Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5](=[O:8])[O:6][CH:7]=1.[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1)([O-:11])=[O:10].C(N(CC)CC)C>ClCCl>[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([S:18][CH2:2][C:3]2[O:4][C:5](=[O:8])[O:6][CH:7]=2)=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: O=c1occ(CBr)o1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1occ(CSc2ccc([N+](=O)[O-])cc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.3 %

Procedure:
In 30 ml of dichloromethane was dissolved 1.0 g of 4-bromomethyl-1,3-dioxol-2-one, and 0.9 g of 4-nitrobenzenethiol was added. Then, 0.6 g of triethylamine was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, the solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The insoluble materials were separated by filtration, and the solvent was evaporated under reduced pressure. The residue was subjected to medium-pressure silica gel column chromatography as in Example 1 [except that the column was eluted with a mixture of chloroform and n-hexane (2/1, v/v)]. The eluate was evaporated under reduced pressure, and the residue was recrystallized from a mixed solvent of chloroform and n-hexane to give 0.5 g of the captioned compound as yellow crystals.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[O:40][CH2:41][CH3:42])[CH:35]=O)[CH3:30]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:34]3[CH:37]=[CH:38][C:39]([O:40][CH2:41][CH3:42])=[C:32]([O:31][CH2:29][CH3:30])[CH:33]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1ccc(C=O)cc1OCC
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: CCOc1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1OCC

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 3,4-diethoxy-benzaldehyde according to the procedure of Example 66. MS (ESI) m/z 557.
Reaction SMILES: [Br:1][C:2]([CH3:7])([CH3:6])[C:3](Br)=[O:4].[CH3:8][C:9]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:10]=1[NH2:11].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]([CH3:7])([CH3:6])[C:3]([NH:11][C:10]1[C:12]([CH3:17])=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=1[CH3:8])=[O:4]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: CC(C)(Br)C(=O)Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(NC(=O)C(C)(C)Br)c(C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
2-bromo-2-methylpropanoyl bromide (4.50 g, 19.57 mmol) was added to a mixture of 2,4,6-trimethylaniline (2.41 g, 17.78 mmol), triethylamine (3.60 g, 35.56 mmol), and CH2Cl2 (20 ml) at 0° C. under Ar atmosphere. The cooling bath was removed after the addition was completed, and the reaction mixture was stirred at room temperature for 1.5 hour, after which time the mixture was diluted with CH2Cl2 (20 ml) and added aqueous solution of NH4Cl. After the aqueous phase was separated, the organic layer was washed with brine and dried over anhydrous MgSO4. Filtration and concentration of the filtrate gave 2-bromo-N-mesityl-2-methylpropanamide as a pale yellow solid (5.05 g, 17.78 mmol, 100%). A solution of this amide (284 mg, 1.00 mmol) in dry THF (5 ml) was added to a mixture of sodium hydride (60% in mineral oil, 80 mg, 2.00 mmol), aniline (112 mg, 1.20 mmol) and THF (5 ml), and the resulting mixture was stirred for overnight at room temperature. The mixture was then added an aqueous solution of NH4Cl (15 ml), extracted with ethyl acetate (20 ml×2), and the combined organic layer was washed with brine then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum, and the residue was purified by column chromatography on silica (eluent: Hexane/Ethyl acetate=5/1˜4/1) to give the amide as a white solid (255 mg, 0.86 mmol, Y=86%). 1H NMR (300 MHz, CDCl3): δ 8.35 (s, 1H), 7.25-7.17 (m, 2H), 6.84-6.71 (m, 5H), 3.98 (s, 1H), 2.23 (s, 3H), 2.11 (s, 6H), 1.63 (s, 6H). 13C NMR (75 MHz, CDCl3): δ 173.8, 144.5, 136.4, 134.8, 131.0, 129.0, 119.2, 116.2, 58.4, 26.2, 20.8, 18.6. IR: 3341 (m), 3310 (s), 2987 (w), 1666 (s), 1607 (m), 1488 (s), 1376 (m), 1318 (m), 1264 (m), 1210 (m), 1162 (m), 850 (m), 749 (s), 696 (m) cm−1. HRMS Calc'd for C19H24N2O: 297.1967. Meas: 297.1956.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([S:12]([CH2:15][CH:16](O)[CH2:17][CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)(=[O:14])=[O:13])[CH2:9]2)=[CH:4][CH:3]=1.CCN(CC)CC.CS(Cl)(=O)=O>C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([S:12]([CH:15]=[CH:16][CH2:17][CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)(=[O:14])=[O:13])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(CC(O)CCc1cccnc1)N1CCc2ccc(Cl)cc2C1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=S(=O)(C=CCCc1cccnc1)N1CCc2ccc(Cl)cc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 116.6 %

