Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH:13]=[O:14])[CH:2]([CH3:4])[CH3:3].P([O-])(O)(O)=O.[Na+].OO.Cl([O-])=O.[Na+].[C:27](=O)([O-])[O-:28].[K+].[K+].IC>C(#N)C.O.C(OCC)(=O)C.CN(C)C=O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]([O:28][CH3:27])=[O:14])[CH:2]([CH3:4])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)COc1ccccc1CC=O
Agent: O=P([O-])(O)O
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1OCC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
To a solution of 17 g of 2-(2-isobutoxyphenyl)ethanal in 170 ml of acetonitrile, 29 g of sodium dihydrogenphosphate dissolved in 200 ml of water and subsequently 15 g of 30% aqueous hydrogen peroxide are added, and further 16 g of sodium chlorite dissolved in 80 ml of water is dropwise added, and the mixture thus obtained is stirred at ambient temperature for one hour. Ethyl acetate and water added to the reaction mixture, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is mixed with 22 g of potassium carbonate and 200 ml of N,N-dimethylformamide. While cooling the mixture with ice water, 19 g of iodomethane is added, and the mixture thus obtained is stirred at ambient temperature for 30 minutes. Ethyl acetate and water are added to the reaction mixture, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=10:1) to obtain 10.4 g of methyl 2-(2-isobutoxyphenyl)acetate as a colorless oily product.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[C:30]([C:39]([F:42])([F:41])[F:40])[CH:29]=1>CC(N(C)C)=O>[CH:34]1([C:31]2[CH:32]=[CH:33][C:28]([CH2:27][O:1][C:2]3[CH:10]=[CH:9][C:8]4[NH:7][C:6]5[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=5[C:4]=4[CH:3]=3)=[CH:29][C:30]=2[C:39]([F:40])([F:41])[F:42])[CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: FC(F)(F)c1cc(CCl)ccc1C1CCCC1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 124.2 %

Procedure:
In a 2 L, 3-necked, round-bottomed flask under nitrogen atmosphere were placed ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (55.85 g, 215 mmol), cesium carbonate (84.2 g, 258 mmol), 4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (68 g, 259 mmol) in DMA (670 mL). The mixture was stirred 15 minutes at room temperature and heated at 50° C. overnight. The mixture was cooled down to room temperature and filtered. The filtrate was concentrated under vacuum. The residue was added hexanes (400 mL) and heated to 40° C. to give a dark solution. The solution was cooled down to room temperature over the weekend. The mixture was concentrated in vacuo and dried under vacuum to give the title compound (129.7 g). LCMS m/z=486.2.
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[CH2:10][C:11]([N:13]1[CH2:34][CH2:33][C:16]2([C:20](=[O:21])[N:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)[CH2:15][CH2:14]1)=[O:12]>C1COCC1.C(Cl)(Cl)Cl>[CH:3]1([O:8][CH2:10][C:11]([N:13]2[CH2:14][CH2:15][C:16]3([C:20](=[O:21])[N:19]([C:22]4[CH:27]=[CH:26][C:25]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)[CH2:33][CH2:34]2)=[O:12])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C(CCl)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Reactant: OC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: O=C(COC1CCCC1)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
To a suspension of NaH (5 mg, 0.13 mmol) in THF (2 mL) at 0° C. was added cyclopentanol (10 uL, 0.11 mmol) and the mixture was stirred for 30 min at 0° C. A solution of 8-(2-chloro-acetyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (example 225, 42 mg, 0.11 mmol) in THF (500 uL) was added drop-wise and the reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was diluted with chloroform and the resultant precipitate was filtered off and the filtrate was concentrated in vacuo to give the crude residue which was purified by flash column chromatography (7:3 AcOEt/heptane) which afforded the desired product as a white solid (16 mg, 34%). MS (ESI): 441.3 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH2:26]1[CH2:31][C@@H:30]([NH2:32])[C@H:29]([NH2:33])[CH2:28][CH2:27]1.C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:32][CH:30]1[CH2:31][CH2:26][CH2:27][CH2:28][CH:29]1[NH2:33])=[O:20]
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: NC1CCCCC1NC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.4 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), (-)-R,R-1,2-diaminocyclohexane (0.314 g, 2.75 mmol), triethylamine (0.306 g, 3.06 mmol) and benzene (30 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(2-aminocyclohexyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.110 g, 8.4% yield).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:34]([O:41][N:42]1[C:48](=[O:49])[N:47]2[CH2:50][C@H:43]1[CH2:44][CH2:45][C@H:46]2[C:51]([OH:53])=O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[NH:54]([C:56](=[O:70])[CH2:57][CH:58]1[CH2:61][CH:60]([NH:62][C:63](=[O:69])[O:64][C:65]([CH3:68])([CH3:67])[CH3:66])[CH2:59]1)[NH2:55]>CN(C=O)C>[CH2:34]([O:41][N:42]1[C:48](=[O:49])[N:47]2[CH2:50][C@H:43]1[CH2:44][CH2:45][C@H:46]2[C:51]([NH:55][NH:54][C:56](=[O:70])[CH2:57][CH:58]1[CH2:61][CH:60]([NH:62][C:63](=[O:69])[O:64][C:65]([CH3:66])([CH3:67])[CH3:68])[CH2:59]1)=[O:53])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CC(CC(=O)NN)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CC(CC(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
HATU (1.6 g, 4.3 mmol) and DIPEA (0.93 g, 7.2 mmol) were added to a 0° C. solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (1.0 g, 3.6 mmol), tert-butyl 3-(2-hydrazinyl-2-oxoethyl)cyclobutylcarbamate (0.97 g, 3.9 mmol) in DMF (10 mL) at. The reaction mixture was stirred at 0° C. for 1 hr. The mixture was quenched with saturated sodium chloride (50 mL) and the organic layer was separated. The water layer was exacted with EtOAc (3×). The combined organic layer was washed with saturated sodium chloride (2×), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (50% EtOAc/petroleum ether) to afford tert-butyl 3-(2-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoethyl)cyclobutylcarbamate (1.5 g, 88%). ESI-MS (EI+, m/z): 502 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH3:12]O.S(=O)(=O)(O)O>O>[CH3:12][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([OH:11])=[C:2]([OH:1])[CH:3]=1
Reactant: O=C(O)c1ccc(O)c(O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc(O)c(O)c1
Temperature: 25 °C

