Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9].C(O)(=O)C.C(OC(=O)C)(=O)C.S(=O)(=O)(O)O.[N+:41]([O-])([OH:43])=[O:42]>>[N+:41]([C:11]1[CH:12]=[CH:13][C:5]([O:4][C:3]2[CH:14]=[CH:15][C:16]([C:18]([F:23])([F:24])[C:19]([F:22])([F:21])[F:20])=[CH:17][C:2]=2[Cl:1])=[CH:6][C:7]=1[C:8]([OH:10])=[O:9])([O-:43])=[O:42]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cccc(Oc2ccc(C(F)(F)C(F)(F)F)cc2Cl)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)c1cc(Oc2ccc(C(F)(F)C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 83.9 %

Procedure:
A 50 ml 3-neck round bottom flash was charged with 2.5 gm (6.83 mmol) of 3-(2-chloro-4-pentafluoroethylphenoxy)benzoic acid, 2.18 gm (2.08 ml, 36.19 mmol) of glacial acetic acid, 2.1 gm (20.49 mmol) of acetic anhydride and 70 mg (683 mmol) of concentrated sulfuric acid. The resulting slurry was stirred vigorously while cooling to 0°-5° C. with the aid of an icewater bath. To the cooled slurry was added dropwise a mixture 280 mg (2.73 mmol) of concentrated sulfuric acid and 620 mg (9.56 mmol) to 97% nitric acid (red fuming). The yellow solution was maintained at 0°-5° C. for about 1.5 hours at which time the reaction mixture was poured into stirred ice water. The gummy residue that formed in the bottom of the flask was extracted with 100 ml of ether, the ether layer separated, and the aqueous acid layer reextracted with a second portion of ether. The combined ether layers were washed with brine, dried and evaporated in vacuo leaving a yellow oil. Much of the yellow color was removed by dissolving the oil in 300 ml of chloroform and eluting through a pad of silica gel. Evaporation of the eluent yielded 2.36 gm (83.9%) of a light yellow oil which crystallized on standing. The product had the following elemental analysis, calculated (found): C: 43.76 (44.43); H: 1.71 (2.24); Cl: 8.61 (8.83); F: 23.07 (18.90); N: 3.40 (2.47); O: 19.43.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[C:32]([F:36])=[CH:33][CH:34]=[CH:35][C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:37](O)=[O:38])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(N(CC)CC)C>[F:36][C:32]1[C:24]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:21]([C:19]([N:14]([CH2:15][CH:16]([CH3:17])[CH3:18])[C@H:12]3[CH2:11][C@@H:10]([C:37]([N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)=[O:38])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:13]3)=[O:20])=[N:22][C:23]=2[CH:35]=[CH:34][CH:33]=1
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2cccc(F)c21
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2cccc(F)c21
Temperature: 50 °C
Reaction time: 1 h

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[7-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (207 mg), morpholine (87 μl), HOBt (40 mg) and triethylamine (210 μl) were dissolved in DMF (10 ml), WSC.HCl (180 mg) was added, and the mixture was stirred at 50° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:9)-ethyl acetate was concentrated under reduced pressure to give the object product (160 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[N:21]=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([S:28]([OH:31])(=O)=[O:29])=[CH:24][CH:23]=5)[CH:19]=[CH:18][CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.O=S(Cl)[Cl:34].CN(C=O)C>O=P(Cl)(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[N:21]=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([S:28]([Cl:34])(=[O:31])=[O:29])=[CH:24][CH:23]=5)[CH:19]=[CH:18][CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Nc1cccc(-c2ccc(S(=O)(=O)O)cc2)n1)C1(c2ccc3c(c2)OCO3)CC1
Reactant: O=S(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2ccc(S(=O)(=O)Cl)cc2)n1)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 75 °C

Procedure:
4-(6-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)pyridin-2-yl)benzenesulfonic acid (1.9 g, 4.3 mmol) was dissolved in POCl3 (30 mL) followed by the addition of SOCl2 (3 mL) and DMF (100 μl). The reaction mixture was heated at 70-80° C. for 15 min. The volatiles were evaporated and then re-evaporated with chloroform-toluene. The residual brown oil was diluted with chloroform (22 mL) and used for sulfonylation immediately. ESI-MS m/z calc. 456.0, found 457.1 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]1[CH2:35][CH2:34][O:33][CH2:32]1>>[CH3:8][C@@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]2[CH2:35][CH2:34][O:33][CH2:32]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCC[C@@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: BrCCCCC1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](C)Oc1nc(N)c2nc(OC)n(CCCCC3CCOC3)c2n1