Procedure:
A solution of 1-[(7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]-4-pyridin-3-ylbutan-2-ol (270 mg of crude compound) and Et3N (0.23 ml, 1.69 mmol) in anhydrous THF (3 ml) was cooled at 0° C., then methanesulfonyl chloride (0.066 ml, 0.85 mmol) was added dropwise. The resulting mixture was stirred at 0° C. for 1 hour, then at 60° C. for 15 hours. The reaction mixture was diluted with DCM, then washed with a saturated aqueous solution of NaHCO3 and brine. The organic layer was dried (MgSO4) and the solvents were removed under reduced pressure to give the title compound as an oil (300 mg) used in the next step without further purification. HPLC, Rt: 3.1 min (purity: 63%). LC/MS, M+(ESI): 363.2, M−(ESI): 361.1.
Reaction SMILES: Cl.O1CCOCC1.[Cl:8][C:9]1[CH:44]=[CH:43][C:12]([CH2:13][N:14]([CH2:33][CH2:34][NH:35]C(=O)OC(C)(C)C)[C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:24]4[C@H:31]([CH3:32])[CH2:30][CH2:29][C:25]=4[N:26]=[CH:27][N:28]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:11][CH:10]=1>CO>[NH2:35][CH2:34][CH2:33][N:14]([CH2:13][C:12]1[CH:43]=[CH:44][C:9]([Cl:8])=[CH:10][CH:11]=1)[C:15]([N:17]1[CH2:18][CH2:19][N:20]([C:23]2[C:24]3[C@H:31]([CH3:32])[CH2:30][CH2:29][C:25]=3[N:26]=[CH:27][N:28]=2)[CH2:21][CH2:22]1)=[O:16]
Reactant: C[C@@H]1CCc2ncnc(N3CCN(C(=O)N(CCNC(=O)OC(C)(C)C)Cc4ccc(Cl)cc4)CC3)c21
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@@H]1CCc2ncnc(N3CCN(C(=O)N(CCN)Cc4ccc(Cl)cc4)CC3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
A solution of HCl/dioxane at 0° C. was added to (R)-tert-butyl 2-(N-(4-chlorobenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxamido)ethylcarbamate (40 mg, 0.075 mmol) in MeOH (1 mL). The reaction mixture was stirred at 25° C. for 1 hour. After removal of the solvent, the crude product was purified by preparative HPLC to afford (R)—N-(2-aminoethyl)-N-(4-chlorobenzyl)-4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxamide (32 mg, 90%). MS (ESI) m/e (M+H+) 429.2. 1H NMR: δ=8.56 (s, 1H), δ=7.23-7.56 (dd, 4H), δ=4.51 (s, 2H), δ=3.97-4.19 (m, 4H), δ=3.70 (m, 1H), δ=3.61 (m, 4H), δ=3.40-3.43 (t, 2H), δ=2.96-3.15 (m, 4H), δ=2.42 (m, 1H), δ=1.89 (m, 1H), δ=1.21-1.22 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][C:5](=[O:7])[C:4]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]3[CH:27]=[N:28][CH:29]=[N:30][CH:31]=3)[CH:20]=2)([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)[N:3]=1.[OH-].[K+].Cl[CH:35]([F:37])[F:36]>CN(C)C=O>[NH2:1][C:2]1[N:6]([CH:35]([F:37])[F:36])[C:5](=[O:7])[C:4]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]3[CH:31]=[N:30][CH:29]=[N:28][CH:27]=3)[CH:20]=2)([C:8]2[CH:9]=[CH:10][C:11]([O:14][C:15]([F:17])([F:16])[F:18])=[CH:12][CH:13]=2)[N:3]=1
Reactant: FC(F)Cl
Reactant: NC1=NC(c2ccc(OC(F)(F)F)cc2)(c2ccc(F)c(-c3cncnc3)c2)C(=O)N1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: NC1=NC(c2ccc(OC(F)(F)F)cc2)(c2ccc(F)c(-c3cncnc3)c2)C(=O)N1C(F)F
Temperature: -45 °C
Yield: 14 %

