Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[CH3:26][C:27]1[N:32]=[C:31]([NH2:33])[CH:30]=[CH:29][CH:28]=1.CC(C)([O-])C.[K+].O1CCCC1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([NH:33][C:31]4[CH:30]=[CH:29][CH:28]=[C:27]([CH3:26])[N:32]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[N:15]=1
Reactant: CN1CCN(c2cc(N3CCc4ccc(Br)cc4C3)nc(N)n2)CC1
Reactant: Cc1cccc(N)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1CCOC1
Product: Cc1cccc(Nc2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)CC3)n1
Temperature: 120 °C

Procedure:
A mixture of 4-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (20.0 mg, 0.0496 mmol), 6-methyl-2-pyridinamine, (8.04 mg, 0.0744 mmol, Aldrich, Cat. No. A75706), a solution of potassium tert-butoxide in tetrahydrofuran (0.0992 mL, 0.0992 mmol, 1.00 M, Aldrich Cat. 328650), palladium acetate (0.445 mg, 0.00198 mmol, Aldrich, Cat. No. 379875), and 2-[dicyclohexylphosphino]biphenyl (0.869 mg, 0.00248 mmol, Aldrich, Cat. No. 638099) in 1,4-dioxane (1 mL) was degassed with nitrogen and then heated at 120° C. for 16 hours. The reaction mixture was cooled to r.t. and concentrated. Then the reaction mixture was dissolved in MeOH and purified by RP-HPLC (pH=10) to afford the desired compound. LCMS(M+H)+: m/z=431.4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:14]3[CH:13]=[C:12]([O:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[N:11]=[C:10]([F:28])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:29][C:30]1[C:35](B(O)O)=[CH:34][CH:33]=[CH:32][N:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[F:28][C:10]1[C:9]2[O:8][C:5]3[C:4]([C:15]4([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]4)[C:14]=2[CH:13]=[C:12]([O:22][CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[N:11]=1)=[CH:3][C:2]([C:35]1[C:30]([F:29])=[N:31][CH:32]=[CH:33][CH:34]=1)=[CH:7][CH:6]=3
Reactant: OB(O)c1cccnc1F
Reactant: CC(C)(C)COc1cc2c(c(F)n1)Oc1ccc(Br)cc1C21COCC(N)=N1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CC(C)(C)COc1cc2c(c(F)n1)Oc1ccc(-c3cccnc3F)cc1C21COCC(N)=N1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
A sealable vial was charged with 7-bromo-1-fluoro-3-(neopentyloxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (200 mg, 0.444 mmol), 2-fluoropyridin-3-ylboronic acid (125 mg, 0.888 mmol), bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (31.4 mg, 0.044 mmol) and potassium phosphate (283 mg, 1.332 mmol). The vial was evacuated and backfilled with nitrogen (procedure was repeated twice). Dioxane (3 mL) and water (1 mL) were added and the reaction mixture was purged for 1 min with nitrogen. The vial was placed in a preheated oilbath (100° C.) for start 1.5 h. The reaction mixture was cooled to rt and water and EtOAc were added to the reaction mixture. The organic phase was separated and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by column chromatography (1-10% MeOH in DCM) to obtain 1-fluoro-7-(2-fluoropyridin-3-yl)-3-(neopentyloxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine as a beige solid (185 mg).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([OH:28])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:29]([O:36][CH2:37][C@H:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[Cl:46])O)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].ClC1C=CC=CC=1[C@H](O)C(O)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].[Si](Cl)(C(C)(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Si:29]([O:36][CH2:37][C@@H:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[Cl:46])[O:28][C:21]1[CH:20]=[C:19]([N:18]2[C:12]3[CH:11]=[C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[N:15]=[CH:14][C:13]=3[N:16]=[CH:17]2)[S:23][C:22]=1[C:24]([O:26][CH3:27])=[O:25])([C:32]([CH3:34])([CH3:35])[CH3:33])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](O)c1ccccc1Cl
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: O=C(O)[C@@H](O)c1ccccc1Cl
Solvent: ClCCl
Product: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O[C@@H](CO[Si](C)(C)C(C)(C)C)c1ccccc1Cl

