Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:26])=[C:11]([CH2:13][CH2:14][O:15]S(C3C=CC(C)=CC=3)(=O)=O)[N:12]=2)=[CH:4][CH:3]=1.[C:27]([O:31][C:32](=[O:50])[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][C:36]=1[CH2:42][NH:43]C(OC(C)C)=O)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:50])[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:15][CH2:14][CH2:13][C:11]2[N:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[O:9][C:10]=2[CH3:26])=[CH:37][C:36]=1[CH:42]([C:32]([O:31][CH:27]([CH3:29])[CH3:28])=[O:50])[NH2:43])([CH3:28])([CH3:29])[CH3:30]
Reactant: CC(C)OC(=O)NCc1cc(O)ccc1CCC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Product: Cc1oc(-c2ccc(Br)cc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(C(N)C(=O)OC(C)C)c1
Yield: 127.1 %

Procedure:
Toluene-4-sulfonic acid 2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl ester (5.06 g, 11.6 mmol) and 3-[4-hydroxy-2-(isopropoxycarbonylamino-methyl)-phenyl]-propionic acid tert-butyl ester (3.01 g, 8.92 mmol) were coupled using Standard procedure A to give the title compound as a white solid (3.41 g, 64%). MS [ES] m/z 601.603 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:45])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:15][C:16]3[N:29]4[C:20](=[N:21][C:22]5[C:27]([C:28]4=[O:30])=[C:26]([F:31])[CH:25]=[CH:24][CH:23]=5)[C:19]4[CH:32]=[CH:33][N:34](S(C5C=CC(C)=CC=5)(=O)=O)[C:18]=4[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[CH3:46][NH2:47].C1COCC1.C(=O)(O)[O-].[Na+].CCOC(C)=O>O1CCCC1>[CH3:1][N:2]([CH3:45])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:15][C:16]3[NH:17][C:18]4=[N:34][CH:33]=[CH:32][C:19]4=[C:20]([NH:21][C:22]4[CH:23]=[CH:24][CH:25]=[C:26]([F:31])[C:27]=4[C:28]([NH:47][CH3:46])=[O:30])[N:29]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2nc(Nc2ccc4c(c2)N(C(=O)CN(C)C)CC4)n2c(=O)c4c(F)cccc4nc32)cc1
Reactant: CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)c1c(F)cccc1Nc1nc(Nc2ccc3c(c2)N(C(=O)CN(C)C)CC3)[nH]c2nccc1-2
Temperature: 120 °C
Yield: 41.2 %

