Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14]([F:25])([F:24])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[C:14]([F:25])([F:24])[CH2:15][CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(F)(F)CCCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(F)(F)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using dichlorobis(triphenylphosphine)palladium(II) as the catalyst and using 5-(4-bromo-phenyl)-4-(1,1-difluoro-4-phenyl-butyl)-3-methyl-isoxazole and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11](=[O:32])[CH:12](P(OCC)(OCC)=O)[CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])([CH3:9])([CH3:8])[CH3:7].[C:33]([O:37][C:38](=[O:48])[NH:39][C:40]1[CH:45]=[C:44]([CH:46]=O)[CH:43]=[CH:42][N:41]=1)([CH3:36])([CH3:35])[CH3:34].O>C1COCC1>[C:6]([O:10][C:11](=[O:32])[C:12](=[CH:46][C:44]1[CH:43]=[CH:42][N:41]=[C:40]([NH:39][C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:48])[CH:45]=1)[CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)Nc1cc(C=O)ccn1
Reactant: CCOP(=O)(OCC)C(CC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(C=C(CC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)ccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
Butyllithium (1.6 M in hexane, 14.8 ml, 23.7 mmol) was added dropwise to a solution of 2-(diethoxy-phosphoryl)-succinic acid 4-benzyl ester 1-tert-butyl ester (9.50 g, 23.7 mmol in THF (75 mL) at 0° C. under nitrogen. After stirring at 0° C. for 1 h, the solution was transferred to a solution of (4-Formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (3.70 g, 16.6 mmol) in THF (75 mL). The resulting reaction mixture was stirred at 0° C. for 1 h before being allowed to warm to 25° C., and the mixture was stirred overnight. Water (400 mL) was added and the product extracted with CH2Cl2 (3×50 mL). The combined organic layers were dried and concentrated. Flash chromatography (hexane/EtOAc, 4:1) gave 2-(2-tert-Butoxycarbonylamino-pyridin-4-ylmethylene)-succinic acid 4-benzyl ester 1-tert-butyl ester 4.30 g (55%).
Reaction SMILES: [N:1]([O-])=O.[Na+].[Cl:5][C:6]1[C:11]([CH3:12])=[C:10]([NH2:13])[C:9]([O:14][CH3:15])=[CH:8][N:7]=1>O.C(O)(=O)C>[Cl:5][C:6]1[C:11]2[CH:12]=[N:1][NH:13][C:10]=2[C:9]([O:14][CH3:15])=[CH:8][N:7]=1
Reactant: O=N[O-]
Reactant: COc1cnc(Cl)c(C)c1N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cnc(Cl)c2cn[nH]c12
Temperature: 75 °C

Procedure:
A solution of sodium nitrite (98%, 326 mg, 4.63 mmol) in water (0.6 mL) was added to a solution of C4 (200 mg, 1.16 mmol) in acetic acid (8 mL), and the reaction mixture was heated at 75° C. for 1 hour. After the reaction mixture had cooled to room temperature, it was concentrated in vacuo, diluted with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (Gradient: 25% to 50% ethyl acetate in heptane) provided the product as a yellow solid. Yield: 140 mg, 0.763 mmol, 66%. LCMS m/z 184.0 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 7.74 (s, 1H), 4.06 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH2:8]O)[CH:5]=[CH:6][CH:7]=1.P(Br)(Br)[Br:12]>C(Cl)Cl>[Br:12][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:10]
Reactant: OCc1cccc(Cl)c1F
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Fc1c(Cl)cccc1CBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3-chloro-2-fluoro-phenyl)-methanol (3.2 g, 20 mmol) in DCM (20 mL) was added dropwise PBr3 (1 mL) at 0° C. The reaction mixture was stirred at room temperature for another 1 hour before quenching with satd. aq. NaHCO3 solution. The organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give the desired product without further purification (4.1 g, 92%). MS: 223.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][CH:5]([C:7]([OH:9])=O)[CH2:4][O:3]1.[NH2:11][C:12]1[CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[C:16]([NH2:18])[CH:17]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.N1C=CC=CC=1.C(OCC)(=O)C>[NH2:18][C:16]1[CH:17]=[C:12]([NH:11][C:7]([CH:5]2[CH2:4][O:3][C:2]([CH3:1])([CH3:10])[O:6]2)=[O:9])[CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=1
Reactant: Nc1cc(N)cc([N+](=O)[O-])c1
Reactant: CC1(C)OCC(C(=O)O)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1(C)OCC(C(=O)Nc2cc(N)cc([N+](=O)[O-])c2)O1
Reaction time: 72 h
Yield: 68.4 %

