Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:13]([Si:15]([CH2:23][CH3:24])([CH2:21][CH3:22])[C:16]#[C:17][CH2:18][CH2:19][OH:20])[CH3:14].[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd](Cl)Cl>[CH2:23]([Si:15]([CH2:13][CH3:14])([CH2:21][CH3:22])[C:16]1[NH:4][C:3]2[C:2]([C:17]=1[CH2:18][CH2:19][OH:20])=[CH:8][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:6][CH:5]=2)[CH3:24]
Reactant: Nc1ccc(C(F)(F)F)cc1I
Reactant: CC[Si](C#CCCO)(CC)CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)c1[nH]c2ccc(C(F)(F)F)cc2c1CCO
Temperature: 100 °C
Reaction time: 15 h
Yield: 61.3 %

Procedure:
2-iodo-4-(trifluoromethyl)aniline (1.0 g; 3.48 mmol), 4-(triethylsilyl)but-3-yn-1-ol (0.807 mL; 3.83 mmol), Bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.142 g; 0.174 mmol), lithium chloride (0.147 g; 3.48 mmol) and sodium carbonate (0.738 g; 6.97 mmol) were suspended in DMF (10 mL) and the mixture was stirred at 100° C. for 15 hours. The solution was concentrated under reduced pressure and diluted in ethyl acetate. The organic layer was successively washed with brine, sodium thiosulphate, dried and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 2 to 40% ethyl acetate in heptane) to afford 0.733 g (61%) of the title compound as a yellow oil.
Reaction SMILES: [O:1]1[C:5]2([CH2:15][CH2:14][C:8]3([CH2:12][CH2:11][NH:10][C:9]3=[O:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[F:16][C:17]([F:28])([F:27])[C@@H:18]([C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=1)[OH:19].CNCCNC.[O-]P([O-])([O-])=O.[K+].[K+].[K+].FC(F)(F)C(C1C=CC(I)=CC=1)O>CN(C=O)C>[F:16][C:17]([F:27])([F:28])[C@@H:18]([C:20]1[CH:25]=[CH:24][C:23]([N:10]2[CH2:11][CH2:12][C:8]3([CH2:14][CH2:15][C:5]4([O:4][CH2:3][CH2:2][O:1]4)[CH2:6][CH2:7]3)[C:9]2=[O:13])=[CH:22][CH:21]=1)[OH:19]
Reactant: O=C1NCCC12CCC1(CC2)OCCO1
Reactant: O[C@H](c1ccc(I)cc1)C(F)(F)F
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Agent: OC(c1ccc(I)cc1)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C1N(c2ccc([C@@H](O)C(F)(F)F)cc2)CCC12CCC1(CC2)OCCO1
Temperature: 80 °C
Yield: 64.6 %

Procedure:
1,4-Dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (352 mg, obtained in example 133, step 3) was dissolved in DMF (22 mL) at RT. Then, (R)-2,2,2-trifluoro-1-(4-iodophenyl)ethanol (755 mg, for synthesis see: J. Org. Chem. 2009, 74, 1605-1610), N,N′-dimethylethylenediamine (sym) (294 mg), cuprous iodide (476 mg) and K3PO4 (1.06 g) were added to the reaction mixture. The mixture was heated to 80° C. for 4.5 hours. The reaction mixture was cooled down to 30° C. and more 2,2,2-trifluoro-1-(4-iodophenyl)ethanol (252 mg) was added. The mixture was re-heated to 80° C. for 2 hours. The reaction mixture was cooled, poured into ice/water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of ethyl acetate in heptane) to give the title compound as a colorless solid (415 mg, 62%). MS (ESI): 386.4 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:4].[NH:18]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@@H:19]([C:28](O)=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>>[C:34]([O:33][C:31]([NH:18][C@H:19]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:28]([N:14]1[CH2:15][CH2:16][N:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:3]([N:2]([CH3:17])[CH3:1])=[O:4])[CH2:12][CH2:13]1)=[O:29])=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: CN(C)C(=O)c1ccccc1N1CCNCC1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Product: CN(C)C(=O)c1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)OC(C)(C)C)CC1

