Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:53][CH2:52][N:51]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:50][CH2:49]3)=[CH:44][CH:43]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:42]4[CH:43]=[CH:44][C:45]([N:48]5[CH2:49][CH2:50][N:51]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:52][CH2:53]5)=[CH:46][CH:47]=4)[CH:3]=3)[N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:9]=2)[CH:12]=[N:13]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Yield: 42.7 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of step-i of example-9) (200 mg, 0.53 mmol) was coupled with tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (intermediate 40) (251 mg, 0.64 mmol) in sodium carbonate (168 mg, 1.59 mmol) PdCl2 (dppf) (19 mg, 0.0265 mmol), 1,2-Dimethoxyethane/water (25/3 ml) to afford 160 mg (59.47% yield) of the titled compound. MS: m/z=707.1 (M+1).
Reaction SMILES: I[C:2]1[N:3]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([CH3:26])[C:18]4[C:23]([C:24]=3[CH:25]=2)=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:4]=[C:5]([C:7]2[S:8][C:9]([CH3:12])=[CH:10][CH:11]=2)[N:6]=1.[CH3:27][C:28]1[S:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>O.CN(C=O)C>[CH3:27][C:28]1[S:32][C:31]([C:2]2[N:3]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([CH3:26])[C:18]5[C:23]([C:24]=4[CH:25]=3)=[CH:22][CH:21]=[CH:20][CH:19]=5)[CH:4]=[C:5]([C:7]3[S:8][C:9]([CH3:12])=[CH:10][CH:11]=3)[N:6]=2)=[CH:30][CH:29]=1
Reactant: Cc1ccc(-c2cn(-c3ccc4c(c3)c3ccccc3n4C)c(I)n2)s1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2cn(-c3ccc4c(c3)c3ccccc3n4C)c(-c3ccc(C)s3)n2)s1
Temperature: 25 °C
Yield: 135.4 %

Procedure:
A mixture of 3-(2-iodo-4-(5-methylthiophen-2-yl)-1H-imidazol-1-yl)-9-methyl-9H-carbazole 10 (920 g, 2.0 mmol), 5-methylthiophene-2-boronic acid pinacol ester (880 mg, 3.9 mmol), Na2CO3 (1.03 g, 9.81 mmol) in H2O (5 mL) and DMF (20 mL) was degassed (N2 bubbling). Pd(PPh3)4 (60 mg) was added and the mixture was heated to reflux for 8 h. The mixture was allowed to cool to room temperature and concentrated. The residue was washed with H2O (3 times) and EtOAc (1 time). The solid material was transferred to a soxlet apparatus and the material extracted with EtOAc. The organic extract was concentrated to ˜10 mL and the solid material was collected and recrystallised (EtOAc) to give 3-(2,4-bis(5-methylthiophen-2-yl)-1H-imidazol-1-yl)-9-methyl-9H-carbazole 11 (1.19 g, 76%) as colourless crystals. A portion of this material was further purified by sublimation (220° C., 10−6 mBar): m.p. 248-255° C. (DSC)1H NMR (CDCl3, 400 MHz) δ 2.33 (s, 3H), 2.51 (d, J=0.6 Hz, 3H), 3.94 (s, 3H), 6.48 (br s, 1H), 6.72 (d, J=2.5 Hz, 1H), 7.22 (s, 1H), 7.30 (t, 7.6 Hz, 1H), 7.43 (dd, J 2.0, 8.6 Hz, 1H), 7.49 (d, 8.5 Hz, 2H), 7.57 (dt, J 1.0, 7.6 Hz, 1H), 8.08 (d, 7.7 Hz, 1H), 8.10 (d, J=1.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 15.1, 15.4, 109.0, 109.2, 117.9, 119.2, 119.8, 120.8, 122.2, 123.3, 124.5, 125.9, 126.1, 126.9, 141.1, 141.8, 142.6; HRMS (EI) m/z 439.1163 C24H22N2S [M]+. requires 439.1171.
