Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][C:14]([N+:16]([O-])=O)=[CH:15][C:8]=3[C:7](=[O:19])[C:6]=2[CH:20]=1>C(O)(=O)C>[NH2:16][C:14]1[CH:13]=[CH:12][C:9]2[CH:10]=[CH:11][C:5]3[CH:4]=[CH:3][C:2]([I:1])=[CH:20][C:6]=3[C:7](=[O:19])[C:8]=2[CH:15]=1
Reactant: O=c1c2cc(I)ccc2ccc2ccc([N+](=O)[O-])cc12
Solvent: CC(=O)O
Product: Nc1ccc2ccc3ccc(I)cc3c(=O)c2c1
Temperature: 0 °C

Procedure:
3-Iodo-7-nitro-5H-dibenzo[a,d]cyclohepten-5-one (23.4 g., 0.062 mole) in 140 ml. of glacial acetic acid is heated to 90° and treated with stannous chloride dihydrate (52 g., 0.23 mole), added in portions as the solid. The temperature of the mixture is maintained between 95° and 100° throughout the addition and for 10-15 minutes thereafter. The mixture is then cooled to ca 50° and poured into 1 liter of ice water.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[SH:5][CH2:6][CH2:7][C:8]([N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12]([OH:14])=[O:13])=[O:9]>N1C=CC=CC=1.[OH-].[Na+]>[CH3:1][NH:2][C:3]([S:5][CH2:6][CH2:7][C:8]([N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12]([OH:14])=[O:13])=[O:9])=[S:4]
Reactant: CN=C=S
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CCS
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CNC(=S)SCCC(=O)N1CCC[C@H]1C(=O)O
Reaction time: 2 h

Procedure:
Methylisothiocyanate (4 g) is added to a solution of 3-mercaptopropanoyl-L-proline (10.1 g) in a mixture of pyridine (250 ml) and 0.5 N sodium hydroxide (100 ml). The solution is kept at 40° for two hours and concentrated to dryness in vacuo. The residue is dissolved in water (100 ml), acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic phase is concentrated to dryness to yield 1-[3-[[(methylamino)thiocarbonyl]thio]propanoyl]-L-proline.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[F:9][C:10]([F:28])([F:27])[C:11]1[CH:12]=[C:13]([CH:24]=[CH:25][CH:26]=1)[CH2:14][N:15]1[CH2:19][CH:18]2[C:20](=O)[CH2:21][CH2:22][CH:17]2[CH2:16]1>O.C(O)C>[F:9][C:10]([F:28])([F:27])[C:11]1[CH:12]=[C:13]([CH:24]=[CH:25][CH:26]=1)[CH2:14][N:15]1[CH2:19][CH:18]2/[C:20](=[N:2]/[OH:3])/[CH2:21][CH2:22][CH:17]2[CH2:16]1
Reactant: O=C1CCC2CN(Cc3cccc(C(F)(F)F)c3)CC12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O/N=C1\CCC2CN(Cc3cccc(C(F)(F)F)c3)CC12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Hydroxylamine hydrochloride (3.47 g, 50.0 mmol) and sodium acetate (4.27 g, 52.0 mmol) were dissolved in 15 mL of water and added to a solution of 2-(3-(trifluoromethyl)benzyl)hexahydrocyclopenta[c]pyrrol-4(5H)-one (11.33 g, 40 mmol) from Step C in ethanol (80 mL). The reaction was brought to reflux for 5 minutes and allowed to cool to 70° C. After 1 hour, the reaction mixture was cooled, and the solvent was removed in vacuo to give (E)-2-(3-(trifluoromethyl)benzyl)hexahydrocyclopenta[c]pyrrol-4(5H)-one oxime which was used without additional purification in the next step.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>CN1C(=O)CCC1.CCOC(C)=O>[F:24][C:14]1[C:13]([CH:11]([C:8]2[N:6]3[N:7]=[C:2]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Reactant: C1CNCCN1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCNCC3)nn12
Temperature: 170 °C
Reaction time: 1 h

