Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:26]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:8]([NH2:28])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:30][CH2:31][CH2:32][CH3:33]>>[NH2:28][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:26])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]1[CH2:21][CH2:22][N:23]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:24][CH2:25]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCC3CCNCC3)c2n1
Reactant: CCCCI
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCCC3CCN(CCCC)CC3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[5-(4-piperidinyl)pentyl]-9H-purin-6-amine and 1-iodobutane.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]2[CH2:13][CH:12]3[N:14]([CH2:15][CH2:16][C:17]4([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH2:22][CH2:21][N:20]([C:23]([C:25]5[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=5[C:27](O)=[O:28])=[O:24])[CH2:19][CH2:18]4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]2[CH:40]=[CH:41][CH:42]=[CH:43][C:4]=2[N:3]=1.N.C([N:47](CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:1][C:2]1[N:6]([CH:7]2[CH2:13][CH:12]3[N:14]([CH2:15][CH2:16][C:17]4([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[CH2:22][CH2:21][N:20]([C:23]([C:25]5[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=5[C:27]([NH2:47])=[O:28])=[O:24])[CH2:19][CH2:18]4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]2[CH:40]=[CH:41][CH:42]=[CH:43][C:4]=2[N:3]=1
Reactant: CCN(CC)CC
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccccc2C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: ClCCl
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccccc2C(N)=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.5 %

Procedure:
To a stirred solution of 2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo-[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzoic acid (69 mg, 0.12 mmol) in methylene chloride (4 mL) was added ammonia (1 mL, 0.5 M in dioxane), triethylamine (18 μL, 0.12 mmol) and HATU (46 mg, 0.12 mmol). The reaction mixture was stirred for 3 hours at ambient temperature before being diluted with methylene chloride and quenched with saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate. After evaporation of the solvent, the crude product was purified by flash chromatography on silical gel, eluting with a gradient of 0-20% methanol in ethyl acetate to afford 2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzamide (57 mg, 83%) 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J=8.6 Hz, 1H), 7.56 (d, J=7.3 Hz, 1H), 7.46-7.42 (m, 2H), 7.38-7.34 (m, 2H), 7.30-7.21 (m, 4H), 7.18-7.08 (m, 3H), 6.91 (br, 1H), 5.74 (br, 1H), 4.63-4.54 (m, 1H), 4.26 (br, 1H), 3.47-3.08 (m, 5H), 2.54 (s, 3H), 2.40-2.30 (m, 3H), 2.11-2.06 (m, 1H), 1.97-1.80 (m, 10H), 1.59 (d, J=7.9 Hz, 2H). HRMS m/z (M+H)+ calcd: 576.3338, obsd: 576.3337.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[N:17][CH:18]=3)[N:11]=[C:10]([C:23]([F:26])([F:25])[F:24])[C:9]=2[CH2:27][CH3:28])=[CH:4][CH:3]=1.BrC1C=CC(C2N([C:41]3C=C[C:44]([S:47](N)(=O)=O)=[N:45][CH:46]=3)N=C(C(F)(F)F)C=2Cl)=CC=1>>[CH2:27]([C:9]1[C:10]([C:23]([F:26])([F:25])[F:24])=[N:11][N:12]([C:13]2[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[N:17][CH:18]=2)[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([C:46]2[N:45]=[CH:44][S:47][CH:41]=2)=[CH:3][CH:4]=1)[CH3:28]
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(Cl)c2-c2ccc(Br)cc2)cn1
Reactant: CCc1c(C(F)(F)F)nn(-c2ccc(S(N)(=O)=O)nc2)c1-c1ccc(Br)cc1
Product: CCc1c(C(F)(F)F)nn(-c2ccc(S(N)(=O)=O)nc2)c1-c1ccc(-c2cscn2)cc1