Procedure:
To a solution of 0.5 g (2.9 mmole) of 2,2-dimethyl-1,3-dioxolane-4-carboxylic acid in 2 ml of methylene chloride, at 0° C., was added a solution of 0.216 g of 3,5-diaminonitrobenzene (1.3 mmole) in 2 ml of methylene chloride and 1 ml of pyridine, followed by 0.61 g (3.0 mmole) of dicyclohexylcarbodiimide. The mixture was stirred 72 hours, diluted with ethyl acetate, filtered and the filtrate evaporated to dryness in high vacuum. The residue was chromatographed over silica gel; elution with 9:1 chloroform-ethyl acetate gave two fractions. The first fraction, 170 mg was the bis-acylated material. The second fraction was evaporated to dryness to give 250 mg of N-(3-amino-5-nitrophenyl)-2,2-dimethyl-1,3-dioxolane-4-carboxamide.
Reaction SMILES: O.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:11])[CH3:10].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[F:2][C:3]1[CH:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[CH:5][C:4]=1[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)c1ccccc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)c1cc([N+](=O)[O-])ccc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a 3-neck flask equipped with an internal thermometer was added sulfuric acid and cooled to 10° C. in an ice/salt/water batch. 2′-fluoroacetophenone (1 eq) in sulfuric acid was added dropwise over 10 minutes via addition funnel to produce a solution of 0.2M. Nitric acid (1.15 eq) in sulfuric acid was then added dropwise at a rate not to exceed 5° C. After complete addition resulting solution was allowed to stir at for 30 minutes. Solution was poured onto ice and extracted with ethyl acetate. Organics were washed with a saturated solution of sodium bicarbonate, brine, dried with sodium sulfate and concentrated. Crude product was purified using flash chromatography (85% Hex:15% EtoAc) on silica to afford 1-(2-fluoro-5-nitrophenyl)ethanone.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:12])[N:4]([CH:9]([CH3:11])[CH3:10])[N:5]=[CH:6][C:7]=1[NH2:8].[H-].[Na+].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>CN(C)C=O.C1C=CC=CC=1>[Cl:1][C:2]1[C:3](=[O:12])[N:4]([CH:9]([CH3:10])[CH3:11])[N:5]=[CH:6][C:7]=1[NH:8][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccccc1
Reactant: CC(C)n1ncc(N)c(Cl)c1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(C)n1ncc(NCc2ccccc2)c(Cl)c1=O
Reaction time: 0.5 h

Procedure:
In 6 ml of dry dimethylformamide, 1.875 g of 4-chloro-5-amino-2-i-propyl-3(2H)pyridazinone was dissolved. 0.48 g of sodium hydride (50% mineral oil suspension) was added thereto at a temperature of from 5° to 10° C., and the mixture was stirred for about 30 minutes. Then, 1.4 g of benzyl chloride was dropwise added thereto at the same temperature. After the dropwise addition, the mixture was stirred at room temperature for 2 hours. To the reaction solution, 50 ml of benzene and 30 ml of a 10% hydrochloric acid aqueous solution were added, and the mixture was vigorously shaken. The organic layer was washed with water, and dried, and then the solvent was distilled off. The crude crystals thereby obtained were recrystallized from ethyl ether to obtain 2.3 g of the above identified compound having a melting point of from 131° to 132° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[C:26]([O:27][CH3:28])=[CH:25][C:23]([NH2:24])=[C:22]([CH3:29])[CH:21]=1>>[ClH:1].[CH3:18][O:19][C:20]1[C:26]([O:27][CH3:28])=[CH:25][C:23]([NH:24][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:17]=[N:16][CH:15]=[CH:14][N:13]=3)[N:3]=2)=[C:22]([CH3:29])[CH:21]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cnccn2)n1
Reactant: COc1cc(C)c(N)cc1OC
Product: COc1cc(C)c(Nc2cc(C(F)(F)F)nc(-c3cnccn3)n2)cc1OC
Product: Cl

