Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH3:11].[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(Cl)Cl.C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:12](=[O:14])[CH3:13])[N:6]=[C:5]2[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1n[nH]c2ccc(Br)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)n1nc(C)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Bromo-3-methyl-1H-indazole (838 mg, 3.97 mmol) was dissolved in methylene chloride (15 mL) and diisopropylethylamine (0.7 mL). Acetic anhydride (500 μL, 5.29 mmol) was added and the mixture was stirred at ambient temperature overnight. The mixture was diluted with ethyl acetate, washed with 1 N sodium hydroxide followed by 1 N hydrochloric acid and then brine. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure to afford the title compound. MS (ESI+) m/z 252.7 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([CH:13]2[C:18](=[O:19])[NH:17][C:16](=[O:20])[NH:15][C:14]2=[O:21])=O)=[CH:5][CH:4]=1.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH:13]2[C:14](=[O:21])[NH:15][C:16](=[O:20])[NH:17][C:18]2=[O:19])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCC(=O)C2C(=O)NC(=O)NC2=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(CCCC2C(=O)NC(=O)NC2=O)cc1
Temperature: 60 °C
Yield: 91.8 %

Procedure:
To a suspension of 10 g of 5-[3-(4-Methoxyphenyl)propionyl]barbituric Acid in 100 ml of acetic acid are added portionwise 4.5 g of sodium cyanoborohydride, then the mixture is heated to 60° C. After 1 hour the reaction mixture is cooled to room temperature and poured into ice. After 30 minutes a solid is recovered by filtration, which is dried under vacuum at 50° C. to give 8.74 g of the product, m.p. 195-197° C.
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28]([C:39]#[C:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH:48]([F:50])[F:49])=[CH:43][CH:42]=2)=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>CO>[F:50][CH:48]([F:49])[O:47][C:44]1[CH:43]=[CH:42][C:41]([CH2:40][CH2:39][C:28]2[CH:29]=[C:30]([OH:31])[C:25](=[O:24])[NH:26][N:27]=2)=[CH:46][CH:45]=1
Reactant: FC(F)Oc1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: C1CCOC1
Solvent: CO
Product: O=c1[nH]nc(CCc2ccc(OC(F)F)cc2)cc1O

Procedure:
Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-((4-(difluoromethoxy)phenyl)ethynyl)pyridazine (Intermediate 36) except that the solvent mixture used for the hydrogenation was made up of tetrahydrofuran and methanol and the final material was recrystallised from 2-propanol and heptanes.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]#[CH:22])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>C(#N)C.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.[Cu]I>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]#[C:22][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: Ic1ccccc1
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.9 %

Procedure:
Iodobenzene (135 μl, 1.2 mmols), 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (209 mg, 1 mmols) and triethylamine (167 μl, 1.2 mmols) were dissolved in acetonitrile (6 ml). Dichlorobis(triphenylphosphine)palladium(II) (35 mg, 0.05 mmols) and CuI (10 mg, 0.05 mmols) were added, and reaction mixture was stirred at room temperature overnight and continued to stir at 50 C for two more hours before partitioning between ethyl acetate and water. Organic layer was isolated, washed with 1 N HCl, brine and dried (MgSO4). Solvents were removed and residue was purified by column chromatography on silica gel using solutions of ethyl acetate in hexanes (1:4; 1:2) to yield the title compound (74 mg). LCMS m/e (230, M-t-Bu+2H)
Reaction SMILES: Br.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:5][CH:4]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].C([O-])(=O)C.[Na+]>O>[C:16]([NH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:7][CH:8]=1)(=[O:18])[CH3:17]
Reactant: Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Reactant: CC(=O)OC(C)=O
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.3 %