Procedure:
The title compound was prepared according to the procedure of step 3 in the Example 4 using 5-[5-(4-bromophenyl)-4-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide, instead of 5-[5-(4-bromophenyl)-4-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19]O>S(=O)(=O)(O)O>[CH3:19][O:9][C:8](=[O:10])[CH:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=1)[CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CO
Reactant: CSc1ccc(C(CC2CCCC2)C(=O)O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)C(CC1CCCC1)c1ccc(SC)cc1
Temperature: 25 °C
Yield: 91 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid (500 mg, 1.89 mmol) in methanol (8 mL) was treated slowly with 2 drops of concentrated sulfuric acid. The resulting reaction mixture was heated under reflux for 15 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo. The orange residue was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to provide pure 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid methyl ester (481 mg, 91%) as a yellow-orange oil which was used without further purification: EI-HRMS m/e calcd for C16H22O2S (M+) 278.1341, found 278.1347.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[C:8]([Cl:14])=[CH:7][C:6]=1[CH3:15].[Sn]>Cl.O.[OH-].[Na+]>[ClH:14].[NH2:11][C:9]1[C:8]([Cl:14])=[CH:7][C:6]([CH3:15])=[C:5]([NH:4][CH2:3][CH2:2][OH:1])[CH:10]=1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])cc1NCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(Cl)c(N)cc1NCCO

Procedure:
670 mg (2.9 mmol) of 2-(2'-hydroxyethyl)amino-5-chloro-4-nitrotoluene and 625 g of tin in 10 ml semiconcentrated hydrochloric acid were heated under reflux for one hour. After cooling, this mixture was diluted with 10 ml of water and 40 ml of 10 percent aqueous sodium hydroxide solution were added. The tin salt precipitate was filtered off and the filtrate was extracted 3 times with 30 ml of methylene chloride each time. After washing with water the filtrate was dried over sodium sulfate and the solvent was completely distilled away. The oily residue was received in 20 ml of methanol and reacted with an equimolar amount of hydrochloric acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].[CH3:32][N:33]1[CH:37]=[CH:36][C:35]([C:38](Cl)=[O:39])=[N:34]1>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:38]([C:35]2[CH:36]=[CH:37][N:33]([CH3:32])[N:34]=2)=[O:39])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1
Reactant: COc1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OCCCN1CCOCC1
Reactant: Cn1ccc(C(=O)Cl)n1
Product: COc1cc2c(Oc3ccc(NC(=O)c4ccn(C)n4)cc3F)ccnc2cc1OCCCN1CCOCC1

Procedure:
Q3 was prepared from 3-fluoro-4-[[6-methoxy-7-(3-morpholinopropoxy)-4-quinolyl]oxy]aniline and 1-methyl-1H-pyrazole-3-carbonyl chloride following the general procedure reported in Preparative Example 1 Step 3. 1H NMR (400 MHz, d4-MeOD, 300K) δ 2.10 (m, 2H), 2.52 (m, 4H), 2.62 (t, J=7.5 Hz, 2H), 3.70 (t, J=4.7 Hz, 4H), 3.99 (s, 3H), 4.00 (s, 3H), 4.22 (t, J=6.2 Hz, 2H), 6.49 (d, J=5.4 Hz, 1H), 6.83 (d, J=2.3 Hz, 1H), 7.33 (m, 2H), 7.58 (d, J=8.8 Hz, 1H), 7.62 (s, 1H), 7.67 (d, J=2.4 Hz, 1H), 7.94 (dd, J=12.7 Hz, J=2.4 Hz, 1H), 8.40 (d, J=5.4 Hz, 1H). MS (ES) C28H30FN5O5 requires: 535. Found: 536 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([NH:17][C:18]2[CH:23]=[C:22]([C:24]3[CH:28]=[CH:27][N:26](COCC[Si](C)(C)C)[N:25]=3)[CH:21]=[C:20]([NH:37][C:38]3[CH:43]=[N:42][CH:41]=[CH:40][N:39]=3)[N:19]=2)[CH3:16])=[CH:11][CH:10]=1>O>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([NH:17][C:18]2[CH:23]=[C:22]([C:24]3[CH:28]=[CH:27][NH:26][N:25]=3)[CH:21]=[C:20]([NH:37][C:38]3[CH:43]=[N:42][CH:41]=[CH:40][N:39]=3)[N:19]=2)[CH3:16])=[CH:11][CH:10]=1
Reactant: C[C@H](Nc1cc(-c2ccn(COCC[Si](C)(C)C)n2)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: C[C@H](Nc1cc(-c2cc[nH]n2)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 28.4 %