Procedure:
In a similar manner as described for example B31, 0.5 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-hydroxythiophene-2-carboxylate, 0.44 g of (1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-(2-chlorophenyl)ethanol (synthesized starting from (S)-(+)-2-chloromandelic acid in a two step sequence including reduction with LiAlH4 and protection of the primary hydroxy group using tert-butyldimethylsilylchloride), 0.63 g of triphenylphosphine (polymer bound, ˜3 mmol/g) and 0.55 g of di-tert-butyl azodicarboxylate in 10 ml anhydrous dichloromethane yield the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([C:12]([OH:14])=[O:13])[NH:8][CH2:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:19]O>>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:12]([O:14][CH3:19])=[O:13])[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)C1Cc2ccc(O)cc2CN1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc2ccc(O)cc2cn1
Yield: 46 %

Procedure:
To a solution of 4.36 g (22.6 mmol) of 7-hydroxy-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid in 100 mL of MeOH was added 4.95 mL (67.7 mmol) of thionyl chloride and the solution was refluxed for 1 hr. After evaporation of the solvent, the residue was stirred vigorously in a mixture of 200 mL of EtOAc, 500 mL of H2O and 100 mL of saturated Na2CO3 (aq) until all solids dissolved. The aqueous layer was then saturated with sodium chloride and extracted twice with EtOAc. The combined organics were then washed with brine, dried over Na2SO4 and concentrated to a solid. To this solid was added 200 mL of xylenes and 3.0 g of palladium on carbon (10%) and the suspension was refluxed for 16 hr. The suspension was filtered through a pad of Celite® and silica gel. The pad was then washed with 50 mL of xylenes. The filtrate was discarded and the filter cake washed with 500 mL of a 4:1 mixture of CH2Cl2:MeOH. This filtrate was then evaporated to give 2.09 g (46%) of methyl 7-hydroxy-3-isoquinolinecarboxylate as a light brown solid. 1H NMR (400 MHz, DMSO-d6): δ 10.58 (s, 1H), 9.08 (s, 1H), 8.49 (s, 1H), 8.04 (d, J=9 Hz, 1H), 7.39 (d, J=9 Hz, 1H), 7.36 (s, 1H), 3.87 (s, 3H). ESI-LCMS m/z 204 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])([CH3:10])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:18](Cl)(=[O:20])[CH3:19].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[C:18]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][C:2]([NH:11][C:12](=[O:17])[C:13]([F:16])([F:14])[F:15])([CH3:1])[CH3:10])=[CH:5][CH:6]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: CC(C)(Cc1ccccc1)NC(=O)C(F)(F)F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(CC(C)(C)NC(=O)C(F)(F)F)cc1
Temperature: 0 °C
Yield: 99 %

Procedure:
A flame-dried 250 ml flask was charged with N-(1,1-dimethyl-2-phenyl-ethyl)-2,2,2-trifluoroacetamide (5.93 g, 24.2 mmol), acetyl chloride (4.00 g, 55.6 mmol), and methylene chloride. The resulting solution was cooled to about 0° C., and aluminum (III) chloride (11.0 g, 82.2 mmol) was added in portions over about thirty minutes. Over the course of the addition, the solution changed from colorless to greenish-brown. After the addition was complete, the solution was heated to reflux for about thirty minutes, and was then cooled to room temperature and poured over 300 ml of ice water. After stirring for about ten minutes, the mixture was diluted with 125 ml of methylene chloride, and the layers were separated. The aqueous layer was extracted with an additional 125 ml of methylene chloride. The combined organic extracts were then washed with water and brine, sequentially, and then dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil, (6.9 g, 99% yield) which was ascertained to be about 85% pure by NMR, was carried into the subsequent reaction without further purification. LRMS ([M+1]+)=288.2.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:18])[C:5](=[N:10][NH:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:19]OC(OC)N(C)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4](=[O:18])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[N:10][N:11]([C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)[CH:19]=1
Reactant: COC(OC)N(C)C
Reactant: COCC(=O)C(=NNc1ccncc1)C(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)c1nn(-c2ccncc2)cc(OC)c1=O
Yield: 44.8 %

