction mixture was allowed to cool, and chloroform (800 ml) was added to the mixture. The mixture was transferred to a separating funnel, washed sequentially with water (200 ml), saturated brine (200 ml), and a saturated sodium hydrogencarbonate solution (100 ml) in this order. The aqueous layer was extracted with chloroform (200 ml×3), washed with saturated brine, combined with the chloroform layer again, and dehydrated over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, to thereby yield the target compound (116.69 g) as a pale-yellow oily product, Since this product contained almost no impurities and was considered to be almost pure by NMR, the product was submitted to the next reaction step without further purification.
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6]CC)=O.[H-].[Na+].[Cl:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([Cl:26])[C:17]=1[N:27]=[C:28]=[O:29]>CN(C)C=O>[Cl:15][C:16]1[CH:21]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:19]=[C:18]([Cl:26])[C:17]=1[N:27]1[C:4](=[O:6])[CH:3]=[C:2]([C:9]([F:10])([F:11])[F:12])[NH:1][C:28]1=[O:29]
Reactant: O=C=Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Yield: 28.5 %

Procedure:
A 20 ml dimethylformamide solution of 2.7 g of ethyl 3-amino-4,4,4-trifluorocrotonate was added dropwise to a 20 ml dimethylformamide solution of 0.78 g of sodium hydride (purity: 55%) with stirring at 0° C. After heated to room temperature under stirring for 15 minutes, the mixed solution was cooled to -30° C. and then added dropwise with 20 ml of a dimethylformamide solution of 3.8 g of 2,6-dichloro-4-trifluoromethylphenyl isocyanate. The resulting solution was again heated to room temperature and stirred at 80° C. for 30 minutes. Then the solvent was distilled away under reduced pressure and the residue was dissolved by adding 100 ml of water. This aqueous solution was washed twice with diethyl ether, then added to a mixed solution of 50 g of ice and 20 ml of concentrated hydrochloric acid, and extracted with ethyl acetate. The obtained organic layer was washed with water and dried, and the solvent was distilled away under reduced pressure to obtain 3.75 g of a crude product. This crude product was recrystallized from a mixed solvent of diisopropyl ether and isopropyl alcohol to obtain 1.65 g of the objective compound.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[C:6]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:7]=1.N([O-])=O.[Na+].[ClH:21]>[Cu]Cl>[Cl:21][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[C:6]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:7]=1
Reactant: CC(=O)c1cc(N)cc(S(F)(F)(F)(F)F)c1
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Product: CC(=O)c1cc(Cl)cc(S(F)(F)(F)(F)F)c1
Reaction time: 8 h

Procedure:
1-[3-Amino-5-(pentafluorosulfanyl)phenyl]ethanone (150 mg, ex. 22a) was dissolved in semiconcentrated hydrochloric acid (6 ml). While stirring and cooling, sodium nitrite solution (40 mg dissolved in water) was added dropwise, in the course of which the temperature was not to exceed 5° C. On completion of formation of the diazonium salt, copper(I) chloride solution (68 mg dissolved in 2 ml of concentrated hydrochloric acid) was cooled to 0° C. while stirring and the above diazonium salt solution was slowly added dropwise. Then the cooling bath was removed, and the mixture was stirred at RT for 3 h and left to stand overnight. Then the reaction mixture was diluted with water and extracted repeatedly with EA. The combined EA phases were washed with saturated sodium hydrogencarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by means of preparative HPLC. The product-containing fractions were combined, freed of the acetonitrile, admixed with saturated sodium hydrogencarbonate solution and extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. 104 mg of the desired compound were obtained.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]2[C:22]3[N:23]=[C:24]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=4)[N:25]=[CH:26][C:21]=3[CH2:20][C:19](=[O:38])[NH:18][C:17]=2[CH:39]=1)=[O:12])(C)(C)C.C(Cl)Cl.CO.Cl>O1CCOCC1>[NH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]2[C:22]3[N:23]=[C:24]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=4)[N:25]=[CH:26][C:21]=3[CH2:20][C:19](=[O:38])[NH:18][C:17]=2[CH:39]=1)=[O:12]
Reactant: COc1ccc(Nc2ncc3c(n2)-c2ccc(C(=O)NCCNC(=O)OC(C)(C)C)cc2NC(=O)C3)cc1OC
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(Nc2ncc3c(n2)-c2ccc(C(=O)NCCN)cc2NC(=O)C3)cc1OC
Reaction time: 8 h

Procedure:
To a mixture of (2-{[2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-9-carbonyl]-amino}-ethyl)-carbamic acid tert-butyl ester (I-71-a) (0.18 mmol) in 1:1 mixture of CH2Cl2:MeOH (4 mL) was added 4M HCl in dioxane (2 mL). The mixture stirred overnight and was concentrated. The mixture was purified by C-18 RP LC-MS chromatography to give I-71 (17%): HRMS Calcd. for C23H24N6O4: 449.1937, Found 449.1935.
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][CH:3]1[CH:11]=[CH:10][CH2:9][CH2:8][CH:4]1[C:5]([OH:7])=O.[CH2:14]([NH2:17])[CH:15]=[CH2:16]>>[CH2:14]([N:17]1[C:1](=[O:13])[CH2:2][C:3]2[CH2:11][CH2:10][CH2:9][CH2:8][C:4]=2[C:5]1=[O:7])[CH:15]=[CH2:16]
Reactant: O=C(O)CC1C=CCCC1C(=O)O
Reactant: C=CCN
Product: C=CCN1C(=O)CC2=C(CCCC2)C1=O

