Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([CH:7]1[CH2:13][C:12]2[S:14][CH:15]=[CH:16][C:11]=2[C:10](=O)[CH2:9][N:8]1[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:6].[Br:23]NC(=O)CCC(N)=O>C(Cl)Cl>[Br:23][C:15]1[S:14][C:12]2[CH2:13][CH:7]([CH2:5][CH3:6])[N:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:9][CH2:10][C:11]=2[CH:16]=1
Reactant: CCOC(=O)N1CC(=O)c2ccsc2CC1CC
Reactant: NC(=O)CCC(=O)NBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)N1CCc2cc(Br)sc2CC1CC
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.1 %

Procedure:
Aluminum chloride (972.2 mg, 7.291 mmol) was added to DCM (60 mL) at 0° C., followed by addition of borane-tert-butylamine complex (1.268 g, 14.58 mmol). To the mixture was added a solution of Compound 1037 (650 mg, 2.431 mmol) in DCM (5 mL). The reaction was allowed to warm up to RT and stirred for 18 hours, followed by quenching the reaction with 2N HCl solution until gas evolution ceased. The mixture was extracted with DCM, dried over Na2SO4, and the volatiles removed under reduced pressure. The resulting residue (Compound 1038) was dissolved in acetonitrile and N-Bromosuccinamide (432.7 mg, 2.431 mmol) was added dropwise. The reaction mixture was stirred at RT for 1 hour, then concentrated under vacuum. The residue was purified by silica gel chromatography, using a 0-20% EtOAC/hexanes gradient as eluant, to give ethyl 2-bromo-7-ethyl-7,8-dihydro-4H-thieno[2,3-d]azepine-6(5H)-carboxylate (Compound 1039, 300 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[N:3]=1.[Br:18]N1C(=O)CCC1=O.ClCCl>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:15])[F:16])[N:3]=1
Reactant: Cc1ccnc(-c2ccccc2C(F)(F)F)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1ccccc1-c1nccc(CBr)n1
Temperature: 25 °C

Procedure:
247 mg (1.04 mmol) of the compound from Example 67A together with 185 mg (1.04 mmol) of N-bromosuccinimide and 17 mg (0.10 mmol) of 2,2′-azobis-2-methylpropanenitrile in 3 ml of carbon tetrachloride were heated under reflux for 18 h. For work-up, the reaction mixture was cooled to RT, and 10 ml of dichloromethane were added. The mixture was washed with 5 ml of water, and the aqueous phase was re-extracted twice with in each case 5 ml of dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was briefly dried under high vacuum and reacted further without further purification. This gave 303 mg of product which contained the target compound in a purity of 20% (corresponds to 20% of theory). The main component of the crude product was unreacted starting material (Example 67A).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=2[NH:11][C:10]1=[O:19])(=O)=O.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[O:28])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)CC(=O)C>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]2[N:9]([CH2:8][CH2:7][CH2:6][N:32]3[CH2:33][CH2:34][CH:29]([C:27](=[O:28])[C:24]4[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=4)[CH2:30][CH2:31]3)[C:10](=[O:19])[NH:11][C:12]=2[CH:17]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: CS(=O)(=O)OCCCn1c(=O)[nH]c2cc(Cl)ccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=C(c1ccc(F)cc1)C1CCN(CCCn2c(=O)[nH]c3cc(Cl)ccc32)CC1
Yield: 10 %