Procedure:
(rac)-6-[1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (Intermediate C, 200 mg, 0.569 mmol), KF (371 mg, 6.26 mmol) and piperazine (490 mg, 5.69 mmol) were suspended in NMP (2.85 mL). The RM was stirred at 170° C. for 1 h. The mixture was diluted with EtOAc and washed with 1M Na2CO3 (1×) and water (2×). The aqueous was further extracted with EtOAc (2×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography and afford the title compound as a yellow foam (tR 2.78 min (conditions 1), MH+=395).
Reaction SMILES: C([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH2:17][CH3:18])(=O)C.[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1CBr>>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:16][O:15][C:13]([C:9]1[CH:8]=[C:7]2[C:12]([CH:4]=[C:5]([CH2:17][CH3:18])[NH:6]2)=[CH:11][CH:10]=1)=[O:14]
Reactant: Clc1ccccc1CBr
Reactant: CCc1[nH]c2cc(C(=O)OC)ccc2c1C(C)=O
Product: CCc1cc2ccc(C(=O)OCc3ccccc3Cl)cc2[nH]1

Procedure:
Methyl 3-acetyl-1-((2-chlorobenzyl)-2-ethylindole-6-carboxylate (170 mg) was prepared from methyl 3-acetyl-2-ethylindole-6-carboxylate (100 mg) and 2-chlorobenzyl bromide (0.06 ml) in a similar manner to that of Example 1.
Reaction SMILES: [F:1]N(C(C)(C)C)S(C1C=CC(C)=CC=1)(=O)=O.[C:17]1([O-:27])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.[K+]>O1CCCC1.CCOCC>[F:1][C:18]1[CH:19]=[CH:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]=1[OH:27]
Reactant: Cc1ccc(S(=O)(=O)N(F)C(C)(C)C)cc1
Reactant: [O-]c1cccc2ccccc12
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Oc1c(F)ccc2ccccc12
Yield: 60 %

Procedure:
Potassium hydride (93.6 mg as a 35% oil dispersion, 0.82 mmol) was suspended in anhydrous tetrahydrofuran (2.5 mL) under nitrogen. 1-Naphthol (72 mg, 0.5 mmole) was added and the mixture was stirred until hydrogen evolution ceased (about 5 minutes) to produce potassium naphtholate. N-Fluoro-N-t-butyl-p-toluenesulfonamide (122 mg, 0.5 mmole) was dissolved in anhydrous tetrahydrofuran (2.5 mL) and the solution was added dropwise to the potassium naphtholate. After 20 minutes the reaction mixture was diluted with ether (100 mL), washed with aqueous 1N oxalic acid solution (30 mL), water (30 mL), and saturated aqueous sodium chloride solution (30 mL), and then dried over anhydrous magnesium sulfate. Filtration, removal of solvent under reduced pressure, and purification by flash column chromatography (silica, 25% methylene chloride in hexane) yielded 2-fluoro-1-naphthol (49 mg, 60% yield) as a white crystalline solid. This material, and an additional sample prepared by this procedure, were analyzed and provided the following results: 1H NMR (90 MHz, CDCl3) δ5.58 (b, 1H, OH), 7.00-8.30 (m, 6H, aromatic); 19F NMR (94.1 MHz, CDCl3) -146.78(m); HRMS calcd. for C10H7OF: 162.0480; found: 162.0439.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:6][CH2:5][CH:4]([CH3:7])[CH:3]1[O:8][C:9](=[O:25])[C@@H:10]([CH2:22][O:23][CH3:24])[NH:11]C(OCC1C=CC=CC=1)=O>CO.[Pd]>[CH3:26][C:2]1([CH3:1])[CH2:6][CH2:5][CH:4]([CH3:7])[CH:3]1[O:8][C:9](=[O:25])[C@@H:10]([CH2:22][O:23][CH3:24])[NH2:11]
Reactant: COC[C@@H](NC(=O)OCc1ccccc1)C(=O)OC1C(C)CCC1(C)C
Agent: [Pd]
Solvent: CO
Product: COC[C@@H](N)C(=O)OC1C(C)CCC1(C)C