Procedure:
Prepared similarly to Intermediate 216 from 2-{[(1R)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 3-(4-bromobutyl)tetrahydrofuran.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([N+:10]([O-])=O)[NH:7][N:6]=1)=[O:4]>C(O)(=O)C.O1CCCC1.[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([NH2:10])[NH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1cc([N+](=O)[O-])[nH]n1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)c1cc(N)[nH]n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.4 %

Procedure:
10.25 g (60 mmol) of 5-nitro-1H-pyrazole-3-carboxylic acid methyl ester was dissolved in 75 mL of acetic acid (AcOH) and 75 mL of tetrahydrofuran (THF). After a vacuum and argon cycle, 2.05 g (20% weight) of palladium on carbon (Pd/C 10 wt %) was added, the mixture was degassed again and filled with hydrogen from a balloon. The reaction mixture was stirred at rt under hydrogen atmosphere for 2 days. Analysis by thin layer chromatography (TLC) showed complete conversion of starting material to product. The mixture was then concentrated, the resulting purple colored oil was taken in 300 mL of ether, the finely dispersed purple impurity was filtered off, and the ether filtrate was evaporated to give 7.23 g (85% yield) of 5-amino-1H-pyrazole-3-carboxylic acid methyl ester as an off-white solid as indicated by 1H NMR; whose structure was confirmed using 1H NMR.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.OC1CCNC1.[C:33]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)(=[O:35])[CH3:34]>>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:39]3[CH2:40][CH2:41][N:36]([C:33](=[O:35])[CH3:34])[CH2:37][CH2:38]3)[CH:7]=2)=[CH:9][C:10]=1[C:23]([F:26])([F:25])[F:24]
Reactant: CC(=O)N1CCNCC1
Reactant: COc1ccccc1Sc1ccc(-c2ccnc(Cl)c2)cc1C(F)(F)F
Agent: OC1CCNC1
Product: COc1ccccc1Sc1ccc(-c2ccnc(N3CCN(C(C)=O)CC3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 96 (0.039 g, 0.0985 mmol) and 3-hydroxypyrrolidine with 1-acetylpiperazine. A yellow solid 104 was obtained (0.0197 g, 41%). 1H-NMR (CDCl3, 400 MHz) δ 2.17 (s, 3H), 3.68-3.72 (m, 2H), 3.73-3.78 (m, 2H), 3.82-3.89 (m, 2H), 3.83 (s, 3H), 3.94-3.99 (m, 2H), 6.95 (s, 1H), 7.00-7.05 (m, 3H), 7.07 (d, J=8.4 Hz, 1H), 7.45-7.52 (m, 3H), 7.86 (s, 1H), 8.29 (d, J=6.2 Hz, 1H), MS (APCI) m/z 488 (M+H)+.
Reaction SMILES: [I:1]I.[CH2:3]([C:5]1[CH:14]=[C:13]([O:15]CC2C=CC(B(O)O)=CC=2)[C:12]2CC[CH2:9][CH2:8][C:7]=2[N:6]=1)[CH3:4].[OH-].[Na+]>O>[CH2:8]([C:7]1[NH:6][C:5]([CH2:3][CH3:4])=[CH:14][C:13](=[O:15])[C:12]=1[I:1])[CH3:9]
Reactant: II
Reactant: CCc1cc(OCc2ccc(B(O)O)cc2)c2c(n1)CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1cc(=O)c(I)c(CC)[nH]1
Reaction time: 1 h
Yield: 75.7 %

Procedure:
Iodine (720 mg) was added to a solution of compound C (430 mg) and sodium hydroxide (120 mg) in water (15 ml) and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration and purified by flash chromatography, eluting with methanol/dichloromethane (1:19 v/v), to give 2,6-diethyl-3-iodo-4(1H)-pyridone (D) (290 mg), m.p. 225°-227° C.; NMR (d6 -DMSO): 1.15(t,6H), 2.5(q,2H), 2.8(q,2H), 5.9(s,1H), 11.4(br s, 1H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.P(Cl)(Cl)Cl.[NH2:19][C:20]1[S:21][C:22]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=2[N:24]=1>O>[Cl:29][C:27]1[CH:26]=[CH:25][C:23]2[N:24]=[C:20]([NH:19][C:12]([C:3]3[C:2]([OH:1])=[C:11]4[C:6]([CH:7]=[CH:8][CH:9]=[N:10]4)=[CH:5][CH:4]=3)=[O:14])[S:21][C:22]=2[CH:28]=1
Reactant: Nc1nc2ccc(Cl)cc2s1
Reactant: O=C(O)c1ccc2cccnc2c1O
Solvent: ClP(Cl)Cl
Solvent: O
Product: O=C(Nc1nc2ccc(Cl)cc2s1)c1ccc2cccnc2c1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.9 %