Procedure:
A suspension of 5-chloro-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one hydrogen chloride (0.600 g, 1.252 mmol) and 1-[(dimethylamino)acetyl]-2,3-dihydro-1H-indol-6-amine (0.274 g, 1.252 mmol) was maintained at 70° C. in tetrahydrofuran (20 ml) in a pressure tube for 16 hours. The reaction was cooled, opened, concentrated under reduced pressure, and redissolved in methylene chloride/2,2,2-trifluoroethanol (ca 15 mL). Saturated sodium bicarbonate was added and all solids dissolve. The organic layer was dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and triturated with diethyl ether to afford 5-{[1-(N,N-dimethylglycyl)-2,3-dihydro-1H-indol-6-yl]amino}-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (0.696 g, 1.112 mmol, 89%) as a yellow solid. A suspension of 5-{[1-(N,N-dimethylglycyl)-2,3-dihydro-1H-indol-6-yl]amino}-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (0.696 g, 1.112 mmol) in tetrahydrofuran (20 ml) was treated with 2.0M methyl amine/THF (3.34 ml, 6.67 mmol) and over 24 hours all solids dissolve. The solution was poured into saturated sodium bicarbonate/EtOAc and the organic layer was dried over sodium sulfate, filtered, and taken to a residue under reduced pressure. The residue was dissolved in 1,4-dioxane (8 ml)/2.0N NaOH (aq) (8 ml) and maintained at 120° C. under microwave heating for 12 minutes. The solution was cooled, poured into ethyl acetate/THF/saturated sodium chloride (aq) and the organic layer was dried over sodium sulfate, filtered, stripped onto celite, and purified by column chromatography to afford 2-[(2-{[1-(N,N-dimethylglycyl)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide (0.230 g, 0.458 mmol, 41.1%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.33 (s, 1H), 10.20 (s, 1H), 8.89 (s, 1H), 8.54 (d, J=7.62 Hz, 1H), 8.21 (s, 1H), 7.83 (d, J=7.22 Hz, 1H), 7.34-7.48 (m, 1H), 7.10 (d, J=8.23 Hz, 1H), 6.85-7.01 (m, 3H), 6.29 (dd, J=3.41, 1.81 Hz, 1H), 4.15 (t, J=8.23 Hz, 2H), 3.21 (s, 2H), 2.99-3.12 (m, 2H), 2.79 (d, J=4.61 Hz, 3H), 2.27 (s, 6H). ESIMS (M+H)+=503.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][N:18]=[C:17]([Cl:26])[N:16]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1>[C:1]([O:5][C:6]([CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:20]([C:21]([OH:23])=[O:22])=[CH:19][N:18]=[C:17]([Cl:26])[N:16]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc(Cl)nc1N1CCC(CC(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC1CCN(c2nc(Cl)ncc2C(=O)O)CC1
Yield: 45.7 %

Procedure:
To a solution of ethyl 4-(4-((tert-butoxycarbonyl)methyl)piperidin-1-yl)-2-chloropyrimidine-5-carboxylate (368 mg, 0.923 mmol) in THF (5 mL), aq. 1M LiOH (2.20 mL, 2.20 mmol) was added. It was heated to reflux for 5 h. THF was removed in vacuo. After being acidified with HOAc (2 mL), the residue was purified by HPLC to give 4-(4-((tert-butoxycarbonyl)methyl)piperidin-1-yl)-2-chloropyrimidine-5-carboxylic acid (150 mg). MS 371.4 and 373.4 (M+H, Cl pattern).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:11][C@H:12]([C:16]([OH:18])=[O:17])[CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CS(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH2:13][CH2:14][CH3:15])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCC[C@H](N)C(=O)O
Reactant: N#Cc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCC[C@H](Nc1ccc(C#N)c(Cl)c1)C(=O)O
Temperature: 90 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 2-chloro-4-fluorobenzonitrile (5.0 g) in dimethyl sulfoxide (80 mL) were added L-norvaline (4.52 g) and cesium carbonate (13.6 g), and the mixture was stirred at 90° C. overnight. After allowing to room temperature, ethyl acetate was added, and the mixture was extracted twice with saturated aqueous sodium hydrogen carbonate solution. The aqueous layers were combined, and acidified with citric acid, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a brown oil (yield: 8.12 g, 100%).
Reaction SMILES: [Br:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:8]([CH3:14])([CH3:13])[CH2:7][CH2:6][C:5]([CH3:16])([CH3:15])[C:4]=2[CH:3]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[C:11]([CH2:12][Br:17])=[CH:10][C:9]2[C:8]([CH3:14])([CH3:13])[CH2:7][CH2:6][C:5]([CH3:16])([CH3:15])[C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)CCC(C)(C)c2cc(CBr)c(Br)cc21
Temperature: 25 °C
Yield: 112.5 %