Procedure:
To a solution of 5 g N-Cbz-D-serine 2,2,5-trimethylcyclopentyl ester in 50 ml dry CH2Cl2 is added 2 equivalents of Ag2O and 2 equivalents of methyl iodide. After stirring for 2 hours, the mixture is filtered and concentrated to yield the methyl ether of N-Cbz-D-serine 2,2 5-trimethylcyclopentyl ester. 3 g of N-Cbz-D-serine methyl ether 2,2,5-trimethylcyclopentyl ester is hydrogenated over 0.5 g 10% Pd/C in 100 ml CH3OH. Upon completion, the mixture is filtered and concentrated to yield 3-methoxy-D-alanine 2,2,5-trimethylcyclopentyl ester. To a magnetically stirred solution of 2 g of 3-methoxy-D-alanine 2,2,5-trimethylcyclopentyl ester in 100 ml DMF at 0° C. is added 1 equivalent of N-Cbz-L-aspartic acid-β-benzyl ester followed by addition of 1 equivalent each of Cu(II) chloride and dicyclohexylcarbodiimide. After 18 hours the mixture is poured into 200 ml 0.1N HCl and extracted with 300 ml ethyl actetate. The organic phase is washed with saturated NaHCO3, and H2O, dried over MgSO4, filtered and concentrated to an oil that is reconstituted in 50 ml CH3OH and hydrogenated over 0.5 g 5% Pd/C. Filtration followed by concentration yields L-aspartyl-D-serine 2,2,5-trimethylcyclopentyl ester methyl ether.
Reaction SMILES: [C:1]([OH:18])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(Cl)(=O)C([Cl:22])=O>ClCCl>[C:1]([Cl:22])(=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCC/C=C\CCCCCCCC(=O)O
Solvent: ClCCl
Product: CCCCCC/C=C\CCCCCCCC(=O)Cl
Reaction time: 16 h

Procedure:
Synthesis of MC810 (FIG. 7). To a solution of palmitoleic acid (cis-9-hexadecanoic acid, 2.00 g, 7.87 mmol, Aldrich Chemical Company) in dichloromethane (75 mL), was added oxalyl chloride (1.72 mL, 19.7 mmol, Aldrich Chemical Company) dropwise under nitrogen. After 16 hrs, the solution was concentrated under reduced pressure (aspirator) and then placed under high vacuum to afford palmitoleoyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH:7]([CH2:11][CH2:12][CH2:13][CH3:14])[C:8]([OH:10])=O)=[CH:4][C:3]=1[CH3:17].[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:24][NH2:25].C1C=CC2N(O)N=NC=2C=1.C[N+]1(C)[C@H]2CC3C=CC(O)=C4O[C@H]5[C@@H](O)C=C[C@@H]2[C@]5(C=34)CC1.CCN=C=NCCCN(C)C>ClCCl.O>[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:24][NH:25][C:8](=[O:10])[CH:7]([CH2:6][C:5]1[CH:15]=[CH:16][C:2]([F:1])=[C:3]([CH3:17])[CH:4]=1)[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: NOC1CCCCO1
Reactant: CCCCC(Cc1ccc(F)c(C)c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: C[N+]1(C)CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@@H]1C5
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCCCC(Cc1ccc(F)c(C)c1)C(=O)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 64 h
Yield: 60 %

Procedure:
To a solution of 2-(4-Fluoro-3-methyl-benzyl)-hexanoic acid (0.498 g, 2.091 mmol), O-(tetrahydro-pyran-2-yl)-hydroxylamine (0.735 g, 6.274 mmol), HOBT (0.282 g, 2.091 mmol), and N-methyl morphine (1.058 g, 10.455 mmol) in 20 mL of dichloromethane, was added EDCI (0.601 g, 3.137 mmol). After stirring at room temperature under N2 for 64 h, the reaction mixture was diluted with 60 mL of water and extracted with dichloromethane (60 mL×3). The organic extracts were combined and dried over anhydrous Na2SO4. After removing the solvents under reduced pressure, the product was isolated by Flash chromatography (silica gel) eluting with 0-40% ethyl acetate/hexanes to give the title compound as a pale yellow solid (0.423 g, 60% yield). LC-MS: tR=9.1 min; m/z 338 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:14]([N:17]([CH2:33][C:34]([O:36]C(C)(C)C)=[O:35])[C:18]2[CH:19]=[CH:20][C:21]3[N:22]([CH2:31][CH3:32])[C:23]4[C:28]([C:29]=3[CH:30]=2)=[CH:27][CH:26]=[CH:25][CH:24]=4)(=[O:16])=[O:15])[CH:5]=[C:6]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:14]([N:17]([CH2:33][C:34]([OH:36])=[O:35])[C:18]2[CH:19]=[CH:20][C:21]3[N:22]([CH2:31][CH3:32])[C:23]4[C:28]([C:29]=3[CH:30]=2)=[CH:27][CH:26]=[CH:25][CH:24]=4)(=[O:15])=[O:16])[CH:5]=[C:6]([C:8]#[C:9][Si:10]([CH3:13])([CH3:11])[CH3:12])[CH:7]=1
Reactant: CCn1c2ccccc2c2cc(N(CC(=O)OC(C)(C)C)S(=O)(=O)c3cc(Cl)cc(C#C[Si](C)(C)C)c3)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1c2ccccc2c2cc(N(CC(=O)O)S(=O)(=O)c3cc(Cl)cc(C#C[Si](C)(C)C)c3)ccc21