Procedure:
A mixture of 5.5 parts of 3-(5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl methanesulfonate, 3.6 parts of (4-fluorophenyl) (4-piperidinyl) methanone, 6 parts of sodium carbonate and 80 parts of 4-methyl-2-pentanone is stirred and refluxed overnight. After cooling, the reaction mixtue is filtered and the filtrate is evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and recrystallized from 4-methyl-2-pentanone, yielding 0.6 parts (10%) of 5-chloro-1-{3-[4-(4-fluorobenzoyl)-1-piperidinyl] propyl} -1,3-dihydro-2H-benzimidazol-2-one; mp. 163.7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(C1NC=CN=1)(C1NC=CN=1)=O.Cl.[N+:26]([C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][NH2:37])=[CH:31][CH:30]=1)([O-:28])=[O:27].Cl>C1COCC1.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH:37][CH2:36][CH2:35][C:32]1[CH:31]=[CH:30][C:29]([N+:26]([O-:28])=[O:27])=[CH:34][CH:33]=1)=[O:9]
Reactant: COc1ccc(Cl)cc1C(=O)O
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
A solution of 8.8 g (47.2 mmol) of 5-chloro-2-methoxybenzoic acid and 8.5 g (51.9 mmol) of carbonylbisimidazole in 180 ml of absolute THF was stirred at room temperature for 2 h. 10 g (49.7 mmol) of 2-(4-nitrophenyl)ethylamine hydrochloride and 9.4 ml of triethylamine were added and the resulting solution was then stirred overnight at room temperature. The reaction solution was then slowly poured onto 1.2 l of 1N hydrochloric acid, and the deposited precipitate was filtered off and washed with water. Drying of the precipitate in a high vacuum yielded 13.8 g of the title compound as a white solid. M.p.: 159-160° C. Rf (silica gel, EA/heptane 4:1)=0.46. MS (ESI): m/z=334 (M+H)+.
Reaction SMILES: B(Br)(Br)Br.ClCCl.[F:8][C:9]([F:38])([F:37])[C:10]1[CH:11]=[C:12]([NH:20][C:21](=[O:36])[C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:24][C:23]=2[O:34]C)[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1>ClCCl.C(OCC)(=O)C>[F:8][C:9]([F:37])([F:38])[C:10]1[CH:11]=[C:12]([NH:20][C:21](=[O:36])[C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:24][C:23]=2[OH:34])[CH:13]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=1
Reactant: COc1cc(-c2ccccc2)ccc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(-c2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
1M Boron tribromide-dichloromethane solution (0.71 mL, 0.71 mmol) was added to a solution of N-[3,5-bis(trifluoromethyl)phenyl]-2-methoxy-4-phenylbenzamide (100 mg, 0.24 mmol) in dichloromethane (5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water and brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=5:1) to give the title compound (69.3 mg, 71.6%) as a white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([F:27])=[C:12]([CH2:17][NH:18][C:19]([C:21]3[NH:25][CH:24]=[N:23][C:22]=3[Cl:26])=[O:20])[CH:13]=[CH:14][C:15]=2[Cl:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:28]1([C:31]#[CH:32])[CH2:30][CH2:29]1>C1COCC1.[Cu]I>[Cl:26][C:22]1[N:23]=[CH:24][NH:25][C:21]=1[C:19]([NH:18][CH2:17][C:12]1[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([O:9][C:4]2[CH:3]=[C:2]([C:32]#[C:31][CH:28]3[CH2:30][CH2:29]3)[CH:7]=[C:6]([Cl:8])[CH:5]=2)[C:11]=1[F:27])=[O:20]
Reactant: C#CC1CC1
Reactant: O=C(NCc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F)c1[nH]cnc1Cl
Agent: [Cu]I
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)c(Oc2cc(Cl)cc(C#CC3CC3)c2)c1F)c1[nH]cnc1Cl
Temperature: 60 °C
Reaction time: 5 h
Yield: 78.3 %