Procedure:
[2-(4-{(2R)-2-[(tert-Butoxy)carbonylamino]-3-(4-chlorophenyl)propanoyl}piperazinyl)phenyl]-N,N-dimethylcarboxamide was prepared according to the procedure described in Preparation V by using N,N-dimethyl(2-piperazinylphenyl)carboxamide (Step 3) (260 mg, 1.1 mmol), Boc-p-Cl-D-Phe-OH (Peptech Corporation) (370 mg, 1.2 mmol), HOAT (Aldrich) (151 mg, 1.11 mmol), and EDC (Aldrich Chemical Company) (430 mg, 2.2 mmol). The compound was isolated as a crude white foam (480 mg) and used in the next step without further purification. MS (ESI, pos.ion) m/z: 515 (M+H). Calc'd for C27H35ClN4O4: 515.04.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:22])[C:13](=[O:21])[N:14]([C:15]4[N:16]([CH3:20])[N:17]=[CH:18][CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[CH:33][C:34]([NH:37][CH2:38][CH2:39][OH:40])=[N:35][CH:36]=2)O1>>[OH:40][CH2:39][CH2:38][NH:37][C:34]1[N:35]=[CH:36][C:31]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:22])[C:13](=[O:21])[N:14]([C:15]5[N:16]([CH3:20])[N:17]=[CH:18][CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:32][CH:33]=1
Reactant: CC1(C)OB(c2ccc(NCCO)nc2)OC1(C)C
Reactant: Cn1nccc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cn1nccc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(NCCO)nc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-3-methyl-1-(2-methyl-2H-pyrazol-3-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate E, 65 mg, 0.181 mmol) and 2-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamino]-ethanol (stage 21.1.1, 82 mg, 0.218 mmol) to give the title compound as an off-white foam. (HPLC: tR 2.08 min (Method A); M+H=416 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.96 (s, 1H), 8.12-8.02 (m, 2H), 7.80-7.75 (m, 2H), 7.51-7.44 (m, 1H), 6.95-6.89 (m, 1H), 6.85-6.73 (br, 1H), 6.69 (s, 1H), 6.60-6.53 (m, 1H), 3.66 (s, 3H), 3.58 (s, 3H), 3.54-3.49 (m, 2H), 3.37-3.31 (m, 2H))
Reaction SMILES: [CH3:1][C:2]([C:4]1([CH2:7][CH3:8])[CH2:6][CH2:5]1)=[O:3].[CH:9](=O)[C:10]1[CH:19]=[CH:18][C:15]([O:16][CH3:17])=[C:12]([O:13][CH3:14])[CH:11]=1>>[CH2:7]([C:4]1([C:2]([CH:1]=[CH:9][C:10]2[CH:19]=[CH:18][C:15]([O:16][CH3:17])=[C:12]([O:13][CH3:14])[CH:11]=2)=[O:3])[CH2:6][CH2:5]1)[CH3:8]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CCC1(C(C)=O)CC1
Product: CCC1(C(=O)C=Cc2ccc(OC)c(OC)c2)CC1

Procedure:
2-(3,4-Dimethoxyphenyl)vinyl 1-ethylcyclopropyl ketone [III; Ar is 3,4-(CH3O)2C6H3, R is C2H5 ] was prepared from 22.4 g. of 1-ethylcyclopropyl methyl ketone and 33.2 g. of veratraldehyde according to the procedure described above in Preparation A1, affording 20.3 g., b.p. 156°-158° C. (0.02 mm.).
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][C@@H:6]([C:27]1[CH:28]=[N:29][C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[CH:32][CH:31]=2)[NH:7][C:8](=[O:26])[CH2:9][NH:10][C:11](=[O:25])[CH2:12][CH2:13][CH2:14][C:15]1[N:24]=[C:23]2[C:18]([CH2:19][CH2:20][CH2:21][NH:22]2)=[CH:17][CH:16]=1)C>Cl>[NH:22]1[C:23]2[C:18](=[CH:17][CH:16]=[C:15]([CH2:14][CH2:13][CH2:12][C:11]([NH:10][CH2:9][C:8]([NH:7][C@H:6]([C:27]3[CH:28]=[N:29][C:30]4[C:35]([CH:36]=3)=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:5][C:4]([OH:37])=[O:3])=[O:26])=[O:25])[N:24]=2)[CH2:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)C[C@H](NC(=O)CNC(=O)CCCc1ccc2c(n1)NCCC2)c1cnc2ccccc2c1
Agent: Cl
Product: O=C(O)C[C@H](NC(=O)CNC(=O)CCCc1ccc2c(n1)NCCC2)c1cnc2ccccc2c1
Temperature: 50 °C