Procedure:
180 mg tert-butyl [(3-chloro-5-trimethylsilylethynyl-phenylsulphonyl)-(9-ethyl-9H-carbazol-3-yl)-amino]-acetate are dissolved in 5 ml dichloromethane. 1 ml of trifluoroacetic acid is added with stirring. The mixture is stirred overnight at ambient temperature and then the solvents are eliminated in vacuo. The residue is chromatographed on silica gel (dichloromethane/methanol 100:0 to 95:5).
Reaction SMILES: FC(F)(F)[C:3]([N:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][N:14]=2)[S:9][C:8]=1[C:16]([O-:18])=[O:17])C)=O.[OH-].[K+]>C1COCC1.C(O)C.O>[CH3:3][NH:5][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][N:14]=2)[S:9][C:8]=1[C:16]([OH:18])=[O:17]
Reactant: CN(C(=O)C(F)(F)F)c1c(C(=O)[O-])sc2nccnc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CNc1c(C(=O)O)sc2nccnc12
Reaction time: 0.17 h
Yield: 98 %

Procedure:
A solution of 7-(2,2,2-trifluoro-N-methylacetamido)thieno[2,3-b]pyrazine-6-carboxylate 11 (9.1 g, 27.3 mmol) and KOH (3 eq) in THF (40 mL), ethanol (40 mL) and water (20 mL) was stirred overnight at 60° C. Concentrated by evaporation (±10 mL), ice cold citric acid solution was added (200 mL) and stirred for 10 min. The resulting precipitate was collected, washed with water and dried to give compound 7-(methylamino)thieno[2,3-b]pyrazine-6-carboxylic acid 12 (5.6 g, 98%). 1H-NMR (400 MHz, DMSO-d6) 3.49 (s, 3H), 7.59 (br s, 2H) 8.72 (d, J=2.3 Hz, 1H), 8.74 (d, J=2.3 Hz, 1H) 12.95 (br s, 1H). (m/z)=210 (M+H)+.
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[C:13]1([N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([C:28]([OH:30])=O)=[N:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N>C1COCC1>[C:13]1([N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([C:28]([NH2:3])=[O:30])=[N:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1nn(-c2ccccc2)c2ccccc12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: C1CCOC1
Product: NC(=O)c1nn(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
To a solution of 1,1′-carbonyldiimidazole (3.4 g, 21 mmol) in 60 mL of dry THF was added dropwise a solution of 1-phenyl-1H-indazole-3-carboxylic acid (5.0 g, 21 mmol) in 60 mL dry THF under nitrogen atmosphere. The resulting reaction mixture was stirred at ambient temperature for 30 minutes and refluxed for 30 minutes; then cooled to ambient temperature under nitrogen atmosphere. Ammonia, generated by warming concentrated aqueous ammonia solution, was bubbled through, and the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was concentrated in vacuo to dryness, the solid was dissolved in 200 mL of ethyl acetate, the solution was successively washed with 1N aqueous HCl solution (2×50 mL), 1N aqueous NaOH solution (5×20 mL) and was dried over Na2SO4. Concentration and drying under vacuum gave 4.65 g (93%) of desired product as a white solid: mp 149° C.
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12](O)[CH2:13][NH:14][CH3:15])=[CH:8][CH:7]=1.O>ClC1C=CC=CC=1>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:6]2[CH:11]=[CH:10][C:9]([Cl:1])=[CH:8][CH:7]=2)[CH2:13][NH:14][CH3:15])=[CH:8][CH:7]=1
Reactant: CNCC(O)c1ccc(Br)cc1
Reactant: [Cl-]
Agent: [Al+3]
Solvent: Clc1ccccc1
Solvent: O
Product: CNCC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Aluminium chloride (278 mg, 2.087 mmol) was added portionwise to a stirred solution of 1-(4-Bromo-phenyl)-2-methylamino-ethanol (160 mg, 0.696 mmol) in chlorobenzene (3 ml) and the reaction mixture stirred at room temperature for 17 hours. Water (2 ml) was added dropwise and the reaction mixture was then partitioned between dichloromethane (100 ml) and saturated NaHCO3 (30 ml). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The crude product was then purified by Phenomenex_Strata_SCX column chromatography eluting with methanol followed by 2N ammonia in methanol to afford the desired product. LC/MS: (PS-B3) Rt 3.58 [M+H]+ 324.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[NH2:15][C@@H:16]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:17][OH:18].C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:15][C@@H:16]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:17][OH:18])=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: CC(C)C[C@H](N)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)C[C@@H](CO)Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 125 °C
Yield: 82.9 %