Procedure:
The title compound was prepared from a mixture of 4-chloro-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.191 mmol) and 4,5-dimethoxy-2-methylaniline (48 mg, 0.287 mmol) similar to Example 117 and isolated as a brown solid (47 mg, 56%). 1H NMR (CDCl3): 9.74 (d, J=1.5 Hz, 1H), 8.76 (dd, J=1.5, 2.4 Hz, 1H), 8.71 (d, J=2.4 Hz, 1H), 7.51 (s, 1H), 6.82 (s, 1H), 6.78 (s, 1H), 6.55 (s, 1H), 3.93 (s, 3H), 3.86 (s, 3H), 2.21 (s, 3H).
Reaction SMILES: [OH:1][C:2]([CH3:43])([CH3:42])[C:3]([NH:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:21]=[C:20]3[C:15]([C:16]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[N:17][C:18]([C:22]4[CH:23]=[N:24][C:25]([NH:28]C(=O)OC(C)(C)C)=[N:26][CH:27]=4)=[N:19]3)=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)=[O:4].FC(F)(F)C(O)=O>CO.C(Cl)Cl>[NH2:28][C:25]1[N:26]=[CH:27][C:22]([C:18]2[N:17]=[C:16]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[C:15]3[C:20](=[CH:21][C:12]([C:8]4[CH:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([OH:1])([CH3:43])[CH3:42])[CH:11]=[CH:10][CH:9]=4)=[CH:13][CH:14]=3)[N:19]=2)=[CH:23][N:24]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ccc(-c4cccc(NC(=O)C(C)(C)O)c4)cc3n2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CC(C)(O)C(=O)Nc1cccc(-c2ccc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3c2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 0 %

Procedure:
In a 25 mL round bottom flask, tert-butyl (5-(7-(3-(2-hydroxy-2-methylpropanamido)phenyl)-4-morpholinoquinazolin-2-yl)pyrimidin-2-yl)carbamate (0.06 g, 0.0001 mol) and DCM (10 mL) were added. To the flask was added trifluoroacetic acid (0.5 mL) and the reaction stirred at room temperature for 5 hours. The volatiles were evaporated under reduced pressure to provide the residue. The residue was dissolved in 5% methanol in DCM and washed with saturated sodium bicarbonate. The organic layer was washed with water, brine, dried over sodium sulfate and evaporated under reduced pressure to provide the crude product. The crude product was purified by preparative HPLC (10 mM NH4OAc and 1:1 MeOH:ACN) to obtain the title compound (0.007 mg, 14%). 1H NMR (DMSO-d6, 400 MHz): δ 9.76 (s, 1H), 9.22 (s, 2H), 8.32 (s, 1H), 8.11 (d, J=8.8 Hz, 1H), 8.05 (s, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.48 (t, J=8.8 Hz, 1H), 7.16 (s, 2H), 3.85 (s, 8H), 1.39 (s, 6H): LC-MS (ESI): Calculated mass. 485.2, Observed mass [M+H]+: 486.2. (RT=0.11 min).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH:7]2[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.[C:17](Cl)(=[O:28])[O:18][CH2:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=1.[OH-].[Na+]>C(Cl)Cl>[Cl:26][C:24]1[CH:25]=[C:20]([CH:21]=[C:22]([Cl:27])[CH:23]=1)[CH2:19][O:18][C:17]([NH:1][CH:2]1[CH2:3][CH:4]2[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:7]([CH2:6][CH2:5]2)[CH2:8]1)=[O:28]
Reactant: O=C(Cl)OCc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(N)C2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C2CCC1CC(NC(=O)OCc1cc(Cl)cc(Cl)c1)C2

