Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]=C(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:17][CH:16]=2)[C@H:11]([CH3:35])[O:10][C:9]1([CH3:37])[CH3:36])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CO>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=2)[C@H:11]([CH3:35])[O:10][C:9]1([CH3:36])[CH3:37])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CCc1ccc(N=C(c2ccccc2)c2ccccc2)cc1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CCc1ccc(N)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To a solution of (4S,5S)-4-{2-[4-(benzhydrylidene-amino)-phenyl]-ethyl}-2,2,5-trimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (3.23 g) in methanol (50 ml) was added ammonium formate (6.13 g). The reaction mixture was degassed by bubbling argon through the mixture for several minutes. 10% Pd/C (207 mg) was added and the reaction mixture was stirred at 60° C. for 1 hour. TLC showed the reaction was complete. The reaction mixture was filtered through celite and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, gradient: 0% to 100% EtOAc in hexane) to afford (4S,5S)-4-[2-(4-amino-phenyl)-ethyl]-2,2,5-trimethyl-oxazolidine-3-carboxylic acid tert-butyl ester as a yellow oil (1.76 g, 81%). MS (ISP): 335.2 ([M+H), 235.2 ([M−C4H8—CO2]+).
Reaction SMILES: [NH2:1][CH:2]([C:8]#[N:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:10](OCC#N)=[O:11]>ClCCl>[C:8]([CH:2]([NH:1][CH:10]=[O:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4])#[N:9]
Reactant: CCOC(=O)C(N)C#N
Reactant: N#CCOC=O
Solvent: ClCCl
Product: CCOC(=O)C(C#N)NC=O
Temperature: 25 °C
Yield: 51.3 %

Procedure:
To ethyl 2-amino-2-cyanoacetate (800 mg, 6.24 mmol) in dichloromethane (5 mL) was added cyanomethyl formate (531 mg, 6.24 mmol) in dichloromethane (5 mL) dropwise at 0° C. The reaction was warmed up to room temperature for twelve hours. The reaction was concentrated and purified by silica gel chromatography to give an oil of ethyl 2-cyano-2-formamidoacetate (500 mg). NMR spectrum shows a mixture of starting material and desired product in a 1:1 ratio. The product was dissolved in methylene chloride (10 mL). To this solution was added cyanomethyl formate (797 mg, 9.37 mmol) and the reaction was stirred for twelve more hours. The reaction was concentrated and purified with silica gel chromatography to give an oil of ethyl 2-cyano-2-formamidoacetate (460 mg). 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 6.61 (s, 1H), 5.55 (d, 2H), 4.36 (q, 2H), 1.35 (t, 3H).
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[N:22]([CH:24]=[CH:25][CH:26]=3)[CH:23]=2)=[CH:8]1)(C)(C)C.Cl.[Cl:28][CH2:29][CH2:30][N:31]1[CH:35]=[CH:34][N:33]=[CH:32]1>>[ClH:28].[N:31]1([CH2:30][CH2:29][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]4[N:22]([CH:24]=[CH:25][CH:26]=4)[CH:23]=2)=[CH:8][C:7]3=[N:6][OH:5])[CH:35]=[CH:34][N:33]=[CH:32]1
Reactant: ClCCn1ccnc1
Reactant: CC(C)(C)ON=c1cc(-c2cn3cccc3cn2)oc2ccc(O)cc12
Agent: Cl
Product: ON=c1cc(-c2cn3cccc3cn2)oc2ccc(OCCn3ccnc3)cc12

Procedure:
6-(2-Imidazol-1-yl-ethoxy)-2-pyrrolo[1,2-a]pyrazin-3-yl-chromen-4-one oxime, hydrochloride was prepared in 13% overall yield using the method described in example 123, starting from 6-Hydroxy-2-pyrrolo[1,2-a]pyrazin-3-yl-chromen-4-one O-tert-butyl-oxime (example 123B) and 1-(2-Chloro-ethyl)-1H-imidazole hydrochloride.