Procedure:
A mixture of 100 g of 3,4-dihydroxy benzoic acid, 600 ml methyl alcohol and 10 ml of concentrated sulfuric acid is heated at reflux for 18 hours. The reaction mixture is cooled to room temperature, poured into water and extracted with methylene chloride. The organic layer is washed with saturated sodium bicarbonate and sodium chloride, dried and concentrated in vacuo to give 50.6 g of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=O)=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13].N1C(Cl)=NC(Cl)=NC=1Cl.O>CN(C)C=O>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]#[N:8])=[CH:4][C:3]=1[O:11][C:12]([F:13])([F:14])[F:15]
Reactant: NC(=O)c1ccc(O)c(OC(F)(F)F)c1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(O)c(OC(F)(F)F)c1

Procedure:
To a solution of 4-hydroxy-3-(trifluoromethoxy)benzamide (532 mg, 2.41 mmol) in dimethylformamide (3 ml) was added cyanuric chloride (223 mg, 1.21 mmol). The mixture was stirred for 25 and then water was added and the resulting solution was extracted 3 times with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford the title compound. Mass spectrum (ESI) 202.1 (M−1).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([CH3:20])([CH3:19])[CH2:17][OH:18].N1C=CN=C1>CN(C=O)C>[C:4]([Si:1]([O:18][CH2:17][C:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[F:9])([CH3:20])[CH3:19])([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(CO)c1ccccc1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)c1ccccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyldimethylsilyl chloride (1.4 g) was added portionwise to a stirred solution of 2-(2-fluorophenyl)-2-methylpropan-1-ol (example 90, step d) (1.3 g) and imidazole (0.631 g) in DMF (7 mL) at 20° C. The reaction mixture was stirred for 3 hours at room temperature and then partitioned between ethyl acetate and brine. The organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 100% isohexane to 1% diethyl ether in isohexane. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 1.4 g.
Reaction SMILES: [CH2:1]([N:9]1[CH2:14][CH2:13][C:12](=O)[CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]1=[O:22])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])(=O)C.[Na+].Cl.[NH2:29][OH:30]>CCO.O>[CH2:1]([N:9]1[CH2:14][CH2:13][C:12](=[N:29][OH:30])[CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]1=[O:22])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NO
Reactant: O=C1CCN(CCc2ccccc2)C(=O)C1c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1C(c2ccccc2)C(=NO)CCN1CCc1ccccc1
Temperature: 0 °C
Yield: 59.6 %