Procedure:
5-(4-Aminophenyl)-2(1H)-pyrazinone hydrobromide (2.5 g) in water (20 ml) was treated with acetic anhydride (1.2 g) and anhydrous sodium acetate (1.4 g). The mixture was stirred at room temperature for 1 hour, and the crude product (1.58 g; m.p. 268°-275° C.) was filtered off. This material was thoroughly washed with water and recrystallised from glacial acetic acid to give 5-(4-acetamidophenyl)-2(1H)-pyrazinone (0.84 g; m.p. 287°-8° C.).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:45]=[CH:44][CH:43]=[CH:42][N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:55])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:45]=[CH:44][CH:43]=[CH:42][N:41]=5)=[O:55])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4ncccn4)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4ncccn4)cc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 61.4 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(2-pyrimidinylmethyl)sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.77 g) was dissolved in methylene chloride (23.1 ml), and a solution of m-chloroperbenzoic acid (0.31 g) in methylene chloride (15.4 ml) was added to the mixture at −78° C., and the mixture was stirred for 15 minutes. The reaction mixture was added to an aqueous solution of saturated sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(2-pyrimidinylmethyl)sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 261) (485 mg).
Reaction SMILES: [OH:1][CH:2]([CH2:21][N:22]1[C:26](=[O:27])[C:25]2([CH2:32][C:31]([CH3:34])([CH3:33])[N:30]([CH3:35])[C:29]([CH3:37])([CH3:36])[CH2:28]2)[NH:24][C:23]1=[O:38])[CH2:3][N:4]1[C:8](=[O:9])[C:7]2([CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([CH3:17])[C:11]([CH3:19])([CH3:18])[CH2:10]2)[NH:6][C:5]1=[O:20]>C(OC(=O)C)(=O)C>[C:2]([O:1][CH:2]([CH2:21][N:22]1[C:26](=[O:27])[C:25]2([CH2:28][C:29]([CH3:37])([CH3:36])[N:30]([CH3:35])[C:31]([CH3:34])([CH3:33])[CH2:32]2)[N:24]([C:26](=[O:27])[CH3:25])[C:23]1=[O:38])[CH2:3][N:4]1[C:8](=[O:9])[C:7]2([CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([CH3:17])[C:11]([CH3:18])([CH3:19])[CH2:10]2)[N:6]([C:8](=[O:9])[CH3:7])[C:5]1=[O:20])(=[O:1])[CH3:3]
Reactant: CN1C(C)(C)CC2(CC1(C)C)NC(=O)N(CC(O)CN1C(=O)NC3(CC(C)(C)N(C)C(C)(C)C3)C1=O)C2=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC(CN1C(=O)N(C(C)=O)C2(CC(C)(C)N(C)C(C)(C)C2)C1=O)CN1C(=O)N(C(C)=O)C2(CC(C)(C)N(C)C(C)(C)C2)C1=O
Reaction time: 8 h

Procedure:
A solution of 5.3 g of 2-hydroxy-1,3-bis(7,7,8,9,9-pentamethyl2,4-dioxo-1,3,8-triazaspiro[4.5]dec-3-yl)propane (prepared as described in Example 22) in 70 ml of acetic anhydride was heated, with stirring, at 120°-130° C. for 8 hours. The reaction mixture was then condensed by evaporation under reduced pressure and the residue was dissolved in 200 ml of benzene. The benzene solution was washed successively with a 3% w/w aqueous solution of sodium carbonate and water and then dried over anhydrous potassium carbonate. The solvent was removed from the solution to give crystals, which were recrystallised from benzene. The desired Compound No. 194 was obtained in the form of white crystals, melting at 105°-108° C.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[C:14]([F:17])([F:16])[F:15])[CH3:3].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.O[NH:33][C:34](=[NH:51])[C:35]1[CH:43]=[CH:42][CH:41]=[C:40]2[C:36]=1[CH:37]=[CH:38][N:39]2[CH2:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47]>CN(C)C=O>[CH3:3][CH:2]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]2[O:11][N:51]=[C:34]([C:35]3[CH:43]=[CH:42][CH:41]=[C:40]4[C:36]=3[CH:37]=[CH:38][N:39]4[CH2:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[N:33]=2)=[CH:7][C:6]=1[C:14]([F:17])([F:16])[F:15])[CH3:1]
Reactant: CCOC(=O)CCn1ccc2c(C(=N)NO)cccc21
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1ccc2c(-c3noc(-c4ccc(OC(C)C)c(C(F)(F)F)c4)n3)cccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.7 %