Procedure:
A solution of 2-amino-5-[4-fluoro-3-(pyrimidin-5-yl)phenyl]-5-[4-(trifluoromethoxy)phenyl]-3,5-dihydro-4H-imidazol-4-one (0.398 g, 0.92 mmol) in dimethylformamide is treated with KOH (0.057 g, 1.01 mmol), cooled to −45° C., and bubbled with chlorodifluoromethane (1.40 g, 17.6 mmol). The reaction vessel is sealed and heated at 70° C. for 18 h. The reaction is cooled to room temperature, quenched by careful addition to water, extracted with ethyl acetate, diluted with brine and extracted again with ethyl acetate. The combined extracts are washed with brine, dried over sodium sulfate and concentrated. The resultant residue is purified twice by flash chromatography (silica, 95:5:0.5 to 90:10:0.5 methylene chloride/methanol/concentrated ammonium hydroxide and 100:0 to 98:2 methylene chloride/methanol as eluents) to afford the title compound as a white solid, 0.064 g (14% yield), mp 82-94° C., identified by HNMR, infrared and mass spectral analyses. 1H NMR (500 MHz, CDCl3) δ 9.21 (s, 1H), 8.89 (s, 2H), 7.64-7.60 (m, 2H), 7.54 (d, J=8.8 Hz, 2H), 7.23-7.18 (m, 3H), 6.95 (t, J=58 Hz, 1H), 4.92 (br s, 2H); IR (ATR) 3497, 3309, 3149, 1761, 1678, 1497, 1449, 1416, 1252, 1212, 1162 cm−1; ESI MS m/z 482 [C21H13F6N5O2+H]+;
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Br:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([Cl:22])=[C:18]([CH:21]=1)[C:19]#[N:20]>CN(C)C=O.C(OCC)(=O)C>[BrH:12].[Cl:11][C:8]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2](=[NH:1])[N:10]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([Cl:22])=[C:18]([C:19]#[N:20])[CH:21]=2)[CH:9]=1
Reactant: NC(=O)c1cc(Cl)cnc1N
Reactant: N#Cc1cc(CBr)ccc1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Br
Product: N#Cc1cc(Cn2cc(Cl)cc(C(N)=O)c2=N)ccc1Cl
Temperature: 100 °C
Reaction time: 14 h
Yield: 26.5 %

Procedure:
To a solution of 2-amino-5-chloronicotinamide (0.15 g) in N,N-dimethylformamide (3 ml) was added 5-(bromomethyl)-2-chlorobenzonitrile (0.31 g), and the mixture was stirred at 100° C. for 14 hr. The reaction mixture was diluted with ethyl acetate. The precipitate was collected by filtration and washed with ethyl acetate. The obtained precipitate was recrystallized from methanol-ethyl acetate to give the title compound (93 mg).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].O[C:9]1[C:18](C)=[C:17]2[C:12]([C:13](=[O:32])[CH2:14][C:15]([CH3:31])([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)[O:16]2)=[CH:11]C=1.N1C=CC=CC=1.C1C=CC=CC=1>O>[C:5]([O:4][C:1]1[C:18]([CH3:9])=[C:17]2[C:12]([C:13](=[O:32])[CH2:14][C:15]([CH3:31])([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)[O:16]2)=[CH:11][CH:2]=1)(=[O:7])[CH3:6]
Reactant: Cc1c(O)ccc2c1OC(C)(COc1ccc([N+](=O)[O-])cc1)CC2=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2c(c1C)OC(C)(COc1ccc([N+](=O)[O-])cc1)CC2=O
Reaction time: 8 h
Yield: 92.9 %