Procedure:
A solution of 8-hydroxyquinoline-7-carboxylic acid (0.30 g) of Preparation 1 in 75 mL xylenes is heated to reflux. PCl3 (0.07 mL) is added dropwise and the mixture stirred for 15 minutes. 2-Amino-6-chlorobenzothiazole (0.31 g) is added in one portion and the reaction refluxed overnight. The reaction is cooled to room temperature and H2O is added to quench excess PCl3. After stirring the solution for 30 minutes, a yellow solid is filtered, dried, and recrystallized from DMSO to give the title product (0.31 g).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CC[N:14](C(C)C)[CH:15]([CH3:17])[CH3:16].C(N)(C)C>C(#N)C>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:14][CH:15]([CH3:17])[CH3:16])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CC(C)N
Product: CC(C)Nc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
2,4-Difluoro-1-nitrobenzene (2.00 g, 12.57 mmol) was dissolved in acetonitrile (20 mL) and DIPEA (2.2 mL, 12.57 mmol) added, followed by isopropylamine (1.07 mL, 12.57 mmol). The bright yellow mixture was stirred at RT overnight. The resultant mixture was concentrated in vacuo and the residue purified by column chromatography (silica gel, gradient 0-5% EtOAc in cyclohexane) to afford the title compound as a yellow gum (2.1 g, 99%). Contaminated with some unreacted 2,4-difluoro-1-nitrobenzene, but used in the next step without any further purification. 1H NMR (CDCl3, 400 MHz): δ 8.20 (1H, dd, J=9.53, 6.21 Hz), 6.48 (1H, dd, J=11.71, 2.63 Hz), 6.33 (1H, m), 3.80-3.64 (1H, m), 1.33 (6H, d, J=6.36 Hz)
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.Br[CH2:32][CH2:33][OH:34].C([O-])(O)=O.[Na+]>CC#N>[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][N:13]([CH2:32][CH2:33][OH:34])[CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Reactant: OCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(CCO)CC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 70.2 %

Procedure:
To a solution of COMPOUND 249 (0.1189 g, 0.38 mmol) in CH3CN (4 mL) was added Et3N (0.08 mL, 0.57 mmol), KI (0.0063 g, 0.04 mmol), and 2-bromoethanol (0.03 mL, 0.46 mmol), and stirred at room temperature for 23 hours. Saturated NaHCO3 (10 mL) was added and extracted with CH2Cl2 (3×30 mL), and the combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification of the crude material by column chromatography on silica gel (25:1:1 CH2Cl2-MeOH—NH4OH) provided 0.0946 g (66%) of COMPOUND 339 as a pale yellow oil. 1H NMR (CDCl3) δ 1.71-1.98 (m, 6H), 2.09 (s, 6H), 2.46 (t, 3H, J=5.1 Hz), 2.94 (d, 3H, J=10.8 Hz), 3.56 (t, 2H, J=5.1 Hz), 3.82 (s, 4H), 7.04-7.08 (m, 2H), 7.34 (d, 2H, J=7.5 Hz), 8.33 (d, 2H, J=4.2 Hz). 13C NMR (CDCl3) δ 18.35, 27.34, 53.93, 55.13, 57.82, 58.52, 59.74, 122.63, 133.76, 138.29, 146.15, 157.80. ES-MS m/z 355.5 (M+H). Anal. Calcd. for C21H30N4O.0.3CH2Cl2: C, 67.33; H, 8.12; N, 14.74. Found: C, 67.46; H, 8.43; N, 14.93.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[N:3]1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]1[CH:18]([NH2:24])[CH2:17][CH2:16][CH2:15][C:14]2=1>>[Cl:10][C:11]1[CH:12]=[C:13]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]1[CH:18]([NH:24][C:7]([C:4]3[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=3)=[O:9])[CH2:17][CH2:16][CH2:15][C:14]2=1
Reactant: Cn1ccc(C(=O)O)n1
Reactant: NC1CCCc2c1[nH]c1ccc(Cl)cc21
Product: Cn1ccc(C(=O)NC2CCCc3c2[nH]c2ccc(Cl)cc32)n1