Procedure:
Ester 25-6 was dissolved in 5 mL 6N HCl and warmed to 50° C. for 1.5 h then concentrated and the residue chromatographed on silica (75% EtOH. NH3/EtOAc) to afford 25-7.
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][C@H:8]([NH:12][C:13]([C@@:15]1([CH:30]([CH3:32])[CH3:31])[O:19][N:18]=[C:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][N:21]=2)[CH2:16]1)=[O:14])[C:9]([OH:11])=O)(C)(C)C.[CH:34]([Mg]Br)=[CH2:35]>>[CH:30]([C@:15]1([C:13]([NH:12][C@H:8]([C:9](=[O:11])[CH:34]=[CH2:35])[CH2:7][C:6]([OH:5])=[O:33])=[O:14])[O:19][N:18]=[C:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][N:21]=2)[CH2:16]1)([CH3:31])[CH3:32]
Reactant: C=C[Mg]Br
Reactant: CC(C)[C@@]1(C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)O)CC(c2nccc3ccccc23)=NO1
Product: C=CC(=O)[C@H](CC(=O)O)NC(=O)[C@]1(C(C)C)CC(c2nccc3ccccc23)=NO1

Procedure:
Weinreb amide derivative of (2S)-4-(tert-butoxy)-2-({[(5R)-5-isopropyl-3-(1-isoquinolinyl)-4,5-dihydro-5-isoxazolyl]carbonyl}amino)-4-oxobutanoic acid (condensed derivative with N,O-dimethylhydroxylamine) and vinyl magnesium bromide were reacted, and the resulting compound was reacted according to the same procedure as Example 2 to give the title compound.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH3:26])[CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:39])(=[O:38])[CH2:29][CH2:28]3)[CH:17]=2)[CH2:13][CH2:12][O:11][CH2:10]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[NH2:8][C:9]1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH3:26])[CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:39])(=[O:38])[CH2:29][CH2:28]3)[CH:17]=2)[CH2:13][CH2:12][O:11][CH2:10]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(N(Cc4ccccc4)Cc4ccccc4)CCOC3)c2c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(N)CCOC3)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.8 %

Procedure:
A mixture of N-{[3-(dibenzylamino)tetrahydrofuran-3-yl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine (270 mg, 0.43 mmol), 10% palladium hydroxide on active carbon (300 mg) in methanol (20 mL) was stirred for 16 hours at room temperature under hydrogen atmosphere (1 bar). The resulting mixture was concentrated in vacuo. The residue was purified by preparative HPLC to afford 21 mg of the desired product (yield was 10.8%). MS obsd. (ESI+) [(M+H)+] 453, 1H NMR (400 MHz, CD3OD) δ ppm 8.06-7.98 (m, 2 H), 7.89-7.87 (d, J=7.6 Hz, 1 H), 7.75-7.66 (m, 2 H), 7.59-7.56 (m, 2 H), 6.22-6.20 (d, J=8.4 Hz, 1 H), 5.35 (s, 2 H), 4.5 (s, 2 H), 4.08-3.97 (m, 4 H), 3.88-3.73 (m, 3 H), 2.81 (s, 2 H), 2.46 (s, 3 H), 2.31 (s, 2 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[C:18]([N+:19]([O-])=O)=[CH:17][N:16]=[C:15]3[N:22]([S:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:27])=[O:26])[CH:23]=[CH:24][C:14]=23)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([NH:12][C:13]2[C:18]([NH2:19])=[CH:17][N:16]=[C:15]3[N:22]([S:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:27])=[O:26])[CH:23]=[CH:24][C:14]=23)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 125 %