Procedure:
To a solution of N-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1H-imidazole-5-carboxamide (125 mg, 0.253 mmol), tetrakistriphenylphosphine palladium(0) (35.6 mg, 0.051 mmol), copper(I) iodide (4.82 mg, 0.025 mmol) and TEA (0.177 ml, 1.266 mmol) in THF (5 ml) was added cyclopropylacetylene (0.043 ml, 0.507 mmol) and the reaction mixture was stirred for 5 hours at 60° C. The reaction mixture was adsorbed onto silica gel and the crude material was purified via silica gel chromatography to give 4-chloro-N-[(4-chloro-3-{[3-chloro-5-(cyclopropylethynyl)phenyl]oxy}-2-fluorophenyl)methyl]-1H-imidazole-5-carboxamide (95 mg, 0.198 mmol, 78% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.70 (s, 1H), 7.21-7.39 (m, 2H), 7.02 (s, 1H), 6.81 (s, 1H), 6.64 (s, 1H), 4.62 (br. s., 2H), 1.35-1.50 (m, 1H), 0.78-0.90 (m, 2H), 0.57-0.77 (m, 2H). LC-MS (ES+) m/z 477.87, [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:10](OC)[CH2:9]2)=[CH:4][C:3]=1[CH3:22].[BH4-].[Na+].C([O-])(O)=O.[Na+]>C(O)(=O)C>[C:16]([O:15][C:13]([N:11]1[CH2:10][CH2:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:22])[CH:4]=2)[CH2:12]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: COC1CC(c2ccc(Cl)c(C)c2)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(C2CCN(C(=O)OC(C)(C)C)C2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
Synthesized according to General Procedure 3. To a stirred solution of crude tert-butyl 4-(4-chloro-3-methylphenyl)-2-methoxypyrrolidine-1-carboxylate (4.25 g, 13.0 mmol) in acetic acid (50 mL) under N2 at 0° C. was added sodium borohydride (2.2 g, 58.7 mmol) in portions over 20 minutes. The resulting solution was allowed to warm to RT and then stirred at RT for 2 hours. The reaction mixture was slowly poured into saturated aqueous NaHCO3 (250 mL) and extracted with ethyl acetate (3×200 mL). The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure to afford tert-butyl-3-(4-chloro-3-methylphenyl)pyrrolidine-1-carboxylate (3.75 g, 12.67 mmol, 97% yield) as a brown oil. 1H-NMR (400 MHz, DMSO-d6) δ 7.33 (d, J=8.2 Hz, 1H), 7.28 (s, 1H), 7.14-7.03 (m, 1H), 3.68 (t, J=8.8 Hz, 1H), 3.48-3.42 (m, 1H), 3.32-3.10 (m, 3H), 2.30 (s, 3H), 2.17-2.15 (m, 1H), 1.78-1.73 (m, 1H) and 1.42 (s, 9H) ppm.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12]>CO>[CH3:1][N:2]([CH2:12][CH2:11][C:10]([O:14][CH3:15])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=CC(=O)OC
Reactant: CNCc1ccccc1
Solvent: CO
Product: COC(=O)CCN(C)Cc1ccccc1
Yield: 100 %

Procedure:
A! Using N-methylbenzylamine (53 ml, 0.41 mole) and methyl acrilate (184 ml, 2.05 mole) in 430 ml of methanol, according to the procedure of Example 15,A!, there were obtained 85 g (quantitative yield) of methyl 3-(N-methyl-N-benzylamino)propanoate which was used as such in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([S:15][C:16](=O)C)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].CI>CO.C(OCC)(=O)C.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([S:15][CH3:16])[CH2:13][CH2:14]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)S[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CO
Product: CS[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred solution of trans thioacetic acid S-(4-tert-butoxycarbonylamino-cyclohexyl) ester (1.31 g, 4.80 mmol) in methanol (31 mL) was treated with sodium methoxide (1.04 g, 19.2 mmol) followed by methyl iodide (0.45 mL, 7.2 mmol). The mixture was stirred at ambient temperature for 3 hours then diluted with ethyl acetate and water. The phases were separated and the aqueous phase was extracted with ethyl acetate (×2). The combined organic extracts were washed with 10% aqueous citric acid solution, saturated sodium hydrogen carbonate solution, and brine, dried with sodium sulphate and concentrated under vacuum to give crude product. Purification by column chromatography on silica gel (10% ethyl acetate in cyclohexane) gave 516 mg (44%) of trans (4-methylsulfanyl-cyclohexyl)-carbamic acid tert-butyl ester as a white solid. 1H NMR (400 MHz, CDCl3) δ: 4.36 (br s, 1H), 3.44 (br s, 1H), 2.72-2.62 (m, 1H), 2.40 (s, 3H), 2.09 (d, 6H), 1.45 (s, 9H), 1.24-1.10 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[N:21]3[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]3)=[C:15]([O:22][CH3:23])[C:14]=2[CH3:24])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:25](OC(=O)C)(=O)[CH3:26]>>[CH3:23][O:22][C:15]1[C:14]([CH3:24])=[C:13]([C:11]([C:8]2[CH:9]=[CH:10][C:2]3[N:1]=[C:25]([CH3:26])[O:5][C:4](=[O:6])[C:3]=3[CH:7]=2)=[O:12])[N:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[CH:20]2
Reactant: CC(=O)OC(C)=O
Reactant: COc1c(C)c(C(=O)c2ccc(N)c(C(=O)O)c2)n2ccccc12
Product: COc1c(C)c(C(=O)c2ccc3nc(C)oc(=O)c3c2)n2ccccc12