Reaction SMILES: [Cl-].[CH3:2][S:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[O:17][N:16]=[C:15]([C:18]2[N:19]=[C:20]([CH:23]3[CH2:28][CH2:27][NH2+:26][CH2:25][CH2:24]3)[S:21][CH:22]=2)[CH2:14]1)(=[O:5])=[O:4].[CH3:29][N:30]([CH3:35])[CH2:31][C:32](O)=[O:33].C(N(C(C)C)CC)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:2][S:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[O:17][N:16]=[C:15]([C:18]2[N:19]=[C:20]([CH:23]3[CH2:28][CH2:27][N:26]([C:32](=[O:33])[CH2:31][N:30]([CH3:35])[CH3:29])[CH2:25][CH2:24]3)[S:21][CH:22]=2)[CH2:14]1)(=[O:4])=[O:5]
Reactant: CN(C)CC(=O)O
Reactant: CS(=O)(=O)Oc1ccccc1C1CC(c2csc(C3CC[NH2+]CC3)n2)=NO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4OS(C)(=O)=O)C3)cs2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 4-[4-(5-{2-[(methylsulphonyl)oxy]phenyl}-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidinium chloride (500 mg) in dimethylformamide (6 ml) under argon were added N,N-dimethylglycine (122 mg), diisopropylethylamine (582 mg) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU, 542 mg). The reaction mixture was stirred at room temperature for 18 hours. Then ice-cold sodium hydrogencarbonate solution was added thereto, the mixture was filtered, and the aqueous phase was removed and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. This gave 2-(3-{2-[1-(N,N-dimethylglycyl)piperidin-4-yl]-1,3-thiazol-4-yl}-4,5-dihydro-1,2-oxazol-5-yl)phenyl methanesulphonate (310 mg, 55%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([OH:10])=[CH:8][C:7]([N:11]2[C:16](=[O:17])[CH2:15][CH:14]([C:18]([F:21])([F:20])[F:19])[CH2:13][C:12]2=[O:22])=[C:6]([F:23])[CH:5]=1.[C:24]1([S:30][CH2:31]Cl)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[Cl:3][C:4]1[C:9]([O:10][CH2:31][S:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:8][C:7]([N:11]2[C:16](=[O:17])[CH2:15][CH:14]([C:18]([F:20])([F:19])[F:21])[CH2:13][C:12]2=[O:22])=[C:6]([F:23])[CH:5]=1
Reactant: O=C1CC(C(F)(F)F)CC(=O)N1c1cc(O)c(Cl)cc1F
Reactant: ClCSc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CC(C(F)(F)F)CC(=O)N1c1cc(OCSc2ccccc2)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23 %

Procedure:
While kept under N2, 0.15 g (3.7 mmol, 60% dispersion in oil) sodium hydride was washed with pentanes (2×0.5 ml), then suspended in 2 ml of dry THF (freshly distilled from sodium/benzophenone). To the suspension, cooled in an ice bath, were added 1.1 g (3.4 mmol) of N-(4'-chloro-2'-fluoro-5'-hydroxyphenyl)-3-(trifluoromethyl)glutarimide (Compound 19) dissolved in 3.5 ml of dry THF (freshly distilled from sodium/benzophenone) and two 1 ml rinses of dry THF. The reaction was then allowed to warm to room temperature and stirred for 15 minutes. The flask was again cooled in an ice bath while a solution of chloromethyl phenyl sulfide (0.46 ml, 0.54 g, 3.4 mmol) in 3 ml dry THF was added dropwise. The reaction mixture was allowed to warm slowly to room temperature and stirred for about 24 hours, then warmed to 50° C. for 54 hours. The THF was evaporated in vacuo (2-10 Torr) and the reaction mixture was taken up in 12 ml anhydrous dimethylformamide. The reaction was heated to 100° C. for 8 hours then cooled to room temperature. The reaction mixture was suction filtered through a short pad of neutral alumina and rinsed with 30 ml EtOAc. The filtrate was evaporated in vacuo and the residue was dried in the vacuum oven for 12 hours (20-50 Torr, 50° C.). The resulting oil was vacuum distilled (2-10 Torr, 70° C.). The residue was chromatographed (silica gel, 1:1 hexanes/methylene chloride) to yield 350 mg (23% yield) of the desired product as a white solid, m.p. 108°-109.5° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Br[CH:10]([CH3:12])[CH3:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 43 %