Procedure:
To a solution of 12.0 g (281 mmol) of 2-bromo-3-methyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene in 84 mL carbon tetrachloride was added 7.59 g (42.7 mmol) of N-bromosuccinimide and 0.310 g (1.28 mmol) of benzoyl peroxide. This was heated to reflux for 40 minutes and then cooled to room temperature. To the cooled solution was added 170 mL petroleum ether and the solution was filtered and concentrated in vacuo to give 17.3 g of 2-bromo-3-bromomethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene which was used without further purification.
Reaction SMILES: [CH:1]1([CH:6]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:29](=[O:30])[C:28]4[C:23](=[C:24]([F:32])[CH:25]=[CH:26][C:27]=4[F:31])[C:22]3=[O:33])=[CH:16][CH:15]=2)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].ClCCl>C(O)C>[CH:1]1([CH:6]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:22](=[O:33])[C:23]4[C:28](=[C:27]([F:31])[CH:26]=[CH:25][C:24]=4[F:32])[CH:29]3[OH:30])=[CH:16][CH:15]=2)[C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C(c1ccc(CN2C(=O)c3c(F)ccc(F)c3C2=O)cc1)C1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(c1ccc(CN2C(=O)c3c(F)ccc(F)c3C2O)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 200.0 mg (0.44 mmol) of tert-butyl(+/−)-cyclopentyl{4-[(4,7-difluoro-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}acetate in 1 ml of ethanol was cooled to 0° C., and 18.3 mg (0.48 mmol) of sodium borohydride were added. 0.2 ml of dichloromethane was added, and the reaction mixture was warmed to RT. After 1 h of stirring, the mixture was concentrated and the residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 6:1 to 4:1). This gave 182 mg (90.6% of theory) of the target compound.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.[CH:12]([SiH:15]([CH:17]([CH3:19])[CH3:18])Cl)([CH3:14])[CH3:13]>CCCCC>[CH:12]([SiH:15]([CH:17]([CH3:19])[CH3:18])[C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])([CH3:14])[CH3:13]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)[SiH](Cl)C(C)C
Agent: [Li]CCCC
Solvent: CCCCC
Product: CC(C)[SiH](C#C[Si](C)(C)C)C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
A flame-dried 250-mL round-bottom flask was cooled under nitrogen and placed in an ice bath. Into this flask was added 30 mL pentane and 3.6 g (36 mmol) trimethylsilylacetylene. n-Butyllithium (13.2, 2.5 M in hexane) was added over 12 minutes, and the reaction was allowed to stir for one hour at 0° C. Diisopropylchlorosilane (5.1 g, 34 mmol) was then added, and the reaction stirred overnight. The solution was extracted with pentane (2×40 mL) and the organic layers were washed with water, dried over magnesium sulfate, filtered, then carefully concentrated using rotary evaporation (product was volatile). Chromatography on silica with pentane as an eluent yielded 6.9 g (33 mmol, 99%) the desired product as a clear oil.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:16]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:15][N:14](COCC[Si](C)(C)C)[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(OC([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][C:39]1([CH3:45])[CH3:44])=O)(C)(C)C>>[CH3:44][C:39]1([CH3:45])[NH:38][CH2:43][CH2:42][N:41]([C:2]2[CH:3]=[C:4]([C:8]3[N:9]=[C:10]4[C:16]([C:17](=[O:22])[C:18]([CH3:20])([CH3:19])[CH3:21])=[CH:15][NH:14][C:11]4=[N:12][CH:13]=3)[CH:5]=[CH:6][CH:7]=2)[CH2:40]1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc(I)c3)nc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1(C)C
Product: CC1(C)CN(c2cccc(-c3cnc4[nH]cc(C(=O)C(C)(C)C)c4n3)c2)CCN1

Procedure:
1-{2-[3-(3,3-Dimethyl-piperazin-1-yl)-phenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-2,2-dimethyl-propan-1-one was prepared starting from 1-[2-(3-iodo-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one and 2,2-Dimethyl-piperazine-1-carboxylic acid tert-butyl ester following general procedures as described in these Examples. M+H=392.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])[CH3:4])#[N:2].C[O-].[Na+].Br[CH2:19][CH:20]1[CH2:22][CH2:21]1.[H-].[Na+]>C(#N)C.C(OCC)C>[C:1]([C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])[CH2:19][CH:20]1[CH2:22][CH2:21]1)#[N:2]
Reactant: COC(=O)c1cccc(C(C)C#N)c1
Reactant: BrCC1CC1
Agent: C[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)c1cccc(C(C)(C#N)CC2CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.7 %