Procedure:
0.100 g (0.31 mmol) of 2-amino-5-[(1-methoxy-2-methylindolizin-3-yl)-carbonyl]benzoic acid (Example 150 described in WO 03/084956) in 1 ml of acetic anhydride is refluxed for 3 hours. The reaction medium is concentrated under reduced pressure. 0.107 g of a yellow solid is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Br-].[CH3:22][C:23]1[CH:24]=[CH:25][C:26]([Zn+])=[N:27][CH:28]=1>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:22][C:23]1[CH:24]=[CH:25][C:26]([C:2]2[CH:3]=[C:4]([CH:12]=[C:13]([CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[CH:14]=2)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])=[N:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(C(O)C(F)(F)F)c1
Reactant: Cc1ccc([Zn+])nc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1COCCO1
Product: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cc(C(O)C(F)(F)F)c2)nc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 3-bromo-5-(2,2,2-trifluoro-1-hydroxyethyl)benzoate (5.0 g, 14.1 mmol) and bis(tri-tert-butylphosphine)palladium(0) (0.22 g, 0.42 mmol) in dioxane (70 mL) was added 5-methyl-2-pyridylzinc bromide (0.5 M in THF; 56.3 mL, 28.2 mmol). The reaction mixture was heated to 70° C. After 1 h, additional 5-methyl-2-pyridylzinc bromide (0.5 M in THF; 10 mL, 5.0 mmol) and bis(tri-tert-butylphosphine)palladium(0) (40 mg, 0.078 mmol) were added. After 30 min, the reaction was concentrated. Saturated aqueous sodium potassium tartrate tetrahydrate and saturated aqueous sodium bicarbonate were added. The mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→70% hexanes/ethyl acetate) gave the title compound. MS 368.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:27][CH2:28][CH3:29])=[C:16]([C:22]([CH3:26])=[C:23]([Cl:25])[CH:24]=3)[C:17]([NH:19][CH2:20][CH3:21])=[O:18])[CH3:13])[N:9]=[C:10](I)[C:3]=12.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][NH:41][CH:42]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=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>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:27][CH2:28][CH3:29])=[C:16]([C:22]([CH3:26])=[C:23]([Cl:25])[CH:24]=3)[C:17]([NH:19][CH2:20][CH3:21])=[O:18])[CH3:13])[N:9]=[C:10]([C:38]3[CH:39]=[N:40][NH:41][CH:42]=3)[C:3]=12
Reactant: CCNC(=O)c1c(C)c(Cl)cc(C(C)n2nc(I)c3c(N)ncnc32)c1OCC
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)c1c(C)c(Cl)cc(C(C)n2nc(-c3cn[nH]c3)c3c(N)ncnc32)c1OCC
Temperature: 100 °C
Yield: 11.3 %