Procedure:
A mixture of 4-fluoro-aniline (1.12 g; 10 mmol), 2-bromopropane (1.13 ml) and K2CO3 (1.38 g, 10 mmol) in anhydrous DMF (6 ml) was stirred for 5 h at reflux. The mixture was cooled to room temperature, diluted to 100 ml with H2O and extracted with EtOAc (50 ml). The organic layer was washed with H2O (2×20 ml) and dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC(SiO2, hexane/EtOAc) to give the title compound (0.65 g; 43%), as light yellow oil. 1H-NMR (CDCl3) 6.89-6.82 (m, 2H); 6.53-6.47 (m, 2H); 3.58-3.49 (m, 1H); 1.18 (d, 6H, J=6.25 Hz).
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Br:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[CH:30][CH:29]=1.[Cl-].[NH4+]>C1COCC1>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:32]([C:31]1[CH:34]=[CH:35][C:28]([Br:27])=[CH:29][CH:30]=1)[OH:33])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: Brc1ccccc1OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(c1ccc(Br)cc1)c1ccccc1OCc1ccccc1
Reaction time: 0.25 h
Yield: 82.8 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (1.59 M, 11.57 mL) was added dropwise to a solution of 1-benzyloxy-2-bromobenzene (4.4 g, 16.72 mmol) in THF (168 mL) at −78° C. and the mixture solution was stirred at the same temperature for 15 minutes. To this solution, a solution of 4-bromobenzaldehyde (2.47 g, 13.34 mmol) in THF (50 mL) was added dropwise at −78° C. The reaction mixture was stirred at the same temperature for 30 minutes and at 0° C. for 30 minutes, and then a saturated ammonium chloride aqueous solution was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:10)] to obtain the title compound (4.08 g, 83%) as a colorless oil.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[CH:10]=[C:9]([C:20]([F:23])([F:22])[F:21])[N:8]=2)[CH:6]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:10]=[C:9]([C:20]([F:23])([F:22])[F:21])[N:8]=[C:7]([N:5]3[CH:6]=[C:2]([C:28]4[CH:29]=[CH:30][C:25]([NH2:24])=[N:26][CH:27]=4)[N:3]=[CH:4]3)[N:12]=2)=[CH:14][CH:15]=1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-n2cnc(Br)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cn(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)cn2)cn1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidine (example E.2) (0.40 g, 1.0 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.22 g, 1.0 mmol) according to the general procedure VI. Obtained as a yellow solid (0.095 g, 23%). MS (ISP) 417.3 [(M+H)+]; mp 254° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1.[CH2:12]([O:19][C:20](=[O:24])[C@@H:21](O)[CH3:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C@@H:21]([C:20]([O:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:24])[CH3:22])[CH:5]=1
Reactant: C[C@H](O)C(=O)OCc1ccccc1
Reactant: COC(=O)c1cccc(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(O[C@H](C)C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.5 %

Procedure:
To a solution of (10.0 g, 55.5 mmol) of 3-hydroxy-benzoic acid methyl ester in tetrahydrofuran (125 mL), cooled to 0° C., is added (8.44 g, 55.5 mmol) of (S)-2-hydroxy-propionic acid benzyl ester, and (14.5 g, 55.5 mmol) of triphenyl phosphine. To this mixture is added a solution of (11.3 mL, 72.2 mmol) of diethylazodicarboxylate in tetrahydrofuran (25 mL) via a syringe pump over a 1 hour period. The reaction mixture is warmed to room temperature and stirred for 18 h then concentrated under reduced pressure. The residue is purified by flash silica gel chromatography to provide 13 g of 3-((R)-1-benzyloxycarbonyl-ethoxy)-benzoic acid methyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]1[C:14]([C:15](OC)=[O:16])=[C:13]([CH:19]([CH3:21])[CH3:20])[O:12][N:11]=1.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[OH-].[Na+]>O1CCCC1.O.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]1[C:14]([CH2:15][OH:16])=[C:13]([CH:19]([CH3:21])[CH3:20])[O:12][N:11]=1
Reactant: COC(=O)c1c(Cc2c(Cl)cccc2Cl)noc1C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1onc(Cc2c(Cl)cccc2Cl)c1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A solution of methyl 3-[(2,6-dichlorophenyl)methyl]-5-(1-methylethyl)-4-isoxazolecarboxylate (1.18 g, 3.6 mmol) (from multiple batches) in tetrahydrofuran (10 mL) was stirred at 0° C. as a 1.5 M solution of diisobutylaluminum hydride in toluene (3.7 mL, 5.6 mmol) was added. The solution was allowed to warm to room temperature and stir overnight. Methanol (0.27 mL) was added followed by water (2.7 mL) then 2 N sodium hydroxide (4 mL). The solution was filtered through celite. The filtrate was partitioned between ethyl acetate and water. An aqueous solution of Rochelle's salt was added. The organic layer was separated, dried with magnesium sulfate, concentrated and purified by chromatography (silica gel, 30% ethyl acetate in hexane) to provide the title compound (1.07 g, 99%). 1H NMR (DMSO-d6): δ 7.46 (d, J=8 Hz, 2H), 7.32 (t, J=8 Hz, 1H), 5.01 (t, J=5 Hz, 1H), 4.36 (d, J=5 Hz, 2H), 4.22 (s, 2H), 3.21 (septet, J=7 Hz, 1H) 1.20 (d, J=7 Hz, 6H). ESI-LCMS m/z 300 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:20])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]CC2C=CC=CC=2)=[CH:8][CH:7]=1.C(O)(=O)C.[H][H]>[Pd].C(O)C>[NH2:1][CH2:2][C@H:3]([OH:20])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1
Reactant: NC[C@H](O)COc1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: NC[C@H](O)COc1ccc(O)cc1
Reaction time: 2 h

Procedure:
A mixture of (2S)-1-amino-3-(4-benzyloxy-phenoxy)-propan-2-ol (which was obtained in Intermediate 4) (0.9 g, 3.3 mmol), 0.2 mL of acetic acid and 10% palladium on carbon (0.3 g) in 70 mL of ethanol was pressurized with 20 psi hydrogen and shaken over 2 hours. The catalyst was then removed by filtering through a short pad of silica gel and the solvent was removed to give the title compound as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.86 (s, 1 H), 2.66 (dd, J=12.8, 5.3 Hz, 1H), 2.85 (dd, J=12.8, 3.5 Hz, 1H), 3.79-3.95 (m, 3 H), 6.67 (d, J=6.6 Hz, 2H), 6.75 (d, J=6.6 Hz, 2 H); MS (ES) m/z: 183.1 (MH+); HRMS Calcd. for C9H13NO3(MH+): 183.0895. Found: 183.0892.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:28]([NH:35][CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:28]([NH:35][CH:36]1[CH2:41][CH2:40][N:39]([C:2]2[CH:3]=[C:4]([CH:8]3[N:12]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=4[F:20])[N:11]=[C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[CH2:9]3)[CH:5]=[CH:6][CH:7]=2)[CH2:38][CH2:37]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cccc(Br)c2)c(F)c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1CCN(c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Temperature: 100 °C
Reaction time: 12 h
Yield: 43.5 %

Procedure:
5-(3-Bromo-phenyl)-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (200.0 mg, 0.44 mmol) prepared in Step 2 of Preparation 5, 4-(N-BOC-amino)-piperidine (132.0 mg, 0.66 mmol), Pd2(dba)3 (20.0 mg, cat.), BINAP (27.0 mg, cat.) and sodium t-butoxide (76.0 mg, 0.79 mmol) were added to toluene (4.0 mL). The reaction mixture was stirred at 100° C. for 12 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3) to give 110.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [N+](=[C:3]([C:8]([O:10][CH:11]([C:16]([Cl:19])([Cl:18])[Cl:17])[CH:12]=[C:13]([CH3:15])[CH3:14])=[O:9])[C:4]([O:6][CH3:7])=[O:5])=[N-]>CCCCCCCC.C(OCC)(=O)C.[Cu]>[Cl:17][C:16]([Cl:19])([Cl:18])[CH:11]1[CH:12]2[C:3]([C:4]([O:6][CH3:7])=[O:5])([C:13]2([CH3:15])[CH3:14])[C:8](=[O:9])[O:10]1
Reactant: COC(=O)C(=[N+]=[N-])C(=O)OC(C=C(C)C)C(Cl)(Cl)Cl
Agent: [Cu]
Solvent: CCOC(C)=O
Solvent: CCCCCCCC
Product: COC(=O)C12C(=O)OC(C(Cl)(Cl)Cl)C1C2(C)C
Yield: 96 %

Procedure:
To a refluxing suspension of copper powder (6.6 g, 0.104 mole) in 320 ml of n-octane was added dropwise in one hour a solution of methyl (±)-3-methyl-1-trichloromethyl-2-butenyl diazomalonate (6.6 g, 0.02 mole, prepared as described above for the ethyl ester) in 80 ml of n-octane. The reaction mixture was heated for 21/2 hours under reflux and then filtered while hot. The n-octane was evaporated from the filtrate under vacuum to produce a residue which was dissolved in ethyl acetate. The solution was washed successively with aqueous 1 N hydrochloric acid, aqueous sodium bicarbonate, and aqueous sodium chloride. After drying the solution over magnesium sulfate, the ethyl acetate was removed by evaporation, yielding methyl (±)-4-trichloromethyl-6,6-dimethyl-2-oxo-3-oxabicyclo[3.1.0]-hexane-1-carboxylate (5.77 g, 96% yield) as an oil. Trituration of the oil with ether afforded the crystalline lactone; mp, 118°-120°.
Reaction SMILES: [F:1][C:2]([F:24])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1)[C:3]1[N:12]=[C:11](SC)[C:10]2[C:5](=[C:6]([CH2:15][CH3:16])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.ClC1C=CC=C(C(OO)=O)C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+].[CH3:48][C:49]1[NH:53][N:52]=[C:51]([NH2:54])[CH:50]=1>C(Cl)Cl.C1COCC1>[F:1][C:2]([F:24])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1)[C:3]1[N:12]=[C:11]([NH:54][C:51]2[CH:50]=[C:49]([CH3:48])[NH:53][N:52]=2)[C:10]2[C:5](=[C:6]([CH2:15][CH3:16])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CCc1cccc2c(SC)nc(C(F)(F)c3ccc(F)cn3)nc12
Reactant: Cc1cc(N)n[nH]1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCc1cccc2c(Nc3cc(C)[nH]n3)nc(C(F)(F)c3ccc(F)cn3)nc12
Reaction time: 0.67 h
Yield: 36.1 %

Procedure:
To 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-ethyl-4-(methylthio)quinazoline (193 mg, 0.55 mmol) in DCM (5 mL) at 0° C. was added 3-chloroperbenzoic acid (70%, 218 mg, 0.89 mmol) and the mixture stirred for 40 min. The mixture was diluted with DCM and then aq sodium thiosulfate was added, followed by addition of saturated aq sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. To the residue were added THF (3 mL) and 5-methyl-1H-pyrazol-3-amine (163 mg, 1.67 mmol) and the mixture was stirred at rt for 4 days. The mixture was concentrated under reduced pressure and purified by preparative HPLC (Varian diphenyl reverse phase column, eluted with gradient of solvent B=0.05% AcOH/ACN and solvent A=5% ACN/0.05% AcOH/H2O) to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-ethyl-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (79 mg, 36%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.21 (t, J=7.44 Hz, 3H) 2.19 (s, 3H) 3.05 (q, J=7.35 Hz, 2H) 6.03 (s, 1H) 7.55 (t, J=7.82 Hz, 1H) 7.74 (d, J=6.97 Hz, 1H) 7.95-8.06 (m, 2H) 8.51 (d, J=8.10 Hz, 1H) 8.67 (s, 1H) 10.58 (br s, 1H) 12.16 (br s, 1H); LC-MS (ESI) m/z 399 (M+H)+.