Reaction SMILES: [C@@H:1]1([N:12]2[C:16]3[C:17]4[NH:18][C:19]5[C:24]([C:25]=4[C:26]4[C:30](=[O:31])[N:29]([CH3:32])[C:28](=[O:33])[C:27]=4[C:15]=3[C:14]3[CH:34]=[CH:35][CH:36]=[N:37][C:13]2=3)=[CH:23][CH:22]=[CH:21][CH:20]=5)[O:9][C@H:8]([CH2:10]O)[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:58].O>N1C=CC=CC=1>[Cl:58][CH2:10][C@H:8]1[O:9][C@@H:1]([N:12]2[C:16]3[C:17]4[NH:18][C:19]5[C:24]([C:25]=4[C:26]4[C:30](=[O:31])[N:29]([CH3:32])[C:28](=[O:33])[C:27]=4[C:15]=3[C:14]3[CH:34]=[CH:35][CH:36]=[N:37][C:13]2=3)=[CH:23][CH:22]=[CH:21][CH:20]=5)[C@H:2]([OH:3])[C@@H:4]([OH:5])[C@@H:6]1[OH:7]
Reactant: CN1C(=O)c2c(c3c4cccnc4n([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)c3c3[nH]c4ccccc4c23)C1=O
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: O
Product: CN1C(=O)c2c(c3c4cccnc4n([C@@H]4O[C@H](CCl)[C@@H](O)[C@H](O)[C@H]4O)c3c3[nH]c4ccccc4c23)C1=O
Temperature: 25 °C
Reaction time: 2.3 h

Procedure:
To a solution of the compound of Example 17 (0.353 mmol) dissolved in 2.5 ml of pyridine there is added a solution of triphenylphosphine (1.415 mmol) and then carbon tetrachloride (0.707 mmol). The mixture is stirred at ambient temperature for 2.30 hours and is then poured into water. The mixture is extracted with ethyl acetate and the organic phase is washed successively with a 1N aqueous solution of hydrochloric acid, water and a saturated solution of NaHCO3. After evaporating off the solvent and then purifying by chromatography over silica gel (ethyl acetate), the expected product is isolated.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:20]=1[NH2:21]>>[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:20]=1[NH:21][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Reactant: Nc1cc(O)ccc1Cl
Product: Oc1ccc(Cl)c(Nc2cc(C(F)(F)F)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from 4-chloro-2-(2-pyridinyl)-6-trifluoromethylpyrimidine (40 mg, 0.154 mmol) and 2-chloro-5-hydroxyaniline (30 mg, 0.231 mmol) similar to Example 185 and was isolated as an off white solid (15 mg, 28%). 1H NMR (DMSO-d6): 9.89 (s, 1H), 9.85 (brs, NH), 8.74 (d, J=5.7, 1H), 8.22 (d, J=7.8 Hz, 1H), 7.97 (ddd, J=1.8, 5.7, 7.8 Hz, 1H), 7.54 (ddd, J=4.5, 6.0, 7.8 Hz, 1H), 7.35 (m, 2H), 7.19 (s, 1H), 6.70 (dd, J=2.7, 5.7 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(O)=O.C1C(=O)N([Br:29])C(=O)C1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([Br:29])=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCc2cccnc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCc2cc(Br)cnc21
Yield: 97.7 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (1.37 g, 5.85 mmole) in. CH2Cl2 (30 μL) was added glacial HOAc (3.4 mL, 58.5 mmole) and NBS (1.09 g, 6.14 mmole). After 72 hr the mixture was washed with 2.0 M NaOH, H2O. and brine. The mixture was dried (MgSO4), filtered, and concentrated under reduced pressure to give the title compound (1.79 g, 98%) which was sufficiently pure for use in the next step: 1H NMR (400 MHz, CDCl3) δ 8.35 (s,1H), 7.51 (s, 1 H), 3.77 (m, 2 H), 2.75 (t,J=6.5 Hz, 2 H), 1.93 (m, 2 H), 1.54 (s, 9 H).