Procedure:
To a solution of methyl 3-(1-cyanoethyl)benzoate (1.5 g, 7.9=mol) in acetonitrile (20 mL) were added sodium methoxide (0.95 g, 17 mmol) and (bromomethyl)cyclopropane (1.3 g, 9.5 mmol), and the reaction mixture was stirred at room temperature for 30 min. To the reaction mixture was added sodium hydride (60% in oil, 0.7 g, 17 mmol) under ice-cooling, and the mixture was stirred at room temperature for 16 hr. The mixture was diluted with diethyl ether, and washed with 5% aqueous sodium hydrogencarbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→40/60) to give the title compound (129 mg, 6.7%) as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](I)=[CH:5][CH:4]=1)[CH3:2].[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12]>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)I.C(N(CC)CC)C>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:15]#[C:14][Si:11]([CH3:13])([CH3:12])[CH3:10])=[CH:5][CH:4]=1)[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CCc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: CCc1ccc(C#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 5.6 mL of 1-ethyl-4-iodobenzene, 75 mL of triethylamine, 6 mL of trimethylsilylacetylene, 0.49 g of dichlorotriphenylphosphine palladium II and 0.314 g copper iodide was magnetically stirred at ambient temperature for 18 hrs. The thick dark brown mixture was filtered, washing the gray precipitate with hexanes. The filtrate and washings were evaporated in vacuo and the residue dissolved in hexanes. This solution was 96.7% pure by GC analysis. The solution was passed down a column of silica gel which had been equilibrated in the same solvent and the eluates evaporated in vacuo to yield 9.3 g of 4-ethyl-1-trimethylsilyl ethynylbenzene as a dark amber liquid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]([O:14]C)=[O:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.Br[CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1.[OH-].[Na+]>CO>[CH2:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH:17]1[N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1
Reactant: COC(=O)c1ccnc(-c2c[nH]cn2)c1
Reactant: BrC1Cc2ccccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccnc(-c2cn(C3Cc4ccccc4C3)cn2)c1
Yield: 48 %

Procedure:
The title compound was prepared in 48% yield from methyl 2-(1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 5) and 2-bromo-2,3-dihydro-1H-indene according to the procedure for the preparation of Example 44, followed by saponification using NaOH in MeOH. 1HNMR (400 MHz, DMSO): δ 2.21 (2H, d), 3.52 (2H, d), 5.22 (1H, m), 7.23 (2H, m), 7.32 (2H, m), 7.45 (1H, t, J=5.4 Hz), 7.59 (1H, s), 7.82 (1H, s), 8.21 (1H, s), 8.35 (1H, d). [M+H] Calc'd for C18H15N3O2, 306. Found, 306.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH2:30][CH2:31][OH:32])(=[NH:29])=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1.N1C=CC=CC=1.[C:39](Cl)(=[O:41])[CH3:40]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH2:30][CH2:31][OH:32])(=[N:29][C:39](=[O:41])[CH3:40])=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: N=S(=O)(CCO)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N=S(=O)(CCO)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Temperature: 27.5 °C
Reaction time: 3 h
Yield: 16.8 %