Procedure:
3.3 g of acetic anhydride were added to a mixture of 9.3 g of 7-hydroxy-2,8-dimethyl-2-(4-nitrophenoxymethyl)-4-oxochroman (prepared as described in Preparation 16), 50 ml of pyridine and 50 ml of benzene and allowed to stand overnight. The reaction mixture was then poured into water and extracted with benzene. The benzene extract was washed with 5% w/v aqueous hydrochloric acid and then with water, after which it was dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was subjected to silica gel column chromatography eluted with a 20:1 by volume mixture of benzene and ethyl acetate, to obtain 9.7 g of the title compound as a pale yellow oily substance.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([CH2:8]Br)[N:5]=[C:4]([CH2:10]Br)[CH:3]=1.[NH:12]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[C:29](=[O:32])([O-:31])[O-].[Na+].[Na+]>C(#N)C>[I:1][C:2]1[CH:7]=[C:6]([CH2:8][N:12]([CH2:13][C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[N:5]=[C:4]([CH2:10][N:12]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH2:21][C:29]([O:31][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:32])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: BrCc1cc(I)cc(CBr)n1
Reactant: CC(C)(C)OC(=O)CNCC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)Cc1cc(I)cc(CN(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-iodo-2,6-bisbromomethylpyridine (0.59 g, 1.5 mmol) and di-t-butyl iminodiacetate (0.74 g, 3.0 mmol) in 40 mL of dry acetonitrile was added 1.59 g of sodium carbonate (15 mmol) and the mixture was stirred for 24 h at room temperature. Filtration and evaporation of the filtrate left a yellow oil. The oil was taken into 20 mL of chloroform, washed twice with 10 mL of water and dried with Na2SO4. Evaporation gave a yellowish oil which was purified by chromatographing on silica with toluene-ethanol (10:1).
Reaction SMILES: [CH2:1]([CH:9]([CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[CH2:10][C:11]1[C:12]([CH2:36][CH:37]([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[C:13]([CH2:16][CH:17]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[N:66]#N.[CH2:68]1[CH2:72]OC[CH2:69]1.C([Li])CCC>C(=O)=O.CC(C)=O.CCCCCC>[CH2:1]([CH:9]([CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[CH2:10][C:11]1[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])([CH2:69][CH2:68][C:72]#[N:66])[C:12]=1[CH2:36][CH:37]([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C1CCOC1
Reactant: CCCCCCCCCCC(CCCCCCCC)CC1=CCC(CC(CCCCCCCC)CCCCCCCCCC)=C1CC(CCCCCCCC)CCCCCCCCCC
Reactant: N#N
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CCCCCCCCCCC(CCCCCCCC)CC1=C(CC(CCCCCCCC)CCCCCCCCCC)C(CCC#N)(CC(CCCCCCCC)CCCCCCCCCC)C=C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tris(2-octyldodecyl)cyclopentadiene (18.12 grams, 20 m mol) was placed in a 3-necked round bottom flask equipped with an additional funnel, a gas inlet adapter, and a septum. After flashing with dried N2 for 2 minutes, 50 ml of dried THF (distilled over K) was added. The solution was cooled in dry ice/acetone bath, followed injected 8.4 M n-butyl lithium in hexane solution (2.40 ml; 20 m mol). The dry ice/acetone bath was removed, and the resulting dark red solution was stirred at room temperature for 1 hour, followed by cooling in dry ice/acetone bath. 3-Bromopropionitrile (2.70 grams, 20 m mol) in 10 ml dried THF solution was then dropwise added from the additional funnel. After the addition, the reaction solution was stirred at room temperature for another 3 hours. The reaction was slowly quenched with 10 ml water. The organic layer was separated, and the aqueous layer was extracted with 50 ml hexane. The organic layers were combined, dried over MgSO4, filtered, and rota-vaporized to give 19.6 grams of yellow liquid. The crude reaction product was purified by column chromatography on SiO2 eluting with 5% ethyl acetate/hexane. The unreacted tri(2-octyldodecyl)cyclopentadiene (3.66 grams) was recovered and the title compound (12.83 grams) was isolated. FTIR: 2248 cm−1 (C≡N); 13C NMR (4 isomers): 152.5–129.1 ppm (C═C), 120.8–119.6 ppm (4 peaks; C≡N), 59.5 ppm, 56.9 ppm, 51.3 ppm, 41.1 ppm, 39.5–26.4 ppm, 22.7 ppm, 14.1 ppm
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([C:13]([O:15]C)=[O:14])=[CH:10][CH:9]=1.[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc(-c2ccccc2Cl)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(-c2ccccc2Cl)s1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
289 mg (1.14 mmol) of the compound from Example 46A were dissolved in 2 ml of THF/methanol (1:1), and 1.14 ml (2.29 mmol) of 2 M aqueous sodium hydroxide solution were added. The reaction mixture was stirred at 80° C. for 2 h. After cooling to RT, the solvent was removed on a rotary evaporator and the residue was taken up in 5 ml of water and washed with 5 ml of ethyl acetate. The aqueous phase was acidified with 1 N hydrochloric acid and extracted twice with in each case 5 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. This gave, in a purity of 91%, 218 mg (73% of theory) of the target compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([NH2:8])[CH:7]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>C(Cl)Cl>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([NH:8][C:10](=[O:12])[CH3:11])[CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(I)cc1N
Solvent: ClCCl
Product: CC(=O)Nc1cc(I)ccc1C
Temperature: 50 °C