Procedure:
A mixture of methyl 4-methoxy-3-oxo-2-(pyridin-4-ylhydrazono)butanoate (18 g, 70 mmol) and N,N-dimethylformamide dimethyl acetal (28 mL, 210 mmol) in toluene (210 mL) was refluxed for 4 h. The mixture was concentrated under reduced pressure to give black crystals. The crystals were washed with 2-propanol/AcOEt (1:4) to give the title compound (8.2 g, 45% yield) as pale yellow crystals: 1H NMR (300 MHz, CDCl3): δ ppm 3.99 (3H, s), 4.00 (3H, s), 7.62 (2H, dd, J=4.5, 1.5 Hz), 8.01 (1H, s), 8.79 (2H, dd, J=4.5, 1.5 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8](Cl)[N:7]=[C:6]([Cl:11])[CH:5]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([Cl:11])[N:7]=[C:8]([NH:26][CH:23]2[CH2:22][CH2:21][N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH2:25][CH2:24]2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Cl)nc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 66.7 %

Procedure:
A stirred suspension of 2,6-dichloro-isonicotinic acid methyl ester (4.52 g, 21.9 mmol 1.0 equiv), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (4.39 g, 21.9 mmol, 1.0 equiv), palladium(II) acetate (0.50 g, 2.2 mmol, 0.1 equiv) and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (1.39 g, 2.2 mmol, 0.1 equiv) in toluene (150 mL) was treated at rt with caesium carbonate (9.39 g, 28.5 mmol, 1.3 equiv) and then warmed to 80° C. After 6 h, the reaction mixture was poured into crashed ice and extracted twice with ethyl acetate. The combined organic layers were washed with brine and water, dried over MgSO4, filtered and concentrated by evaporation under reduced pressure. The crude product was purified by column chromatography on silica eluting with a gradient of dichloromethane/methanol to give 5.40 g (67%) of the title compound as a light yellow solid. MS (ISP): 370.1 [M+H]+.
Reaction SMILES: Br[C:2](Br)=[CH:3][CH2:4][C:5]([CH3:18])([CH3:17])[CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.C([Li])CCC>O1CCCC1>[CH3:17][C:5]([CH3:18])([CH2:4][C:3]#[CH:2])[CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1
Reactant: CC(C)(CC=C(Br)Br)CCCCOC1CCCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#CCC(C)(C)CCCCOC1CCCCO1
Yield: 101.8 %

Procedure:
5.04 g of 2-(8,8-Dibromo-5,5-dimethyl-oct-7-enyloxy)-tetrahydro-pyrane (example1/step i]) (12.66 mmol) was dissolved in 55 ml of abs. tetrahydrofuran and treated at −78° with 25.3 ml of n-butyllithium (1.5 M, hexane, 3 eq.). 30 Min. later, the reaction mixture was poured onto crushed ice/NH4Cl, extracted twice with ether, washed with brine, dried over sodium sulfate and evaporated to dryness. Flash chromatography (SiO2, hexane/ethylacetate=95/5) gave 3.07 g of 2-(5,5-dimethyl-oct-7-ynyloxy)-tetrahydro-pyrane which was deprotected as follows: 2.00 g thereof (8.39 mmol) was dissolved in 57 ml of methanol, treated with 211 mg of pyridinium-(toluene-4-sulfonate) (0.1 eq.), and kept at room temperature for 1 night. The reaction mixture was then poured onto crushed ice/Na2CO3, extracted twice with ether, washed with water, dried over sodium sulfate and evaporated to dryness. Flash chromatography (SiO2, pentane/methylacetate=75/25) gave 1.27 g of the title compound as colourless oil, 99% pure according to GC.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](C)([CH3:11])[C:9]#N)=[CH:4][CH:3]=1.C[Li].Cl.C([O:18][CH2:19][CH3:20])C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:9])[C:19](=[O:18])[CH3:20])=[CH:4][CH:3]=1
Reactant: CC(C)(C#N)c1ccc(F)cc1
Reactant: CCOCC
Agent: Cl
Agent: [Li]C
Product: CC(=O)C(C)(C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5.84 g 2-(4-fluorophenyl)-2-methylpropionitrile in abs. diethylether are added dropwise at -30° and under inert gas, 22 ml of a 1.6M solution of methyllithium in diethylether. The cooling bath is then taken away and the mixture stirred for 3 hours at room temperature. The reaction mixture is poured onto ice, the organic phase stirred overnight with 6N HCl, washed after separation of the acid phase, dried and evaporated in vacuum. The thus obtained oily residue is reacted further without purification.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[C:13]([C:15]2[C:16]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[N:17][N:18]([C:20]3[CH:21]=[CH:22][C:23]4[N:24]([C:26]([C:29]([F:32])([F:31])[F:30])=[N:27][N:28]=4)[N:25]=3)[CH:19]=2)[CH:12]=[CH:11][N:10]=1)=O)(C)(C)C.C(OC(NC1C=C(C2C(C3C=CC=CC=3)=NN(C3C=CC4N(C=NN=4)N=3)C=2)C=CN=1)=O)(C)(C)C>>[NH2:8][C:9]1[CH:14]=[C:13]([C:15]2[C:16]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[N:17][N:18]([C:20]3[CH:21]=[CH:22][C:23]4[N:24]([C:26]([C:29]([F:31])([F:30])[F:32])=[N:27][N:28]=4)[N:25]=3)[CH:19]=2)[CH:12]=[CH:11][N:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(-c2cn(-c3ccc4nnc(C(F)(F)F)n4n3)nc2-c2ccc(F)cc2)ccn1
Agent: CC(C)(C)OC(=O)Nc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2ccccc2)ccn1
Product: Nc1cc(-c2cn(-c3ccc4nnc(C(F)(F)F)n4n3)nc2-c2ccc(F)cc2)ccn1
Yield: 70.6 %