Procedure:
A mixture of tetrahydrohomophthalic acid (9.2 g., 0.05 mole) and allylamine (2.8 g., 0.05 mole) is heated by an oil bath until molten for 40 minutes. The mixture solidifies upon cooling, and is recrystallized twice from isopropanol, giving 2-allyl-5,6,7,8-tetrahydroisoquinoline-1,3(2H, 4H)-dione.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:5]([OH:14])=[N:6][C:7]([CH3:13])=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1.[F-].[Cs+].FS([C:21]([F:30])([F:29])C(O[Si](C)(C)C)=O)(=O)=O>>[F:29][CH:21]([F:30])[O:14][C:5]1[C:4]([CH3:3])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([CH3:13])[N:6]=1
Reactant: Cc1cc([N+](=O)[O-])c(C)nc1O
Reactant: C[Si](C)(C)OC(=O)C(F)(F)S(=O)(=O)F
Agent: [Cs+]
Agent: [F-]
Agent: [H-]
Product: Cc1cc([N+](=O)[O-])c(C)nc1OC(F)F
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 92.2 %

Procedure:
Sodium hydride (6.63 g, 166 mmol, 60% in mineral oil) was washed with hexanes (100 mL) to remove the mineral oil and was then suspended in dry acetonitrile (1500 mL) at room temperature. 3,6-Dimethyl-5-nitropyridin-2-ol (27.9 g, 166 mmol) was added in portions over 30 minutes to give a yellow suspension. During the addition there was some bubbling but negligible temperature change. Cesium fluoride (2.50 g, 16.6 mmol) was then added followed by the slow addition of trimethylsilyl 2-(fluorosulfonyl)difluoroacetate (36.0 mL, 182 mmol) over 30 minutes. During the addition there was some bubbling, the temperature rose from 23° C. to 30° C., and the suspension became noticeably less turbid. After stirring for 15 min, TLC indicated that starting material still remained, so additional trimethylsilyl 2-(fluorosulfonyl)difluoroacetate (6.5 mL, 33 mmol) was added over 10 minutes. After an additional 15 min, TLC indicated consumption of starting material. The reaction was quenched by the addition of water (20 mL) dropwise at such a rate that the bubbling did not become too vigorous. After bubbling ceased, additional water (200 mL) was added. Most of the solvent was removed in vacuo and the aqueous residue was extracted with ethyl acetate (3×200 mL). The combined organic layers were dried over Na2SO4 and evaporated to a brown syrup which solidified upon standing. This residue was dissolved in ethanol (400 mL) and decolorizing charcoal (15 g) was added. The suspension was heated at 70° C. for 20 min and then filtered through a pad of Celite and sand. The filtrate was collected and the solvent was evaporated. The residue was dissolved in methylene chloride and the solution was evaporated to give 2-(difluoromethoxy)-3,6-dimethyl-5-nitropyridine (33.4 g, 92% yield) as a pale yellow solid: mp 51-52° C.; 1H NMR (400 MHz, CDCl3) δ8.21 (s, 1H), 7.55 (t, J=72.0 Hz, 1H), 2.76 (s, 3H), 2.30 (s, 3H). Anal. calcd. for C8H8N2O3F2: C, 44.04, H, 3.69, N, 12.84. Found: C, 43.78, H, 3.55, N, 12.58.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Br>CN(C=O)C>[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: Fc1ccccc1CBr
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccccc1Cn1ccc2cc(Br)ccc21
Reaction time: 0.5 h

Procedure:
5-Bromoindole (1.96 g, 10 mmol) was dissolved in 20 mL of DMF, 60%-NaH (0.44 g, 11 mmol) was added. It was stirred for 30 minutes, then 2-fluorobenzyl bromide (1.33 mL, 11 mmol) was added. Stirring continued at 50° C. for 5 hours. After dilution with EtOAc, the organic layer washed with brine (5×), dried over MgSO4. After evaporation to dryness, it was then dried under high vacuum to yield N-2-Fluorobenzyl-5-bromoindole in quantitative yield. The title compound was prepared by substituting N-2-Fluorobenzyl-5-bromoindole (3.04 g, 10 mmol) for 4-bromo-2-nitrophenylamine in EXAMPLE 2A. Crude material was purified by silica gel column chromatography, eluting with 2.5% EtOAc in hexane. 2.18 g of the title compound was obtained. MS: ESI(+) m/e 352.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[S:17][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][C:20]=1[O:27][CH3:28]>>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:14]2[CH2:13][CH2:12][CH:11]([NH:10][C:9]3[C:4]4[CH:3]=[C:2]([Cl:1])[S:17][C:5]=4[N:6]=[CH:7][N:8]=3)[CH2:16][CH2:15]2)=[CH:21][C:20]=1[O:27][CH3:28]
Reactant: COc1cc(C=O)ccc1F
Reactant: Clc1cc2c(NC3CCNCC3)ncnc2s1
Product: COc1cc(CN2CCC(Nc3ncnc4sc(Cl)cc34)CC2)ccc1F

Procedure:
The title compound was prepared (64 mg, 43%) from 6-chloro-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine (100 mg, 0.37 mmol) and 4-fluoro-3-methoxybenzaldehyde (57 mg, 0.37 mmol) by following the general procedure described for Preparation 11. 1H NMR (400 MHz, CDCl3): δ 8.45 (s, 1H), 7.00 (m, 3H), 6.85 (m, 1H), 5.00 (d, 1H), 4.20 (m, 1H), 3.90 (s, 3H), 3.50 (s, 2H), 2.90 (m, 2H), 2.20 (m, 2H), 2.10 (m, 2H), 1.60 (m, 2H). MS (ESI) m/z: Calculated: 406.90; Observed: 407.2 (M++1).