Procedure:
A solution of 3-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (425 mg, 898 μmol) in THF (15 ml) containing palladium (10% on carbon, 95.0 mg, 90.0 μmol) was stirred at ambient temperature under a hydrogen atmosphere for 24 hours. The mixture was filtered through Celite®, the filter cake thoroughly washed with THF, and the combined filtrates concentrated under vacuum to give 498 mg of 3-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-azetidine-1-carboxylic acid tert-butyl ester, which was used without further purification. LCMS (Method B, ESI): RT=4.04 min, m+H=444.4.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][O:5][C:6]([N:8]1[CH2:13][C:12](=[O:14])[N:11]2[CH:15]([C:18]([O:20]CC)=[O:19])[CH2:16][CH2:17][CH:10]2[CH2:9]1)=[O:7].Cl>O.CO.O1CCCC1>[CH3:4][O:5][C:6]([N:8]1[CH2:13][C:12](=[O:14])[N:11]2[CH:15]([C:18]([OH:20])=[O:19])[CH2:16][CH2:17][CH:10]2[CH2:9]1)=[O:7]
Reactant: CCOC(=O)C1CCC2CN(C(=O)OC)CC(=O)N21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)N1CC(=O)N2C(CCC2C(=O)O)C1
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of lithium hydroxide monohydrate (16.8 mg, 0.38 mmol) in water (0.5 mL) was added to a solution of 4-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2,6-dicarboxylic acid 6-ethyl ester 2-methyl ester (86 mg, 0.32 mmol) in methanol (1 mL) and tetrahydrofuran (1 mL). After 2 hours, an aqueous solution of hydrogen chloride (1N, 0.41 mL, 0.41 mmol) was added and the organic solvents were removed under reduced pressure. The resulting aqueous solution was lyophilized for 16 hours to give 4-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2,6-dicarboxylic acid 2-methyl ester. A yield of 100% was assumed for the subsequent step. C10H14N2O5 calculated 242.1, observed [M+1]+ 242.9, [M+1]− 241.1; rt=1.54 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][C:9](OC)=[O:10])[CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][CH2:9][OH:10])[CH:2]=1
Reactant: COC(=O)COc1cccnc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OCCOc1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
Methyl [(3-pyridinyl)oxy]acetate (3.6 g) in diethyl ether (80 ml) was added dropwise to a stirred suspension of lithium aluminium hydride (826 mg) in diethyl ether (100 ml) at 0°. The mixture was stirred overnight at room temperature under nitrogen, water (1 ml) was added, followed by 2N sodium hydroxide (1 ml) and water (3 ml). The suspension was filtered and washed with ethyl acetate (3×100 ml) then dichloromethane (300 ml). The combined organic extracts were dried and concentrated to give the title compound (2.6 g) as an oil. T.l.c. (System E 80:20:1) Rf 0.31
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([O:29][CH3:30])=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=O)[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[C:35]([F:39])=[CH:34][C:33]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:43]>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([O:29][CH3:30])=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=[S:43])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[C:35]([F:39])=[CH:34][C:33]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)c(F)cc2C)C12C(=O)Nc1cc(Cl)ccc12
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=S)NC(c2cc(F)c(F)cc2C)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 50 °C
Yield: 24.1 %

Procedure:
A mixture of racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(4,5-difluoro-2-methyl-phenyl) spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (40 mg, 0.067 mmol) and P2S5 (45 mg, 0.20 mmol) in THF (2 mL) was heated at 50° C. for 2 h, and then diluted with toluene (10 mL). The mixture was concentrated in vacuo and the residue was washed with DCM twice. The DCM extracts were combined and concentrated. The residue was purified by flash chromatography to give the title compound as white solid (10 mg).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][N:6]([C@@H:8]([CH2:16][CH3:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:5](=[O:18])[CH2:4]1>C(Cl)Cl.N1C=CC=CC=1>[C:12]([O:11][C:9]([C@@H:8]([N:6]1[C:5](=[O:18])[CH2:4][CH:3]([CH:2]=[O:1])[CH2:7]1)[CH2:16][CH3:17])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC[C@@H](C(=O)OC(C)(C)C)N1CC(CO)CC1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC[C@@H](C(=O)OC(C)(C)C)N1CC(C=O)CC1=O
Temperature: 25 °C
Yield: 49.7 %