Procedure:
4-[(1-Methylethyl)oxy]-3-(trifluoromethyl)benzoic acid (D71) (136 mg, 0.55 mmol), EDC (116 mg, 0.61 mmol) and HOBt (82 mg, 0.61 mmol) were stirred in N,N-dimethylformamide (5 mL) for 20 min. Ethyl 3-{-4-[(hydroxyamino)(imino)methyl]-1H-indol-1-yl}propanoate (D57) (150 mg, 0.55 mmol) was added and the reaction stirred at room temperature for 3 h and then 80° C. for 18 h. The reaction mixture was partitioned between ethyl acetate (25 mL) and water (25 mL). The organic layer was washed with aqueous sodium bicarbonate (25 mL) and water (25 mL) before it was dried (phase separator), filtered and concentrated in vacuo. The residue was triturated with ethanol to give the title compound (85 mg). δH (d6-DMSO, 400 MHz): 8.44 (1H, dd), 8.35 (1H, d), 7.95 (1H, d), 7.81 (1H, d), 7.62-7.58 (2H, m), 7.36 (1H,app. t), 7.07 (1H, d), 4.99 (1H, septet), 4.54 (2H, t), 4.02 (2H, q), 2.89 (2H, t), 1.36 (6H, d), 1.11 (3H, t). MS (ES+): C26H24F3N3O4 requires 487; found 488 (MH+).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[CH2:10][CH2:9]1)=[O:7]>C(O)C.[Pd]>[F:25][C:2]([F:1])([F:24])[CH2:3][CH2:4][O:5][C:6]([N:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)=[O:7]
Reactant: O=C(OCCC(F)(F)F)N1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: O=C(OCCC(F)(F)F)N1CCNCC1
Reaction time: 12 h

Procedure:
To a solution of 3.2 g Piperazine-1,4-dicarboxylic acid benzyl ester 3,3,3-trifluoro-propyl ester in 60 ml ethanol were added 200 mg Pd/C (10%) and the suspension stirred under an atmosphere of hydrogen (3 bar) for 12 h. The reaction mixture was filtrated over a plug of Celite®, washed with ethanol and concentrated. Yield: 2.0 g colorless oil.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2I.[H-].[Na+].C([Mg]Cl)(C)C.[CH2:22]([Sn:26]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:28][CH2:29][CH2:30][CH3:31])Cl)[CH2:23][CH2:24][CH3:25]>C1COCC1>[F:1][CH:2]([F:14])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[Sn:26]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: FC(F)Oc1ccc2[nH]nc(I)c2c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2ccc(OC(F)F)cc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In a round-bottomed flask, 5-difluoromethoxy-3-iodo-1H-indazole (200 mg, 0.6 mmol) was dissolved in THF (3.6 ml) and sodium hydride (60% in mineral oil, 64 mg, 1.6 mmol) was added. The reaction mixture was stirred at room temperature for 10 min then cooled to −16° C. (NaCl/ice bath) and isopropylmagnesium chloride (2.0 M in THF, 0.46 ml, 0.920 mmol) was added dropwise. The reaction mixture was stirred at −16° C. for 30 min then tributylchlorostannane (0.22 ml, 0.81 mmol) was slowly added. The reaction mixture was allowed to warm to room temperature and stirred for 1 h then quenched with saturated NH4Cl— solution and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated to give 5-difluoromethoxy-3-tributylstannanyl-1H-indazole as a yellow oil which was used without further purification.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([CH3:17])=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)=[O:4].[C:18]1([SH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]2[O:8][N:7]=[C:6]([CH3:17])[C:5]=2[C:3](=[O:4])[CH2:2][S:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][CH:12]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CBr
Reactant: Sc1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CSc1ccccc1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 2-bromo-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-ethanone and benzenthiol.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:17])=[C:7]([C:12]([O:14]CC)=[O:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[O:18][CH3:19].[OH-].[Na+].Cl>O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:17])=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[O:18][CH3:19]
Reactant: CCOC(=O)c1cnc2cc(F)c(OC)cc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc2c(O)c(C(=O)O)cnc2cc1F
Temperature: 25 °C