Procedure:
Phenethyl-3-phenyl-piperidine-2,4-dione (781 mg), sodium acetate (1.15 g) and hydroxylamine hydrochloride (925 mg) were suspended in EtOH/water 1:1 (25 ml) and the mixture was refluxed for 4 hours. The mixture was then poured into ice/water/1N NaOH and extracted with ethyl acetate. The organic layer was washed with brine, dried and evaporated to give the crude product that was purified by flash chromatography (DCM/MeOH/NH4OH 98:2:0.25) to give the compound as a white foam (489 mg). MS (ESI): 309.4 (MH+).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:28])=[C:11]([N:15]4[CH2:18][C:17]([CH2:20][NH:21]C(=O)C(F)(F)F)([CH3:19])[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:29])[C:6]([C:30]([OH:32])=[O:31])=[CH:5]2)[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:28])=[C:11]([N:15]4[CH2:18][C:17]([CH2:20][NH2:21])([CH3:19])[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:29])[C:6]([C:30]([OH:32])=[O:31])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CC1(CNC(=O)C(F)(F)F)CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(CN)CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Yield: 73.4 %

Procedure:
A solution of 1.5 g (3.3 mmoles) of 1-cyclopropyl-6,8-difluoro-7-(3-trifluoroacetamidomethyl-3-methyl-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (example 24), 15 ml of 1N sodium hydroxide and 6 ml of ethanol are heated under reflux for 3 hours, and evaporated under vacuum. Acetic acid is added, and the product filtered and washed with water. 0.88 g (74%) of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-aminomethyl-3-methyl-1-azetidinyl)-3-quinolinecarboxylic acid are obtained, melting at 268°-70° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:24][C:8]2[N:9]=[C:10]([NH2:23])[N:11]=[C:12]([NH:13][C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][N:18]=[CH:17]4)[C:7]=2[CH:6]=1)=O.[NH3:25]>>[NH2:23][C:10]1[N:11]=[C:12]([NH:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][N:18]=[CH:17]3)[C:7]2[CH:6]=[C:5]([C:3]([NH2:25])=[O:2])[S:24][C:8]=2[N:9]=1
Reactant: COC(=O)c1cc2c(Nc3ccc4[nH]ncc4c3)nc(N)nc2s1
Reactant: N
Product: NC(=O)c1cc2c(Nc3ccc4[nH]ncc4c3)nc(N)nc2s1
Temperature: 60 °C
Yield: 31 %

Procedure:
A mixture of 2-amino-4-(1H-indazol-5-ylamino)-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (Example #N.7.1, 0.050 g, 0.15 mmol) and ammonia (ca. 7N in methanol, 1.0 mL) was heated at about 60° C. in a sealed vessel for about 1.5 hours. The mixture was allowed to cool to ambient temperature and additional ammonia (ca. 7N in methanol, 5.0 mL) was added. The reaction mixture was then heated at about 75° C. for about 18 hours, cooled to ambient temperature, additional ammonia (ca. 7N in methanol, 2.0 mL) was added, and heating at about 75° C. was continued for about another 3 days. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (Thermo Hypersil-Keystone 250×21.2 mm 8μ Hypersil® HS C18 column; 5% CH3CN/50 mM aqueous ammonium acetate hold for 5 min, 5-100% CH3CN/50 mM aqueous ammonium acetate over 30 min, hold at 100% CH3CN for 5 minutes, 21 mL/min) to give 2-amino-4-(1H-indazol-5-ylamino)-thieno[2,3-d]pyrimidine-6-carboxylic acid amide (0.015 g, 31%) as a beige solid; RP-HPLC (Table 1, Method a) Rt 0.68 min, m/z (ESI+) 325.9 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]([OH:39])[C:20]([NH:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]#[C:34][CH2:35][CH3:36])=[C:27]([O:37][CH3:38])[CH:26]=2)=[O:21])[CH:15]=[CH:16][C:17]=1[Cl:18].C(N(CC)CC)C>C(Cl)Cl.O>[Cl:11][C:12]1[CH:13]=[C:14]([C:19](=[O:39])[C:20]([NH:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]#[C:34][CH2:35][CH3:36])=[C:27]([O:37][CH3:38])[CH:26]=2)=[O:21])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: CCC#CCOc1ccc(CCNC(=O)C(O)c2ccc(Cl)c(Cl)c2)cc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCC#CCOc1ccc(CCNC(=O)C(=O)c2ccc(Cl)c(Cl)c2)cc1OC
Yield: 76.7 %