Procedure:
The reaction was carried out in the same manner as in Example 37-2) except for using 200 mg (0.37 mmol) of 4-(2-t-butoxycarbonylaminopyridin-4-yl)-3-(4-fluorophenyl)-1-(3-trifluoromethyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazole obtained in Example 47-1) in place of 4-(2-t-butoxycarbonylaminopyridin-4-yl)-3-phenyl-1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazole to obtain 115 mg of the title compound as a beige powder. (Yield: 71%)
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:11])[C@H:6]([CH:8]([CH3:10])[CH3:9])[NH2:7])[CH3:3].[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1[O:21][C:20](=[O:22])[C:19]2([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[N:18]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH2:2]([O:4][C:5](=[O:11])[C@H:6]([CH:8]([CH3:10])[CH3:9])[NH:7][C:20]([C:19]1([NH:18][C:17]([C:13]2[O:12][CH:16]=[CH:15][CH:14]=2)=[O:21])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1)=[O:22])[CH3:3]
Reactant: O=C1OC(c2ccco2)=NC12CCCCC2
Reactant: CCOC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](NC(=O)C1(NC(=O)c2ccco2)CCCCC1)C(C)C
Reaction time: 72 h

Procedure:
30 ml of dimethylformamide was added to a flask charged with 5 g (27 mmol) of L-valine ethyl ester hydrochloride and 5 g (22.8 mmol) of 2-(2-furanyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one. Then, 3.53 g (27.4 mmol) of diisopropylethylamine was added thereto, and the mixture was stirred for 3 days. After the solvent was distilled off under reduced pressure, ethyl acetate was added thereto, and the mixture was successively washed with a 10% aqueous potassium hydrogensulfate solution and saturated brine, followed by drying with sodium sulfate. After the solvent was distilled off under reduced pressure, it was purified by silica gel chromatography to obtain 8.3 g (quantitative) of the title compound.
Reaction SMILES: C(O[C:6]([NH:8][CH:9]1[CH:13]([O:14]S(C)(=O)=O)[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1)=[O:7])(C)(C)C.O=C1NC2CN(C(OC(C)(C)C)=O)CC2O1.C(O)(C)C.FC(F)(F)C(O)=O.C(Cl)Cl>ClC(Cl)C>[O:14]1[CH:13]2[CH2:12][NH:11][CH2:10][CH:9]2[NH:8][C:6]1=[O:7]
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)OC(C)(C)C)CC1OS(C)(=O)=O
Agent: CC(C)(C)OC(=O)N1CC2NC(=O)OC2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: O=C1NC2CNCC2O1