Reaction SMILES: C([O:8][CH2:9][CH:10]1[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11]1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[CH3:15][C:12]1([CH3:16])[O:11][CH:10]([CH2:9][OH:8])[CH2:14][O:13]1
Reactant: CC1(C)OCC(COCc2ccccc2)O1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)OCC(CO)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.8 %

Procedure:
10% Palladium-carbon (1.68 g) was added to 4-benzyloxymethyl-2,2-dimethyl-1,3-dioxolane (5.949 g, 26.76 mmol) in ethanol (150 ml) and the mixture was stirred for 3 hours at 25° C. under an atmosphere of hydrogen. After the reaction was over, palladium-carbon was filtered off and the solution was condensed in vacuo. The crude product was distilled to give 3.07 g of 2,2-dimethyl-1,3-dioxolane-4-methanol (yield 87%, b.p. 72° C. at 8 mmHg).
Reaction SMILES: [C:1]1([C@H:7]([NH:25][C:26]([O:28][C@@H:29]2[CH:34]3[CH2:35][CH2:36][N:31]([CH2:32][CH2:33]3)[CH2:30]2)=[O:27])[C:8]2[CH:9]=[C:10]([CH:22]=[CH:23][CH:24]=2)[O:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH:71]1[CH2:76][CH2:75][CH:74]([C:77]([O:79][CH2:80][CH2:81][CH2:82][CH:83]2[O:87][CH2:86][CH2:85][O:84]2)=[O:78])[CH2:73][CH2:72]1>CN(C=O)C.C(OCC)(=O)C>[C:1]1([C@H:7]([NH:25][C:26]([O:28][C@@H:29]2[CH:34]3[CH2:35][CH2:36][N:31]([CH2:32][CH2:33]3)[CH2:30]2)=[O:27])[C:8]2[CH:9]=[C:10]([CH:22]=[CH:23][CH:24]=2)[O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([N:71]3[CH2:76][CH2:75][CH:74]([C:77]([O:79][CH2:80][CH2:81][CH2:82][CH:83]4[O:84][CH2:85][CH2:86][O:87]4)=[O:78])[CH2:73][CH2:72]3)=[O:18])=[CH:20][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OCCCC1OCCO1)C1CCNCC1
Reactant: O=C(N[C@@H](c1ccccc1)c1cccc(OCc2ccc(C(=O)O)cc2)c1)O[C@H]1CN2CCC1CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](c1ccccc1)c1cccc(OCc2ccc(C(=O)N3CCC(C(=O)OCCCC4OCCO4)CC3)cc2)c1)O[C@H]1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoic acid (0.300 g, 0.57 mmol) in DMF (2.5 mL) was added di-iso-propylethylamine (0.40 mL, 2.29 mmol) and HATU (0.262 g, 0.69 mmol) and the mixture stirred at RT for 30 minutes. To the resultant solution was added a solution of 3-(1,3-dioxolan-2-yl)propyl piperidine-4-carboxylate hydrochloride (0.241 g, 0.86 mmol) in DMF (1.8 mL). The mixture was stirred at RT for 18 hours. The mixture was diluted with ethyl acetate, washed with 10% aqueous potassium carbonate, brine (×2), dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The residue was used directly in the next step with no further purification.