Procedure:
A reaction mixture comprising of tert-butyl 3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (210 mg, 0.928 mmol), 3,5-dichlorobenzyl carbonochloridate (222 mg, 0.928 mmol), and sodium hydroxide (4.64 ml, 93 mmol) in DCM (3.1 ml) was stirred at room temperature for 4 hours. The reaction mixture separated and the organic portion dried over MgSO4, filtered and concentrated under reduced pressure. No further purification was carried out and the material was taken on crude to the next step.
Reaction SMILES: [O:1]=[C:2]([N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)/[CH:3]=[CH:4]/[C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>C(Cl)Cl>[F:30][C:29]([F:32])([F:31])[C:27]([OH:33])=[O:28].[N:22]1([C:2](=[O:1])/[CH:3]=[CH:4]/[C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[CH2:11][NH:10][CH2:9][CH2:8]3)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(/C=C/C(=O)N3CCCC3)ccc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(/C=C/c1ccc2c(c1)CCNC2)N1CCCC1
Reaction time: 16 h
Yield: 91.6 %

Procedure:
A solution of 125c (400 mg, 1.12 mmol) in CH2Cl2 (4 ml) was treated with TFA (1.28 g, 11.21 mmol)) at 20-35° C. for 16 h. The progress of the reaction was monitored by TLC. After 16 h of stirring, the clear solution was concentrated under vacuum and the resultant solid was washed with diethyl ether to get the desired compound as a gummy liquid (380 mg, 91%). 1H NMR (400 MHz, DMSO-d6) δ 9.05 (bs, 2H), 7.58 (d, J=8.3 Hz, 2H), 7.43 (d, J=15.6 Hz, 1H), 7.25 (d, J=7.8 Hz, 1H), 6.99 (d, J=15.6 Hz, 1H), 4.32-4.24 (m, 2H), 3.63 (t, J=6.9 Hz, 2H), 3.39 (t, J=6.9 Hz, 4H), 3.01 (t, J=6.1 Hz, 2H), 1.98-1.89 (m, 2H), 1.88-1.76 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([CH3:17])=[C:10]([C:14]([OH:16])=O)[N:11]([CH3:13])[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([N:20]([CH2:26][CH3:27])[CH:21]1[CH2:25][CH2:24][NH:23][CH2:22]1)[CH3:19]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([CH3:17])=[C:10]([C:14]([N:23]3[CH2:24][CH2:25][CH:21]([N:20]([CH2:26][CH3:27])[CH2:18][CH3:19])[CH2:22]3)=[O:16])[N:11]([CH3:13])[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)C1CCNC1
Reactant: Cc1c(-c2cccc(Br)c2)nn(C)c1C(=O)O
Product: CCN(CC)C1CCN(C(=O)c2c(C)c(-c3cccc(Br)c3)nn2C)C1
Yield: 77 %

Procedure:
In analogy to the procedure described in example 12D), 5-(3-bromo-phenyl)-2,4-dimethyl-2H-pyrazole-3-carboxylic acid and 3-(diethylamino)pyrrolidine gave the title compound in 77% yield as light yellow viscous oil. MS: 419.0 (MH+, 1 Br).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[C:15]([CH:16]=[CH:17][CH:18]=1)=[C:14]([C:19]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=1[F:26])[C:13](=[O:27])[CH:12]=[CH:11]2.[Br:28]Br.C(Cl)Cl>C(Cl)Cl>[Br:28][C:12]1[C:13](=[O:27])[C:14]([C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])=[C:15]2[N:10]([CH:11]=1)[C:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])=[CH:18][CH:17]=[CH:16]2
Reactant: O=c1ccn2c(-c3ccc(F)cc3F)cccc2c1-c1c(F)cccc1F
Reactant: BrBr
Solvent: ClCCl
Product: O=c1c(Br)cn2c(-c3ccc(F)cc3F)cccc2c1-c1c(F)cccc1F