Procedure:
A mixed solvent of 3 ml of trifluoroacetic acid and 0.3 ml of water was added to 95 mg of (S)—N2-[1-(4-fluorophenyl)ethyl]-N6-(pyrazin-2-yl)-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl)pyridine-2,6-diamine obtained by Step 6, and the mixture was stirred at 60° C. for 1 hour. The solvent was distilled off under reduced pressure, and then the obtained residue was diluted with water and alkalified with a saturated aqueous solution of sodium bicarbonate. The reaction solution was subjected to extraction with ethyl acetate, and the organic layer was washed with water and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 20 mg of the objective compound as pale yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC1C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:9][C:4]=2[CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc(Br)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1ccc2nc(-c3ccccc3)[nH]c2c1
Temperature: 100 °C
Yield: 65.8 %

Procedure:
4-Bromobenzene-1,2-diamine (0.5 g, 2.67 mmol), benzaldehyde (0.284 g, 2.67 mmol), and 4-methylbenzenesulfonic acid (0.046 g, 0.267 mmol) in DMF (8 mL) were combined and heated at 100° C. for 1 hour in a microwave reactor. The reaction mixture was subsequently diluted with EtOAc, washed with brine (4×100 mL), concentrated, and purified by CombiFlash® chromatography, eluting with a gradient of MeOH (0-30%) in DCM over 120 minutes. The product-containing fractions were combined and concentrated to give the title compound as light yellow liquid (0.48 g, 66%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][CH:8]2[NH2:13].[C:14]1([C:20]2[N:21]=[C:22]([CH2:31]Br)[O:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:14]1([C:20]2[N:21]=[C:22]([CH2:31][NH:13][CH:8]3[C:9]4[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=4)[CH2:5][CH2:6][CH2:7]3)[O:23][C:24]=2[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc2c1CCCC2N
Reactant: BrCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc2c1CCCC2NCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Yield: 76.5 %

Procedure:
A solution of 1,2,3,4-tetrahydro-5-methoxy-1-naphthalenamine (0.34 g), (4,5-diphenyloxazol-2-yl)methyl bromide (0.50 g) and potassium carbonate (0.60 g) in DMF (7 ml) was stirred for 5 hours at room temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 1-[(4,5-diphenyloxazol-2-yl)methylamino]-1,2,3,4-tetrahydro-5-methoxynaphthalene (0.50 g) MS (m/z): 411 (M+ +1) NMR (CDCl3, δ): 1.64-2.12 (4H, m), 2.38-2.92 (2H, m), 3.81 (3H, s), 3.94 (1H, m), 4.07 (2H, s), 6.73 (1H, d, J=7.9 Hz), 7.04 (1H, d, J=7.9 Hz), 7.15 (1H, dd, J=7.9, 7.9 Hz), 7.32-7.42 (6H, m), 7.58-7.69 (4H, m)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[S:13][C:14]([CH3:18])=[C:15]([CH3:17])[CH:16]=2)=[N:4][N:3]=1.[CH3:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([O:31][C:32]3[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=3)=[CH:26][CH:27]=[N:28]2)=[N:23][CH:22]=1>C(O)(C)(C)C>[CH3:17][C:15]1[CH:16]=[C:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([NH:38][C:35]3[CH:34]=[CH:33][C:32]([O:31][C:25]4[C:24]5[C:29](=[CH:30][C:21]([O:20][CH3:19])=[CH:22][N:23]=5)[N:28]=[CH:27][CH:26]=4)=[CH:37][CH:36]=3)=[N:3][N:4]=2)[S:13][C:14]=1[CH3:18]
Reactant: COc1cnc2c(Oc3ccc(N)cc3)ccnc2c1
Reactant: Cc1cc(-c2nnc(Cl)c3ccccc23)sc1C
Solvent: CC(C)(C)O
Product: COc1cnc2c(Oc3ccc(Nc4nnc(-c5cc(C)c(C)s5)c5ccccc45)cc3)ccnc2c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
In a nitrogen purged sealed tube, 1-chloro-4-(4,5-dimethylthiophen-2-yl)phthalazine (0.040 g, 0.146 mmol) was dissolved in tert-butanol (1.00 mL). 4-(7-Methoxy-1,5-naphthyridin-4-yloxy)benzenamine (0.039 g, 0.146 mmol) was added, and the reaction mixture in the tube was stirred at 100° C. for 3 h. The mixture was concentrated in vacuo, and the crude material was purified by silica gel chromatography using 0-100% CH2Cl2:MeOH(90:10)/CH2Cl2. Product-containing fractions were concentrated to yield 4-(4,5-dimethylthiophen-2-yl)-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amine as light yellow solid. MS [N+H]=506.0; Calc'd 505.6 for C29H23N5O2S.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[CH2:12]([C:14]1[CH:28]=[C:17]2[C:18]([C:23](=[O:27])[CH:24](Br)[CH3:25])=[CH:19][C:20]([F:22])=[CH:21][N:16]2[N:15]=1)[CH3:13]>CN(C=O)C>[CH2:12]([C:14]1[CH:28]=[C:17]2[C:18]([C:23](=[O:27])[CH:24]([CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])[CH3:25])=[CH:19][C:20]([F:22])=[CH:21][N:16]2[N:15]=1)[CH3:13]
Reactant: CCc1cc2c(C(=O)C(C)Br)cc(F)cn2n1
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc2c(C(=O)C(C)C(C(=O)OC)C(=O)OC)cc(F)cn2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Dimethyl malonate (327 μL) was added to DMF (4.6 mL) in an argon atmosphere. While the solution was kept at 0° C., 60% sodium hydride (105 mg) was added and the mixture was stirred at room temperature for 30 min. Subsequently, the compound of Example 188 (655 mg) in DMF (10 mL) was added at 0° C. and the mixture was stirred at room temperature for 4 hours. The reaction was terminated by adding a saturated aqueous solution of ammonium chloride and the mixture was extracted three times with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. Evaporation of the solvent under reduced pressure and purification by silica gel column chromatography (hexane:ethyl acetate=6:1) afforded the title compound as a yellow oil (680 mg).
Reaction SMILES: F[C:2]1[C:3]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([F:21])[CH:14]=3)[O:10][N:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:22][N:23]([CH3:40])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30]CCCCCCN(C)C.[K].O1CCOCCOCCOCCOCCOCC1>CN(C)C=O>[CH3:22][N:23]([CH3:40])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:2]1[C:3]([C:8]2[N:12]=[C:11]([C:13]3[CH:14]=[C:15]([F:21])[CH:16]=[C:17]([C:19]#[N:20])[CH:18]=3)[O:10][N:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CCCCCCOCCCCCCN(C)C
Reactant: N#Cc1cc(F)cc(-c2nc(-c3ncccc3F)no2)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K]
Solvent: CN(C)C=O
Product: CN(C)CCCCCCOc1cccnc1-c1noc(-c2cc(F)cc(C#N)c2)n1