Procedure:
A mixture of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (0.85 g, 3.10 mmol), (S)-2-amino-4-methylpentan-1-ol (0.544 g, 4.64 mmol) and diisopropylethylamine (1.082 mL, 6.19 mmol) in DMA (Volume: 10 mL) was heated to 125° C. for 1.25 hr. After cooling to rt, ice cold water (˜60 ml) was added to the rapidly stirring reaction mixture. The reaction mixture was stirred for 15 minutes, was sonicated for 15 minutes and was stirred and additional 15 minutes. The resulting suspension was filtered and the filter cake was washed with water. Drying afforded (S)-6-bromo-4-(1-hydroxy-4-methylpentan-2-ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide (0.94 g, 2.57 mmol, 83% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.80 (d, J=6.4 Hz, 3H) 0.91 (d, J=6.4 Hz, 3 H) 1.40 (m, 1 H) 1.56-1.60 (m, 1 H) 1.61-1.70 (m, 1 H) 3.39-3.48 (m, 1 H) 3.58 (m, 1 H) 4.08-4.17 (m, 1 H) 4.98 (dd, J=6.2, 4.8 Hz, 1 H) 7.04 (d, J=1.5 Hz, 1 H) 7.84 (d, J=1.8 Hz, 1 H) 8.21 (s, 1 H) 10.59 (d, J=8.6 Hz, 1 H). MS (ES+) m/z: 354.9, 356.9 (M+H); LC retention time: 2.517 min (analytical HPLC Method B).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[CH3:18])=[CH:4][N:3]=1>[Pd].C(OCC)(=O)C.C(O)C>[CH3:18][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][C:9]=1[O:8][C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][CH:6]=1)[NH2:15]
Reactant: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2C)cn1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(Oc2ccc(N)cc2C)cn1
Reaction time: 5 h
Yield: 97 %

Procedure:
A mixture of 2-methyl-5-(2-methyl-4-nitrophenoxy)pyridine (141 g, 0.58 mol) and 10% palladium on charcoal (13 g) in ethyl acetate (200 ml) and ethanol (700 ml) was stirred under an atmosphere of hydrogen (1.2 bar) for 5 hours. After reaction completion, the mixture was purged with nitrogen and the catalyst was filtered off. The filtrate was evaporated to dryness to give 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (120.6 g, 98%) as a white solid; Mass spectrum MH+ 215.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1Br.B(O)O.[C:15]([O-:18])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:3]1[CH:8]=[CH:7][C:6]([CH:15]=[O:18])=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccccc1Br
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OBO
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1ccc(-c2ccccc2C(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 177.3 %

Procedure:
To a stirred solution of 2-trifluoromethyl-bromobenzene (0.7 g, 2.75 mmol) and 4-carbaldehyde boronic acid (0.5 g, 3.3 mmol) in dioxane (20 mL) under nitrogen at 80° C. was added Pd(PPh3)4 (0.05 g) followed by the addition of a solution of Na2CO3 (0.7 g) in H2O (5 m). The mixture was stirred at 100° C. for 6 h. The solvent was evaporated and the residue was diluted to 50 ml with EtOAc and washed with H2O. The solvent was evaporated to dryness and the residue was purified by FCC (SiO2) to give the title compound (0.61 g; 88%), as creamy solid. 1H-NMR (CDCl3) 7.49 (d, 1H, J=7.41 Hz); 7.48 (d, 2H, J=8.13 Hz); 7.61-7.53 (m, 2H); 7.76 (d, 1H, J=7.8 Hz); 7.91 (d, 2H, J=8.34 Hz); 10.07 (s, 1H).
Reaction SMILES: [S:1]([C:4]1[NH:5][CH:6]=[CH:7][CH:8]=1)[C:2]#N.[CH:9]1(CBr)[CH2:11][CH2:10]1.[OH-].[K+]>CO>[CH:9]1([CH2:2][S:1][C:4]2[NH:5][CH:6]=[CH:7][CH:8]=2)[CH2:11][CH2:10]1
Reactant: BrCC1CC1
Reactant: N#CSc1ccc[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: c1c[nH]c(SCC2CC2)c1
Reaction time: 1.5 h