Procedure:
In a three necked flask, under argon, a solution of tert-butyl (2S)-2-[4-(hydroxymethyl)-2-oxo-1-pyrrolidinyl]butanoate 398 (4.0 g, 0.016 mol.) in CH2Cl2 (8 ml) is added to a suspension of CrO3 (6.2 g, 0.062 mol.) in pyridine (11.3 ml)/CH2Cl2 (80 ml) stirred at room temperature. The temperature increases to 30° C. and the suspension is stirred for 0.2 h. The suspension is filtered through celite and the filtrate is washed successively with HCl 1N, brine, dried over magnesium sulfate and concentrated in vacuo to afford the crude aldehyde which is purified by column chromatography on silicagel (hexane/acetone 70/30 (v/v)) to afford 2.03 g of 1-[(1S)-1-(tertbutoxycarbonyl)propyl]-5-oxo-3-pyrrolidinecarboxaldehyde 396 (41%). Alternatively, the reaction can also be conducted with racemic ester to afford the racemic aldehyde with a similar yield. Analysis of a 1/1 mixture of 1-[(1S)-1-(tertbutoxycarbonyl)propyl]-5-oxo-3-pyrrolidinecarboxaldehyde 396: 1H NMR (250 MHz, (CDCl3): 0.91 (t, 3H), 1.44 (s, 9H), 1.55-1.77 (m, 1H), 1.90-2.15 (m, 1H), 2.63-2.82 (m, 2H), 3.47-3.61 (m, 1H), 3.65-3.79 (m, 1H), 3.83-3.94 (m, 1H of one of the diastereoisomers), 4.48-4.62 (m, 1H), 9.74 (s (broad), 1H).
Reaction SMILES: C[O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][CH2:15][CH2:16][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20].B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][CH2:15][CH2:16][P:17](=[O:24])([O:18][CH2:19][CH3:20])[O:21][CH2:22][CH3:23]
Reactant: CCOP(=O)(CCCCc1ccc2ccccc2c1OC)OCC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCOP(=O)(CCCCc1ccc2ccccc2c1O)OCC
Reaction time: 2 h
Yield: 39 %

Procedure:
A solution of diethyl 4-(1-methoxy-2-naphthyl)butylphosphonate (5.50 g, 0.016 mole) in methylene chloride (80 mL) was stirred at -78°, and treated with boron tribromide (1.0M in methylene chloride; 24.0 mL, 0.024 mole) over 20 minutes. Stirring was continued for 2 hours at this temperature, then at room temperature for 16 hours. Water (80 mL) was added, and the mixture was extracted with ether. The organic layer was extracted with 1.0N aqueous sodium hydroxide, the aqueous layer was acidified with concentrated hydrochloric acid, and the crude product was isolated from this by extraction with ether. The residue was recrystallized (hexane) to provide the title compound (2.10 g, 40%) as a white solid, mp 90°-91°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].[CH3:31][C:32]1[C:37]([Sn](CCCC)(CCCC)CCCC)=[CH:36][CH:35]=[CH:34][N:33]=1.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.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>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([C:37]3[C:32]([CH3:31])=[N:33][CH:34]=[CH:35][CH:36]=3)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1C
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1nc(-c2cccnc2C)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 34.5 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (80 mg, 0.17 mmol), 2-methyl-3-tributylstannanyl-pyridine (103 mg, 0.26 mmol) and PdCl2(PPh3)2 (24 mg, 0.034 mmol) in 4 mL of DMF was heated at 120° C. for 3 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and brine were added. 1 M HCl was added with stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (5-90% EtOAc/hexanes+1% AcOH) to give 28 mg of the title compound. MS: (+) m/z 478.39 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[H-].[Na+].Cl[CH2:24][O:25][CH2:26][CH3:27].ClCCl>CO>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:24][O:25][CH2:26][CH3:27])=[CH:13][CH:14]=2)=[O:7])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19]
Reactant: O=C(Nc1ccc(O)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCOCOc1ccc(NC(=O)c2ccc(Cl)c([N+](=O)[O-])c2)cc1
Temperature: 0 °C
Yield: 81 %