Procedure:
Alternatively, treatment of 3-(3-fluoropyrid-2-yl)-5-(3-fluoro-5-cyanophenyl)-1,2,4-oxadiazole with potassium 6-dimethylaminohexyloxide in N.N-dimethylformamide with a catalytic amount of 1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown-6) and heating at 110° C. affords crude product. Standard work up and purification by one or more methods, including silica gel chromatography, recystallization, trituration, and reversed-phase high-performance liquid chromatography (RP-HPLC) affords purified 3-(3-(6-dimethylaminohexyloxy)-pyrid-2-yl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole.
Reaction SMILES: C1(C[O:8][CH2:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([N:21]4[CH2:25][C@H:24]([C:26]([O:28][CH3:29])=[O:27])[O:23][C:22]4=[O:30])=[CH:18][CH:19]=3)[CH2:14][C@H:13]2[CH3:31])=[O:11])C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].CO>[OH:8][CH2:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([N:21]3[CH2:25][C@H:24]([C:26]([O:28][CH3:29])=[O:27])[O:23][C:22]3=[O:30])=[CH:18][CH:19]=2)[CH2:14][C@H:13]1[CH3:31])=[O:11]
Reactant: COC(=O)[C@H]1CN(c2ccc3c(c2)C[C@@H](C)N3C(=O)COCc2ccccc2)C(=O)O1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)[C@H]1CN(c2ccc3c(c2)C[C@@H](C)N3C(=O)CO)C(=O)O1