Procedure:
A solution of 5-iodo-2-methyl-phenylamine (20.4 g, 87.6 mmol) in 200 mL of dry CH2Cl2 was cooled to 0° C. and acetic anhydride (16.5 mL, 175 mmol) was added dropwise. The mixture was heated to 50° C. for 2 h and then cooled to 22° C. The resulting white precipitate was filtered to give c (18.4 g, 76%): MS m/z=276 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([C:6]1[N:10]([CH3:11])[C:9]([CH2:12][C:13]([O:15]CC)=[O:14])=[CH:8][C:7]=1[CH3:18])=[O:5].C(I)CC>>[CH2:12]([C:9]1[N:10]([CH3:11])[C:6]([C:4](=[O:5])[C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]=2[CH3:1])=[C:7]([CH3:18])[CH:8]=1)[CH3:13].[CH2:9]([CH2:12][C:13]([O-:15])=[O:14])[CH2:8][CH3:7]
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccccc2C)n1C
Solvent: CCCI
Product: CCCCC(=O)[O-]
Product: CCc1cc(C)c(C(=O)c2ccccc2C)n1C

Procedure:
The alkylation procedure of Example 77A is performed upon ethyl 5-(o-methylbenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example 92), using an equivalent quantity of n-propyl iodide instead of methyl iodide used in Example 77A to yield ethyl 5-(o-methylbenzoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-acetate.
Reaction SMILES: ClC1C=CC([N:8]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][N:13]=2)[C:9](=O)[O-:10])=CC=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[C:31]([CH2:39][N:40]3[CH2:46][CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[N:32]3[C:37]=2[C:36]([NH2:38])=[N:35][CH:34]=[N:33]3)=[CH:25][C:24]=1[F:47].C(NC(C)C)(C)C.[O:55]1CCOCC1>>[NH2:38][C:36]1[C:37]2=[C:29]([C:26]3[CH:27]=[CH:28][C:23]([NH:22][C:9]([NH:8][C:12]4[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][N+:13]=4[O-:55])=[O:10])=[C:24]([F:47])[CH:25]=3)[CH:30]=[C:31]([CH2:39][N:40]3[CH2:46][CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[N:32]2[N:33]=[CH:34][N:35]=1
Reactant: O=C([O-])N(c1ccc(Cl)cc1)c1cc(C(F)(F)F)ccn1
Reactant: Nc1ccc(-c2cc(CN3CCCOCC3)n3ncnc(N)c23)cc1F
Reactant: C1COCCO1
Solvent: CC(C)NC(C)C
Product: Nc1ncnn2c(CN3CCCOCC3)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)cc[n+]4[O-])c(F)c3)c12
Temperature: 80 °C
Yield: 24 %