Procedure:
To a solution of 6-(2,4-difluorophenyl)-1-(2,6-difluorophenyl)-2H-quinolizin-2-one (Example 11, 78 mg, 0.211 mmol) in CH2Cl2 was added a solution of Br2:CH2Cl2 (1:1) at room temperature. The reaction was stirred for a couple hours until complete by LCMS. The reaction mixture was concentrated in vacuo and the crude material was purified via silica gel chromatography (100% EtOAc).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[CH:11]=[C:10]([CH3:12])[O:9][N:8]=1.[Br:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH:18]([CH2:21]Br)[CH2:17][CH2:16]1>O1CCCC1>[Br:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:12][C:10]2[O:9][N:8]=[C:7]([CH3:6])[CH:11]=2)[CH2:17][CH2:16]1
Reactant: Cc1cc(C)on1
Reactant: BrCC1CCC(CBr)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(CCC2CCC(CBr)CC2)on1
Reaction time: 0.5 h
Yield: 58 %

Procedure:
Butyllithium (23.3 ml, 8.0M in tetrahydrofuran) was added dropwise to a solution of 18.3 g of 3,5-dimethylisoxazole in 800 ml of tetrahydrofuran held at -77° C. under nitrogen, and the mixture was stirred for 30 minutes. 1,4-bis(Bromomethyl)cyclohexane (50.4 g) was then added, and the reaction mixture was stirred for 3 hours at -70° C. and at room temperature overnight. The product was isolated and purified by chromatography to give 31 g (58%) of 5-[2-(4-bromomethylcyclohexyl)ethyl]-3-methylisoxazole as a liquid used directly in the next reaction.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:34]=[CH:33][C:20]([C:21]([N:23]([CH3:32])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:30][OH:31])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[C:35](OC(=O)C)(=[O:37])[CH3:36].C(OCC)C>N1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:23]([CH3:32])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:30][O:31][C:35](=[O:37])[CH3:36])=[O:22])=[CH:33][CH:34]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3CO)cc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)OCc1ccccc1N(C)C(=O)c1ccc(NC(=O)c2ccccc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96 %