Procedure:
N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-1-methyl-1H-pyrazole-3-carboxamide was prepared from 1-methyl-1H-pyrazole-3-carboxylic acid and 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine in a similar manner as described above to give an off-white solid (20% yield). 1H-NMR (CDCl3): δ 8.95 (s, 1H), 7.43 (m, 1H), 7.37 (m, 1H), 7.22 (d, 1H), 7.07 (dd, 1H), 6.80 (m, 1H), 5.30 (m, 1H), 3.88 (s, 3H), 2.71 (m, 2H), 2.27 (m, 1H), 1.97 (m, 3H); MS m/z 327 (M−1).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9].[CH3:32][N:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1>>[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH:39][CH:36]4[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]4)=[O:27])=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CN1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NC3CCN(C)CC3)cn2)c1O

Procedure:
The title compound, as a TFA salt, was prepared in a manner similar to Example 74 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-methylpiperidin-4-amine 1H NMR (400 MHz, DMSO-d6) δ ppm 1.71-1.85 (m, 2 H) 1.92-2.14 (m, 2 H) 2.38-2.47 (m, 3 H) 2.70-2.89 (m, 3 H) 3.06-3.18 (m, 2 H) 3.24-3.40 (m, 1H) 3.49 (d, J=11.87 Hz, 1 H) 3.98-4.24 (m, 1 H) 7.67 (d, J=7.58 Hz, 1 H) 7.71-7.87 (m, 2H) 8.21 (d, J=12.13 Hz, 1 H) 8.35-8.59 (m, 2 H) 8.72 (d, J=6.32 Hz, 1 H) 8.88-8.98 (m, 1H) 9.46 (br. s., 1 H) 12.72-13.42 (m, 1 H). MS m/z [M+H]+ 417.2.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:9][CH:10]=2)[C:5]1=[O:18].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[O:18]=[C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:14]([O:16][CH3:17])=[O:15])[CH:7]=2)[CH:12]=[CH:13][N:4]1[CH2:3][CH2:2][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: C1CCNCC1
Reactant: COC(=O)c1ccc2ccn(CCBr)c(=O)c2c1
Product: COC(=O)c1ccc2ccn(CCN3CCCCC3)c(=O)c2c1

Procedure:
The title compound was prepared from methyl 2-(2-bromoethyl)-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (96 mg, 0.31 mmol) and piperidine (0.31 mL, 3.1 mmol) following the procedure outlined in Example 44, step 2 (80 mg, 82%). LC-MS: (FA) ES+ 315.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[C:4]([CH2:16]O)[CH:3]=1.C([Mg]Cl)(C)C.CN(C)P(Cl)(N(C)C)=O>O1CCCC1.CN1CC(=O)C=C1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:14][CH:15]=1)[C:6](=[O:7])[N:8]([CH2:9][C:10]([F:13])([F:12])[F:11])[CH2:16]2
Reactant: O=C(NCC(F)(F)F)c1ccc(Br)cc1CO
Agent: CC(C)[Mg]Cl
Agent: CN(C)P(=O)(Cl)N(C)C
Agent: CN1C=CC(=O)C1
Solvent: C1CCOC1
Product: O=C1c2ccc(Br)cc2CN1CC(F)(F)F
Temperature: 5 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
To a stirred solution of 4-bromo-2-hydroxymethyl-N-(2,2,2-trifluoro-ethyl)-benzamide (3.37 g, 10.8 mmol) in anhydrous tetrahydrofuran (50 ml), N-methyl-2-pyrrolinone (20 mL), cooled to 5° C. under a nitrogen atmosphere was added a solution of 2M isopropyl magnesium chloride in anhydrous THF (25 ml) at a rate to keep the temperature of the reaction mixture under 10° C., After complete addition, approximately 45 minutes the reaction was stirred at this temperature for an additional 60 minutes, and then at room temperature for 60 minutes. After that time the reaction mixture was re-cooled to 5° C. and a solution of bis(dimethyl amino)phosphoryl chloride (1.85 g, 14.1 mmol) was added dropwise. No exotherm was observed and the reaction was heated at reflux for 72 hours once the addition was completed. After this time no starting material was observed by both TLC and LCMS and the reaction mixture was carefully quenched with water, and acidified with 1M aqueous hydrochloric acid. The aqueous layer was extracted with ethyl acetate (3×100 ml) and the organic layers were combined and dried over Magnesium sulfate powder, filtered and concentrated under reduced pressure. Purification by column chromatography eluting with 25% ethyl acetate 75% petroleum ether gave product as a white powder 2.81 g (88% yield). NMR (DMSO 400 MHz) 4.36-4.43 (2H, m, alk), 4.62 (2H, s, alk), 7.68-7.74 (2H, m, ar) and 7.93 (H, s, ar). F19 NMR (DMSO 400 Mhz) −69.03. ES+296
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][C@H:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][OH:9])[CH2:5][CH2:4]1.Br[CH2:19][CH2:20][O:21][CH3:22]>C1COCC1>[CH:3]1([CH2:6][C@H:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[CH2:8][O:9][CH2:19][CH2:20][O:21][CH3:22])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC1CC1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOC[C@H](CC1CC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49.3 %