Procedure:
4-chlorophenyl[4-(trifluoromethyl)pyridin-2-yl]carbamate (35 mg, 0.098 mmol) and 5-(4-amino-3-fluorophenyl)-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (36 mg, 0.11 mmol) were combined in 1,4-dioxane (1 mL) and treated with N,N-diisopropylamine (34 mL, 0.20 mmol). The reaction was heated to 80° C. overnight. The reaction was then concentrated and purified over silica (0-20%, MeOH/CH2Cl2) to yield an orange solid (13 mg, 24%). 1H-NMR (DMSO-d6) 10.83 (d, J=5.1 Hz, 1 H), 10.09 (s, 1H), 8.61 (d, J=2.4 Hz, 1 H), 8.57 (d, J=6.6 Hz, 1 H), 8.22 (td, J1=9.2 Hz, J2=2.4 Hz, 1 H), 7.92 (s, 1 H), 7.44 (dd, J1=6.7 Hz, J2=2.9 Hz, 1 H), 7.36 (dd, J1=12.1 Hz, J2=2.0 Hz, 1 H), 7.27 (dd, J1=8.3 Hz, J2=1.6 Hz, 1 H), 6.69 (s, 1 H), 3.99 (s, 2 H), 3.67 (t, J=6.0 Hz, 2 H), 3.61-3.59 (m, 2 H), 2.75-2.68 (m, 4 H), 1.80 (q, J=5.7 Hz, 2 H); MS [M+H]+=561.0; LCMS RT=1.62 min.
Reaction SMILES: N(CC)CC.CC([NH:10][CH2:11][CH:12]([OH:22])[C:13]1[CH:14]=[CH:15][C:16]([OH:21])=[C:17]([CH2:19][OH:20])[N:18]=1)(C)C>CO>[OH:20][CH2:19][C:17]1[C:16]([OH:21])=[CH:15][CH:14]=[C:13]([CH:12]([OH:22])[CH2:11][NH2:10])[N:18]=1
Reactant: CC(C)(C)NCC(O)c1ccc(O)c(CO)n1
Solvent: CO
Solvent: CCNCC
Product: NCC(O)c1ccc(O)c(CO)n1

Procedure:
A solution of 2.0 g., (0.005 mole) of 2-acetoxymethyl-3-acetoxy-6-(1-acetoxy-2-N-acetyl-tert-butylaminoethyl)pyridine in 50 ml. of methanol containing 1 ml. of concentrated hydrochloric acid was heated to reflux for 12 hours. The solvents were removed in vacuo and the residue recrystallized from ethyl acetate to give pirbuterol hydrochloride (900 mg., 58%) m.p. 172°-175° C. (dec.), NMR and tlc in 6:3:1 EtOAz:CH3OH:Et2NH identical to pirbuterol. Prolonged heating results in the formation of 2-hydroxymethyl-3-hydroxy-6-(1-hydroxy-2-aminoethyl)pyridine, m.p. 184°-186° dec.
Reaction SMILES: C([N:3](CC)CC)C.N1C=NC=N1.P(Cl)(Cl)(Cl)=O.C([O:26][C@@H:27]1[C@H:31]([O:32]C(=O)C2C=CC=CC=2)[C@@H:30]([CH2:41][O:42]C(=O)C2C=CC=CC=2)[O:29][C@H:28]1[N:51]1[C:58]([CH3:59])=[CH:57][C:55](=O)[NH:54][C:52]1=[O:53])(=O)C1C=CC=CC=1>C(#N)C>[CH3:59][C:58]1[N:51]([C@@H:28]2[O:29][C@H:30]([CH2:41][OH:42])[C@@H:31]([OH:32])[C@H:27]2[OH:26])[C:52](=[O:53])[N:54]=[C:55]([NH2:3])[CH:57]=1
Reactant: CCN(CC)CC
Reactant: Cc1cc(=O)[nH]c(=O)n1[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: c1nc[nH]n1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(N)nc(=O)n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.2 %

Procedure:
Triethylamine (13.4 ml, 100 mmol) was added dropwise to a stirred ice-cooled mixture of 1,2,4-triazole (6.22 g, 90 mmol) and phosphorous oxychloride (1.89 ml, 20 mmol) in 50 ml of anhydrous acetonitrile. To the resulting suspension the solution of 2',3',5'-tri-O-Benzoyl-6-methyl uridine (5.7 g, 10 mmol) in 30 ml of acetonitrile was added dropwise and the reaction mixture was stirred for 4 hours at room temperature. Then it was concentrated in vacuo to minimal volume (not to dryness). The residue was dissolved in chloroform and washed with water, saturated aq sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and the solvent was removed in vacuo. The residue was dissolved in 100 ml of 1,4-dioxane and treated with 50 mL of 29% aq NH4OH overnight. The solvents were removed in vacuo. The residue was dissolved in the mixture of pyridine (60 mL) and methanol (10 mL), cooled to -15° C. and ice-cooled 2M aq solution of sodium hydroxide was added under stirring. The reaction mixture was stirred at -10° to -15° C. for additional 30 minutes and then neutralized to pH 7 with Dowex 50 (Py+). The resin was filtered off and washed with 200 mL of the mixture H2O--Py (4:1). The combined mother liquor and washings were evaporated to dryness. The residue was crystallized from aq methanol to give 1.6 g (62%) of 6-methyl cytidine.