Procedure:
A solution of 2-thiocyanopyrrole (12.4 g., 0.1 mole) and cyclopropylmethyl bromide (14.85 g., 0.11 mole) in methanol (500 ml.) was cooled below 0° (ice-salt bath), and stirred vigorously under nitrogen while a solution of potassium hydroxide (12.3 g., 0.22 mole) in 1:1 (by volume) aqueous methanol (400 ml.) was added dropwise during 0.75 hours. The cooling bath was removed and stirring continued for 1.5 hours before neutralization of the excess alkali with solid carbon dioxide. The reaction mixture was poured into 20% brine (500 ml.) and extracted with methylene chloride (3×100 ml.). The combined organic extracts were dried (Na2SO4 +K2CO3), then evaporated in vacuo to provide a red oil (12.1 g.). Distillation of this crude oil afforded 2-cyclopropylmethylthio-pyrrole as a colorless oil (5.8 g. 38%), B.P. 138°-141° at 11 mm. (B) The product from Part A was reacted with ethyl oxalyl chloride as described in Example 39, Part B. Chromatography on silica followed by recrystallization from petroleum ether (B.P. 40°-60°) and hexane gave 5-cyclopropylmethylthio-2-pyrrolylglyoxylic acid ethyl ester as a yellow solid, M.P. 46°. Found: C, 56.81; H, 6.23; N, 5.38. C12H15NO3S requires: C, 56.89; H, 5.97; N, 5.53%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH:14]3[CH2:17][N:16]([C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][C:3]=1[O:28]C.B(Br)(Br)Br>ClCCCl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH:14]3[CH2:17][N:16]([C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][C:3]=1[OH:28]
Reactant: COc1cc(-c2nccnc2C2CN(c3ccc4ccccc4n3)C2)ccc1F
Agent: BrB(Br)Br
Solvent: ClCCCl
Solvent: O
Product: Oc1cc(-c2nccnc2C2CN(c3ccc4ccccc4n3)C2)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a solution of 2-{3-[3-(4-fluoro-3-methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-quinoline (193 mg, 0.5 mmol) in 1,2-dichloro-ethane (5 mL) was added BBr3 (250 mg, 1.0 mmol). The reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with water, extracted with DCM (2×30 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel to give 2-fluoro-5-[3-(1-quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-phenol (111 mg, 0.31 mmol yield 62%).
Reaction SMILES: C(OC[C:6]1[CH:11]=[C:10]([C:12]2[CH2:16][C:15]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)([C:17]([F:20])([F:19])[F:18])[O:14][N:13]=2)[CH:9]=[CH:8][C:7]=1[B:29]1[O:33]C(C)(C)[C:31](C)(C)[O:30]1)(=O)C.O[Li].O.Cl>C1COCC1.O.CC(=O)OCC.Cl.CCO.O>[Cl:27][C:25]1[CH:26]=[C:21]([C:15]2([C:17]([F:19])([F:20])[F:18])[O:14][N:13]=[C:12]([C:10]3[CH:9]=[CH:8][C:7]4[B:29]([OH:33])[O:30][CH2:31][C:6]=4[CH:11]=3)[CH2:16]2)[CH:22]=[C:23]([Cl:28])[CH:24]=1
Reactant: CC(=O)OCc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl
Agent: [Li]O
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OB1OCc2cc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.7 %

Procedure:
A mixture of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (50 mg, 0.09 mmol) and LiOH H2O (15 mg, 0.36 mmol) in THF—H2O (1 mL/0.2 mL) was stirred at rt for 1 h and diluted with EA (2 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to give a residue that was dissolved in HCl-EtOH (4 N, 5 mL) and H2O (0.3 mL). The mixture was stirred at 35° C. for 20 h. To it was added conc HCl (1.7 mL) and the reaction mixture was stirred at 60° C. for 20 h. The mixture was cooled to rt, concentrated under reduced pressure. The residue was purified by preparative TLC to give the desired title compound (10 mg; yield 27%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.81 (d, J=6.8 Hz, 1 H), 7.68 (s, 1 H), 7.63 (d, J=8.0 Hz, 1 H), 7.51 (s, 2 H), 7.43 (d, J=1.2 Hz, 1 H), 5.13 (s, 2 H), 4.12 (m, 1 H), 3.74 (m, 1 H) ppm; MS: m/z=416 (M+1, ESI+).