Procedure:
To a stirring solution of S-[4-(N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-chlorophenyl}carbamoyl)phenyl]-S-(2-hydroxy ethyl)-sulfoximide (0.550 g, 0.00111 mol) in DCM(10 mL) was added pyridine (0.131 g, 0.001665 mol) at 5-10° C. under nitrogen atmosphere followed acetyl chloride (0.105 g, 0.00134 mol). Reaction mixture was stirred for 3 hr at 25-30° C. Subsequent work up and column purification (55% ethyl acetate in hexane and 100-200 mesh silica gel) gave 100 mg of desired product in 17% yield.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])=[C:4]([C:9]([N:11]2[CH2:14][CH:13]([NH:15]C(=O)OC(C)(C)C)[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[C:3]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])=[C:4]([C:9]([N:11]2[CH2:14][CH:13]([NH2:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A solution of 1,1-dimethylethyl [1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]carbamate (113 mg, 0.20 mmol) and trifluoroacetic acid (500 μL) in dichloromethane (2 mL) was added stirred at room temperature for one hour then was partitioned between saturated aqueous sodium bicarbonate, and dichloromethane. The organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford a colorless residue which was purified by column chromatography eluting with 10% methanol in dichloromethane to afford 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine (85 mg, 95% yield) as a white foam. 1H NMR (400 MHz, CDCl3): 8.53 (s, 1H), 7.39 (d, 1H), 7.32 (d, 1H), 7.13-7.09 (m, 1H), 6.84-6.77 (m, 1H), 6.63-6.57 (m, 1H), 4.46-4.39 (m, 2H), 3.98-3.75 (br m, 4H); MS (EI) for C16H13F3IN3O: 448 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[C:13]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)=[N:12]2)[CH2:7][CH2:6]1)=[O:4].[NH:29]1[C:34](=[O:35])[CH2:33][O:32][CH2:31][C:30]1=[O:36].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:13]2[C:14]([CH3:18])([CH3:17])[C:15](=[O:16])[N:11]([CH:8]3[CH2:7][CH2:6][N:5]([C:3](=[O:4])[CH2:2][N:29]4[C:34](=[O:35])[CH2:33][O:32][CH2:31][C:30]4=[O:36])[CH2:10][CH2:9]3)[N:12]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: O=C1COCC(=O)N1
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)CCl)CC3)C(=O)C2(C)C)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C2=NN(C3CCN(C(=O)CN4C(=O)COCC4=O)CC3)C(=O)C2(C)C)cc1OC

Procedure:
1.0 g 2-[1-(chloroacetyl)piperidin-4-yl]-5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound A1), 0.5 g morpholine-3,5-dione and 1.0 g K2CO3 in 20 ml of DMF is heated for 17 h at 80-100° C. The DMF is removed in vacuo and the residue dissolved in 70 ml of DCM, washed four times with 30 ml of water and 20 ml of 0.5 M H2SO4. The DCM layer is dried over MgSO4 and concentrated in vacuo. The title product is crystallized from diethyl ether.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[C:18]4[CH:28]=[CH:27][C:26]([O:29]CC5C=CC=CC=5)=[CH:25][C:19]=4[S:20][C:21]=3N(C)C)=O)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:38]1[CH:43]=[CH:42][C:41]([O:44][Si](C(C)C)(C(C)C)C(C)C)=[CH:40][CH:39]=1>C1COCC1>[OH:29][C:26]1[CH:27]=[CH:28][C:18]2[C:17]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:10][CH:11]=3)=[C:21]([C:38]3[CH:39]=[CH:40][C:41]([O:44][CH2:5][CH2:4][CH2:3][C:2]#[N:1])=[CH:42][CH:43]=3)[S:20][C:19]=2[CH:25]=1
Reactant: CN(C)c1sc2cc(OCc3ccccc3)ccc2c1C(=O)c1ccc(OCCN2CCCC2)cc1
Reactant: CC(C)[Si](Oc1ccc(Br)cc1)(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#CCCCOc1ccc(-c2sc3cc(O)ccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Yield: 57 %