Procedure:
4-Chloro-N-(4-hydroxy-phenyl)-3-nitro-benzamide (14.6 g, 0.05 mol) was placed in an oven dried 2-necked 500 ml round-bottomed flask and flushed with N2. Enough Dimethoxyethane (DME, 100 ml) was added to dissolve the amide. The mixture was cooled in ice bath and sodium hydride (NaH, 50% in oil, 3.6 g total, 0.075 mol) added in small portions with vigorous stirring. An hour after addition was complete, chloromethoxy-ethane (7.13 g, 0.075 mol, commercially available) was added drop wise via a pressure-equalising dropping funnel. The reaction was followed by TLC (dichloromethane, DCM:methanol, MeOH, 95:5). The reaction mixture was poured into ice water and extracted with EtOAc (3×50 ml). The organic phase was dried (MgSO4) and evaporated under reduced pressure. The crude product was recrystallised form Hexane/ethyl acetate, 1:4. to give 81% of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH:7](C(C)(C)C)[N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([C:18]#[N:19])=[N:9]1)([CH3:4])([CH3:3])[CH3:2].C(C1C2C(=CC=C(O[CH2:38][C:39]3[N:44]=[CH:43][CH:42]=[CH:41][N:40]=3)C=2)N(CC(OC)=O)N=1)(=O)C>>[C:18]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:17][CH2:38][C:39]3[N:44]=[CH:43][CH:42]=[CH:41][N:40]=3)[CH:12]=2)[N:8]([CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:24])[N:9]=1)#[N:19]
Reactant: COC(=O)Cn1nc(C(C)=O)c2cc(OCc3ncccn3)ccc21
Reactant: CC(C)(C)OC(=O)C(n1nc(C#N)c2cc(O)ccc21)C(C)(C)C
Product: CC(C)(C)OC(=O)Cn1nc(C#N)c2cc(OCc3ncccn3)ccc21

Procedure:
The title compound was prepared from tert-butyl (3-cyano-5-hydroxy-indazol-1-yl)-acetic acid tert-butyl ester in a similar manner as described in step G of Scheme A4 for the preparation of methyl 2-(3-acetyl-5-(pyrimidin-2-ylmethoxy)-1H-indazol-1-yl)acetate. MS (LC-MS): 366.0 [M+H]+, tR (HPLC conditions e): 4.63 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][CH2:9][C:10]([O:12]CC)=O)=[CH:4][CH:3]=1.[CH2:15]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][CH:29]2[CH2:31][CH2:30]2)[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([N:22]1[CH2:23][CH2:24][CH:25]([N:28]([CH:29]2[CH2:30][CH2:31]2)[C:10](=[O:12])[CH2:9][O:8][C:5]2[N:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:26][CH2:27]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)COc1ccc(Cl)nn1
Reactant: c1ccc(CN2CCC(NC3CC3)CC2)cc1
Product: O=C(COc1ccc(Cl)nn1)N(C1CC1)C1CCN(Cc2ccccc2)CC1

Procedure:
The title compound was synthesized from ethyl 2-(6-chloropyridazine-3-yloxy)acetate and 1-benzyl N-cyclopropylpiperidine-4-amine in the same manner as in Example 104.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1I.[CH3:13][N:14](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.Cl.CNOC.CCN(C(C)C)C(C)C>CN(C=O)C>[C:13]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7])#[N:14]
Reactant: COC(=O)c1ccc(O)c(I)c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(O)c(C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 295.8 %

Procedure:
To a solution of 2 (1.49 g, 2.29 mmol), HBTU (1.3 g, 3.44 mmol), HOBt (530 mg, 3.44 mmol), and N,O-dimethylhydroxylamine HCl salt (340 mg, 3.44 mmol) in DMF (20 mL) was added DIEA (785 uL, 4.58 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated. The resulting residue was purified using silica gel (Hexanes/EtOAc=1:3) to give pure compound 3 (1.20 g, 78%) as an off-white, foamy solid.