Reaction SMILES: [F:1][C:2]1[CH:45]=[CH:44][C:5]([CH2:6][NH:7][C:8]2[N:43]=[CH:42][CH:41]=[CH:40][C:9]=2[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])=[C:15]([O:26][CH2:27][CH:28]3[CH2:32][CH2:31][CH2:30][N:29]3C(OC(C)(C)C)=O)[CH:14]=2)=[O:11])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]2[N:43]=[CH:42][CH:41]=[CH:40][C:9]=2[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:24])([F:25])[C:20]([F:21])([F:22])[F:23])=[C:15]([O:26][CH2:27][CH:28]3[CH2:32][CH2:31][CH2:30][NH:29]3)[CH:14]=2)=[O:11])=[CH:44][CH:45]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1COc1cc(NC(=O)c2cccnc2NCc2ccc(F)cc2)ccc1C(F)(F)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(C(F)(F)C(F)(F)F)c(OCC2CCCN2)c1)c1cccnc1NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
2-(4-Fluoro-benzylamino)-N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenyl]-nicotinamide (Example 43) was dissolved in CH2Cl2 (8 mL) and TFA (8 mL) was added. After stirring at RT for 70 min, the mixture was concentrated in vacuo, diluted with 2N NaOH and CH2Cl2. The layers were separated and the aqueous layer was back extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to provide an light pink-orange solid. M+H 539.5. Calc'd for C26H24F6N4O2: 538.2.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].C(Cl)(=O)C(Cl)=O.[CH3:31][CH:32]([CH3:35])[CH2:33]O.N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:31][CH:32]([CH3:35])[CH3:33])=[O:13])(=[O:6])=[O:7]
Reactant: CC(C)(COS(=O)(=O)CCCCl)[C@@H](OCc1ccccc1)C(=O)O
Reactant: CC(C)CO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)COC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Yield: 46 %

Procedure:
Following the general procedure for the preparation of carboxylic esters from carboxylic acids of Description 15, (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoic acid (11) (1.1 g, 3.1 mmol) dissolved in 30 mL of dichloromethane was reacted with 1.8 mL (3.6 mmol) of oxalyl chloride (2.0 M in DCM). After completion of the reaction, a solution of 2-methylpropanol (0.57 mL, 0.46 g, 6.2 mmol) and 0.50 mL of pyridine (0.49 g, 6.2 mmol) in 20 mL of anhydrous dichloromethane (DCM) was added to the acid chloride. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) as eluent (EtOAc/Hxn=1:5) to provide 0.62 g (48% yield) of the title compound (30a) as a colorless oil. Rf=0.69 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3): δ=0.98 (d, J=6.4 Hz, 1H), 1.07 (s, 3H), 1.09 (s, 3H), 1.99 (septet, J=6.4 Hz, 1H), 2.25-2.34 (m, 2H), 3.22-3.26 (m, 2H), 3.64 (t, J=6.0 Hz, 2H), 3.86 (s, 1H), 3.89-4.01 (m, 3H), 4.23-4.25 (m, 1H), 4.35 (d, J=11.2 Hz, 1H), 4.64 (d, J=11.2 Hz, 1H), 7.29-7.39 (m, 5H) ppm. MS (ESI) m/z 435.16 (M+H)+, 457.11 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[N:14]=[N:15][C:16]([C:17]([O:19]CC)=[O:18])=[C:12]3[CH2:11][CH2:10][CH2:9][C:8]=2[CH:22]=1.[OH-].[Na+]>C1COCC1.CO>[F:24][C:2]([F:1])([F:23])[O:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[N:14]=[N:15][C:16]([C:17]([OH:19])=[O:18])=[C:12]3[CH2:11][CH2:10][CH2:9][C:8]=2[CH:22]=1
Reactant: CCOC(=O)c1nnn2c1CCCc1cc(OC(F)(F)F)ccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1nnn2c1CCCc1cc(OC(F)(F)F)ccc1-2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of ethyl 8-(trifluoromethoxy)-5,6-dihydro-4H-benzo[f][1,2,3]triazolo[1,5-a]azepine-3-carboxylate (384 mg, 1.125 mmol) in THF (5 mL) and methanol (3 mL) was added 2M NaOH (aq) (2.81 mL, 5.63 mmol) and the mixture was stirred at RT for 45 mins. The resulting mixture was concentrated under reduced pressure to give a residue that was partitioned between EtOAc and water. The layers were separated and the aqueous layer was washed with EtOAc. The organic portions were discarded and the aqueous layer was treated with 2M HCl (aq) until acidic. The resulting solution was extracted with EtOAc and the organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1)=[O:3].N1C=CC=CC=1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])O.[Na+]>ClCCl>[C:2]([C:4]1[CH:9]=[C:8]([O:10][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1cccc(O)c1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)c1cccc(OC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.2 %

Procedure:
Under an argon atmosphere, 3-hydroxyacetophenone (0.68 g, 5 mmol) was dissolved in dichloromethane (5 mL), and pyridine (2.0 mL, 25 mmol) and benzoyl chloride (0.70 mL, 6.0 mmol) were added thereto, and then, the mixture was stirred at room temperature for 4 hours. To the mixture, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with a 2 mol/L aqueous sodium hydroxide solution, 2 mol/L hydrochloric acid, and saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 50/50) to give benzoic acid (3-acetylphenyl)ester (1.19 g, 4.96 mmol, yield: 99%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:12][OH:13])[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH:10]([CH2:12][O:13][C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCC(O)COCc1ccccc1
Solvent: c1ccncc1
Product: OC(COCc1ccccc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 71.9 %

Procedure:
rac-1-O-Benzylglycerol (5.37 g, 29.5 mmol), trityl chloride (8.31 g, 29.8 mmol) and anhydrous pyridine (35 ml) were placed in a flame-dried 200 ml round-bottomed flask. The reaction mixture was stirred under anhydrous conditions at room temperature for two days. The precipitate which formed was filtered before H2O and ether were added. The ether layer was extracted with H2O, 1N HCl and H2O, and dried (MgSO4). The solvent was removed by reduced pressure to provide a viscous yellow oil. The crude product was purified by column chromatography (180 g silica gel; hexanes:ethyl acetate, gradient 8:1 to 3:1) to yield pure compound 12, rac-1-O-benzyl-3-O-tritylglycerol (9.00 g, 72% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[NH2:27][CH2:28][CH2:29][N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][CH2:28][CH2:29][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: NCCN1CCCC1
Product: O=C(NCCN1CCCC1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to N-(2-aminoethyl)pyrrolidine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(2-(pyrrolidin-1-yl)ethyl)terephthalamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)[C:15](=[O:29])[CH2:14][CH2:13][CH2:12]1.I[CH3:31]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:27])([F:26])[F:28])=[CH:20][CH:19]=2)[C:15](=[O:29])[CH:14]([CH3:31])[CH2:13][CH2:12]1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(OC(F)(F)F)cc1
Reactant: CI
Product: COc1cccc(OC)c1C1CCC(C)C(=O)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 8 (GP8) by C-alkylation of 6-(2,6-dimethoxyphenyl)-1-(4-(trifluoromethoxy)benzyl)piperidin-2-one with commercially available iodomethane. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.84 min.; [M+H]+: 424.22 g/mol.
Reaction SMILES: [Sn](Cl)[Cl:2].[N+:4]([C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([C:18](=[O:21])[NH:19][N:20]=3)[C:13](=[O:17])[NH:14][C:15]=2[CH:16]=1)([O-])=O>Cl>[ClH:2].[NH2:4][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([C:18](=[O:21])[NH:19][N:20]=3)[C:13](=[O:17])[NH:14][C:15]=2[CH:16]=1
Reactant: O=c1[nH]nc2c3ccc([N+](=O)[O-])cc3[nH]c(=O)n12
Reactant: Cl[Sn]Cl
Agent: Cl
Product: Nc1ccc2c(c1)[nH]c(=O)n1c(=O)[nH]nc21
Yield: 62.1 %

Procedure:
1.98 g (8.8 mmol) of tin dichloride were dissolved in 10 ml of conc. hydrochloric acid at 80° C. 494 mg (2 mmol) of 8-nitro-2,3,5,6-tetrahydro-1,2,4-triazolo[4,3-c]quinazoline-3,5-dione were added portionwise thereto. After heating at reflux for 2 hrs. the precipitate was filtered off, washed with water and dried in a vacuum. 315 mg (62%) of 8-amino-2,3,5,6-tetrahydro-1,2,4-triazolo[4,3-c]quinazoline-3,5-dione hydrochloride were obtained as white crystals;
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][C:6]([N:16]2[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:17]2)=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].CCN(C(C)C)C(C)C.[F:35][C:36]([F:51])([F:50])[C:37]1[CH:38]=[C:39]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[C:40](Cl)=[O:41]>C(Cl)Cl>[CH3:25][S:22]([N:19]1[CH2:18][CH2:17][N:16]([C:6]2[N:5]=[CH:4][C:3]([N:2]([CH3:1])[C:40](=[O:41])[C:39]3[CH:38]=[C:37]([C:36]([F:51])([F:50])[F:35])[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=3)=[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH3:15])[CH:7]=2)[CH2:21][CH2:20]1)(=[O:24])=[O:23]
Reactant: CNc1cnc(N2CCN(S(C)(=O)=O)CC2)cc1-c1ccccc1C
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1cc(N2CCN(S(C)(=O)=O)CC2)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 79.9 %

Procedure:
A solution of N-methyl-6-(4-(methylsulfonyl)piperazin-1-yl)-4-o-tolylpyridin-3-amine (37 mg, 0.10 mmol) and DIPEA (50 μL, 0.29 mmol) in CH2Cl2 was treated with 3,5-bis-trifluoromethylbenzoyl chloride (43 mg, 0.15 mmol, CAS RN 1271-19-8). After stirring for 1 h, the reaction mixture was loaded directly onto a silica gel column. Elution with 50% EtOAc in n-hexane afforded the title compound as a yellow solid (48 mg, 80%). MS (ESI): m/z=601.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([F:13])[CH:3]=1.[C:14](Cl)(Cl)=[S:15].[OH-].[Na+]>O.Cl>[F:13][C:4]1[CH:3]=[C:2]([N:1]=[C:14]=[S:15])[C:11]([CH3:12])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2
Reactant: Cc1c(N)cc(F)c2cccnc12
Reactant: S=C(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c(N=C=S)cc(F)c2cccnc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 7-amino-5-fluoro-8-methylquinoline (0.39 g) and thiophosgene (0.2 mL) in water (5 mL) and 1N hydrochloric acid (5 mL) is stirred at room temperature for 1.5 hours. An additional amount of thiophosgene (0.1 mL) is added and the mixture stirred another hour. The mixture is treated with 1N sodium hydroxide (25 mL) and extracted with methylene chloride (4×50 mL). The combined extracts are dried over sodium sulfate and rotary evaporated. The residue is purified by flash chromatography on silica gel, eluting with 15% ethyl acetate/hexanes, to afford 5-fluoro-7-isothiocyanato-8-methylquinoline as a tan solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].I[CH:24]([CH3:26])[CH3:25]>CN(C)C=O>[F:16][C:2]([F:1])([F:15])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[N:7]([CH:24]([CH3:26])[CH3:25])[CH:6]=1)=[O:4]
Reactant: O=C(c1c[nH]c2cc(Br)ccc12)C(F)(F)F
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(C(=O)C(F)(F)F)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.5 %

Procedure:
A solution of 2,2,2-trifluoro-1-(6-bromo-1H-indol-3-yl)-ethanone (3.0 g, 10.27 mmol) in N,N-dimethylformamide (20 mL) at 25° C. was treated with potassium carbonate (3.54 g, 25.68 mmol). The resulting mixture was stirred at 25° C. for 15 min and then treated with 2-iodopropane (1.54 mL, 15.41 mmol). The reaction was heated at 65° C. for 18 h. At this time, the reaction was cooled to 25° C. and was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic layer was then washed with a 1N aqueous hydrochloric acid solution (1×25 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 2/1 hexanes/ethyl acetate) afforded 2,2,2-trifluoro-1-(6-bromo-1-isopropyl-1H-indol-3-yl)-ethanone (3.38 g, 99%) as a pink solid: mp 77-79° C.; EI-HRMS m/e calcd for C13H11BrF3NO (M) 332.9976, found 332.9975.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([C:18]3[N:26]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[C:21]4=[N:22][CH:23]=[CH:24][CH:25]=[C:20]4[CH:19]=3)=[CH:13][N:14]2[CH3:17])=[CH:10][C:9]=1[O:37][CH3:38].Br[CH:40]([CH3:42])[CH3:41]>CN(C)C=O.O>[CH:40]([O:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([C:18]3[N:26]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[C:21]4=[N:22][CH:23]=[CH:24][CH:25]=[C:20]4[CH:19]=3)=[CH:13][N:14]2[CH3:17])=[CH:10][C:9]=1[O:37][CH3:38])([CH3:42])[CH3:41]
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1O
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC(C)C
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
Potassium carbonate (70 mg) was added to a solution of 2-(6-hydroxy-5-methoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine [112 mg, Reference Example 83] in dry dimethylformamide (5 mL) under an argon atmosphere at ambient temperature. The mixture was allowed to stir for 10 minutes then treated with 2-bromopropane (66 μl) and heated at 70° C. for 3 hours. Additional portions of potassium carbonate (70 mg) and 2-bromopropane (66 μl) were then added and the mixture was stirred and heated at 70° C. for 4 hours. The cooled reaction mixture was poured in water (20 mL) and extracted three times with ethyl acetate (40 mL). The combined organic phases were washed with brine (20 mL), then dried over magnesium sulfate and then evaporated. The brown residue was subjected to flash column chromatography on silica eluting with a mixture of cyclohexane and ethyl acetate (3:2, v/v) to give the title compound (56 mg) as an off-white foam. TLC: RF=0.47 (cyclohexane/ethyl acetate, 1/1). MS: CI (NH3); m/z=490 MH+.