Procedure:
A solution of tert-butyl 3-[(tert-butoxycarbonyl)amino]-4-[(methylsulfonyl)oxy]pyrrolidine-1-carboxylate (850 mg) in dichloroethane (50 mL) was refluxed overnight, evaporated and the resulting residue purified on a Biotage Horizon® system (silica, gradient 10-15% methanol in dichloromethane) to yield a racemic mixture of tert-butyl 2-oxohexahydro-5H-pyrrolo[3,4-d][1,3]oxazole-5-carboxylate which was resolved by chiral HPLC (Chiralcel OJ column, isopropyl alcohol/hexptane 13:87) to yield fast moving isomer A and slow moving isomer B. Each of isomer A and isomer B was treated with trifluoroacetic acid/methylene chloride (1:1) and passed through ion exchange resin (Strata-X-C™) and eluted with methanol containing 5% ammonium hydroxide to yield hexahydro-2H-pyrrolo[3,4-d][1,3]oxazol-2-one isomer A2 and isomer B2, respectively.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C@H:5]1[CH2:10][O:9][CH2:8][CH2:7][N:6]1[CH2:11][C@H:12]1[CH2:17][NH:16][CH2:15][CH2:14][NH:13]1.[N+:18]([C:21]1[S:25][C:24]([S:26](Cl)(=[O:28])=[O:27])=[CH:23][CH:22]=1)([O-:20])=[O:19]>C(Cl)Cl>[N+:18]([C:21]1[S:25][C:24]([S:26]([N:16]2[CH2:15][CH2:14][NH:13][C@@H:12]([CH2:11][N:6]3[CH2:7][CH2:8][O:9][CH2:10][C@@H:5]3[CH3:4])[CH2:17]2)(=[O:28])=[O:27])=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)s1
Reactant: C[C@H]1COCCN1C[C@H]1CNCCN1
Agent: Cl
Solvent: ClCCl
Product: C[C@H]1COCCN1C[C@H]1CN(S(=O)(=O)c2ccc([N+](=O)[O-])s2)CCN1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 84 %

Procedure:
A 150-mL round-bottomed flask was charged with (3S)-3-methyl-4-((2R)-2-piperazinylmethyl)morpholine trihydrochloride (0.750 g, 2.43 mmol, step 3), TEA (2.03 mL, 14.6 mmol) and CH2Cl2 (10 mL). To this was added a solution of 5-nitrothiophene-2-sulfonyl chloride (0.560 g, 2.46 mmol, Enamine LLC, Monmouth Jct., NJ) in CH2Cl2 (5 mL). The reaction mixture was stirred at room temperature for 20 min. The reaction mixture was partitioned between water (20 mL) and CH2Cl2 (20 mL). The aqueous phase was extracted with CH2Cl2 (2×20 mL). The combined organic phases were washed with water (40 mL) and saturated aqueous NaCl (40 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (50 g of silica gel, 0 to 12.5% iPrOH (with 10% NH4OH) in CHCl3) to afford (3S)-4-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-2-piperazinyl)methyl)-3-methylmorpholine (0.797 g) as a light orange glass.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH:6]=[C:7]([CH3:9])[CH3:8])[CH:3]=[O:4]>[Pd]>[CH3:1][CH:2]([CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH:3]=[O:4]
Reactant: CC(C)=CCC(C)C=O
Agent: [Pd]
Product: CC(C)CCC(C)C=O

Procedure:
One gram of 5% palladium-on-carbon and 8 g. of 2,5-dimethylhex-4-en-1-al is stirred in 50 ml. of ethanol under excess hydrogen at one atomsphere pressure and at room temperature until the theoretical amount of hydrogen is absorbed (about 24 hours). Then, 2 ml. of dichloromethane is added and the mixture filtered. The filtrate is concentrated under reduced pressure to yield 2,5-dimethylhexan-1-al.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[C:7]#[N:8].Br[CH2:12][CH2:13][O:14][CH2:15]CBr.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.C(OC(=O)C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:12][CH2:13][O:14][CH3:15])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: BrCCOCCBr
Reactant: N#Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc(Br)cc1C#N
Reaction time: 8 h