Procedure:
NaH (70%, 0.504 g, 15 mmol) was added in portions to a solution of (S)-tert-butyl 1-cyclopropyl-3-hydroxypropan-2-ylcarbamate (1.6 g, 7.5 mmol) in THF (30 mL) at room temperature. The mixture was stirred at room temperature for 20 min. 1-Bromo-2-methoxyethane (2.07 g, 15 mmol) was added and stirring was continued for 2 h. The reaction was quenched by careful addition of H2O (5 mL). After evaporation of solvent the residue was diluted with ethyl acetate (20 mL) and H2O (20 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, and concentrated to give the title product as yellow oil (1.01 g, 50%); MS (EI): m/e=296.2 [M+Na]+.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14]([OH:16])=[O:15])[CH:2]=1.[C:17]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:17][N:12]1[C:13]2[CH:1]=[CH:2][C:3]([C:14]([OH:16])=[O:15])=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=C(O)c1ccc2[nH]c3ccccc3c2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: Cn1c2ccccc2c2cc(C(=O)O)ccc21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
A mixture of 9H-carbazole-3-carboxylic acid (300 mg, 1.42 mmol), K2CO3 (800 mg) and methyl iodide (1 mL) in 25 mL of acetone was heated under reflux overnight, then cooled and evaporated in vacuo. A mixture of the resultant residue and NaOH (170 mg) in aqueous MeOH (90%, 25 mL) was stirred at 50° C. for 30 minutes. The reaction mixture was concentrated and acidified with diluted HCl. The solids were collected by filtration and dried to give the title compound (280 mg, 87%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][N:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][CH2:18][C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]1=2)#[N:7].CN([CH:33]=[O:34])C>>[CH:33]([C:24]1[CH:23]=[CH:22][C:21]2[N:15]([CH2:14][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[C:6]#[N:7])[C:16]3[CH:29]=[CH:28][CH:27]=[CH:26][C:17]=3[CH2:18][CH2:19][C:20]=2[CH:25]=1)=[O:34]
Reactant: CN(C)C=O
Reactant: N#Cc1ccccc1CN1c2ccccc2CCc2ccccc21
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccccc1CN1c2ccccc2CCc2cc(C=O)ccc21
Temperature: 70 °C
Reaction time: 6 h
Yield: 75 %

Procedure:
DMF (5 ml) was added dropwise to 5 ml of phosphorus oxychloride with cooling. To the solution was added dropwise 40 ml of a solution of 7.0 g of Compound 37-a in DMF, followed by stirring at 70° C. for 6 hours. The reaction mixture was poured onto ice, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluent: hexane/ethyl acetate (2/1)] to give 5.83 g (75%) of the product as a yellow amorphous solid.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[C:22]([O:26][C:27]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C.[CH3:41][C:42]1[C:43]([N:58]2[CH2:67][CH2:66][C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[CH:59]2[CH3:68])=[N:44][C:45]([NH:50][C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=2)=[N:46][C:47]=1[CH2:48]O>C(Cl)Cl>[CH3:41][C:42]1[C:43]([N:58]2[CH2:67][CH2:66][C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[CH:59]2[CH3:68])=[N:44][C:45]([NH:50][C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=2)=[N:46][C:47]=1[CH2:48][O:32][C:31](=[O:33])[CH2:30][NH:29][C:27]([O:26][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:28]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Cc1c(CO)nc(Nc2ccc(F)cc2)nc1N1CCc2ccccc2C1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(COC(=O)CNC(=O)OC(C)(C)C)nc(Nc2ccc(F)cc2)nc1N1CCc2ccccc2C1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-hydroxybenzotriazole(26.8 mg, 0.198 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(32.9 mg, 0.171 mmol), N-t-butoxycarbonylglycine(27.8 mg, 0.158 mmol) and triethylamine(23.9 μl 0.171 mmol) were added to a suspension of 5-methyl-6-hydroxymethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(50 mg, 0.132 mmol) in anhydrous methylene chloride(1 ml). The reaction mixture was stirred for 1 day at room temperature, washed with water. The separated organic layer was concentrated and the residual oil was purified by a silica gel column chromatography (dichloromethane/methanol 20/1) to give the titled compound.