Procedure:
A mixture of methyl(5R)-3-[(2R)-2,3-dihydro-1-[(phenylmethoxy)acetyl]-2-methyl-1H-indol-5-yl]-2-oxo-5-oxazolidinecarboxylate (Step 1, 0.301 g, 0.71 mmol) and Pearlman's catalyst (0.032 g) in methanol (30 mL) is shaken on a Parr apparatus under a 36 psi hydrogen atmosphere for approximately 24 h, during which additional Pearlman's catalyst (0.044 g) is added. The catalyst is removed by filtration through a pad of Celite, and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on a Biotage Flash 40S silica gel cartridge (2% MeOH(CH2Cl2 eluent) to give the title compound, MS (ESI+) for C16H18N2O6 M/Z 335 (M+H)+.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[CH:11]=[C:12]([NH:21][C:22]2[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=2)[CH:13]=[C:14]([C:16]2[S:20][CH:19]=[N:18][CH:17]=2)[CH:15]=1.[Br:32][C:33]1[N:38]=[CH:37][C:36]([C:39](=[O:41])[CH3:40])=[CH:35][CH:34]=1>C1COCC1>[Br:32][C:33]1[N:38]=[CH:37][C:36]([C:39]([C:19]2[S:20][C:16]([C:14]3[CH:13]=[C:12]([NH:21][C:22]4[N:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][N:23]=4)[CH:11]=[C:10]([CH3:9])[CH:15]=3)=[CH:17][N:18]=2)([OH:41])[CH3:40])=[CH:35][CH:34]=1
Reactant: CC(=O)c1ccc(Br)nc1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncs2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(C)(O)c3ccc(Br)nc3)s2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 21.9 %

Procedure:
THF (10 ml) was cooled to −78° C., and lithium diisopropylamide (4.13 ml, 7.43 mmol) was added. N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (INTERMEDIATE 4, 1.00 g, 2.97 mmol) in THF (10 ml) was added dropwise, and the reaction was stirred at −78° C. for 30 min. 1-(6-Bromopyridin-3-yl)ethanone (0.595 g, 2.97 mmol) in THF (5 ml) was subsequently added in one portion. The reaction was stirred for 10 min at −78° C. The dry ice bath was removed, and the reaction was allowed to warm to room temperature. The dark brown reaction mixture was quenched with aqueous saturated NH4Cl and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated. Chromatography on silica gel (Biotage 100 g SNAP, 0-30% EtOAc/toluene) afforded 1-(6-bromopyridin-3-yl)-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]ethanol (348 mg, 0.649 mmol, 21.8% yield) as a yellow solid. MS ESI: [M+H]+ m/z 538.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:11][C:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][N:23]=[C:22](F)[CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[NH2:27][C@@H:28]([CH3:31])[CH2:29][OH:30]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:11][C:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:27][CH:28]([CH3:31])[CH2:29][OH:30])[CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC(CO)c1cccc(Cl)c1)C1CCN(c2ccnc(F)c2)CC1
Reactant: C[C@H](N)CO
Solvent: CS(C)=O
Product: CC(CO)Nc1cc(N2CCC(C(=O)NC(CO)c3cccc(Cl)c3)CC2)ccn1
Temperature: 160 °C

Procedure:
The 2′-fluoro-3,4,5, 6-tetrahydro-2H-[1,4′]bipyridinyl-4-carboxylic acid [1 -(3-chloro-phenyl)-2-hydroxy-ethyl]-amide compound (10 mg, 0.026 mmol) was combined with (S)-2-amino-propanol (0.2 mL) in DMSO and heated in an oil bath to 160° C. for 18 hours. The crude mixture was pipetted onto a preparative TLC plate (1 mm silica) and the compound eluted with ethyl acetate. Isolation of the most UV active band afforded 2.6 mg of the title product as a colorless oil. Rt=4.40 minutes, LCMS 447.3 (M=1), 1H NMR δ 7.66 (s, 1H) 7.32–7.20 (m, 4H) 6.34 (NH) 5.94 (s, 1H) 5.07–5.06 (m, 1H) 4.17 (m, 1H) 3.90 (m, 1H) 3.62 (m, 2H) 3.36 (m, 2H) 2.85 (m, 1H) 2.63 (m, 2H) 2.33 (m, 1H) 2.08 (s, 3H) 1.94 (m, 4H) 1.19 (d, 3H).
Reaction SMILES: [H-].[Na+].[CH:3]1[N:7]2[C:8]3[CH2:19][C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[C:9]=3[NH:10][C:11](=[O:12])[C:6]2=[N:5][CH:4]=1.[N:20](OCCC(C)C)=[O:21].C>CS(C)=O.CN(C)C=O.C(O)(=O)C.O>[OH:21]/[N:20]=[C:19]1\[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:9]2[NH:10][C:11](=[O:12])[C:6]3[N:7]([CH:3]=[CH:4][N:5]=3)[C:8]\1=2
Reactant: O=c1[nH]c2c(n3ccnc13)Cc1ccccc1-2
Reactant: CC(C)CCON=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=c1[nH]c2c(n3ccnc13)/C(=N/O)c1ccccc1-2
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 50.7 %