Procedure:
To a solution of 0.8 ml oxalyl chloride (9.0 mmol) in 8 ml methylenchloride at −63° C is added in 15 minutes a solution of 0.84 ml DMSO (12.0 mmol) in 4 ml CH2Cl2. A solution of 2.6 g (6.0 mmol) of 2-(3,4-dichloro-phenyl)-2-hydroxy-N-[2-(3-methoxy-4-pent-2-ynyloxy-phenyl)-ethyl]-acetamide in 30 ml CH2Cl2 is added in 10 minutes. After 10 minutes at −65° C. a solution of 3.2 ml (24.0 mmol) triethylamine in 8 ml CH2Cl2 is added in 15 minutes. After 15 more minutes at that temperature the mixture is hydrolysed with 6.0 ml water and warmed up to +20° C. The solution is washed with solutions of KHSO4 (20%), saturated NaHCO3 and saturated NaCl. After evaporation the residue is submitted to flash-chromatography (ethyl acetate 25, hexanes 75) to give 2.0 g (77%) of the 2-(3,4-dichloro-phenyl)-N-[2-(3-methoxy-4-pent-2-ynyloxy-phenyl)-ethyl]-2-oxo-acetamide. 1H-NMR (300 MHz, CDCl3): 1.15 (t, 3 H, CH2CH3), 2.22 (m, 2 H, CH2CH3), 2.87 (t, 2 H, CH2CH2), 3.64 (t, 2 H, CH2CH2), 3.88 (s, 3 H, OCH3), 4.72 (m, 2 H, OCH2), 6.77 (m, 2 H, CH arom.), 6.99 (d, 1 H, CH arom.), 7.16 (t, 1 H, NH), 7.57 (d, 8.22, m) and 8.49 (m, 3 H, CH arom.).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH:31]=[C:30]([Br:38])[C:29]4=[O:39])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[ClH:40].O1CCOCC1>O1CCOCC1>[ClH:40].[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH:31]=[C:30]([Br:38])[C:29]4=[O:39])[CH2:22][CH2:21]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)c(Br)cc3ccccc32)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1c(Br)cc2ccccc2n1CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 0.30 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(3-bromo-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 6 mL of 1,4-dioxane and 2 mL of 4.0 mol/L hydrogen chloride/1,4-dioxane were added, and stirred at room temperature overnight. The resulting solid was filtered to give 0.21 g of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-3-bromoquinolin-2(1H)-one hydrochloride as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].I[CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C.O>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[N:12]([CH2:21][CH3:22])[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)NN1C(=O)c2ccccc2C1=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC#N
Solvent: O
Product: CCN(C(=O)OC(C)(C)C)N1C(=O)c2ccccc2C1=O
Temperature: 50 °C
Yield: 71.6 %

Procedure:
tert-Butyl N-(1,3-dioxoisoindolin-2-yl)carbamate (1.0 g, 3.8 mmol), iodoethane (460 μL, 5.7 mmol), potassium carbonate (2.1 g, 15 mmol), and benzyl-triethyl-ammonium bromide (210 mg, 0.80 mmol) were combined in acetonitrile (15 mL) and heated at 50° C. for 48 h. The reaction mixture was diluted with water (30 mL) and was extracted with ether (3×15 mL). The combined organics were washed with brine, dried over sodium sulfate and evaporated to dryness. The crude material was purified by column chromatography (0-20% ethyl acetate in hexanes) to afford tert-butyl 1,3-dioxoisoindolin-2-yl(ethyl)-carbamate (0.79 g, 71%). ESI-MS m/z calc. 290.1. found 291.3 (M+1)+; Retention time: 1.64 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.98-7.85 (m, 2H), 7.84-7.69 (m, 2H), 3.86-3.57 (m, 2H), 1.52 (s, 3H), 1.32 (s, 6H), 1.27-1.04 (m, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[NH:20][CH:21]2[CH2:23][CH2:22]2)=O)[CH:7]=[N:8][CH:9]=1)(=[O:3])[CH3:2]>C(O)(=O)C>[CH:21]1([N:20]2[C:14]3[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=3[N:12]=[C:10]2[C:6]2[CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:9]=[N:8][CH:7]=2)[CH2:23][CH2:22]1
Reactant: CC(=O)c1cncc(C(=O)Nc2ccc(F)cc2NC2CC2)c1
Solvent: CC(=O)O
Product: CC(=O)c1cncc(-c2nc3ccc(F)cc3n2C2CC2)c1
Temperature: 25 °C