Procedure:
A mixture of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-hydroxymethylphenyl)benzamide (100 mg) and acetic anhydride (34 mg) in pyridine (5 ml) was stirred at ambient temperature for 3 days and the solvent was evaporated in vacuo. The residue was dissolved in chloroform and the organic solution was washed successively with 1N hydrochloric acid, water and brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo to give an oil and the oil was solidified with diethyl ether to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-acetoxymethylphenyl)benzamide (105 mg) as a white powder.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH2:2]1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[CH2:12]Cl.O>O1CCCC1.CCCCC>[CH3:20][O:19][C:15]1[CH:14]=[C:11]([CH2:12][CH:2]2[S:3][CH2:4][CH2:5][CH2:6][S:1]2)[CH:10]=[C:9]([O:8][CH3:7])[C:16]=1[O:17][CH3:18]
Reactant: COc1cc(CCl)cc(OC)c1OC
Reactant: C1CSCSC1
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1cc(CC2SCCCS2)cc(OC)c1OC
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of 26.7 g of 1,3-dithiane in 222 ml of tetrahydrofuran which has been cooled to -78° C. was added over a period of 15 minutes, 137 ml of 1.7M solution of tetra-butyl lithium in pentane. The resultant mixture was then stirred for 45 minutes, while maintaining the temperature at -78° C., after which time it was warmed to 0° C. The mixture was then added to an ice-cold solution of 48.0 g of 3,4,5-trimethoxybenzyl chloride in 222 ml of tetrahydrofuran over a period of 20 minutes, after which time it was stirred for an additional 90 minutes at 0° C. 50 ml of water was then carefully added and the tetrahydrofuran was removed by evaporation at a temperature below 40° C. The resultant white slurry was then extracted with a mixture of methylene chloride and water. The organic layer was then evaporated and the crude product was washed with petroleum ether to yield a white solid.
Reaction SMILES: [CH3:1]CCP(=O)=O.C[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:20]=[C:19]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:18]=[CH:17][N:16]=2)=[CH:10][C:9]=1[NH2:27].[CH2:28]([N:30]([CH2:44][CH3:45])[C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][C:32]=1[C:40]([F:43])([F:42])[F:41])[CH3:29].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:28]([N:30]([CH2:44][CH3:45])[C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:27][C:9]2[CH:8]=[CH:13][C:12]([CH3:1])=[C:11]([NH:14][C:15]3[N:20]=[C:19]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:18]=[CH:17][N:16]=3)[CH:10]=2)=[O:36])=[CH:33][C:32]=1[C:40]([F:43])([F:42])[F:41])[CH3:29]
Reactant: CCN(CC)c1ccc(C(=O)O)cc1C(F)(F)F
Reactant: Cc1ccc(Nc2nccc(-c3cccnc3)n2)cc1N
Reactant: CCCP(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)c1ccc(C(=O)Nc2ccc(C)c(Nc3nccc(-c4cccnc4)n3)c2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution containing approximately 50% of propylphosphonic anhydride in N,N-dimethylformamide (Fluka, Buchs, Switzerland; 1.14 mL, ˜1.8 mmol) is added to a stirred mixture of 4-methyl-N-[4-(3-pyridinyl)-2-pyrimidinyl]-1,3-benzenediamine (277.3 mg, 1 mmol), 4-diethylamino-3-(trifluoromethyl)-benzoic acid (261.3 mg, 1 mmol) and triethylamine (1.33 mL, 9.6 mmol) in 3 mL N,N-dimethylformamide. After stirring for 24 hours at room temperature, the mixture is treated with a half-saturated aqueous solution of sodium hydrogen carbonate and extracted three times with ethyl acetate. The combined organic extracts are dried (Na2SO4) and the solvent is evaporated off under reduced pressure. The crude product is purified by column chromatography on silica gel, eluent dichloromethane/methanol. The pure fractions are combined, evaporated and the residue is crystallised from acetone to give the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[NH:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19]([O:21][CH3:22])=[O:20].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][N:35]([CH2:38]CO)[CH2:34][CH2:33]2)=[CH:28][CH:27]=1.[H-].[Na+]>C1(C)C=CC=CC=1>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[NH:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19]([O:21][CH2:22][CH2:38][N:35]1[CH2:34][CH2:33][N:32]([C:29]2[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=2)[CH2:37][CH2:36]1)=[O:20]
Reactant: COC(=O)c1sccc1Nc1ccnc2c(C(F)(F)F)cccc12
Reactant: OCCN1CCN(c2ccc(Cl)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(OCCN1CCN(c2ccc(Cl)cc2)CC1)c1sccc1Nc1ccnc2c(C(F)(F)F)cccc12
Temperature: 60 °C
Reaction time: 16 h
Yield: 76.7 %

Procedure:
A mixture of 7.04 g of methyl 3-(8-trifluoromethyl-4-quinolylamino)-2-thiophene-carboxylate, 5.5 g of 4-(4-chlorophenyl)-1-piperazine ethanol and 50 ml of anhydrous toluene was refluxed for an hour while passing condensed toluene through a column filled with siliporite and after cooling the mixture to 60° C, 150 ml of sodium hydride were added. The mixture was refluxed with stirring for 16 hours and the toluene was distilled. The residue was extracted with methylene chloride, was washed and dried. The product was crystallized from 95% ethanol, iced and vacuum filtered. The precipitate was washed with ethanol and dried to obtain 8.6 g of 2-[4-(4-chlorophenyl)-1-piperazinyl]-ethyl 3-(8-trifluoromethyl 4-quinolylamino)-2-thiophene-carboxylate melting at 155° C.