Procedure:
To a solution of 3-[1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-N-ethyl-6-methylbenzamide (9.0 mg, 0.017 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.6 mg, 0.034 mmol), sodium carbonate (11 mg, 0.10 mmol) in N,N-dimethylformamide (0.1 mL)/water (51 μL) under N2 was added tetrakis(triphenylphosphine)palladium(0) (2.0 mg, 0.0017 mmol). The mixture was heated at 100° C. overnight. After cooling to room temperature, the mixture was filtered and purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (0.9 mg, 10%). The product was isolated as a racemic mixture. LCMS calculated for C22H26ClN8O2 (M+H)+: m/z=469.2; Found: 469.0.
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1.[Cl:18][C:19]1[C:24](Cl)=[N:23][CH:22]=[CH:21][N:20]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.O>C1COCC1>[Cl:18][C:19]1[C:24]([C:4]2([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2][N:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5]2)=[N:23][CH:22]=[CH:21][N:20]=1
Reactant: Clc1nccnc1Cl
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1(c2nccnc2Cl)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.6 %

Procedure:
To a vial containing 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (408 mg, 1.678 mmol) and 2,3-dichloropyrazine (250 mg, 1.678 mmol) in THF (2.5 mL) at rt under N2 is added dropwise LiHMDS (1.678 mL, 1.678 mmol). The reaction was stirred at rt 16 h. The reaction mixture was poured into H2O (10 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with saturated NaCl (10 mL), dried (MgSO4), and concentrated. Purification by ISCO (40 g SiO2, 0-75% EtOAc/Hexane) gives 1-tert-butyl 4-methyl 4-(3-chloropyrazin-2-yl)piperidine-1,4-dicarboxylate (565 mg, 1.588 mmol, 95% yield) as a clear, colorless oil. [M+Na]=378.0
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][C:6]([NH2:8])=[S:7])[CH3:4].[C:9]1(=[O:27])[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([CH2:20]Br)=O)[C:12](=[O:22])[C:11]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:10]12>C(O)C>[CH3:2][N:3]([CH2:5][C:6]1[S:7][CH:20]=[C:18]([CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[C:12](=[O:22])[C:11]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:10]3[C:9]2=[O:27])[N:8]=1)[CH3:4]
Reactant: O=C(CBr)CCCCN1C(=O)c2ccccc2C1=O
Reactant: CN(C)CC(N)=S
Agent: Cl
Solvent: CCO
Product: CN(C)Cc1nc(CCCCN2C(=O)c3ccccc3C2=O)cs1