Procedure:
5-Bromo-2-hydroxy-benzonitrile (5.4 g, 27.0 mmol), 2-bromoethylether (2.76 ml, 29.7 mmol) and K2CO3 (4.5 g, 32.4 mmol) are mixed in 50 ml DMF. The reaction mixture is stirred at 50 C overnight. Addition of water and extraction into ethylacetate yields the title compound which is further purified by tituration with ether/hexanes. 1H-NMR (400 MHz; DMSO-d6): 7.99 (d, 1H), 7.82 (dd, 1H), 7.23 (d, 1H), 4.27 (t, 2H), 3.69 (t, 2H), 3.33 (s, 3H). LC-MS (m/z, ES+): 273 (M+NH4+), retention time: 2.77 mins (LC-MS method 3)
Reaction SMILES: C(C1C=C(CCC2C=CN3C(=O)C(/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27])=C(N4CCOCC4)N=C3C=2)SC=1)C.[CH:32]([O:34][CH:35]1[CH2:40][CH2:39][CH2:38][N:37]([C:41]2[N:42]=[C:43]3[CH:53]=[C:52]([C:54]([NH:56][C:57]4[S:58][CH:59]=[C:60]([CH:62]5[CH2:65][CH2:64][CH2:63]5)[N:61]=4)=[O:55])[CH:51]=[CH:50][N:44]3[C:45](=[O:49])[C:46]=2C=O)[CH2:36]1)=[O:33]>>[CH:62]1([C:60]2[N:61]=[C:57]([NH:56][C:54]([C:52]3[CH:51]=[CH:50][N:44]4[C:45](=[O:49])[C:46](/[CH:24]=[CH:25]/[C:26]([O:28][C:52]([CH3:54])([CH3:53])[CH3:51])=[O:27])=[C:41]([N:37]5[CH2:38][CH2:39][CH2:40][CH:35]([O:34][CH:32]=[O:33])[CH2:36]5)[N:42]=[C:43]4[CH:53]=3)=[O:55])[S:58][CH:59]=2)[CH2:63][CH2:64][CH2:65]1
Reactant: O=COC1CCCN(c2nc3cc(C(=O)Nc4nc(C5CCC5)cs4)ccn3c(=O)c2C=O)C1
Reactant: CCc1csc(CCc2ccn3c(=O)c(/C=C/C(=O)O)c(N4CCOCC4)nc3c2)c1
Product: CC(C)(C)OC(=O)/C=C/c1c(N2CCCC(OC=O)C2)nc2cc(C(=O)Nc3nc(C4CCC4)cs3)ccn2c1=O

Procedure:
Reactions were performed in the same manner as in Example 1, (J) by using 1-(8-{[(4-cyclobutyl-1,3-thiazol-2-yl)amino]carbonyl}-3-formyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)-3-piperidyl formate (36 mg, 0.075 mmol), and the resulting reaction solution was purified by thin layer silica gel chromatography (chloroform:methanol=30:1) to obtain 35 mg of the title compound as orange crystals in a mixture with triphenylphosphine oxide.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[O:11][C:10]=2[CH2:22][O:23][CH3:24])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:27])=O.N1C=CC=CC=1.O>C1(C)C=CC=CC=1>[Cl:27][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[N:16][CH:15]=2)[O:11][C:10]=1[CH2:22][O:23][CH3:24]
Reactant: O=S(Cl)Cl
Reactant: COCc1oc(-c2ccc(OC)nc2)cc1C(O)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COCc1oc(-c2ccc(OC)nc2)cc1C(Cl)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of cyclohexyl[2-(methoxymethyl)-5-(6-methoxypyridin-3-yl)furan-3-yl]methanol (0.8 g) in toluene (10 mL) were added thionyl chloride (0.2 mL) and pyridine (0.3 mL) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (0.8 g, 100%) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:31]=[CH:30][C:14]([O:15][CH2:16][CH2:17][CH2:18][N:19]4C(=O)C5C(=CC=CC=5)C4=O)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.CN>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:31]=[CH:30][C:14]([O:15][CH2:16][CH2:17][CH2:18][NH2:19])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCOc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1
Agent: CN
Solvent: CCO
Product: NCCCOc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1

Procedure:
The title compound was prepared by stirring 2-{3-[4-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)phenoxy]propyl}-1H-isoindole-1,3(2H)-dione with a large excess of methylamine in ethanol for two days and was purified by column chromatography on silica.