Procedure:
A stirred solution of 23.57 g of ethyl 7-fluoro-4-hydroxy-6-methoxyquinoline-3-carboxylate in 71 cm3 of an aqueous 5N sodium hydroxide solution is brought to 100° C. for 3 hours. After cooling to ambient temperature, the reaction medium is acidified by adding 32.5 cm3 of an aqueous 37% hydrochloric acid solution. After addition of 150 cm3 of water, the precipitate obtained is filtered off and the solid is washed with water. After drying in the open air, 22 g of 7-fluoro-4-hydroxy-6-methoxyquinoline-3-carboxylic acid are obtained, in the form of a cream solid which melts at 275° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH2:24][CH3:25])[CH:17]=O.Cl>CO>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCOc1ccc(C=O)cc1OC
Reactant: O=C1COc2cc(O)ccc21
Agent: Cl
Solvent: CO
Product: CCCOc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1OC
Temperature: 25 °C
Yield: 34 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3-methoxy-4-propyloxybenzaldehyde 1.55 g were dissolved in methanol 70 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for two hours. After the solution was cooled to room temperature, the precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 0.74 g.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([CH3:23])[CH:3]=1.[Br-].[CH2:25]([Zn+])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1COCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:25]([C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([CH3:23])[CH:3]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: [Zn+]Cc1ccccc1
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(Cc4ccccc4)cc3C)c(C)nc12
Yield: 20 %

Procedure:
Using a procedure similar to Example 32, 3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.30 g, 0.765 mmol) and PdCl2(dppf) (0.028 g, 0.038 mmol) and 0.5 M solution of benzylzinc bromide in THF (4.6 mL, 2.29 mmol) are reacted. The residue is purified by ISCO column chromatography (15%-20% EtOAc/hexane gradient) and is chromatographed (50×250 C18 Symmetry column, 40-65% water: 0.1% TFA/ACN: 0.1% TFA gradient) furnish the title compound (0.062 g, 0.15 mmol, 20%). 1H NMR (CDCl3), δ 0.88 (t, J=7.5 Hz, 6H), 1.73-1.92 (m, 4H), 2.06 (s, 3H), 2.45 (s, 3H), 2.51 (s, 3H), 3.29-3.39 (m, 1H), 4.16 (s, 2H), 6.65 (s, 1H), 6.68 (s, 1H), 7.22-7.29 (m, 1H), 7.31-7.36 (m, 4H). LC/MS (m/z): calcd. for C25H29N3S (M+H)+: 404.3; found: 404.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[S:20]([O:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:22])(=[O:21])[CH3:19]
Reactant: Cc1ccc(CCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(CCCOS(C)(=O)=O)cc1