Procedure:
A solution of the title compound from Step B (0.10 g, 0.32 mmol) in acetic acid (1.60 mL) was heated at 100° C. for 1 hour, then cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate, washed sequentially with aqueous 1 N sodium hydroxide solution and brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (50-80% ethyl acetate in hexanes) provided the title compound: LCMS m/z 296.07 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 9.41 (d, J=1.9 Hz, 1 H), 9.26 (d, J=1.9 Hz, 1 H), 8.22 (m, 1 H), 7.75 (dd, J=8.8, 4.8 Hz, 1 H), 7.32 (dd, J=8.6, 2.3 Hz, 1 H), 7.10-7.06 (m, 1 H), 3.65-3.61 (m, 1 H), 2.73 (s, 3H), 1.26-1.20 (m, 2 H), 0.81-0.77 (m, 2 H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH:3]=1.CCOC(C)=O.[CH3:39][N:40](C=O)C>O.CCCCCC.[C-]#N.[Zn+2].[C-]#N>[C:39]([C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH:3]=1)#[N:40]
Reactant: CN(C)C=O
Reactant: Cc1ccccc1-c1cc(Cl)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: Cc1ccccc1-c1cc(C#N)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
A stirring solution of N-(6-chloro-4-o-tolylpyridin-3-yl)-N-methyl-3,5-bis(trifluoromethyl)benzamide (100 mg, 0.21 mmol, example 12), tetrakis-triphenylphosphine palladium(0) (24 mg, 0.020 mmol, CAS RN 14221-01-3) and zinc cyanide (31 mg, 0.26 mmol, CAS RN 557-21-1) in DMF (1.5 mL) was heated to 100° C. for 30 min, 120° C. for 30 min and 150° C. for 30 min by microwave irradiation. After cooling, the reaction mixture was diluted with water and extracted three times with EtOAc. The combined organic layers were washed three times with water and once with brine and dried over Na2SO4. Filtration followed by removal of volatiles under reduced pressure gave crude product. The title compound was isolated by flash chromatography (25% EtOAc in n-hexane) as a viscous oil (7.5 mg, 8%). MS (ESI): m/z=463.9 [M+H]+.
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([NH:20][CH2:21][C:22]([CH:24]3[CH2:40][C:26]4([CH2:29][N:28]([S:30]([C:33]5[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=5)(=[O:32])=[O:31])[CH2:27]4)[CH2:25]3)=O)[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]>CC#N>[S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:22]([CH:24]4[CH2:40][C:26]5([CH2:29][N:28]([S:30]([C:33]6[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=6)(=[O:32])=[O:31])[CH2:27]5)[CH2:25]4)=[CH:21][N:20]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)N2CC3(CC(C(=O)CNc4cnc5c(ccn5S(=O)(=O)c5ccc(C)cc5)n4)C3)C2)cc1
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)N2CC3(CC(c4cnc5cnc6c(ccn6S(=O)(=O)c6ccc(C)cc6)n45)C3)C2)cc1
Temperature: 60 °C
Yield: 76.3 %

Procedure:
To a solution of 2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)-1-(2-tosyl-2-azaspiro[3.3]heptan-6-yl)ethanone (0.631 g, 1.089 mmol, prepared using R with 2-tosyl-2-azaspiro[3.3]heptane-6-carboxylic acid [prepared as described in J. Org. Chem, 2010, 75, 5941] and trimethylsilyl diazomethane, S with Example #3 Step E, E with TFA) in MeCN (5 mL) was added PFPAA (2.15 mL, 10.9 mmol). The mixture was heated at about 60° C. for about 2 h. The reaction mixture was partitioned between DCM (30 mL) and saturated aqueous NaHCO3 (50 mL). The layers were separated and the aqueous layer was extracted further with DCM (2×30 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated to dryness under reduced pressure. The crude material was purified using silica gel flash chromatography eluting with a gradient of 50-100% EtOAc in heptane to give 3-tosyl-8-(2-tosyl-2-azaspiro[3.3]heptan-6-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine (0.467 g, 76%) as a white solid: LC/MS (Table 1, Method b) Rt=2.53 min; MS m/z 562 (M+H)+.