Procedure:
Following the procedure of Example 1, a stirred solution containing 3.2 g. of dimethylaminothioacetamide hydrochloride, and 6.48 g of bromomethyl 4-phthalimidobutyl ketone [prepared by the procedure of Chem. Listy., 49, 1385 (1955); C.A., 50, 5573c (1956)]; in 50 ml. of ethanol was heated at refluxing temperature for about 5 hours and was then cooled. Volatile constituents were removed by evaporation in vacuo leaving 2-dimethylaminomethyl-4-(4-phthalimido-1-butyl)thiazole as a semi-solid residue. The compound was utilized without further purification.
Reaction SMILES: C([O:3][C:4]([CH:6]([C:31]1[CH:36]=[CH:35][C:34]2[O:37][CH2:38][O:39][C:33]=2[CH:32]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[C:19]3=[N:20][C:21]([CH3:25])=[CH:22][C:23]([CH3:24])=[C:18]3[N:17]=[C:16]2[CH2:26][CH3:27])=[CH:10][C:9]=1[CH2:28][CH2:29][CH3:30])=[O:5])C.[OH-].[Na+].Cl>CO>[C:4]([CH:6]([C:31]1[CH:36]=[CH:35][C:34]2[O:37][CH2:38][O:39][C:33]=2[CH:32]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[C:19]3=[N:20][C:21]([CH3:25])=[CH:22][C:23]([CH3:24])=[C:18]3[N:17]=[C:16]2[CH2:26][CH3:27])=[CH:10][C:9]=1[CH2:28][CH2:29][CH3:30])([OH:5])=[O:3]
Reactant: CCCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)ccc1OC(C(=O)OCC)c1ccc2c(c1)OCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)ccc1OC(C(=O)O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
To a solution of 0.340 g (0.64 mmol) of the product of step A dissolved in 2 mL methanol was added 130 μL of a 5.0N solution of sodium hydroxide and the reaction mixture was stirred at room temperature for 2 hours. At this point the reaction mixture was adjusted to pH=6 with dropwise addition of 6.0N hydrochloric acid and the reaction mixture was concentrated in vacuo. The residue was applied to a silica gel flash chromatography column and eluted with CHCl3 -MeOH--NH4OH (80:15:1). The purified fractions were combined, evaporated and dried in vacuo to afford 0.278 g (86%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[C:7](=[CH:9][C:10]3[CH:18]=[CH:17][C:16]4[O:15][CH2:14][O:13][C:12]=4[CH:11]=3)[O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:33](I)[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>C(OCC)(=O)C>[CH2:33]([O:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[C:7](=[CH:9][C:10]3[CH:18]=[CH:17][C:16]4[O:15][CH2:14][O:13][C:12]=4[CH:11]=3)[O:8][C:4]=2[CH:3]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: O=C1C(=Cc2ccc3c(c2)OCO3)Oc2cc(O)ccc21
Reactant: CCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCOc1ccc2c(c1)OC(=Cc1ccc3c(c1)OCO3)C2=O
Temperature: 25 °C

Procedure:
After 6-hydroxy-2-piperonylidene-3(2H)-benzofuranone 1 g and potassium carbonate 1.95 g were added to dimethylformamide 10 ml, n-hexyl iodide 0.89 ml was added, and the mixture was reacted at a temperature of 100° C. for two hours. After the solution was cooled to room temperature, ethyl acetate 200 ml was added. The ethyl acetate solution was washed with water 100 ml twice and a saturated sodium chloride solution 50 ml twice. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate, and concentrated to 40 ml under reduced pressure, and hexane 100 ml was added. 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 0.82 g.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:39]=[CH:38][C:13]([C:14]([NH:16][CH2:17][C:18]2[C:19]([NH:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[C:20]3[CH:28]=[N:27][N:26]([CH2:29][CH3:30])[C:21]3=[N:22][C:23]=2[CH2:24][CH3:25])=[O:15])=[CH:12][CH:11]=1.[CH3:40][NH:41][CH2:42][CH2:43][OH:44].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:29]([N:26]1[C:21]2=[N:22][C:23]([CH2:24][CH3:25])=[C:18]([CH2:17][NH:16][C:14](=[O:15])[C:13]3[CH:38]=[CH:39][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:41]([CH2:42][CH2:43][OH:44])[CH3:40])=[CH:11][CH:12]=3)[C:19]([NH:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[C:20]2[CH:28]=[N:27]1)[CH3:30]
Reactant: CNCCO
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(CCCCCCCCBr)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(CCCCCCCCN(C)CCO)cc1
Temperature: 60 °C

Procedure:
A solution of 4-(8-bromooctyl)-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}benzamide (36.3 mg, 0.06 mmol, e.g. which can be as prepared in Intermediate 41) in N,N-dimethylformamide (6 ml) was treated with 2-(methylamino)ethanol (0.0195 ml, 0.24 mmol, commercially available e.g. from Aldrich) and N,N-diisopropylethylamine (0.042 ml, 0.24 mmol) and heated at 60° C. for 16 hours. The solvent was evaporated and the residue purified by mass directed preparative HPLC (Method A). Fractions containing product were pooled and evaporated to give the title compound (7 mg). LCMS showed MH+=593; TRET=2.37 min.