Procedure:
Following the procedure described in example 1§B, but starting from 3-(4-methylphenyl)propan-1-ol (6.02 g), triethylamine (2.9 mL), methanesulfonyl chloride (3.67 mL) and dichloromethane (39 mL), affords 3-(4-methylphenyl)propan-1-ol mesylate (3.4 g) used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH:8]1[N:14]([CH3:17])[CH2:15][CH2:16][C:7]21[CH3:18])([O-])=O.[C:19]([O:22][CH2:23]C)(=[O:21])C>O=[Pt]=O>[CH3:23][O:22][C:19]([NH:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH:8]1[N:14]([CH3:17])[CH2:15][CH2:16][C:7]21[CH3:18])=[O:21]
Reactant: CCOC(C)=O
Reactant: CN1CCC2(C)c3cc([N+](=O)[O-])ccc3N(C)C12
Agent: O=[Pt]=O
Product: COC(=O)Nc1ccc2c(c1)C1(C)CCN(C)C1N2C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1,2,3,3a,8,8a-Hexahydro-5-nitro-1,3a,8-trimethylpyrrolo[2,3-b]indole (1.0 g) was dissolved in ethyl acetate (100 ml) and hydrogenated in a Parr apparatus at 45 psi using PtO2 (100 mg) as a catalyst. The reduction was complete within 2 hours. The reduction mixture was filtered directly into a nitrogen flushed flask. 4-Dimethylaminopyridine (50 mg) was added, the mixture was cooled to 0° C. and a solution of dimethylpyrocarbonate (0.54 g) in ethyl acetate (50 ml) was added over a period of 1 hour. The mixture was concentrated and purified by flash chromatography on silica gel (eluting with 15% MeOH/EtOAc). The pure fractions were concentrated to give 1,2,3,3a,8,8a-hexahydro-5-(methyloxycarbonylamino)-1,3a,8-trimethylpyrrolo[2,3-b]indole (0.4 g) and the oxalate salt was prepared by dissolving the free base in ether and a minimal amount of methanol and adding a solution of oxalic acid in ether.
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2.C([Li])(CC)C.CN([CH:21]=[O:22])C.Cl.C(=O)(O)[O-].[Na+]>C1COCC1>[NH:9]1[C:10]2[C:6](=[CH:5][C:4]([CH:21]=[O:22])=[CH:12][CH:11]=2)[CH:7]=[N:8]1
Reactant: CN(C)C=O
Reactant: Brc1ccc2[nH]ncc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: C1CCOC1
Product: O=Cc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2.60 g (65.00 mmol) sodium hydride (60% in mineral oil) was added batchwise to a solution of 11.64 g (59.08 mmol) 5-bromo-1H-indazole in 150 mL THF under argon within 10 minutes and the mixture was stirred for 15 minutes at RT. The reaction mixture was cooled to −70° C. and within 30 minutes 100.00 mL (130.00 mmol) sec-butyllithium (1.3 M in cyclohexane) were added dropwise, while the temperature was kept below −60° C. The mixture was stirred for a further 2 h at −70° C. and then a solution of 20.00 mL (0.260 mol) DMF in 20 mL THF was added dropwise, while the temperature was kept below −50° C. The reaction mixture was slowly heated to RT and stirred for 16 h. Then the mixture was slowly cooled to 0° C. and slowly 180 mL of 2N aqueous HCl was added dropwise, the mixture was stirred for a further 15 minutes and the pH was adjusted to 9–10 with sat. aqueous sodium bicarbonate solution. The aqueous phase was exhaustively extracted with EtOAc, the combined org. phases were dried over magnesium sulphate and evaporated down i. vac. Column chromatography (silica gel, petroleum ether/EtOAc 1:1 v/v), trituration with hexane and drying i. vac. at 50° C. yielded the product.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH3:25])=[O:23].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]1[CH2:32][OH:33]>>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[C:4]([C:22]([O:24][CH3:25])=[O:23])=[C:3]([CH2:2][N:26]2[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]2[CH2:32][OH:33])[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6]1
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Reactant: OC[C@H]1COCCN1
Product: COC(=O)C1=C(CN2CCOC[C@@H]2CO)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Yield: 39.5 %

Procedure:
Methyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.89 g, 2 mmol) was reacted with (S)-morpholin-3-ylmethanol (0.24 g, 2 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a pale yellow solid (0.38 g, 39%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([OH:24])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(=O)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.9 %

Procedure:
To a cooled (-65° C.) solution of DMSO (1.42 ml; 20 mmol) in CH2Cl2 (30 ml) was added oxalyl chloride (0.87 ml; 10 mmol). The resulting suspension was stirred for an additional 15 minutes at -65° C., whereupon the product of Step A (2.17 g; 10 mmol) dissolved in 5 ml of CH2Cl2 was added portionwise and the reaction was stirred for an additional 15 minutes at that temperature. Triethylamine (5.56 ml; 40 mmol) was then added dropwise, and the solution was allowed to warm to room temperature, whereupon the reaction was stirred for an additional 1.5 hours. The reaction was quenched with H2O and extracted several times with EtOAc. The combined organic phase was washed with 10% aqueous citric acid, H2O, saturated aqueous NaCl, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 25% EtOAc-hexanes. The fractions containing pure material were combined and concentrated in vacuo to afford 1.87 g of the title compound as a yellow oil.