Procedure:
By essentially following the proceedure described in Example 16, Part C, the title compound was prepared as an oil starting from 6-benzyloxy-2-dimethylaminobenzo[b]thiophene-3-yl 4-[2-(1-pyrrolidinyl)ethoxy]phenyl ketone (Part A) and 1-bromo-4-(triisopropylsilyloxy)benzene in 57% yield following MPLC (SiO2; 10% then 15% then 20% THF with 5% TEA in hexanes).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][NH:26]1>C(#N)C>[O:13]1[C:14]2[CH:18]=[CH:17][S:16][C:15]=2[C:11]([C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[O:4][CH2:3][CH2:2][N:26]2[CH2:27][CH2:28][C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25]2)=[N:12]1
Reactant: c1ccc2c(c1)CCNC2
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1cc(OCCN2CCc3ccccc3C2)cc(-c2noc3ccsc23)c1
Temperature: 75 °C
Yield: 61.5 %

Procedure:
Mix 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole (0.400 g, 1.23 mmol), potassium carbonate (0.345 g, 2.50 mmol), 1,2,3,4-tetrahydroisoquinoline (0.532 g, 3.99 mmol) and acetonitrile (5.0 mL) and heat at 75° C., overnight. Cool the reaction mixture and filter through a Waters Sep-Pak 1 g silica cartridge (ethyl acetate). Combine the appropriate fractions and concentrate to give a residue. Purify the residue by column (10 g silica) chromatography using a graded solvent mixture of 10% ethyl acetate in dichloromethane to 20% ethyl acetate in dichloromethane. Dissolve the free base in ethanol and acidify with ethereal hydrochloric acid, concentrate to a sticky residue, triturate (methanol:ethyl acetate) and collect the powder. Recrystallize the powder (methanol:ethyl acetate) to obtain the title compound as white crystals (0.285 g, 56%). mp=202–204° C. Microanalysis (C, H, N) is consistent with the final, desired compound.
Reaction SMILES: [CH3:1][Li].CC1C=CC(S(O[CH2:14][C@@H:15]2[CH2:19][CH2:18][CH2:17][N:16]2[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])(=O)=O)=CC=1>CCOCC.C(Cl)Cl.[Cu]I>[CH2:14]([C@@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])[CH3:1]
Reactant: [Li]C
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OCc2ccccc2)cc1
Agent: [Cu]I
Solvent: CCOCC
Solvent: ClCCl
Product: CC[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 45.2 %

Procedure:
To copper(I) iodide (1.25 g, 6.55 mmol) in Et2O (25 mL) was added methyllithium (8.2 mL, 13.1 mmol) at 0° C. A solution of phenylmethyl(2S)-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1-pyrrolidinecarboxylate (0.85 g, 2.182 mmol) in CH2Cl2 (4 mL) was added next, and the reaction mixture was stirred for 2 hours at 0° C. The reaction was quenched with saturated aqueous NH4Cl, and extracted with CH2Cl2 (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. Flash chromatography on SiO2 (gradient: 100% hexanes to 20% EtOAc/hexanes) afforded the title compound (230 mg, 45%) as a colorless oil. LC-MS (ES) m/z=234 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][C:6]2([CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[C:5](=[O:20])[NH:4]1)[CH3:2].CC1CC2(CCNCC2)C(=O)N1[C:33]1[CH2:34][O:35][C:36](=[O:38])[CH:37]=1>>[CH2:1]([CH:3]1[CH2:7][C:6]2([CH2:8][CH2:9][NH:10][CH2:11][CH2:12]2)[C:5](=[O:20])[N:4]1[C:33]1[CH2:34][O:35][C:36](=[O:38])[CH:37]=1)[CH3:2]
Reactant: CCC1CC2(CCN(C(=O)OC(C)(C)C)CC2)C(=O)N1
Reactant: CC1CC2(CCNCC2)C(=O)N1C1=CC(=O)OC1
Product: CCC1CC2(CCNCC2)C(=O)N1C1=CC(=O)OC1

Procedure:
The title compound was prepared in two steps from tert-butyl 3-ethyl-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate in an analogous fashion as described for 3-methyl-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (I-22).