Procedure:
0.4 g of 80% sodium hydride is added to a suspension of 1.1 g of 5H,10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-4-one in 10 ml of anhydrous dimethyl sulphoxide. After stirring for 10 minutes at a temperature in the region of 20° C., a solution of 0.7 g of isoamyl nitrite in 2 ml of anhydrous dimethyl sulphoxide is added dropwise over 5 minutes and the mixture is then stirred for 1 hour at the same temperature. 10 ml of distilled water are added slowly and the mixture is subsequently poured into 120 g of water and ice, acidified with 1 ml of acetic acid and then centrifuged. After removal of the supernatant solution, the solid is suspended in 25 ml of distilled water, filtered, washed with 10 ml of acetone and dried under reduced pressure (15 mmHg; 2 kPa) at 20° C. The product obtained (1.5 g) is dissolved in 100 ml of boiling dimethylformamide and, after 0.1 g of decolorizing charcoal has been added, the solution is filtered while hot, cooled, poured into 800 ml of distilled water and centrifuged. The solid is suspended in 20 ml of distilled water, filtered, washed with 20 ml of acetone and dried under reduced pressure (15 mmHg; 2 kPa) at 20° C. The product obtained (0.9 g) is dissolved in 75 ml of dimethyl sulphoxide at 20° C. and, after 0.1 g of decolorizing charcoal has been added, the solution is filtered. The filter is washed twice with 20 ml in total of dimethyl sulphoxide and the filtrate and the washings are then combined, 75 ml of distilled water are added and they are centrifuged. The solid is suspended in 25 ml of distilled water, filtered, washed twice with 50 ml in total of acetone and then dried under reduced pressure (1 mmHg; 0.13 kPa) at 60° C. 0.63 g of 10-(E-hydroxyimino)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one is thus obtained, decomposing without melting above 300° C. [N.M.R. spectrum: (200 MHz; DMSO d6 ; δ in ppm): 7.40 and 7.48 (2t, J=7 Hz, 2H: --H7 and --H8); 7.60 and 8.00 (2s broad, 1H each: --H of the imidazole); 7.82 and 8.20 (2d, J=7 Hz, 1H each: --H6 and --H9); 12.70 and 13.00 (2 cplx, 1H each: --NH-- and --OH)].
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1.[Br:14]Br>C(Cl)Cl>[Br:14][C:8]1[C:7]([O:12][CH3:13])=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([Cl:1])=[N:3]2
Reactant: BrBr
Reactant: COc1ccc2nc(Cl)ccc2c1
Solvent: ClCCl
Product: COc1ccc2nc(Cl)ccc2c1Br
Reaction time: 14 h
Yield: 101.7 %

Procedure:
A solution of 2-chloro-6-methoxyquinoline (4.4 g, 22 mmol) in CH2Cl2 (60 mL) was treated by slow addition of Br2 (3.5 mL, 11 g, 68 mmol). After 14 hours, the mixture was partitioned between NaCl and CH2Cl2. The aqueous layer was extracted with CH2Cl2. The organic layer was worked-up. HPLC (1:10 EtOAc/hexane) gave 6.1 g (99%) of 5-bromo-2-chloro-6-methoxyquinoline as a light yellow solid, (M+) 273(100).
Reaction SMILES: [Cl:1][CH:2]1[CH:12]=[CH:11][CH:5]2[C:6]([O:8][C:9](=[O:10])[CH:4]2[CH2:3]1)=[O:7].BrBr>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1
Reactant: O=C1OC(=O)C2CC(Cl)C=CC12
Agent: BrBr
Product: O=C1OC(=O)c2cc(Cl)ccc21

Procedure:
A co-pending application, Ser. No. 07/405,606, discloses that 4-chlorotetrahydrophthalic anhydride reacts with elemental bromine to form 4-chlorophthalic anhydride. 4-Bromophthalic anhydride is sometimes found as a side product in low percentage, but is not economically recoverable.